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Volume 28
Number 3
July 2015
The peer-reviewed journal of Baylor Scott & White Health
Scott & White Hospital -Brenham
McLane Children’s Scott & White Hospital - Temple
Baylor Medical Center at McKinney
Metroplex Health System - Killeen
Baylor All Saints Medical Center at Fort Worth
Baylor Scott & White Hospital - Hillcrest
Baylor Regional Medical Center at Grapevine
Baylor University Medical Center Proceedings
Baylor University Medical Center at Dallas
Volume 28, Number 3 • July 2015
Pages 289–432
www.BaylorScottandWhite.com
The largest not-for-profit health care system in Texas,
and one of the largest in the United States, Baylor Scott
& White Health was born from the 2013 combination of
Baylor Health Care System and Scott & White Healthcare.
For more information on our 43 hospitals and more than
500 patient care sites, please visit www.BaylorHealth.com
and www.sw.org.
Original Research
291 West Nile virus and the 2012 outbreak: the Baylor University Medical
Center experience by A. Mora Jr. et al
296 Comparison of long-term follow up of laparoscopic versus open
colectomy for transverse colon cancer by S. Agarwal et al
300 Mortality by treatment in patients ≥80 years of age with
gastroesophageal cancer seen in a 20-year period at a single
medical center by T. Barnett et al
304 Trends in the neonatal mortality rate in the last decade with respect
to demographic factors and health care resources by V. Govande et al
307 Effect of adding tetracaine to bupivacaine on duration of
analgesia in supraclavicular brachial plexus nerve blocks for
ambulatory shoulder surgery by L. T. Pearson et al
312 Comparison of documentation and evidence-based medicine
use for non–ST-segment elevation myocardial infarction among
cardiology, teaching, and nonteaching teams by A. Metting et al
317 Assessment of leadership training needs of internal medicine
residents at the Massachusetts General Hospital by T. N. Fraser et al
321 Abstracts from the First Annual Scholarly Day
Review Article
325 Uses, limitations, and complications of endobronchial ultrasound
by B. A Jalil et al
Case Studies
331 Recurrent hospitalization for self-injuries and suicide attempts:
case study of a super-utilizer by J. W. Roden-Foreman et al
334 Radiographic findings in the nail-patella syndrome by J. A. West and
T. H. Louis
337 Solitary supratentorial Listeria monocytogenes brain abscess in an
immunocompromised patient by J. A. West et al
340 Asplenia and fever by M. L. Huebner and K. A. Milota
342 Myroides odoratimimus bacteremia in a diabetic patient
by T. R. Endicott-Yazdani et al
344 Right-sided hydropneumothorax as a presenting symptom of
Boerhaave’s syndrome (spontaneous esophageal rupture)
by S. Rassameehiran et al
347 Pneumomediastinum in inflammatory bowel disease
by N. Mihatov and A. Z. Fenves
350 Pulmonary veno-occlusive disease as a cause of pulmonary
arterial hypertension by M. Porres-Aguilar et al
353 Pulmonary artery catheter–induced perforation treated with coil
embolization by D. S. Kumar et al
355 A hybrid repair of a superior mesenteric artery pseudoaneurysm
using open mesenteric bypass and endovascular exclusion
by T. A. Cumbie et al
358 Allergic acute coronary syndrome (Kounis syndrome)
by S. Memon et al
363 Blood cyst of the anterior mitral leaflet causing severe mitral
regurgitation by S. Madhavan et al
365 Right-sided superior vena cava draining into the left atrium in a
patient with persistent left-sided superior vena cava emptying into
the right atrium diagnosed by echocardiography by C. Clark and L.
MacDonald
367 Spontaneous coronary artery dissection in a 22-year-old man on
lisdexamfetamine by A. M. Afzal et al
369 Worsening dyspnea in a 38-year-old woman by D. L. Glancy et al
371 Chronic pulmonary embolism in a young athletic woman
by T. R. Larsen and T. C. Ball
375 Nonhepatic hyperammonemic encephalopathy due to undiagnosed
urea cycle disorder by T. Mahmood and K. Nugent
378 Anaplastic large-cell lymphoma in AIDS by M. Krol et al
381 Primary follicular lymphoma of the duodenum by R. Graham et al
384 Tubulocystic carcinoma of the kidney by V. Podduturi et al
386 Unusual presentation of metastatic ovarian carcinoma as an
enlarged intramammary lymph node by C. Mason et al
389 Leukoencephalopathic changes on magnetic resonance imaging
associated with a thermogenic dietary supplement (Thermatrim)
by C. I. Olivas-Chacon et al
Editorials and Interview
397 Precision medicine: hype or hope? by R. G. Mennel
401 Update on the Baylor Scott & White Quality Alliance by C. E. Couch
404 Nobel laureates and their medical schools: who selected whom?
by A. B. Weisse
406 On camel rides and Moses Maimonides by J. D. Cantwell
409 David Bruce Hellmann, MD: a conversation with the editor
by D. B. Hellmann and W. C. Roberts
From the Editor
421 Facts and ideas from anywhere by W. C. Roberts
Miscellany
290
295
303
320
370
380
383
392
420
Clinical research studies enrolling patients
Acknowledgment of contributors
Proceedings’ annual editorial board meeting
Avocations: Photograph by Dr. Solis
Avocations: Photograph by Dr. Rosenthal
Avocations: Poem by Dr. Khan
In memoriam
Baylor news
Reader comments: Low-voltage electrocardiogram in a patient
with takotsubo syndrome associated with hyperthyroidism
(J. E. Madias, with response by S. Omar)
www.BaylorHealth.edu/Proceedings
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Proceedings
Editor in Chief
William C. Roberts, MD
Associate Editor
Michael A. E. Ramsay, MD
Founding Editor
George J. Race, MD, PhD
Dennis R. Gable, MD
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H. A. Tillmann Hein, MD
Daragh Heitzman, MD
Priscilla A. Hollander, MD, PhD
Roger S. Khetan, MD
Göran B. Klintmalm, MD, PhD
Sally M. Knox, MD
John R. Krause, MD
Bradley T. Lembcke, MD
Jay D. Mabrey, MD
Michael J. Mack, MD
David P. Mason, MD
Peter A. McCullough, MD, MPH
Gavin M. Melmed, JD, MBA, MD
Robert G. Mennel, MD
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Joyce A. O’Shaughnessy, MD
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S. Michelle Shiller, DO
[email protected]
Editorial Board
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James W. Choi, MD
Cristie Columbus, MD
Barry Cooper, MD
Gregory J. Dehmer, MD
R. D. Dignan, MD
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Giovanni Filardo, PhD
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Residents/Fellows
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Baylor University Medical Center Proceedings (ISSN 0899-8280), a peer-reviewed
journal, is published quarterly (January, April, July, and October). Proceedings is
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July 2015
Permission is granted to students and teachers to copy material herein for
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289
Clinical research studies enrolling patients through
Baylor Research Institute
Currently, Baylor Research Institute is conducting more than 800 research projects. Studies open to enrollment are listed in
the Table. To learn more about a study or to enroll patients, please call or e-mail the contact person listed.
Research area
Specific disease/condition
Contact information (name, phone number, and e-mail address)
Asthma and
pulmonary disease
Chronic obstructive pulmonary disease, asthma (adult)
Rose Boehm, CCRC, RRT, RCP
Jana Holloway, RRT, CRC
Cara Kraft, RRT/RCP, AE-C
214-818-9495
214-820-9888
214-865-1169
[email protected]
[email protected]
[email protected]
Breast, ovarian, endometrial, prostate, brain, lung, bladder, colorectal,
pancreatic, and head and neck cancer; hematological malignancies,
leukemia, multiple myeloma, non-Hodgkin’s lymphoma; melanoma
vaccine; bone marrow transplant
Grace Townsend
214-818-8472
[email protected]
Treatment-naive colorectal cancer
Allison Cox
214-820-6779
[email protected]
Type 1 and type 2 diabetes, cardiovascular events
Kris Chionh
214-820-3416
[email protected]
Pancreatic islet cell transplantation for type I diabetics, who either have
or have not had a kidney transplant
Kerri Purcell, RN
817-922-4640
[email protected]
Type 2; cardiac events
Trista Bachand, RN
817-922-2587
[email protected]
Pancreatic islet cell transplantation for type I diabetics, who either have or
have not had a kidney transplant; high cholesterol
Kerri Purcell, RN
817-922-4640
[email protected]
Gastroenterology
Inflammatory bowel disease
Dr. Themistocles Dassopoulos
469-800-7180
[email protected]
Heart and vascular
disease (Dallas)
Aortic aneurysms, coronary artery disease, hypertension, poor leg circulation, heart
attack, heart disease, congestive heart failure, angina, carotid artery disease, familial
hypercholesterolemia, renal denervation for hypertension, diabetes in heart disease, Merielle Boatman
cholesterol disorders, heart valves, thoracotomy pain, stem cells, critical limb
ischemia, cardiac surgery associated with kidney injury, pulmonary hypertension
214-820-2273
[email protected]
Heart and vascular disease
(Fort Worth)
Atrial fibrillation, atrial fibrillation post PCI
Meagan King
817-922-2583
[email protected]
Heart and vascular disease
(Legacy Heart)
At risk for heart attack/stroke; previous heart attack/stroke/PAD; cholesterol
disorders; atrial fibrillation; overweight/obese; other heart-related conditions
Angela Germany
469-800-6409
[email protected]
Heart and vascular
disease (Plano)
Aortic aneurysm; coronary artery disease; renal stent for uncontrolled
hypertension; poor leg circulation; heart attack; heart disease; heart valve
repair and replacement; critical limb ischemia; repair of aortic dissections
with endografts; surgical leak repair; atrial fibrillation; heart rhythm
disorders; carotid artery disease; congestive heart failure; gene profiling
Tina Worley
469-814-4712
[email protected]
Cancer
Diabetes (Dallas)
Diabetes (Fort Worth)
Hepatology
Infectious disease
Nephrology
Neurology
Liver disease
Jonnie Edwards
214-820-6243
[email protected]
HIV/AIDS
Bryan King, LVN
214-823-2533
[email protected]
Hepatitis C, hepatitis B
Jonnie Edwards
214-820-6243
[email protected]
Homocysteine and kidney disease, dialysis fistulas, urine/protein disorders
in cancer patients
Lisa Mamo, RN
Dr. Harold Szerlip
214-818-2526
214-358-2300
[email protected]
[email protected]
Stroke
Quynh Lan Doan
214-818-2522
[email protected]
Migraine
Quynh Lan Doan
214-818-2522
[email protected]
[email protected]
Multiple sclerosis
Portland Pleasant, RN
214-820-7903
Neurosurgery
Cerebral aneurysms
Kennith Layton, MD
214-827-1600
[email protected]
Rheumatology (9900 N.
Central Expressway)
Rheumatoid arthritis, psoriatic arthritis, lupus, gout,
ankylosing spondylitis
Giselle Huet
Michael Thomas
214-987-1253
214-987-1249
[email protected]
[email protected]
Surgery
Chronic limb ischemia, pain management with chest tubes, colon polyps,
diaphragm stimulators, and surgery as it pertains to GERD, breast cancer,
esophagus, colon, colon cancer, pancreas, lung, hernias, dialysis access,
per-oral endoscopic myology (POEM), thoracic outlet syndrome
Tammy Fisher
Martha Mueller
214-820-7221
214-820-7755
[email protected]
[email protected]
Bone marrow, blood stem cells
Grace Townsend
Gabrielle Ethington
214-818-8472
214-818-8326
[email protected]
[email protected]
Solid organs
Jonnie Edwards
214-820-6243
[email protected]
Obesity
Kris Chionh
214-820-3416
[email protected]
Transplantation
Weight management
Baylor Research Institute is dedicated to providing the support and tools needed for successful clinical research. To learn
more about Baylor Research Institute, please contact Kristine Hughes at 214-820-7556 or [email protected].
290
Proc (Bayl Univ Med Cent) 2015;28(3):290
West Nile virus and the 2012 outbreak: The Baylor University
Medical Center experience
Adan Mora Jr., MD, Mariangeli Arroyo, MD, Kyle L. Gummelt, DO, MPH, Gates Colbert, MD, Anna L. Ursales, MD, Michael
J. Van Vrancken, MD, MPH, George J. Snipes, MD, Joseph M. Guileyardo, MD, and Cristie Columbus, MD
West Nile virus (WNV) has been responsible for multiple outbreaks and
has shown evolution in its clinical manifestation. The Centers for Disease
Control and Prevention has provided diagnostic criteria in classifying the
variety of WNV infection; however, application of these criteria can prove
challenging during outbreaks, and understanding the array of presentations and patient population is clinically important. In this article, we
present the challenges encountered during the 2012 outbreak at one
institution.
I
n 1937, West Nile virus (WNV) was isolated in Uganda’s
West Nile region (1). Initial outbreaks described self-limited
febrile illnesses with polyarthralgias and rash (2, 3). After
1990, outbreaks reported neurological symptoms (4). In
1999, the first US epidemic was in New York City, resulting
in 59 encephalitis cases and 7 deaths (5). The most common
presentation is West Nile fever (WNF), a self-limited illness with
fever, fatigue, myalgia, rash, and headache lasting 3 to 10 days.
Patients may experience persistent fatigue, difficulty concentrating, and a delayed return to baseline functioning (6). The virus
may penetrate the central nervous system (CNS), causing several
forms of West Nile neuroinvasive disease (WNND). West Nile
meningitis, characterized by fever, headache, nuchal rigidity,
and cerebrospinal fluid (CSF) pleocytosis, is associated with
favorable outcomes (7–9). Most feared, West Nile encephalitis
varies from mild confusion to severe encephalopathy, leading to
coma or death in 10% to 20% of cases (7). Symptoms include
myoclonus, parkinsonism, extrapyramidal symptoms, ataxia,
cranial nerve involvement, altered consciousness, and seizures
(9–11) resulting in prolonged hospital courses requiring mechanical ventilation and intensive care. WNND is associated
with long-term morbidity, delayed physical and cognitive recovery, and prolonged disability (12). Baylor University Medical Center (BUMC) at Dallas cared for many WNV-infected
patients during the 2012 epidemic. This study was conducted
to explore challenges faced and lessons learned.
METHODS
A retrospective medical record review identified cases of
WNV cases in the emergency department and inpatient service at BUMC from January to December 2012. Cases were
Proc (Bayl Univ Med Cent) 2015;28(3):291–295
identified using two databases. The hospital’s reference laboratory (med fusion) was queried for positive results that included
serum or CSF WNV IgM and IgG antibodies and WNV polymerase chain reaction (PCR) tests. Our laboratory used the IgM
Capture DxSelectTM enzyme-linked immunosorbent assay and
Focus Diagnostics IgG DxSelectTM enzyme-linked immunosorbent assay for qualitative detection of WNV IgM and IgG
antibodies. Positive results were submitted to the Texas Department of State Health Services for confirmatory testing. Tests for
WNV PCR were submitted to ARUP Laboratories, which uses
qualitative real-time PCR to test serum and CSF in accordance
with Roche Molecular Systems methods (13).
The institutional administrative coding database was crossreferenced for diagnoses of WNV infection. Patients with prior
WNV disease or only WNV IgG antibodies whose clinical
picture wasn’t compatible with acute disease were excluded.
Extracted data included demographics, comorbidities, symptoms, relevant physical examination findings, admission location, complications, diagnostic test results, and disposition.
Immunosuppression was considered if records documented
another disease known to affect the immune system or immunosuppressive therapy with systemic steroids (prednisone
>20 mg or equivalent steroid longer than 2 weeks), biologic
agents, or other immunomodulatory drugs.
Cases were classified as confirmed WNF, probable WNF,
confirmed WNND, or probable WNND per case definition criteria of the Centers for Disease Control and Prevention (CDC)
(14). To address variable clinician evaluation and capture patients not fulfilling CDC definitions whose composite clinical
and laboratory data suggested WNF or WNND, categories of
“possible” WNF and WNND were created. For example, some
patients not meeting the definition of fever had laboratory evidence in serum or CSF supporting active WNV infection. The
study was approved by the institutional review board of BUMC.
From the Division of Pulmonary Disease (Mora), Department of Internal Medicine
(Arroyo, Gummelt, Colbert, Ursales), Department of Pathology (Van Vrancken,
Snipes, Guileyardo), and Division of Infectious Diseases (Columbus), Baylor
University Medical Center at Dallas.
Corresponding author: Adan Mora Jr., MD, Division of Pulmonary Disease,
Department of Internal Medicine, Baylor University Medical Center at Dallas,
3500 Gaston Avenue, Dallas, TX 75246 (e-mail: [email protected]).
291
RESULTS
Sixty-eight cases were identified and 13 eliminated by our
exclusion criteria. Fifty-five cases were evaluated: 12 comprised
the WNF group (7 probable, 5 possible, and none confirmed),
and 43 comprised the WNND group (7 confirmed, 29 probable, and 7 possible). Patient characteristics and comorbidities are
summarized in Table 1. The age range was 19 to 84 years, with
a mean of 53.4 years. Most patients were white, non-Hispanic
men. Body mass index ranged from 15.7 to 62.4 kg/m2, with
a mean of 28.8 kg/m2. The most common comorbid condition
was hypertension.
Presenting complaints and findings are outlined in Table 2.
Subjective fevers were reported by 52 patients (42 had a documented fever of >100.4°F), classifying 10 patients as “possible”
WNV infection (5 WNF, 5 WNND). Other findings were
headache, altered mental status, hyponatremia, and gastroenteritis. Less common were seizures, acute kidney injury, acute
respiratory failure, elevated transaminases, elevated total bilirubin, acute flaccid paralysis, rhabdomyolysis, tremors, myoclonus, and atrial fibrillation. In the WNND group, 26 had
headache, 27 had altered mental status, 12 had seizures, and
3 had acute flaccid paralysis. The most commonly reported
symptoms in the WNF group were headache and gastrointestinal symptoms. In this group, fever >100.4°F was documented
in 7 patients and altered mental status was an uncommon
presentation.
Table 2 also outlines diagnostic laboratory findings. Serum
WNV IgM antibodies were positive in most patients. Two patients (both WNND) had detectable total WNV antibodies
that weren’t fractionated into IgM or IgG components, deeming
them “possible” WNV infection. Serum PCR WNV was performed in one patient and was undetectable. Serum arbovirus
panels were obtained in six patients and were negative.
In the WNND group, a serum WNV IgM test was positive
in 35 patients, negative in 2, and not obtained in 6 (including
the two with positive total unfractionated WNV antibody).
Serum WNV PCR was not obtained in any WNND patient.
However, all had clinical neurological findings compatible with
WNND, as defined by CDC clinical criteria (Table 3). Fortythree patients underwent lumbar puncture. Cell counts were
available on 42, and 37 had pleocytosis. In the WNND group,
cell counts were available in 37, and 35 had pleocytosis. Thirtytwo patients had CSF analysis for WNV IgM, and 19 had detectable CSF WNV IgM antibodies. Three had a positive CSF
WNV PCR, but the test was only ordered in 14. CSF WNV
IgG antibody testing was performed in 8 of the 43 patients;
only one patient tested positive.
Thirty-two patients (25 WNND) were initially admitted to
a medicine floor; 19 (17 WNND) to the intensive care unit,
and 4 (1 WNND) were seen and discharged in the emergency department. The mean length of stay for all was 7.7 days
(WNND, 8.9 days; WNF, 3.2 days). In the WNF group, 11
were discharged home and one to a rehabilitation facility. In
contrast, for WNND, 23 were discharged home, 7 to a rehabilitation unit, 2 to a long-term acute care facility, 2 to a skilled
nursing facility, and 9 died. The mortality rate was 21%. Of all
292
Table 1. Demographic characteristics of 55 West Nile patients
treated at Baylor University Medical Center in 2012
Category
Age (years)
Race
Variable
N
%
18–30
5
9%
31–40
10
18%
41–50
9
16%
51–60
13
24%
61–70
6
11%
71–80
10
18%
80+
2
4%
White
30
55%
Black
11
20%
Hispanic
14
26%
Asian
0
0%
Sex
Male
36
65%
Female
19
35%
Body mass index
<18.5
3
6%
18.5–24.9
14
26%
25–29.9
17
31%
30–24.9
Length of stay (days)
Admission status
Discharge status
10
18%
>35
6
11%
Not done
5
9%
0
4
7%
1–3
12
22%
4–6
14
26%
7–10
10
18%
11–14
10
18%
15–21
1
2%
21+
4
7%
Emergency room
4
7%
Medical/surgical floor
32
58%
Intensive care unit
19
35%
Home
34
62%
Long-term acute care
2
Skilled nursing facility
2
4%
Rehabilitation unit
8
15%
Died, no autopsy
5
9%
Died, with autopsy
History
4
7%
Hypertension
33
60%
Diabetes
38
69%
Transplant
1
2%
Chronic kidney disease
6
11%
Immunocompromised
Current conditions
4%
7
13%
Hypertension
22
40%
Diabetes mellitus
17
31%
Transplant recipient
1
2%
Chronic kidney disease/
end-stage renal disease
6
11%
Immunocompromised
7
13%
Volume 28, Number 3
Table 2. Signs and symptoms and laboratory data for 55 West
Nile patients treated at Baylor University Medical Center in 2012
Table 3. Comparison of cases with West Nile fever and West Nile
neuroinvasive disease
WNF
WNND
Confirmed cases
0
7
Probable cases
7
29
Possible cases
5
7
Positive
Total
reported
Percent*
Subjective fevers
52
55
95%
Objective fever >100.4°F
42
55
76%
Any fever
42
55
76%
Total
12
43
Elevated WBC on CSF
37
42
88%
Mean age (years)
44.5
55.8
Headache
32
49
65%
Mean body mass index (kg/m2)
30.1
28.6
AMS/encephalopathy
28
52
54%
Symptoms
Acute flaccid paralysis
4
16
25%
Fever
5
35
Myoclonus
3
11
27%
Headache
6
26
Tremors
3
11
27%
Gastrointestinal illness
5
19
Rhabdomyolysis
3
12
25%
Altered mental status
1
27
Atrial fibrillation
2
14
13%
Seizures
0
11
Elevated total bilirubin
5
50
10%
Acute flaccid paralysis
0
3
11
54
20%
Serum WNV IgM positive
11
35
Acute respiratory failure
9
55
16%
Serum WNV IgM negative
1
2
Transaminitis
8
52
15%
Serum WNV IgM not drawn
0
6
Gastroenteritis
24
42
57%
CSF WNV IgM positive
0
19
1
11
9%
CSF WNV IgM negative
4
9
CSF WNV IgM not drawn
8
15
Serum sodium <120 mEq/L
0
55
0%
CSF WNV PCR positive
0
3
Sodium 120–124 mEq/L
1
55
2%
CSF WNV PCR negative
1
28
5
55
9%
Mean length of stay (days)
3.2
20
55
36%
23
55
42%
Home
6
55
11%
Variable
Acute kidney injury
Epididymitis
Hyponatremia
Sodium >145 mEq/L
Laboratory results
Serum antibody screen
2
2
100%
Serum IgM
46
49
94%
Serum IgG
26
42
62%
Serum PCR
0
1
0%
Serum arbovirus
0
6
0%
CSF IgM
19
33
58%
CSF IgG
1
8
13%
CSF PCR
3
15
20%
CSF arbovirus
0
6
0%
*The percentage reflects the total number of positive responses among those for whom
data were available (which was not always the full group of 55 patients).
AMS indicates altered mental status; CSF, cerebrospinal fluid; PCR, polymerase chain
reaction; WBC, white blood cells.
WNV deaths in the four-county area, 24% were hospitalized
at BUMC.
Among the 9 patients who died, 8 were older than 50 years
of age; 6 were men, 4 were white, 3 were Hispanic, and 2
were black. Six had hypertension, 6 had diabetes mellitus, 5
had chronic or end-stage renal disease, and 3 were immunoJuly 2015
8.9
Discharge status
11
23
Rehabilitation facility
1
7
Long-term care facility
0
2
Skilled nursing facility
0
2
Death
0
9
Mortality rate (%)
0%
21%
compromised. Several patients had multiple comorbidities. All
presented with altered mental status and subjective fever (8
documented a fever of ≥100.4°F). Eight were admitted to the
intensive care unit. Seven had acute respiratory failure requiring
mechanical ventilation, and six had seizures.
DISCUSSION
This study highlights WNV outbreak challenges. One challenge was related to case classification, given strict CDC criteria (14). Twenty-two percent of patients didn’t fulfill CDC
case definitions for confirmed or probable WNND or WNF
(Table 3). They lacked a documented fever >100.4°F and/or specific confirmatory testing. Elderly patients and those with renal
failure or receiving corticosteroids may have had compromised
febrile response mechanisms (15, 16). Another challenge was
underutilization of nucleic acid amplification techniques early in
West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience
293
acute illness or in immunosuppressed populations. Such testing
can be costly, and with decreasing reimbursement, physicians
may be reluctant to order molecular diagnostics when effective
therapeutic options are lacking. Additionally, tests measuring
neutralizing antibodies aren’t widely available (limited to state
departments of health and the CDC).
Physician unfamiliarity with the presentations of WNV illness, coupled with the lack of standardized testing protocols for
suspected disease, contributed to uncertainty in the classification
of some cases. To avoid excluding potential cases, we employed
a category of “possible” WNV infection as described previously.
We suggest the CDC adopt a definition of “possible WNV
infection” for reporting and potentially therapeutic purposes.
For case definition, arboviral testing should be limited to
known regional endemic viruses. The presence of endemic viruses in sentinel populations could be utilized in CDC case
definitions. In the absence of active endemic viruses in humans
or sentinel populations, no further arboviral testing is necessary.
For example, St. Louis encephalitis virus infections previously
endemic to our area were not detected in humans, sentinel
flocks, or mosquito pools during the 2012 season (17, 18).
We suggest the CDC laboratory diagnostic criterion “negative
arboviral serologies for endemic arboviruses” be revised to reflect
the absence of other endemic arboviruses in mosquitoes and sentinel birds in the affected geographic area during an epidemic.
Additional difficulties involved distinguishing between true
WNND and WNF with nonspecific neurologic symptoms.
Determining whether WNV infection was a primary or contributory cause of death was problematic. Although most of the
autopsied patients had CNS lesions that were clearly sufficient
to explain death, one patient did not have well-developed CNS
pathology.
The literature cites evidence that systemic WNV infection
may cause direct injury to organs, exacerbating preexisting diseases (19–21). This may complicate the diagnostic evaluation
when attempting to decipher what is or is not attributable to
WNV infection. WNV may contribute to the death of patients
with significant underlying comorbidities in the absence of definitive CNS involvement. Data published by Schanzer et al
reviewed the potential contributory role of influenza and found
many comorbidities to be associated with influenza-attributed
deaths, particularly pulmonary and cardiac diseases (21). It is
important to realize that WNV may have systemic implications.
We caution that misidentification of potentially treatable conditions could delay appropriate therapy.
Furthermore, historical data review found distribution differences in WNF and WNND cases in 2003 versus 2012 (22,
23). In 2003, the WNF:WNND ratio was approximately 2.4:1;
in 2012, this ratio was approximately 1:1. Both observations
raise the possibility that the virus may have become more neurotropic due to viral mutation and genetic drift. Other possibilities
include changes in testing patterns with improved detection
related to patient and physician awareness and immunity of
the population at risk. Of concern, despite increased awareness
and prevention with DEET, mortality has not substantially
decreased.
294
Data analysis suggests opportunities to improve our response to outbreaks. Lessons learned include the need to 1)
remain vigilant for the diagnosis of WNV; 2) educate staff in
recognizing real-world manifestations of WNV infection, which
doesn’t neatly lend itself to published criteria for diagnosis; 3)
develop standardized diagnostic testing algorithms; 4) develop
recommendations for multisystem supportive care in WNF and
WNND patients; and 5) research strategies for better detection,
prevention, and treatment, including refined molecular tools for
viral identification. Plans are currently under way at BUMC to
optimize response to future outbreaks. Some activities involve
developing standardized testing protocols and guidelines for the
care of patients with possible WNV infection. However, further
studies are needed as we search for more effective diagnostic,
supportive, and therapeutic measures.
1.
2.
3.
4.
5.
6.
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Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus
isolated from the blood of a native of Uganda. Am J Trop Med Hyg
1940;20:471–492.
Petersen LR, Roehrig JT. West Nile virus: a reemerging global pathogen.
Emerg Infect Dis 2001;7(4):611–614.
Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the
Mediterranean basin: 1950–2000. Ann N Y Acad Sci 2001;951:117–
126.
Klein C, Kimiagar I, Pollak L, Gandelman-Marton R, Itzhaki A, Milo
R, Rabey JM. Neurological features of West Nile virus infection during
the 2000 outbreak in a regional hospital in Israel. J Neurol Sci 2002;
200(1–2):63–66.
Nash D, Mostashari F, Fine A, Miller J, O’Leary D, Murray K, Huang
A, Rosenberg A, Greenberg A, Sherman M, Wong S, Layton M; 1999
West Nile Outbreak Response Working Group. The outbreak of West
Nile virus infection in the New York City area in 1999. N Engl J Med
2001;344(24):1807–1814.
Watson JT, Pertel PE, Jones RC, Siston AM, Paul WS, Austin CC, Gerber
SI. Clinical characteristics and functional outcomes of West Nile fever.
Ann Intern Med 2004;141(5):360–365.
Sejvar JJ, Marfin AA. Manifestations of West Nile neuroinvasive disease.
Rev Med Virol 2006;16(4):209–224.
Crichlow R, Bailey J, Gardner C. Cerebrospinal fluid neutrophilic pleocytosis in hospitalized West Nile virus patients. J Am Board Fam Pract
2004;17(6):470–472.
Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van
Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen LR. Neurologic manifestations and outcome of West Nile virus infection. JAMA
2003;290(4):511–515.
Gandelman-Marton R, Kimiagar I, Itzhaki A, Klein C, Theitler J, Rabey
JM. Electroencephalography findings in adult patients with West Nile
virus-associated meningitis and meningoencephalitis. Clin Infect Dis
2003;37(11):1573–1578.
Kanagarajan K, Ganesh S, Alakhras M, Go ES, Recco RA, Zaman MM.
West Nile virus infection presenting as cerebellar ataxia and fever: case
report. South Med J 2003;96(6):600–601.
Sejvar JJ. The long-term outcomes of human West Nile virus infection.
Clin Infect Dis 2007;44(12):1617–1624.
ARUP Laboratory. Laboratory test directory: West Nile virus RNA by
RT-PCR. Available at http://www.aruplab.com/guides/ug/tests/0050229.
jsp; accessed April 28, 2015.
National Notifiable Diseases Surveillance Systems. Arboviral diseases,
neuroinvasive and non-neuroinvasive. Available at http://wwwn.cdc.
gov/NNDSS/script/casedef.aspx?CondYrID=616&DatePub=1/1/2011;
accessed April 28, 2015.
Norman DC. Fever in the elderly. Clin Infect Dis 2000;31(1):148–151.
Roghmann MC, Warner J, Mackowiak PA. The relationship between age
and fever magnitude. Am J Med Sci 2001;322(2):68–70.
Volume 28, Number 3
17. Unites States Geological Survey. St. Louis encephalitis, human, Texas,
2012. Available at http://diseasemaps.usgs.gov/2012/sle_tx_human.html;
retrieved April 28, 2015.
18. Unites States Geological Survey. St. Louis encephalitis, sentinel, Texas,
2012. Available at http://diseasemaps.usgs.gov/2012/sle_tx_sentinel.html;
retrieved April 28, 2015.
19. Pergam SA, DeLong CE, Echevarria L, Scully G, Goade DE. Myocarditis
in West Nile virus infection. Am J Trop Med Hyg 2006;75(6):1232–1233.
20. Georges AJ, Lesbordes JL, Georges-Courbot MC, Meunier DMY,
Gonzalez JP. Fatal hepatitis from West Nile virus. Ann Inst Pasteur Virol
1987;138(2):237–244.
21. Schanzer DL, Tam TW, Langley JM, Winchester BT. Influenza-attributable
deaths, Canada 1990–1999. Epidemiol Infect 2007;135(7):1109–1116.
22. Centers for Disease Control and Prevention. West Nile virus disease cases
and presumptive viremic blood donors reported to ArboNET, United
States, 2003. Available at http://www.cdc.gov/westnile/statsMaps/finalMapsData/data/2003WNVHumanInfectionsbyState.pdf; accessed April
28, 2015.
23. Centers for Disease Control and Prevention. West Nile virus disease cases
and presumptive viremic blood donors reported to ArboNET, United States,
2012. Available at http://www.cdc.gov/westnile/statsMaps/finalMapsData/
data/2012WNVHumanInfectionsbyState.pdf; accessed April 28, 2015.
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West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience
295
Comparison of long-term follow up of laparoscopic versus
open colectomy for transverse colon cancer
Samir Agarwal, MD, Mikhail Gincherman, MD, Elisa Birnbaum, MD, James W. Fleshman, MD, and Matthew Mutch, MD
Clinical Outcomes of Surgical Therapy (COST) was a landmark study
demonstrating that laparoscopic-assisted colectomy had oncologic outcomes similar to those of open colectomy for colon cancer, but transverse
colon cancers (TCCs) were excluded from that study. Oncologic results
of a laparoscopic resection for TCC are unknown. This single-institution
retrospective 3:1 case-matched review examined patients treated for
TCC from January 1, 1996, to April 15, 2009. Laparoscopic colectomy
(LC) and open colectomy (OC; extended right, extended left, and total
abdominal) cases completed for Stage I to III adenocarcinoma of the
transverse colon (hepatic flexure, transverse colon, and splenic flexure) were analyzed. Patients were matched for age, tumor location, and
stage. Primary endpoints were overall survival and disease-free survival.
Secondary endpoints were length of stay and pathologic parameters. One
hundred and twenty-three OC cases were matched with 41 LC cases.
There were four conversions (9.7%) in the LC group. Length of stay
was reduced by 28% in the LC group (P = 0.02). Complication rate and
severity were similar between the two groups (29% vs 24%; P = 0.68).
Lymph node harvest was higher in the LC group than in the OC group
(23.3 vs 18.6; P = 0.03). All pathologic margins were clear, and no local
recurrence was found in either group. Five-year overall survival (61% vs
59%; P = 0.39) and disease-free survival (88% vs 82%; P = 0.23) were
similar in the two groups. Short-term recovery was faster and lymph node
harvest was improved in the LC group. Thus, laparoscopic management
of TCC is a safe and feasible procedure.
T
he Clinical Outcomes of Surgical Therapy (COST) trial
demonstrated the oncological equivalence of laparoscopic
surgery and open surgery in the treatment of colon cancer (1). Transverse colon cancers were excluded from the
COST trial. It is well known that the laparoscopic management
of transverse colon cancers is more challenging than other cancers
of the colon. This is primarily due to anatomic reasons. The
transverse colon has at least two collateralizing sources of blood
flow and therefore multiple possibilities of divergent lymphatic
drainage. The transverse (middle colic) mesentery is short over
the anterior surface of the pancreas, and the venous drainage is
fragile at the base of the mesentery. Consideration of tumor site
along the transverse colon will influence which operation will
provide the appropriate extent of mesenteric resection. There
are no data regarding the appropriateness of laparoscopic resec296
tion for curable cancer from the randomized controlled trials
published to date since all excluded transverse colon cancer in
their protocols (2). The question of whether laparoscopic surgery
is equivalent to open surgery in the management of transverse
colon cancer should be addressed before assuming the appropriateness of this technique. Specifically, evaluation of 5-year overall
survival and disease-free survival for patients undergoing a laparoscopic approach to curable transverse colon cancer is needed.
METHODS
The colorectal cancer database containing over 3000 patients
at Washington University in St. Louis was queried to obtain
patients that would be suitable for our retrospective comparison.
The study was approved by the institutional review board at
Washington University in St. Louis/Barnes Jewish Hospital. All
operations were performed by surgeons in the Section of Colon
and Rectal Surgery at Washington University in St. Louis from
January 1, 1996, to April 15, 2009.
A retrospective review of 164 patients with curable (Stage
I–III) transverse colon cancer was performed. Complete removal
of the colon mesentery and high ligation of major feeding vessels was performed in all cases according to practice parameter
recommendations of the American Society of Colon and Rectal Surgeons. All patients treated laparoscopically for a curable
transverse colon cancer (41) were matched 3:1 with 123 patients
who underwent an open operation. Patients were matched according to age, gender, tumor location, and pathologic stage
(I–III). All patients had histologically confirmed adenocarcinoma between the hepatic and splenic flexures found on colonoscopy and confirmed at the time of surgery. Patients with
Stage IV disease, perforated cancers, and emergency operations
were excluded from the study.
From the George Washington University Hospital, Washington, DC (Agarwal); the
Division of Colon and Rectal Surgery, Washington University in St. Louis, St. Louis,
Missouri (Gincherman, Birnbaum, Mutch); and the Department of Surgery, Baylor
University Medical Center at Dallas, Dallas, Texas (Fleshman).
Presented in poster form at the 2009 meeting of the American Society
of Colon and Rectal Surgeons in Minneapolis, Minnesota.
Corresponding author: James W. Fleshman, MD, Department of Surgery, Baylor
University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246
(e-mail: [email protected]).
Patients underwent extended right colectomy (removal of
right and transverse colon), extended left colectomy (removal of
left and transverse colon), or total abdominal colectomy based
on patient characteristics and tumor location to remove the
colon and blood supply to the affected area. No segmental,
wedge resections were performed for transverse colon cancer.
The omentum was removed in all patients with transaction of
the gastrocolic ligament outside the gastroepiploic arcade along
the greater curvature of the stomach. The laparoscopic group
included laparoscopic-assisted procedures (with intracorporeal
dissection and vessel ligation with extraction and anastomosis
through a 5 cm midline umbilical incision) and hand-assisted
laparoscopic procedures (with the hand port placed at the suprapubic transverse incision used to extract and anastomose
the bowel).
Postoperative complications occurring within 30 days of the
operation were classified according to the Accordion Severity
Grading System of Surgical Complications (ASGS) (3). Mild
complications are those that only require a minor procedure at
the bedside to resolve. Examples of these include drainage of
wound infections and nasogastric tubes. Moderate complications are those that require more aggressive intervention, such
as antibiotics, blood transfusions, or total parenteral nutrition.
Severe complications are those that require some form of intervention such as an endoscopic procedure, interventional radiologic procedure, or operation. Additionally, severe complications
are those that result in the failure of one or more organ system.
The final classification in the ASGS is death.
Primary endpoints of our study were 5-year overall and
disease-free survival. Secondary endpoints were length of stay,
complications, and quantity of lymph node retrieval.
Patients were followed by the Section of Colon and Rectal
Surgery every 3 months with physical exam and carcinoembryonic antigen level for the first year, at which time colonoscopy and computed tomography (CT) was performed.
Patients were followed every 6 months with physical exam
and carcinoembryonic antigen level until 5 years. CT scan
and colonoscopy were repeated as indicated. Stage III and
some stage II patients received adjuvant chemotherapy with
5-flurouracil–based therapy.
Comparisons were made between the laparoscopic and open
groups using unpaired two-tailed t tests for continuous variables
and chi-square or Fisher’s exact test for categorical variables.
Survival was estimated using the Kaplan-Meier method with log
rank estimation used to assess differences in survival between the
two groups. Statistical significance was set at P < 0.05 and results are presented as mean ± standard deviation for continuous
variables and as percentages for categorical variables. Statistical
analysis was performed using GraphPad 5 Prism Software (San
Diego, CA).
RESULTS
Patient demographics and tumor characteristics are shown
in Table 1 for the matched groups. No statistically significant
differences were found in age or gender between the laparoscopic and open surgical groups. Stratifying the two groups
July 2015
according to American Society of Anesthesiologists score >3
or <3 revealed similar groups. Comparison of tumor location
along the transverse colon revealed no significant differences.
The tumors were considered hepatic flexure tumors if they were
in the proximal one-third of the transverse colon and were considered splenic flexure tumors if they were in the distal one-third
of the transverse colon.
There were four conversions to open surgery (9.7%) in the
laparoscopic group (poor visualization = 3, body habitus = 1).
Length of stay was shortened by 28% in the laparoscopic surgery
group (P = 0.02) (Table 1). Complication rate and severity of
complications were similar between the two groups (29% vs
24%; P = 0.68). There were 4 (3.3%) anastomotic leaks in
the open group and 2 (4.9%) in the laparoscopic group, and
no perioperative deaths. Lymph node harvest was significantly
higher in the laparoscopic group than in the open group (23.3 vs
Table 1. Demographic characteristics and outcomes of the
laparoscopic and open surgery groups
Variable
Laparoscopic
(n = 41)
Open
(n = 123)
P
value
67.0 ± 13.7
68.6 ± 12.7
0.51
62%
49%
Demographic characteristics
Age (years)
Men
ASA classification
0.19
0.53
<3
88%
92%
>3
12%
8%
Tumor location
0.47
Hepatic flexure
40%
33%
Transverse colon
49%
48%
Splenic flexure
11%
19%
I
38%
38%
II
35%
35%
III
27%
27%
Pathologic stage
1.0
Outcomes
5-year survival
61%
59%
0.39
Stage I
55%
75%
0.80
Stage II
83%
61%
0.19
Stage III
58%
35%
0.82
88%
82%
0.23
Lymph node retrieval
23.3 ± 12.9
18.6 ± 10.7
0.03
Length of stay (days)
6.8 ± 2.9
9.4 ± 6.3
0.02
24%
29%
0.68
Mild
44%
50%
Moderate
22%
16%
Severe
34%
34%
Death
0%
0%
5-year disease-free survival
Complication rate
ASA indicates American Society of Anesthesiologists.
Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer
297
a
b
c
d
Figure 1. Overall survival for (a) all patients, (b) patients with Stage I disease; (c) patients with Stage II disease; and (d) patients with Stage III disease receiving
either a laparoscopic procedure (solid line) or open procedure (dashed line).
18.6; P = 0.03). All pathologic margins were clear. There were
no perforations of the cancer or violation of the tumor during
the procedure. Operative times were longer for the laparoscopic
group.
Five-year overall survival was similar between the laparoscopic group and open group (61% vs 59%, respectively;
P = 0.39) (Figure 1a). There was no local recurrence in either
group. No differences were found when comparing the stage
of disease and the method of resection (Figure 1b, 1c, 1d).
Disease-free 5-year survival, comparing all stages together,
was 88% and 82% for the laparoscopic and open groups,
respectively (P = 0.23) (Figure 2).
DISCUSSION
The COST trial excluded patients with transverse colon
lesions from its analysis (1). The purpose of this paper was to
retrospectively analyze our outcomes for laparoscopic resection
of transverse colon cancers when compared to the previous gold
standard of open resection. Only three other reports have addressed this issue (4–7). Our data represent the largest review
298
of laparoscopic versus open surgery for transverse colon cancer
with long-term follow up.
The data presented here support the supposition that laparoscopic resection of transverse colon cancer is feasible and
similar to open surgery in experienced hands. Hospital stay is
shortened and oncologic outcomes are the same as for open
resection. The benefits of laparoscopic resection are less pain,
better cosmesis, improved quality of life, and a shorter recovery without an oncologic or long-term survival detriment.
These long-term survival data are consistent with previous data
on other site colon resections (2). The complication rate for
transverse colectomy is the same for laparoscopic and open
techniques (24% vs 29%), and there is no difference in the
frequency of moderate or severe events. The rate of anastomotic
leak was also similar.
Laparoscopic resection of transverse colon cancers is considered challenging for laparoscopic surgeons. Exposure at the base
of the mesentery is difficult. Multiple vessels must be controlled,
and vessel-sealing instrumentation has reduced this problem.
Injury to the superior mesenteric artery can result from excessive
Volume 28, Number 3
Figure 2. Disease-free survival for all patients receiving either a laparoscopic
procedure (solid line) or open procedure (dashed line).
retraction of the colon to expose the base of the middle colic
arteries. It is usually during this excessive retraction to obtain
exposure that bleeding occurs. This was not a problem in this
group of patients, and bleeding did not result in an increased
conversion to open operation. It is helpful to approach the
middle colic vessels from the avascular windows on either side
of the middle colic vessels. A familiarity with upper abdominal
anatomy is essential. This maneuver is facilitated by a hand
assist approach.
An interesting result of our study was the statistically significant finding of a greater lymph node harvest with the laparoscopic approach, 23.3 vs 18.6 lymph nodes (P = 0.03). This
may reflect a greater number of total colectomy procedures in
the laparoscopic group. This could also be a result of better
visualization of the base of the middle colic vessels and ligation
at a level closer to the surface of the pancreas compared with
open surgery. The significance of these findings is unclear. The
higher ligation of the vessels was not associated with an increase
in bleeding.
The four conversions in the laparoscopic group were primarily a result of poor visualization. One was done for large body
habitus. We feel that as we became more adept in laparoscopic
July 2015
resection of transverse colon cancers, our skills allowed us to
approach more difficult resections without the need for conversion. A conversion rate of 10% is compatible with expected
conversion rates for elective laparoscopic colectomy and is less
than the rate reported by the COST trial (2).
This report was limited by its retrospective nature and the
inherent selection bias that occurs without a randomization
process. The selection of patients for laparoscopic resection of a
transverse colon cancer will be influenced by the appearance of
the tumor on staging CT. Less advanced tumors will naturally
be selected for laparoscopic approaches, and this may influence
the oncologic outcomes of the patients.
In conclusion, laparoscopic colectomy performed by experienced surgeons for transverse colon cancer is oncologically similar to open colectomy with no significant difference in long-term
overall or disease-free survival. Short-term recovery and lymph
node harvest are improved in the laparoscopic group compared
to the open group. Laparoscopic colectomy for transverse colon
cancer seems safe and feasible in expert hands, and there is no
difference in oncologic outcomes.
1.
Clinical Outcomes of Surgical Therapy Study Group. A comparison of
laparoscopically assisted and open colectomy for colon cancer. N Engl J
Med 2004;350(20):2050–2059.
2. Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RW
Jr, Hellinger M, Flanagan R Jr, Peters W, Nelson H; Clinical Outcomes of Surgical Therapy Study Group. Laparoscopic colectomy for
cancer is not inferior to open surgery based on 5-year data from the
COST Study Group trial. Ann Surg 2007;246(4):655–662; discussion
662–664.
3. Strasberg SM, Linehan DC, Hawkins WG. The accordion severity grading
system of surgical complications. Ann Surg 2009;250(2):177–186.
4. Lee YS, Lee IK, Kang WK, Cho HM, Park JK, Oh ST, Kim JG, Kim YH.
Surgical and pathological outcomes of laparoscopic surgery for transverse
colon cancer. Int J Colorectal Dis 2008;23(7):669–673.
5. Zmora O, Bar-Dayan A, Khaikin M, Lebeydev A, Shabtai M, Ayalon A,
Rosin D. Laparoscopic colectomy for transverse colon carcinoma. Tech
Coloproctol 2010;14(1):25–30.
6. Kim HJ, Lee IK, Lee YS, Kang WK, Park JK, Oh ST, Kim JG, Kim YH.
A comparative study on the short-term clinicopathologic outcomes of
laparoscopic surgery versus conventional open surgery for transverse colon
cancer. Surg Endosc 2009;23(8):1812–1817.
7. Akiyoshi T, Kuroyanagi H, Fujimoto Y, Konishi T, Ueno M, Oya M,
Yamaguchi T. Short-term outcomes of laparoscopic colectomy for transverse colon cancer. J Gastrointest Surg 2010;14(5):818–823.
Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer
299
Mortality by treatment in patients ≥80 years of age with
gastroesophageal cancer seen in a 20-year period at a
single medical center
Tara Barnett, MD, James Mason, DO, Yolanda Munoz Maldonado, PhD, and Lucas Wong, MD
The treatment approach to patients 80 years of age and older with
gastroesophageal cancer at Baylor Scott and White in Temple, Texas,
has historically favored conservative measures in the form of palliation
and observation. To evaluate this trend in practice, the administered
treatments and subsequent patient outcomes of this group were retrospectively reviewed. The study group included all patients 80 years of
age and older with a diagnosis of gastroesophageal cancer seen at our
facility between 1991 and 2010. Of the 117 cases, 49% received none
of the available treatment modalities. The median overall survival (OS) of
patients who received treatment, however, was significantly longer than
the OS of those who did not, regardless of modality. Specifically, surgical intervention offered an almost double median OS compared with no
therapy (6.8 vs. 3.9 months, respectively; P = 0.02); chemotherapy, an
almost 4-fold OS benefit (14.8 vs. 3.9 months; P = 0.03); and radiation
therapy, a >3-fold OS benefit (11.1 vs. 3.5 months; P = 0.04). These
results further substantiate chronological age as an inaccurate predictor
of treatment benefit, and age alone should not dictate the administration
or withholding of available treatment options.
T
he treatment approach to patients 80 years of age and
older with gastroesophageal cancer at Baylor Scott and
White in Temple, Texas, has historically favored conservative measures in the form of palliation and observation.
To evaluate this trend in practice, the administered treatment(s)
and subsequent patient outcomes of this group were retrospectively reviewed.
METHODS
The study group included all patients 80 years of age and
older with a diagnosis of gastroesophageal cancer, regardless of
stage (I–IV) or performance status (Eastern Cooperative Oncology Group 0–4), seen in our facility from 1991 to 2010. The
treatment course (i.e., surgery, chemotherapy, radiation therapy,
or any combination of these modalities) and overall survival in
months were retrospectively reviewed.
Descriptive statistics were reported using minimum, 25th
percentile, median (or 50th percentile), mean, 75th percentile,
maximum, and standard deviation for continuous variables.
Categorical variables were described as counts and percentages.
Kaplan-Meier curves were constructed for gender, age group,
300
chemotherapy, radiation, and surgery. Cox proportional hazard
models were fitted to the data. The variables included in the
model were all variables with a P value < 0.25 in the univariate
survival analysis. Residual diagnostics indicated a good fit of the
model and no significant deviations from the model assumptions. A level of 0.05 was considered statistically significant for
all other tests. SAS 9.2 was used for the statistical analysis. R
software version 3.1.0 was used for the survival curves.
RESULTS
Between 1991 and 2010, a total of 117 patients over the age
of 80 were diagnosed with gastroesophageal cancer at our facility. Table 1 depicts overall demographic and baseline characteristic information, highlighting the heterogeneity in presentation
and treatment approach of gastroesophageal cancer, even in this
highly specific age group. Of note, 62% of the study population
was male, and 62% were between the ages of 80 and 84 at the
time of inclusion. Only 29 patients (31%) presented with stage
I disease, while stages II, III, and IV comprised 10%, 25%,
and 34%, respectively. The most common site of primary malignancy was the gastric fundus (50%), followed by esophageal
(30%) and gastric cardia (20%).
Table 2 details the frequency of treatment modalities
administered. Interestingly, 57 (49%) patients received no
treatment; 25% of patients underwent surgery, 11% received
chemotherapy, and 27% received radiation therapy, alone or
in combination with another modality. Table 3 illustrates the
effects baseline characteristics may have had on treatment
decisions, demonstrating that most patients who received at
least one of the available treatments were between the ages of
80 and 84 and had more advanced (stage 3–4) or aggressive
(grade III) disease.
The median overall survival for patients who received treatment was significantly longer relative to those without treatment, regardless of modality (Figure 1). Specifically, the median
From the Division of Hematology and Oncology (Barnett, Wong), the Department
of Internal Medicine (Mason), and the Office of Biostatistics (Munoz Maldonado),
Baylor Scott & White Health, Scott & White Memorial Hospital, Temple, Texas.
Corresponding author: Tara Barnett, MD, Baylor Scott & White Health, Scott
& White Memorial Hospital, MS-01-692, 2401 South 31st Street, Temple, TX
76508 (e-mail: [email protected]).
Table 1. Patient characteristics for 117 patients with gastroesophageal cancer over the age of 80 treated at a single institution*
Variable
N (%)
Hazard ratio
(95% CI)
Table 3. Patient characteristics by treatment for patients with
gastroesophageal cancer over the age of 80 treated
at a single institution*
P value
Variable
Demographics
Gender
Female
44 (38%)
Male
73 (62%)
Age (years) 80–84
Race
72 (62%)
85+
45 (38%)
White
102 (87%)
1.6 (1.04, 2.39)
0.31
0.04
Age (years)
0.6 (0.33, 1.11)
0.14
15 (13%)
Race
0–1
29 (31%)
0.24 (0.13, 0.44)
<0.001
2
10 (10%)
0.41 (0.78, 0.87)
0.03
Follow-up,
months: mean, SD
3
24 (25%)
0.54 (0.30, 0.94)
0.03
4
32 (34%)
I–II
22 (23%)
0.27 (0.12, 0.64)
0.002
III
63 (67%)
0.65 (0.18, 0.78)
0.005
Nonwhite
Grade
IV
Site
Treatment
10 (35%)
2 (15%)
8 (26%)
19 (65%)
11 (85%)
23 (74%)
80–84
20 (69%)
10 (77%)
17 (55%)
85+
9 (31%)
3 (23%)
14 (45%)
White
27 (93%)
10 (77%)
24 (77%)
2 (7%)
3 (23)
7 (23%)
6.3
(0.33, 173.5)
14.1
(3.0, 48.0)
10.2
(2.2, 48.0)
0–1
9 (33%)
2 (20%)
10 (38%)
2
3 (11%)
1 (10%)
3 (12%)
3
9 (33%)
3 (30%)
10 (38%)
4
6 (23%)
4 (40%)
3 (12%)
Esophagus
I–II
3 (13%)
4 (40%)
6 (24%)
III
19 (79%)
6 (60%)
16 (64%)
IV
2 (8%)
0 (0%)
3 (12%)
Esophagus
6 (21%)
3 (23%)
18 (58%)
Gastric
20 (69%)
5 (38%)
6 (19%)
Cardia
3 (10%)
5 (38%)
7 (23%)
Classification
Stage
9 (10%)
35 (30%)
Gastric
58 (50%)
Cardia
24 (20%)
Surgery
29 (25%)
0.99 (0.56, 1.79)
1.25 (0.75, 2.20)
1.76 (1.1, 2.9)
0.97
0.02
Chemotherapy
13 (11%)
0.48 (0.23, 0.89)
0.03
Radiotherapy
31 (27%)
1.57 (1.02, 2.48)
0.047
overall survival for patients who underwent surgical intervention was nearly double that of those who did not (6.8 months
[95% confidence interval (CI) 3.9–19.9] vs. 3.9 months [95%
CI 2.8–6.3]; P = 0.02; Figure 1a); chemotherapy offered an almost 4-fold overall survival benefit (14.8 months [95% CI 5.3–
30.6] vs. 3.9 months [95% CI 3.0–5.8]; P = 0.03; Figure 1b);
Table 2. Frequency of treatment modalities administered for
117 patients with gastroesophageal cancer over the age of
80 treated at a single institution
Treatment modality
Frequency
Percent
No treatment
57
49%
Surgery alone
25
21%
3
3%
Chemotherapy alone
Radiation alone
Grade
0.41
*Univariate hazard ratios compared with overall mortality. Baseline references for variables with more than one level in the hazard ratio are always the last level. CI indicates
confidence interval.
22
19%
Surgery and chemotherapy
1
<1%
Chemotherapy and radiation
6
5%
Surgery, chemotherapy, and radiation
3
3%
July 2015
Female
Male
Nonwhite
Classification
Stage
Chemotherapy Radiation
(N = 13)
(N = 31)
Demographics
Gender
0.7 (0.44, 0.98)
Surgery
(N = 29)
Site
*Tests between the treatments could not be performed since any given patient could
have one or more treatment modality.
and radiation therapy, a greater than 3-fold overall survival
benefit (11.1 months [95% CI 6.3–15.0] vs. 3.5 months [95%
CI 2.4–4.6]; P = 0.04; Figure 1c).
A Cox proportional hazards model was fitted to the data.
Backward, forward, and stepwise variable selection procedures
chose gender, stage, and treatment with chemotherapy to be part
of the model. Age group was also included in the reduced model.
The model was statistically significant (P < 0.0001). Stage and
chemotherapy had coefficient estimates significantly different
than 0 (Table 4). Gender and age group were not significant.
Patients without chemotherapy treatment were 2.4 times more
likely to die than patients treated with chemotherapy. Patients
with stage 4 disease were 5 times more likely to die than patients with stage 1, but otherwise no higher hazards for other
stage combinations was identified. A Cox model was fitted to
the data stratified by age group. Although this model seemed
to indicate an interaction between age group and gender, this
interaction could not be explored due to the small sample size.
DISCUSSION
The complexity of gastrointestinal oncologic resection
imposes significant morbidity and mortality. A recently published study found that increasing age independently impacted
Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer
301
No Surgery
Surgery
0.0
0.2
0.4
0.6
Survival Rate
0.8
1.0
a
0
3
6
9
15
21
27
33
39
45
51
57
63
69
45
51
57
63
69
51
57
63
69
Time(months)
0.4
0.6
0.8
No Chemo
Chemo
0.0
0.2
Survival Rate
1.0
b
0
3
6
9
15
21
27
33
39
Time(months)
0.8
0.4
0.6
No Radiation
Radiation
0.0
0.2
Survival Rate
1.0
c
0
3
6
9
15
21
27
33
39
45
Time(months)
Figure 1. Kaplan-Meier estimates of survival for patients who did and did not
receive (a) surgery, (b) chemotherapy, and (c) radiation.
Table 4. Coefficient estimators for the final model using all
patients in a Cox proportional hazard model*
Parameter
Age group
(80–84)
Parameter Standard
Hazard 95% CI for
estimate
error
P value ratio hazard ratio
–0.34
0.24
0.17
0.71
0.45, 1.16
0.45
0.26
0.08
1.56
0.94, 2.58
Stage (0–1)
–1.65
0.33
<.001
0.19
0.09, 0.36
Stage (2)
–0.90
0.41
0.03
0.41
0.17, 0.88
Stage (3)
–0.62
0.30
0.04
0.54
0.30, 0.96
Chemotherapy
–0.89
0.39
0.02
0.41
0.18, 0.83
Gender (Female)
*Analysis of maximum likelihood estimates. The final model considered mortality as
a function of age group, gender, stage, and chemotherapy. The model was significant
with a P < 0.001. Variables were selected using backward, forward, and stepwise
selection. All three methods agreed on the final model. All regression diagnoses were
checked and model assumptions satisfied. CI indicates confidence interval.
302
outcome following esophagectomy, particularly mortality and
discharge disposition, and patients who are at least 80 years
of age considering esophagectomy should be recognized as a
high-risk cohort (1). The same study also concluded that age
should not necessarily be a contraindication for esophagectomy,
but patients over the age of 80 must be carefully selected on
a case-by-case basis and serious consideration of nonoperative
treatment is warranted. Similarly, a systematic review published
in 2007 found no evidence of inferior survival or increased
treatment-related mortality in the elderly with experimental
treatments compared with younger patients (2). The available
data also suggest that older patients are just as willing to undergo chemotherapy as their younger counterparts, although
less willing to endure severe treatment-related side effects (3).
This perspective, however, is uncommonly the standpoint from
which treatment strategies for older patients are formulated. In
reviewing our data, almost 50% of patients 80 years of age or
older with a diagnosis of gastroesophageal cancer did not receive
any of the three available modalities of treatment, even though
patients who received treatment fared far better.
This study had limitations. It failed to consider treatment
bias, in that perhaps those patients selected to undergo treatment fared better because they were “healthy” enough to undergo treatment, while those who were not offered, or opted
against, treatment had inferior survival because they were more
“sick” as a cohort and not candidates for therapy. It also did
not reflect quality of life during the gained months of survival
in those who underwent treatment. Safety data and side effects
were also not discussed.
With over 20 years of data, we hoped to also identify trends
in mortality among the treatment and nontreatment groups
over time, to perhaps demonstrate the effectiveness of modern
therapies compared to those used 20 years ago. Unfortunately,
our sample size was not sufficient for such an analysis, but
the question would be an interesting avenue of future study.
Of note, within the timeframe studied, there were no major
advances largely affecting overall survival. The development of
minimally invasive approaches to gastroesophageal cancer resection offered an attractive alternative to traditional transthoracic
open surgery, although retrospective evaluation demonstrated
identical mortality and overall surgical morbidity (4). To date,
there remains no standard chemotherapy regimen for use in
the neoadjuvant, combined modality setting (4). In addition,
targeted therapies with known survival benefit in gastroesophageal cancer are currently limited to trastuzumab and ramucirumab, although both were approved for use after the close of
our study (5).
These data represent a significant contribution to the ongoing debate over treatment strategies for those over the age
of 80 diagnosed with gastroesophageal cancer. Based on these
findings, while age is an important predictor of overall outcome
and should play a substantial role in the decision making on
approach to treatment, age alone should not be the deciding
factor, but one of many patient-specific variables that warrant
consideration. As our institution, the treatment of patients over
the age of 80 with gastroesophageal cancer should be considered
Volume 28, Number 3
more frequently and advocated with proper selection and appropriate counseling.
Acknowledgments
The authors acknowledge the contributions of Alejandro
Arroliga, MD, and Mark Holguin, MD.
1.
2.
Stahl CC, Hanseman DJ, Wima K, Suton JM, Wilson GC, Hohmann SF,
Shah SA, Abbott DE. Increasing age is a predictor of short-term outcomes
in esophagectomy: a propensity score adjusted analysis. J Gastrointest Surg
2014;18(8):1423–1428.
Kumar A, Soares HP, Balducci B; National Cancer Institute. Treatment
tolerance and efficacy in geriatric oncology: a systematic review of phase III
3.
4.
5.
randomized trials conducted by five National Cancer Institute–sponsored
cooperative groups. J Clin Oncol 2007;25(10):1272–1276.
Yellen SB, Cella DF, Leslie WT. Age and clinical decision making in
oncology patients. J Natl Cancer Inst 1994;86(23):1766–1770.
Lockhart CA, El-Khoueiry AB, Krasna M. Update on upper gastrointestinal cancers: what’s new since the 2009 ASCO annual meeting? ASCO
University 2010 Education Book. Category: Gastrointestinal (Noncolorectal)
Cancer. Available at http://meetinglibrary.asco.org/content/34-74; accessed April 20, 2015.
Burtness B, Ilson D, Iqbal S. New directions in perioperative management of locally advanced esophagogastric cancer. ASCO University
2014 Education Book. Category: Gastrointestinal (Noncolorectal) Cancer.
Available at http://meetinglibrary.asco.org/EdBookTracks/2014%20
ASCO%Annual%20Meeting; accessed April 29, 2015.
B
aylor University Medical Center Proceedings held
its annual editorial board meeting on April 2,
2015. Some of the points discussed were as
follows:
• In 2014, Proceedings published 125 manuscripts and 396
pages (Table), with an acceptance rate of 80%. The number
of manuscripts was at an all-time high.
• A little over half (52%) of the manuscripts were submitted
by Baylor Scott and White physicians—an all-time low since
we are receiving more submissions from outside the system.
• In response to the merger, we modified the tagline and images on the cover and have published several articles from
Baylor Scott & White physicians in Temple. In addition,
two board members now represent the Central Division.
• New electronic options were added in 2014, including an
ePub version and an improved eTOC.
• A reader survey was conducted in spring 2014.
• For 2014, 6800 copies of each issue were printed, and the
eTOC was sent to 500 individuals.
• There were 2.1 million visits to the journal’s PubMed Central
website in 2014 (plus more for the BaylorHealth.edu/
Proceedings site).
July 2015
Table. Numbers of articles and pages published in BUMC
Proceedings in 2014
Jan 14
Apr 14
Jul 14
Oct 14
Content
Art Pp Art Pp
Art Pp
Art Pp
Case reports
12 30
19
15
40
17
37
50
Total
Art
Pp
63 157
Original articles
2 12
8
29
3
11
4
22
17
74
Editorials, tributes
4 10
7
19
3
11
3
6
17
46
Interviews
1
1
13
1
8
3
28
Facts and ideas
Reviews
Miscellaneous*
Total
7
1
6
4 11
24 76
1
11
6
24
39 120
1
8
4
7
31 100
1
10
4
35
1
4
1
4
6
10
20
52
31 100 125 396
*Miscellaneous includes the copyright page, Baylor news, obituaries, journal notices,
abstracts, guidelines for authors, ads, and publications list. Not included are items
that appear at the end of articles. The miscellany items are not included in the total
article count.
Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer
303
Trends in the neonatal mortality rate in the last decade with
respect to demographic factors and health care resources
Vinayak Govande, MBBS, Amy R. Ballard, MD, Madhavi Koneru, MD, and Madhava Beeram, MD
To understand factors contributing to the neonatal mortality rate (NMR),
we studied trends in the NMR during 2000 to 2009 with respect to
demographic factors and health care resources. Birth- and death-linked
mortality data for 14,168 neonatal deaths that occurred between 2000
and 2009 were obtained from the Texas Department of Health and Human
Services. Demographic factors and health care resource data were analyzed using analysis of variance, chi-square tests, and linear regression
analysis. The average NMR increased from 3.37 in 2000 to 3.77 in 2009.
The NMR in blacks ranged from 6.57 to 8.97 during the study period.
Among the babies who died, the mean birthweight decreased from 1505
to 1275 g (P < 0.001) and the mean gestational age decreased from
28.4 to 27.8 weeks (P < 0.001). Cesarean section deliveries increased
from 32.7% to 44.9% (P < 0.001). The percentage of mothers receiving
prenatal care increased from 81.4% to 86.6% (P < 0.001). Mothers with
a college education increased from 8.8% to 20.5% (P < 0.001). The median household income increased from $41,047 to $49,189 (P < 0.001).
The number of neonatal intensive care unit beds increased from 33.4 to
56 per 10,000 births, and the number of neonatologists increased from
0.27 to 0.40 per 10,000 women of 15 to 44 years of age. In conclusion,
the NMR didn’t improve despite improvements in demographic factors
and health care resources. Racial disparities persist, with a high NMR
in the black population. We speculate a possible genetic predisposition
related to ethnicity, and a potentially higher rate of extreme prematurity
might have contributed to a high NMR in the study population.
T
he neonatal mortality rate (NMR) and the infant mortality rate are often used to indicate the effectiveness of
maternal and child health care services (1, 2). In the
United States, neonatal mortality has decreased steadily
during the previous three decades. However, in the last 10 years,
the decrease has been marginal. The US NMR was 4.19 in 2009
(3). Texas is the second-largest state in population, and in 2009,
it ranked 18th regarding NMR in the USA (3). Because it is
a large state with diverse sociodemographic factors and has a
high NMR, Texas is an important context in which to study
the effectiveness of maternal and child health care services. This
study examined trends in the NMR and their relation to underlying variables such as maternal sociodemographic factors
and available health care resources in the state of Texas from
2000 to 2009.
304
METHODS
In this study, we used publicly available information obtained from the Texas Department of Health and Human
Services (TDHHS). The study received approval from the institutional review board of Baylor Scott and White Healthcare.
Data for neonates who died under the age of 28 days were
collected from TDHHS for the period of 2000 to 2009. Birth and
death certificate data were linked by TDHHS during the study
period. The number of obstetrics and gynecology providers and
neonatologists, along with the number of beds available in neonatal intensive care units (NICU), was also obtained from TDHHS.
Important outcome variables studied included NMR, ethnicity (white, black, Hispanic, and other), and key demographic
determinants of NMR including maternal age, birthweight,
educational level, socioeconomic status, gestational age, prenatal care, cause of death, method of delivery, and maternal
smoking. Variables regarding health care included number of
available beds in the NICU and number of obstetrics providers
and neonatologists. The NMR is the number of neonatal deaths
during a year, divided by the number of live births during the
same year, expressed per 1000 live births.
Characteristics were summarized according to ethnicity and
year by descriptive statistics: mean (± standard deviation) for
continuous variables and frequency (percent) for categorical
variables. Multivariable Poisson regression analysis and multivariable negative binomial regression analysis were utilized to
investigate the significance of ethnicity, median income, and
year on NMR. Proportion comparisons were assessed utilizing chi-square test. Linear regression analysis or the CochranArmitage trend test was used for trend analysis. A P value of
< 0.05 indicates statistical significance. SAS 9.2 (SAS Institute
Inc, Cary, NC) was used for data analysis.
RESULTS
Between 2000 and 2009, a total of 14,168 death records of
neonates younger than 28 days old and associated birth records
From the Department of Pediatrics, McLane Children’s Hospital at Baylor Scott
and White, Temple, Texas.
Corresponding author: Vinayak Govande, MBBS, Department of Pediatrics,
Baylor Scott and White Health, Texas A&M College of Medicine, 2401 S. 31st
Street, Temple, TX 76508 (e-mail: [email protected]).
Table 1. The neonatal mortality rate in Texas and accompanying socioeconomic factors from 2000 to 2009 using information
collected from records of 14,168 neonatal deaths
Variables
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
NMR (all)
3.37
3.71
3.90
4.37
4.13
4.10
3.97
3.81
3.81
3.77
NMR (blacks)
6.61
7.17
8.36
8.97
8.17
8.81
7.63
7.53
6.57
6.57
NMR (whites)
2.83
3.25
3.34
3.69
3.54
3.05
3.44
2.97
3.21
3.32
Mean birthweight (g)*
1505
1436
1358
1310
1333
1217
1270
1295
1268
1275
Mean GA (weeks)*
28.4
28.4
27.8
27.4
27.5
27.4
27.7
27.7
27.5
27.8
Mode of delivery
(cesarian section)*
32.7%
30.2%
28.9%
27.5%
29.0%
41.9%
42.6%
44.1%
41.9%
44.9%
Prenatal care
81.4%
80.0%
80.1%
80.9%
82.2%
85.1%
87.1%
85.0%
84.5%
86.6%
Maternal age (years)
26.4
26.7
26.5
26.8
27.0
27.2
26.9
27.1
27.2
27.7
Maternal education
(college)*
8.8%
7.5%
7.6%
7.9%
8.9%
17.8%
17.7%
18.6%
17.6%
20.5%
Smokers
8.4%
8.2%
7.0%
8.0%
6.7%
8.9%
8.6%
9.6%
7.0%
7.6%
Median household
income* (thousands/year)
41.0
41.0
40.9
41.4
42.0
43.2
45.8
48.8
50.7
49.2
NICU beds/10,000 births
33.4
34.9
35.7
38.1
40.4
42.3
43.6
48.9
52.2
56.0
Neonatologists/10,000
females of 15–44 yr
0.27
0.28
0.29
0.32
0.35
0.35
0.34
0.37
0.39
0.40
Obstetricians/10,000
females of 15–44 yr
0.05
0.04
0.04
0.04
0.06
0.06
0.06
0.06
0.05
0.04
NMR indicates neonatal mortality rate; GA, gestational age; NICU, neonatal intensive care unit.
*P < 0.001.
were obtained and the characteristics of neonatal death were
assessed. The NMR according to ethnicity, mean birthweight,
mean gestational age, mode of delivery, prenatal care, maternal age, maternal education, incidence of smoking, median
household income, number of NICU beds per 10,000 births,
and number of neonatal providers and obstetricians per 10,000
females of 15 to 44 years are shown in Table 1. Figures 1 to 3
highlight the NMR by ethnicity and by cause and the growing
number of resources over the time period.
DISCUSSION
The NMR declined from 15.1 in the 1970s to about 6.1 in
the 1990s due to advances in neonatal critical care; however,
the NMR has remained relatively unchanged in recent years
(4). Advances in the care of sick neonates did not impact the
NMR, unlike the previous few decades (4). In our study, we
found similar results, suggesting the NMR did not change significantly from 2000 to 2009.
In 2009, the NMR was 3.78 in Texas, compared with 2.69
in Minnesota (3). Texas ranked 18th in the USA in NMR (3).
In the black population in Texas, the NMR remained relatively
unchanged and high (6.61 in 2000 and 6.57 in 2009). These
findings are consistent with current neonatal outcomes in the
USA (5).
The percentage of women receiving prenatal care and
average maternal age remained the same over the period of
9.5
25
8.5
20
Percetange
NMR according to ethnicity
30
7.5
6.5
5.5
15
10
4.5
5
3.5
0
2000
2.5
2001
2002
2003
2004
2005
2006
2007
2008
2009
Years
1.5
2000
2001
Total
2002
2003
Black
2004
White
2005
2006
Hispanics
2007
2008
2009
Others
Figure 1. Neonatal mortality rate among various ethnicities from 2000 to 2009
in Texas.
July 2015
ELBW, 500-749 grams
ELBW, 750-999 grams
Extreme prematurity (Total)
RDS
Figure 2. Leading causes of neonatal deaths from 2000 to 2009 in Texas.
ELBW indicates extremely low birthweight; RDS, respiratory distress syndrome.
Trends in the neonatal mortality rate in the last decade with respect to demographic factors and health care resources
305
Figure 3. Number of neonatal intensive care unit beds per 10,000 births and
number of perinatal providers in Texas per 10,000 females 15 to 44 years of
age from 2000 to 2009.
the study. We noticed an increasing trend of mothers with a
college education. This trend is similar to the trend found in
the country as a whole by Hamilton et al (6). There is also an
increasing trend for cesarean deliveries. Multiple studies have
shown a negative relation between cesarean section rates and
neonatal outcomes (7). The cesarean section rate increase can
be correlated with decreased gestational age and birthweight,
as more premature and sicker babies tend to be born via cesarean section. In our study, cesarean section rates increased from
32.7% to 44.9%. Our study did not show a similar correlation.
In our study, the median household income increased from
$41,000 to $49,200 from 2000 to 2009. In spite of increasing
median household income, the NMR remained relatively unchanged. Olson et al documented a negative association between
median family income and all birth outcomes (8). Subramanian
et al (9) and Shmueli (10) have shown an inverse association
between median income and health disparities. We were unable
to show a similar trend in our study.
Advances in neonatal critical care medicine, and better resource availability as evidenced by higher numbers of neonatologists, obstetricians, and available NICU beds, did not have an
effect on the NMR. These findings correlate with the findings
of Thompson et al (11), who found that in spite of having
greater resources regarding neonatal care per capita compared
with Canada, the United Kingdom, and Australia, neonatal
outcomes in the US are lagging. This may suggest that neonatal
care providers, NICU beds, and hospitals are one part of the
health care delivery system, and it may suggest a need to focus
on sociodemographic factors.
The mean birthweight and gestational age showed decreasing trends in our analysis. Extremely low birthweight infants
306
with a birthweight of 500 to 999 g and respiratory distress
syndrome or respiratory failure were leading causes of mortality
in the study group. This finding suggests that extreme prematurity and its complications are still leading contributors to the
NMR. Efforts targeted against extreme prematurity may help
to decrease the NMR.
We obtained our data set from TDHHS and thus were dependent on the accuracy of data reporting. The data set could
have been limited by poor reporting and the misclassification
of births as stillbirths.
In conclusion, in our study, NMR did not change significantly from 2000 to 2009 despite improvements in maternal
age, decreased smoking, improved education, higher median
household income, and an increased number of NICU beds and
perinatal providers. Racial disparities persist, with a high NMR
in the black population. We speculate that a possible genetic
predisposition related to ethnicity and a potentially higher rate
of extreme prematurity might have contributed to a high NMR
in the study population. However, additional studies are needed
to explore these factors.
Heisler EJ. The U.S. Infant Mortality Rate: International Comparisons,
Underlying Factors, and Federal Programs [CRS Report for Congress].
Washington, DC: Congressional Research Service, April 4, 2012. Available at https://www.fas.org/sgp/crs/misc/R41378.pdf; accessed March 30,
2015.
2. MacDorman MF, Mathews TJ. Behind International Rankings of Infant
Mortality: How the United States Compares with Europe [NCHS Data Brief
No. 23]. Hyattsville, MD: National Center for Health Statistics, 2009.
Available at http://www.cdc.gov/nchs/data/databriefs/db23.htm; accessed
March 30, 2015.
3. Kochanek KD, Kirmeyer SE, Martin JA, Strobino DM, Guyer B. Annual
summary of vital statistics: 2009. Pediatrics 2012;129(2):338–348.
4. MacDorman MF, Mathews TJ. Recent Trends in Infant Mortality in the
United States [NCHS Data Brief No. 9]. Hyattsville, MD: National Center
for Health Statistics, 2008. Available at http://www.cdc.gov/nchs/data/
databriefs/db09.htm; accessed March 30, 2015.
5. Collins JW Jr, David RJ. Racial disparity in low birth weight and infant
mortality. Clin Perinatol 2009;36(1):63–73.
6. Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual
summary of vital statistics: 2010–2011. Pediatrics 2013;131(3):548–558.
7. MacDorman MF, Declercq E, Menacker F, Malloy MH. Neonatal mortality for primary cesarean and vaginal births to low-risk women: application
of an “intention-to-treat” model. Birth 2008;35(1):3–8.
8. Olson ME, Diekema D, Elliott BA, Renier CM. Impact of income and
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9. Subramanian SV, Kawachi I. Income inequality and health: what have
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11. Thompson LA, Goodman DC, Little GA. Is more neonatal intensive care
always better? Insights from a cross-national comparison of reproductive
care. Pediatrics 2002;109(6):1036–1043.
1.
Volume 28, Number 3
Effect of adding tetracaine to bupivacaine on duration of
ambulatory shoulder surgery
Linda T. Pearson, MD, Benjamin P. Lowry, MD, William C. Culp Jr., MD, Olen E. Kitchings, MD, Tricia A. Meyer, PharmD,
Russell K. McAllister, MD, Charles R. Roberson, MD, and Christopher J. Burnett, MD
The objective of this study was to determine if the addition of 1%
tetracaine to 0.25% bupivacaine prolonged the duration of postoperative
analgesia of supraclavicular brachial plexus nerve blockade for patients
undergoing ambulatory shoulder surgery. We conducted a prospective,
double-blinded, randomized controlled clinical study at an ambulatory
surgery center utilizing ultrasound- and nerve stimulation-guided supraclavicular nerve blockade for postoperative analgesia. The control group
received 30 mL of 0.25% bupivacaine plus 4 mL preservative-free saline.
The study group received 30 mL of 0.25% bupivacaine plus 4 mL of 1%
tetracaine. Patients documented their visual analog scale scores and
intake of pain medications for 3 days. Primary outcomes included time
of first postoperative pain, time of first postoperative pain pill, and time
of return of motor and sensory function. Secondary outcomes included
pain score and pain medication intake trends and adverse events secondary to the nerve block. A total of 84 patients completed the study,
42 patients in each group. The study group was statistically significantly
older than the control group (mean age, 54 vs 48 years; P = 0.04).
The mean duration of analgesia was 16.6 ± 8.3 h for the control group
and 17.1 ± 7.3 h for the study group (P = 0.69). No outcomes were
statistically different. In conclusion, there was no significant difference
in duration of postoperative analgesia with the addition of 1% tetracaine
to 0.25% bupivacaine in supraclavicular brachial plexus nerve blockade.
No differences were identified in postoperative pain medications, pain
scores, or complications.
B
rachial plexus blockade for upper-extremity surgery has
been shown to be an effective form of postoperative analgesia, resulting in reduced opioid requirements, length of
stay in the postanesthetic care unit, and time to discharge
in the ambulatory surgery setting (1–3). Numerous studies have
described the addition of adjunctive agents to a primary local
anesthetic for peripheral nerve blockade resulting in longer duration of analgesia and decreased opioid requirements (4–10).
Adjunctive agents include rapid-onset local anesthetics, sedative
hypnotics, opioids, tramadol, and dexamethasone. A few studies
have evaluated the addition of the long-acting amino-ester local
anesthetic tetracaine to peripheral nerve blockade to prolong
duration of anesthesia and analgesia (6, 11, 12). Tetracaine hydrochloride has a duration of action similar to that of the amino
amide local anesthetic bupivacaine, both averaging 3 to 10 hours
(13). Pflug et al and Van Gessel et al reported a similar duration
of action between tetracaine and bupivacaine for spinal anesthesia
(14, 15). Several studies have utilized tetracaine as the primary
local anesthetic for trigeminal neuralgia and peripheral nerve
blockade (5, 16–18). Moore reported a duration of analgesia of
4 to 10 hours utilizing tetracaine as a sole anesthetic in peripheral
nerve blocks (16, 17). Moore et al compared sensory anesthesia
between bupivacaine, mepivacaine, lidocaine, and tetracaine in
peripheral nerve blocks and found that sensory anesthesia with
bupivacaine was 20% to 30% longer than that of tetracaine (19).
Sensory anesthesia with tetracaine was approximately twice as
long as that of lidocaine or mepivacaine. At our institution, it
is routine practice to combine tetracaine with other local anesthetics for peripheral nerve blocks in an effort to prolong anesthesia and analgesia. This practice is based on many years of
anecdotal evidence from patient reports of prolonged analgesia
(often >24 hours) and no reports of adverse events. Therefore,
we hypothesized that the addition of 1% tetracaine to 0.25% bupivacaine for supraclavicular nerve blockade would significantly
prolong the duration of postoperative analgesia after shoulder
surgery in the ambulatory setting.
METHODS
After obtaining approval from the local institutional review
board, informed consent was obtained from 100 patients. Selection criteria included patients 1) who were 18 years and older;
2) who had an American Society of Anesthesiologists (ASA)
physical status of I, II, or III; 3) who were undergoing shoulder
surgery at the ambulatory surgery center; and 4) who preferred
regional anesthesia for postoperative pain control. Patients provided informed consent for general anesthesia for the surgical
procedure, as well as regional anesthesia for postoperative pain
control. Patients were randomly allocated to one of two groups.
The control group received a supraclavicular nerve block containing 30 mL of 0.25% bupivacaine plus 4 mL preservative-free
From the Department of Anesthesiology, Baylor Scott and White Health, and
the Texas A&M University System Health Science Center College of Medicine,
Temple, Texas.
Corresponding author: Christopher J. Burnett, MD, Scott and White Pain
Clinic Pavilion, 2401 South 31st Street, MS 32-P2032, Temple, TX 76508
307
saline (34 mL total). The study group received a supraclavicular
nerve block containing 30 mL of 0.25% bupivacaine plus 4
mL of 1% tetracaine (34 mL total). The dose and amount of
medications assigned were based on the routine practice at the
institution’s ambulatory surgery center.
A pharmacist filled empty vials with either 4 mL of 1%
tetracaine or 4 mL of preservative-free saline and labeled the
vials with a study identification number according to a randomization log. The pharmacist had no direct patient interaction or access to the collected data. To minimize the technique
variability, only five attending physician anesthesiologists and
two anesthesiology pain fellows performed the supraclavicular
nerve blocks using a protocoled approach.
Following placement of a peripheral intravenous line, each
patient received 2 mg of midazolam intravenously prior to the
performance of the supraclavicular nerve block. All nerve blocks
were conducted utilizing a nerve-stimulating needle (Braun
Stimuplex® A; Bethlehem, PA) and under direct sonographic
guidance (Sonosite M-Turbo™ Ultrasound System; Bothell,
WA) with a 10 to 13 MHz linear array transducer. The minimum amplitude when motor stimulation could no longer be
identified ranged from 0.3 to 0.8 mA. After negative aspiration
for blood, incremental doses of the local anesthetic solution were
injected around nerve trunks consisting of the radial, ulnar,
median, and musculocutaneous nerves. All images using the
ultrasound machine were documented in the patient’s medical record. After completion of the regional anesthetic in the
preoperative area, all patients received a general anesthetic for
the surgical procedure. No limitations were placed on the intraoperative use of opioids and/or adjuncts that could be utilized.
All intraoperative medications were documented and utilized
in the analysis.
Postoperatively, patient pain scores were assessed and
managed according to routine practice with intravenous or
oral medications in the postanesthesia care unit. No limitations were placed on the use of opioids and/or adjuncts
in the postanesthesia care unit. All postanesthesia care unit
medications were documented and utilized in the analysis.
As per local standard practice, patients reporting pain in the
shoulder in the postanesthesia care unit were evaluated by a
physician and could receive a supplemental superficial cervical
plexus nerve block if appropriate. The supplemental superficial cervical plexus nerve block was performed in a subset of
patients (n = 23) who experienced significant postoperative
pain along the superior and anterior aspect of the shoulder.
These patients received a solution of 8 mL of 0.25% bupivacaine distributed along the superficial cervical plexus using
a 25-gauge needle.
At the time of discharge, patients received a pain diary
to document their pain scores using an 11-point visual analog scale. Pain scores were documented every 2 hours while
awake from the time of discharge to the end of postoperative
day 2. Patients were instructed not to take pain medications
until they started to feel pain in the operated shoulder. They
were also instructed to document when and how many pain
pills they consumed during this period. Patients were issued
308
a questionnaire to rate their satisfaction with the regional
anesthetic for their postoperative pain control. Study personnel contacted patients via telephone on postoperative days 1
and 2 to verify their continued participation and to answer
any questions. Subjects were required to return their completed pain diaries and questionnaires for inclusion in the
final analysis of the study.
It was determined that 74 subjects (37 in each group)
would be required using a two-tailed sample t test to achieve
80% power to detect a 4-hour difference in duration of analgesia between the two groups. The estimation assumed a
group standard deviation of 6 hours with an alpha of 0.05.
One hundred subjects were enrolled to account for an expected
25% attrition rate. To compare the duration of analgesia, the
Wilcoxon rank-sum test was chosen. Linear regression analysis
was used to compare duration of analgesia when there were
significant differences between the groups in other variables.
Significant variables were adjusted as covariates in the regression models. To assess all the variables related to quality of
analgesia, need for additional pain medications, side effects,
and/or complications between the two groups, the two-tailed
sample t test and Wilcoxon rank-sum test were used for mean
comparisons and the chi-square test or Fisher’s exact test for
proportion comparisons. A P value of <0.05 indicated statistical significance. SAS 9.2 (SAS Institute Inc.; Cary, NC) was
used for data analysis.
RESULTS
Of the 100 patients initially enrolled, 84 completed and
returned the pain diary and questionnaire. Two patients from
the experimental group reported a failed block, as they had no
analgesia or anesthesia immediately postoperatively. All results
were similar when excluding the two patients who had a failed
nerve block.
Analysis of the demographic data revealed that the study
group was significantly older than the control group (mean
age, 54 vs 49 years; P = 0.04). No significant differences were
detected with regard to gender, body mass index, or ASA classification scores (Table 1). There was no statistically significant
difference between the groups with regard to preexisting diabetes
mellitus or resultant neuropathy of the operative extremity. Preoperative pain score was reported on an 11-point visual analog
scale with an average score of 3 out of 10 for both groups. No
significant difference was noted in the preoperative consumption of opioids, neuropathic medications, or daily nonsteroidal
antiinflammatory use between the two groups. The surgical approach (arthroscopic vs open) and the different types of surgical
repairs and/or procedures were not significantly different between the two groups (Table 2). Total opioid and adjunctive pain
medications administered during the intraoperative and postoperative period were similar in both groups, with no significant
differences (Tables 2 and 3). Supplemental superficial cervical
plexus blocks were provided for 27% of all patients: 29% in the
control group and 26% in the study group (P = 0.80) (Table 3).
Visual analog pain scores at the time of discharge were similarly
low (1 out of 10) for both groups. There were no significant
Volume 28, Number 3
Table 1. Demographics and preoperative data
Saline
(N = 42)
Variable
Patient age (years), mean ± SD
Gender: Female
Body mass index (kg/m2), mean ± SD
ASA class
I
II
III
Preexisting neuropathy
Preexisting diabetes mellitus
Prenerve block pain score, mean ± SD
Premedication with midazolam
Preop opioids: pills daily, mean ± SD
Preop neuropathics: pills daily, mean ± SD
Preop NSAIDS: pills daily, mean ± SD
Tetracaine
(N = 42)
Total
(N = 84)
P
value
48.7 ± 13.8 54.1 ± 15.4 51.4 ± 14.8 0.04†
16 (38%)
19 (45%)
35 (42%) 0.51‡
30.2 ± 5.7 30.6 ± 5.7 30.4 ± 5.7 0.74†
0.89*
4 (10%)
4 (10%)
8 (10%)
26 (62%)
23 (55%)
49 (58%)
12 (29%)
15 (36%)
27 (32%)
6 (14%)
9 (21%)
15 (18%) 0.39‡
8 (19%)
10 (24%)
18 (21%) 0.59‡
0.76†
3.2 ± 2.9
3.0 ± 2.9
3.1 ± 2.9
42 (100%)
42 (100%)
84 (100%)
NA
0.50†
3.5 ± 2.5
4.5 ± 3.2
4.1 ± 3.0
0.49†
2.3 ± 3.2
2.8 ± 1.6
2.7 ± 1.9
0.98†
2.2 ± 1.9
2.0 ± 1.4
2.1 ± 1.7
Fisher’s exact test was used.
rank-sum test was used.
‡ Chi-square test was used.
ASA indicates American Society of Anesthesiologists; NSAIDs, nonsteroidal antiinflammatory agents.
† Wilcoxon
Table 2. Surgical and intraoperative data
Variable
Surgical approach
Arthroscopic
Open
Major surgical repair type
Labral reconstructions
Rotator cuff repair
Both
Other
Additional procedures: shoulder
Acromioplasty
Coracoplasty
Debridement
Subacromial decompression
None
Additional procedures: clavicle
Distal clavicle excision
None
Additional procedures: biceps
Biceps tenodesis
Biceps tenotomy
None
Total narcotic dose and adjuncts during surgery
Intraop fentanyl (mcg), mean ± SD
Intraop ketorolac (mg), mean ± SD
* Fisher’s
exact test was used.
rank-sum test was used.
‡ Chi-square test was used.
† Wilcoxon
July 2015
Saline
(N = 42)
Tetracaine
(N = 42)
Total
(N = 84)
31 (74%)
11 (26%)
33 (79%)
9 (21%)
64 (76%)
20 (24%)
P
value
0.61‡
0.67*
13 (31%)
23 (55%)
2 (5%)
4 (10%)
8 (19%)
26 (62%)
3 (7%)
5 (12%)
21 (25%)
49 (58%)
5 (6%)
9 (11%)
0.37‡
11 (26%)
1 (2%)
11 (26%)
7 (17%)
12 (29%)
5 (12%)
4 (10%)
13 (31%)
7 (17%)
13 (31%)
16 (19%)
5 (6%)
24 (29%)
14 (17%)
25 (30%)
1.00‡
11 (26%)
31 (74%)
11 (26%)
31 (74%)
22 (26%)
62 (74%)
1.00*
2 (5%)
4 (10%)
36 (86%)
3 (7%)
4 (10%)
35 (83%)
103 ± 52
12 ± 16
99 ± 48
12 ± 15
5 (6%)
8 (10%)
71 (85%)
101 ± 50 0.62†
12 ± 15 1.00†
differences in the average surgery time or in
the average time to discharge home (Table 3).
Patient satisfaction with the nerve block
was favorable, with 90% of all patients stating
they would undergo the same nerve block for
any subsequent surgeries and would recommend the nerve block to a family member.
There were no patient reports of permanent
paresthesia from the nerve block. One patient
from the study group reported dissatisfaction
with temporary paresthesia from a dense nerve
block on postoperative day 1. This sensation
resolved with the return of motor function after about 24 hours. One patient from the control group reported flushing and mild itching
on postoperative day 2, which resolved with
oral diphenhydramine. Among patients in the
control group, 53% reported being awakened
from sleep by pain on the first night home,
while 37% from the study group reported the
same (P = 0.33). Similarly, 55% of the control
group and 70% of the study group reported
pain that awakened them from sleep on the
second night home (P = 1.00).
Average pain scores during the study time
period were similar between both groups, with
no significant difference identified (Figure 1a).
The mean duration of analgesia was 16.6 hours
for the control group and 17.1 hours for the
study group (P = 0.69). The time to return of
motor function was 21 hours in both groups
(P = 0.88). The time to first pain pill was
11.6 hours in the control group and 10.5 hours
in the study group (P = 0.76); Figure 1b shows
the total number of pills taken in each group.
DISCUSSION
There is an ongoing search to identify adjunct medications to add to local anesthetics in
order to prolong the anesthetic and analgesic
effect to improve postoperative pain experiences. Reviews of additives to local anesthetics
for peripheral nerve blocks provide insight on
the efficacy of these additives along with their
potential safety risks and neurotoxic effects
(20, 21). Few studies have added the longacting amino ester tetracaine to a long-acting
amino amide such as bupivacaine to prolong
anesthesia and analgesia. The purpose of this
study was to identify differences in duration of
analgesia of supraclavicular nerve blocks with
the addition of tetracaine. No significant difference was identified in the duration of postoperative analgesia with the addition of 1%
tetracaine to 0.25% bupivacaine in supraclavicular nerve blocks. There were no significant
Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks
309
Table 3. Postoperative data
Variable
Saline
(N = 42)
Tetracaine
(N = 42)
Total narcotic dose and adjuncts postoperatively
Hydromorphone (mg), mean ± SD
0.7 ± 0.6
0.6 ± 0.7
Acetaminophen (mg), mean ± SD
386 ± 296
356 ± 307
No
30 (71%)
31 (74%)
Yes
12 (29%)
11 (26%)
Pain score at discharge, mean ± SD
1.1 ± 1.6
1.3 ± 1.9
Average surgery time (hours), mean ± SD
1.2 ± 0.9
1.4 ± 0.9
Average time in PACU (hours), mean ± SD
1.5 ± 0.6
1.5 ± 0.5
Supplemental superficial cervical plexus block
*Fisher’s
exact test was used.
†Wilcoxon rank-sum test was used.
‡Chi-square test was used.
PACU indicates postanesthesia care unit.
differences in postoperative pain medication intake, pain scores,
or complications between the two groups either.
The safety of utilizing tetracaine in peripheral nerve blockade was a theoretical concern based on prior literature. Previous
animal studies have shown neurotoxicity from the intrathecal administration of tetracaine (22, 23). However, there was
minimal toxicity when ≤1% tetracaine was administered (23).
Subsequent animal studies have shown similar neurotoxicity
a
with intrathecal administration of lidocaine,
bupivacaine, and ropivacaine (24). Kitawaga
et al reported that the mechanism of action is
Total
P
hypothesized to be secondary to the detergent(N = 84) value
like properties of the local anesthetics (25).
These were all animal studies focused on intra0.6 ± 0.6 0.49†
thecal administration of the local anesthetics.
369 ± 298 0.80†
No studies have shown any clinically relevant
0.81‡
neurological sequelae from intrathecal or peripherally administered tetracaine in humans.
61 (73%)
Leonard et al reported that intrathecal admin23 (27%)
istration of tetracaine produced a longer and
†
1.2 ± 1.7 0.62
denser motor blockade (40–50 minutes) than
1.3 ± 0.9 0.33
intrathecal bupivacaine (26). In this study,
1.5 ± 0.5 0.73
no persistent paresthesias, prolonged block,
or other neurological sequelae were observed
or reported.
Limitations of this study include a relatively small sample size in conjunction with
the inability to directly observe patients following discharge home. Neurologic exams were not performed
on these patients at the time of discharge. Return of motor
function was determined by the patient reporting the ability
to make a full fist. Furthermore, the study was limited by the
subjective nature of patients’ self-reporting their pain scores.
An additional confounding variable was the timing of the
first onset of postoperative pain. The average time of first
pain was reported between 16 and 17 hours after placement
of the nerve block, and most of these outpatient cases were
performed between 7:30 am and 4:00 pm. Consequently, many
patients would have experienced first pain during the late
night or early morning hours, making it difficult to ascertain
the exact time of the onset of this pain. Additionally, patients
were instructed to take pain medication only at the time of
first pain; however, some patients likely took pain medication
as a preemptive measure.
Acknowledgments
The investigators would like to thank Jared E. Anderson,
MD, Rodney Lange, MD, Andrew L. Barker, MD, Adam M.
Savage, MD, Juhee Song, PhD, and Ying Fang, MS, MPH, for
their contributions to this study. This study was supported by
funding from the Scott and White Office of Academic Research
Development and the Department of Anesthesiology.
b
1.
Figure 1. (a) Mean pain scores and (b) total number of pain pills over 3 days.
Blue = control group (saline; 42 patients); Red = experimental group (tetracaine;
42 patients).
310
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Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks
311
Comparison of documentation and evidence-based medicine
use for non–ST-segment elevation myocardial infarction
among cardiology, teaching, and nonteaching teams
Austin Metting, MD, Daniel Binz, MD, Colleen Y. Colbert, PhD, Juhee Song, PhD, Chris Chiles, MD, and Curtis Mirkes, DO
Non–ST-segment elevation myocardial infarctions (NSTEMI) are common
and cause significant morbidity and mortality. Following evidence-based
medicine (EBM) guidelines is one way to ensure that these patients are
cared for appropriately. This pilot study examined data from patients
with NSTEMI to assess both documentation quality and use of EBM
across multiple teams. Medical records were reviewed for significant
differences in documentation quality in areas including history and physical exam, treatment, and inpatient mortality. While total documentation
quality and mortality were not significantly different between groups,
cardiology teams adhered to evidence-based recommendations more
often than other teams.
L
ack of proper documentation has been associated with
poor patient outcomes. Cox et al found that documentation of cardiac risk factors was quite poor when reviewing
history and physical documentation for patients hospitalized for myocardial infarction and congestive heart failure.
It was even worse in the elderly and females (1). The absence
of documented cardiovascular risk factors has led to higher
mortality in non–ST-segment elevation myocardial infarctions
(NSTEMI) (2). It was unknown locally how well physicians at
Scott & White Memorial Hospital, part of the Baylor Scott &
White Health system, document in these situations. This quality
improvement study examined medical record documentation
associated with three types of inpatient medicine treatment
teams to determine if there were differences in documentation
and use of evidence-based medicine (EBM) across provider
teams.
METHODS
This study was approved by the institutional review board at
Scott & White Healthcare. This was a retrospective chart review
designed to examine the following questions: 1) In a comparison
of cardiology, nonteaching, and teaching teams, which team
scored higher in the quality of the medical record documentation and EBM use? 2) Does better physician documentation
translate into a decrease in patient mortality at our institution?
The study took place at Scott & White Memorial Hospital
in Temple, Texas, a 636-bed hospital part of an integrated health
care system in Central Texas. Medical records of patients aged 18
312
to 99 with a primary diagnosis of NSTEMI who were admitted
to our teaching, nonteaching, or cardiology teams between January 1, 2006, and December 31, 2009, were eligible for inclusion.
Inclusion dates were chosen by the research team based upon
when team structure, guidelines, and medical record systems
were the most stable. After this timeframe, many changes in the
institution occurred that did not allow for a long enough period
of stability. Exclusion criteria included sepsis, demand infarction,
NSTEMI as a secondary diagnosis, admission to a non–internal
medicine team, and a troponin level <0.04 ng/mL. Based upon
these criteria, 442 patients with a diagnosis of NSTEMI were
initially included in this study.
Teaching teams comprised internal medicine residents and
a hospitalist attending; nonteaching teams comprised a midlevel provider and a hospitalist; and cardiology teams comprised
residents, fellows, and cardiology attendings.
As part of a mentored research grant at Scott & White/
Texas A&M Health Sciences Center College of Medicine, the
first author, who was an internal medicine resident at the time,
conducted a retrospective chart review to examine the quality
of medical record documentation and use of EBM across teams
that cared for NSTEMI patients. The authors compared teams’
use of EBM and documentation in the history, physical exam,
lab findings, and tests performed. The purpose of this quality
improvement project was to determine which team (cardiology, teaching, nonteaching inpatient team) needed the most
improvement in documentation and EBM use.
The history and physical checklist used in this study was
based upon a 20-point rating scale developed by Dunlay et al
(3). The scale was modified to include 25 items evaluating the
history and physical, as well as five items designed to evaluate the
use of EBM. The modified scale included an expanded history
and physical checklist, with a maximum score of 30, compared
From Scott & White Healthcare and Texas A&M Health Science Center College of
Medicine. Dr. Binz is currently with the University of Oklahoma Health Sciences
Center, Tulsa, Oklahoma; Dr. Colbert is currently with the Cleveland Clinic Lerner
College of Medicine of Case Western Reserve University, Cleveland, Ohio; and Dr.
Song is currently with MD Anderson Cancer Center, Houston, Texas.
Corresponding author: Austin Metting, MD, Assistant Professor, Scott & White
Healthcare, Texas A&M Health Science Center College of Medicine, 2401 South
31st Street, Temple, TX 76508 (e-mail: [email protected]).
to 20 in the Dunlay study. The additional items covered were
EBM, history of present illness, chief complaint, type and duration of pain, past medical history including lipids or previous
cardiac imaging, family history, social history including drug
and activity, and adding electrocardiogram and chest x-ray to
studies. We excluded creatinine from labs and removed the
problem list. Unlike the Dunlay study, partial credit for items
was not given in this quality improvement study.
Charts were reviewed and scored using the initial history and
physical. Each chart was reviewed and the history and physical
was evaluated using the 30-point checklist described above. Use
of EBM was determined on a 5-point scale and inpatient mortality was recorded. Patient team data (teaching, nonteaching,
cardiology) and demographics were also recorded for each patient. For patients who were admitted overnight by hospitalists,
the team recorded was the team to which they were assigned.
Specific criteria were used when examining each variable
within the history and physical. For example, the chief complaint must have been listed specifically. A description of the
type and duration of the complaint must have been listed, as
well as any associated symptoms. The history of present illness
was also inspected for mention of prior events like the current
one. The medical history was reviewed for mention of current
medical problems, recent lipid panels or hemoglobin A1C, or
previous stress tests or angiograms or lack thereof. In the family
history, the physician must have discussed the age at which a
relative had a myocardial infarction, and other family history
was counted as a separate item. Documentation of social history
must have contained a positive or negative response to any drug,
which includes alcohol, tobacco, and illegal drugs. A separate
point was given if physical activity was included. Individual
portions of the physical exam included vital signs, cardiovascular
exam, respiratory exam, and peripheral vascular exam (peripheral pulses). For labs and studies, we concentrated on cardiac
enzymes, electrocardiogram, chest x-ray, and hemoglobin. We
also examined lipid, glucose, and hemoglobin A1C values.
The assessment and plan were reviewed for a differential
diagnosis, five specific evidence-based therapies for NSTEMI,
and treatments of other comorbidities. We reviewed for the
following five specific therapies: aspirin, beta-blockers, heparin
or a heparinoid, statin on discharge, and glycoprotein IIb/IIIa
inhibitors. One point each was given if these were mentioned
in the assessment and plan by documenting use or reason for
not using. Angiotensin-converting enzyme inhibitors were not
included due to specific requirements about ejection fraction.
Clopidogrel was not included on the checklist since eptifibatide
was the preferred agent when providers anticipated invasive
management during this time period.
All variables, including 30 checklist items, overall checklist
scores, and patient demographics, were summarized according
to care team using descriptive statistics: mean for continuous
variables and frequency for categorical variables. The three care
teams were compared utilizing analysis of variance or KruskalWallis test for continuous variables. Chi-square test or Fisher’s
exact test was used to compare groups of categorical variables.
Pairwise comparisons utilized Bonferroni adjustment or Tukey’s
July 2015
pairwise comparison when significant differences were detected.
A P value of <0.05 was the threshold for statistical significance.
SAS version 9.2 (SAS Institute Inc., Cary, NC) was used for
data analysis.
RESULTS
Based upon a retrospective review of 442 charts of patients
with a diagnosis of NSTEMI and a troponin level >0.04 ng/
mL, 252 (57.0%) were NSTEMI cases that had been treated by
one of the three teams. Excluded were 91 cases (20.6%) with
ST-elevation myocardial infarctions, 59 cases (12%) treated by
teams not in the study, and 40 cases (9%) wherein myocardial
infarction was a secondary diagnosis.
Among patients with NSTEMI as a primary diagnosis
(N = 252), 151 cases (60%) were treated by a cardiology team,
60 cases (24%) were treated by a teaching team, and 41 cases
(16%) were treated by a nonteaching team. Based on pairwise
comparisons, the nonteaching team had older patients than
the cardiology team, who had significantly more male patients
than the teaching team. There were no significant differences
in other demographics across teams (Table 1).
The three teams differed significantly on EBM use (P < 0.0001).
Based on Bonferroni-adjusted pairwise comparisons, cardiology
had a significantly higher mean EBM score than the other teams.
No significant differences were detected among the three teams in
total history and physical score (0–25) or the 30-item total score
(Table 2, Figure 1).
Significant differences were also found on eight of 30 history and physical checklist items (Table 3). Teams differed significantly on documentation of the following items: type and
duration of pain; whether the pain had ever occurred before;
social history of activity; chest x-ray results; whether lipids,
glucose, or A1C were mentioned; differential diagnosis; treatment of other comorbidities; and the use of glycoprotein IIb/
IIIa inhibitors. No significant differences were detected across
teams on other items. Social history of activity and differential
diagnosis were found in only 45 subjects (18%), and those items
were documented least often. Pulmonary exam was listed for
all subjects in the cohort, and it was most often documented.
DISCUSSION
The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation
of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) initiative is being conducted
at multiple institutions across the country and deals with the
care of patients with unstable angina and NSTEMI. Several
studies that referenced the CRUSADE database analyzed the
quality of medical record documentation and EBM use within
their own institutions (4).
Dunlay et al utilized CRUSADE data to evaluate the quality of documentation, use of EBM, and mortality rates when
comparing academic versus nonacademic hospitals, and cardiologists versus noncardiologists. Results showed that academic
institutions and cardiologists scored higher than their counterparts, and these higher scores demonstrated better use of EBM
Comparison of documentation and evidence-based medicine use for NSTEMI
313
adherence to guidelines drastically improved. One
study showed that institutions that were accredited
by the Society of Chest Pain Centers had better
Cardiology Teaching Nonteaching Entire cohort
P
outcomes due to an improved use of EBM (9).
Variable
(N = 151) (N = 60)
(N = 41)
(N = 252)
value*
These studies inspired us to assess documentation
b
0.01
Age (years), mean ± SD 64 ± 13
67 ± 13
72 ± 14
66 ± 14
and EBM use within our institution and compare
Female
50 (33%) 32 (53%)
21 (51%)
103 (41%)
0.009a
outcomes across care teams.
Male
101 (67%) 28 (47%)
20 (49%)
149 (59%)
Based upon the results of our study, cardiolRace
ogy teams performed better than teaching and
Black
16 (11%) 11 (18%)
5 (12%)
32 (13%)
0.63
nonteaching teams in giving glycoprotein IIb/IIIa
inhibitors. However, teaching teams performed
Hispanic
18 (12%)
9 (15%)
4 (10%)
31 (12%)
better in discussing the results of chest x-rays and
Unknown
3 (2%)
0 (0%)
0
3 (1%)
evaluating other comorbidities in the assessment
White
114 (76%) 40 (67%)
32 (78%)
186 (74%)
and plan. Findings also indicated that nonteachComorbidity
ing teams scored lower than cardiology teams in
Diabetes mellitus
63 (42%) 27 (45%)
21 (51%)
111 (44%)
0.55
discussing the symptom type and duration, if the
106 (70%) 50 (83%)
33 (80%)
189 (75%)
0.09
Hypertensione
symptoms had ever occurred before, and use of gly83 (55%) 26 (43%)
22 (54%)
131 (52%)
0.30
Coronary artery
coprotein IIb/IIIa inhibitors. Nonteaching teams
diseasee
performed better than cardiology teams at documenting a differential diagnosis. The only difference
Congestive heart
25 (17%) 11 (18%)
7 (17%)
43 (17%)
0.95
failure
noted between teaching and nonteaching teams
was the discussion of other comorbidities in the
Hyperlipidemiae
92 (61%) 35 (58%)
22 (54%)
149 (59%)
0.70
assessment and plan.
Sleep apnea
4 (3%)
4 (7%)
3 (7%)
11 (4%)
0.20
The present study design differed from previous
Current smoker
44 (29%) 19 (32%)
7 (17%)
70 (28%)
0.23
studies
in that we compared different teams within
3 (2%)
1 (2%)
0
4 (2%)
1.00
Current drug used
the same hospital to determine if there were differInpatient death
3 (2%)
3 (5%)
0
6 (2%)
0.35
ences in quality of care and documentation. Also,
aSignificant difference between Cardiology vs. Teaching.
while CRUSADE studies included patients with unbSignificant difference between Cardiology vs. Nonteaching.
stable angina, transient ST elevations, and NSTEMI
cSignificant difference between Teaching vs. Nonteaching.
who presented within 24 hours, our study included
dCurrent drug use is defined as the use of any illegal drugs found in the history and physical.
eHypertension, hyperlipidemia, and coronary artery disease are defined as a history of these diagnoses
only NSTEMI whenever it presented.
in their medical chart.
Our results differed from other studies (10–12)
in that we found no difference in medical record
total scores or mortality among groups. Detecting
differences in mortality between groups was difficult due to
and improved mortality rates (3). Patel et al (5) and O’Brien
the small total number of deaths (N = 6). While other studies
et al (6) found that academic institutions were better at folhave found that teaching hospitals adhere to guidelines more
lowing guidelines than nonacademic institutions, but they did
frequently than nonteaching hospitals (5, 13, 14), our findings
not examine specific history and physical exam documentation.
indicated there was no significant difference between our teachBottorff et al (7) found that academic institutions were better at
ing and nonteaching teams in EBM use. Overall documentation
prescribing antiplatelet agents in the hospital than nonacademic
did not seem to influence EBM use. The quality of documentainstitutions. Mehta et al (8) reported that once groups were in
tion on medicine teams at our institution appears to be similar
the CRUSADE trial and were notified of their own results,
to that reported in the Dunlay study (3). In our
facility, mean scores were 17.7/25 (70.8%) for the
Table 2. Score comparison according to care team
history and physical score and 21.8/30 (72.6%)
for history and physical score with EBM added.
Score
Cardiology Teaching Nonteaching Entire cohort
Dunlay et al (3) reported a mean score of 12.5/20
(mean ± SD)
(N = 151)
(N = 60)
(N = 41)
(N = 252)
P value
(62.5%).
History and physical 17.7 ± 2.9 18.2 ± 2.6 17.2 ± 2.6
0.20
17.7 ± 2.8
Our findings appear to mirror those of Dunlay
(25 items)
et al (3) in that cardiology teams adhered to EBM
Evidence-based
<.0001a,b
4.3 ± 1.0 3.8 ± 1.1
3.7 ± 0.9
4.1 ± 1.0
guidelines significantly more than other teams.
medicine (5 items)
However, this difference appears to be due to the
Total (30 items)
0.08
21.9 ± 3.4 22.0 ± 2.9 20.9 ± 2.8
21.8 ± 3.2
use of glycoprotein IIb/IIIa inhibitors, which was
aSignificant difference between Cardiology vs. Teaching.
also found in another study (7). The reason may be
bSignificant difference between Cardiology vs. Nonteaching.
lack of knowledge of this particular guideline or a
discomfort in prescribing additional blood thinners.
Table 1. Patient characteristics of the entire cohort and according to care team
314
Volume 28, Number 3
a
b
Figure 1. Distribution of history and physical scores (a) with and (b) without the evidence-based medicine score added.
Table 3. Inclusion of each item according to care team
Variable
Cardiology
(N = 151)
Teaching
(N = 60)
Nonteaching Entire cohort
(N = 41)
(N = 252)
P value
Chief complaint
119 (79%)
53 (88%)
29 (71%)
201 (80%)
0.09
Type and duration of pain
128 (85%)
46 (77%)
28 (68%)
202 (80%)
0.05b
Associated symptoms
124 (82%)
51 (85%)
33 (80%)
208 (83%)
0.82
Previous occurrence
78 (52%)
22 (37%)
10 (24%)
110 (44%)
0.004b
Past medical history
149 (99%)
59 (98%)
40 (98%)
248 (98%)
0.79
Recent lipids or A1C
27 (18%)
19 (32%)
11 (27%)
57 (23%)
0.08
Previous stress test or angiogram
52 (34%)
18 (30%)
9 (22%)
79 (31%)
0.30
Medications
149 (99%)
59 (98%)
40 (98%)
248 (98%)
0.79
Allergies
145 (96%)
55 (92%)
40 (98%)
240 (95%)
0.41
Family history of CAD
88 (58%)
34 (57%)
22 (54%)
144 (57%)
0.87
Other family history
79 (52%)
37 (62%)
20 (49%)
136 (54%)
0.36
145 (96%)
54 (90%)
38 (93%)
237 (94%)
0.23
34 (23%)
8 (13%)
3 (7%)
45 (18%)
147 (97%)
60 (100%)
40 (98%)
247 (98%)
0.55
Cardiovascular exam
150 (99%)
60 (100%)
41 (100%)
251 (100%)
1.00
Pulmonary exam
151 (100%) 60 (100%)
41 (100%)
252 (100%)
–
Peripheral vascular exam
115 (76%)
41 (68%)
28 (68%)
184 (73%)
0.39
Cardiac enzymes
146 (97%)
57 (95%)
41 (100%)
244 (97%)
0.45
Electrocardiogram
137 (91%)
55 (92%)
34 (83%)
226 (90%)
0.29
Chest x-ray
80 (53%)
43 (72%)
27 (66%)
150 (60%)
0.03a
Hemoglobin
118 (78%)
52 (87%)
37 (90%)
207 (82%)
0.12
Lipids, glucose, or A1C
93 (62%)
47 (78%)
31 (76%)
171 (68%)
0.03a,b
Differential diagnosis
19 (13%)
14 (23%)
12 (29%)
45 (18%)
0.02b
120 (79%)
59 (98%)
34 (83%)
213 (85%)
0.003a,c
Social history of any drugs
Social history of activity
Vitals documented
Other comorbidities and treatment
TIMI score done
0.046a,b
75 (50%)
27 (45%)
15 (37%)
117 (46%)
0.32
Aspirin
140 (93%)
57 (95%)
36 (88%)
233 (92%)
0.44
Beta-blocker
141 (93%)
55 (92%)
37 (90%)
233 (92%)
0.71
Statin on discharge
140 (93%)
54 (90%)
40 (98%)
234 (93%)
0.40
Anticoagulation
133 (88%)
49 (82%)
31 (76%)
213 (85%)
0.12
90 (60%)
14 (23%)
9 (22%)
113 (45%)
<.0001a,b
Glycoprotein IIb/IIIa inhibitors
aSignificant
difference between Cardiology vs. Teaching.
difference between Cardiology vs. Nonteaching.
CAD indicates coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction.
bSignificant
July 2015
We also found that patients treated by
the cardiology team were significantly
younger and more often male than those
served by noncardiology teams, which
is similar to demographics seen in other
studies (5, 11, 12).
Differences from the Dunlay study
include that this retrospective study
was performed at one site with a small
population. Only NSTEMI patients
confirmed with a troponin level >0.04
ng/mL were included in our study. The
small sample size could inhibit our ability to detect differences among the teams.
Another factor is that other teams in our
facility had patients with NSTEMI, but
these were excluded in order to compare
only medicine teams. Our rating scale
was based upon a scale used in the Dunlay study, but was not validated, which
could be a limitation.
In an attempt to improve the overall
quality of patient care, medicine teams
have been notified of the results, and
we will reevaluate the documentation
and use of EBM across provider teams.
Since the onset of the study, the use of
certain medications upon admission to
the hospital for NSTEMI patients has
changed. The frequency of glycoprotein
IIb/IIIa inhibitor use decreased during
the study period, and it will be removed
from future checklists. We believe this
may be related to results of the ACUITY
Timing trial (15) and EARLY ACS study
(16), as well as the increasing use of bivalirudin in the catheterization lab. Most
NSTEMI patients at our institution undergo an early invasive strategy and now
receive clopidogrel, ticagrelor, or prasugrel as a second antiplatelet agent. Use of
Comparison of documentation and evidence-based medicine use for NSTEMI
315
these medications will be tracked in future studies. To enhance
generalizability of findings, we hope to collaborate with other
teaching institutions.
Our quality improvement study demonstrated that cardiology teams at Scott & White/Texas A&M adhered to EBM guidelines more frequently than other medicine teams. Statistically
significant differences in mortality rates or documentation were
not found. This study appears to be only the second to examine
the influence of documentation on patient care in myocardial
infarction (3). A small improvement in mortality in a disease this
common can translate to a large effect. Studies with an increased
sample size may find a difference related to documentation alone.
Recent events in our institution have included the integration of
a new electronic health record and the merger between Scott &
White and Baylor Health Care Systems. These two changes will
allow for a larger study to be performed and likely an intervention including a standardized history and physical with order
set to ensure appropriate use of EBM.
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Volume 28, Number 3
Assessment of leadership training needs of internal
medicine residents at the Massachusetts General Hospital
Traci N. Fraser, MD, Daniel M. Blumenthal, MD, MBA, Kenneth Bernard, MD, MBA, and Christiana Iyasere, MD, MBA
Internal medicine (IM) physicians, including residents, assume both
formal and informal leadership roles that significantly impact clinical
and organizational outcomes. However, most internists lack formal
leadership training. In 2013 and 2014, we surveyed all rising secondyear IM residents at a large northeastern academic medical center
about their need for, and preferences regarding, leadership training.
Fifty-five of 113 residents (49%) completed the survey. Forty-four
residents (80% of respondents) reported a need for additional formal
leadership training. A self-reported need for leadership training was
not associated with respondents’ gender or previous leadership training and experience. Commonly cited leadership skill needs included
“leading a team” (98% of residents), “confronting problem employees” (93%), “coaching and developing others” (93%), and “resolving
interpersonal conflict” (84%). Respondents preferred to learn about
leadership using multiple teaching modalities. Fifty residents (91%)
preferred to have a physician teach them about leadership, while 19
(35%) wanted instruction from a hospital manager. IM residents may
not receive adequate leadership development education during pregraduate and postgraduate training. IM residents may be more likely
to benefit from leadership training interventions that are physician-led,
multimodal, and occur during the second year of residency. These findings can help inform the design of effective leadership development
programs for physician trainees.
E
ffective clinical leadership is critical to the success of cost
control and quality improvement efforts (1). Although
no universal definition of leadership exists, effective leaders articulate and build consensus around a vision and
empower their team members (2). For physicians in the modern
interdisciplinary practice environment, clinical leadership is
crucial to health care quality and organizational performance
(2). Evidence suggests that leadership training can improve leadership quality (3–5). However, medical schools and residency
programs do not emphasize leadership training (2, 6). Moreover,
we know little about the leadership development needs of internal medicine (IM) residents, and a paucity of quantitative data
exists to guide the development of leadership training programs
for them. We report the results of a leadership needs assessment
survey of IM residents at an academic medical center.
METHODS
The Massachusetts General Hospital is a 1057-bed teaching
hospital affiliated with Harvard Medical School. The Department of Medicine residency program at Massachusetts General
Hospital includes approximately 55 categorical, primary care,
and medicine-pediatrics residents in each residency class.
A Leadership Needs Assessment Survey (LNAS) was designed by IM residents at Massachusetts General Hospital to
characterize residents’ need for and preferences regarding leadership training. Several survey questions were adapted from
a previously published needs assessment survey of Dutch IM
residents (7). Answers to LNAS questions were structured on a
5-point Likert scale, yes/no, “choose all that apply,” “choose only
one,” or free-text format. The LNAS was reviewed by Dr. Eric
Campbell, a professor of medicine at Harvard Medical School
and an expert in survey design, for face and content validity
and by two IM residents for clarity. The LNAS contained questions about resident demographics and leadership experience,
perceived need for leadership training, and content and format
of desired leadership training.
In May 2013 and 2014, we administered surveys to rising
junior residents in the categorical, primary care, and combined
medicine-pediatrics programs. Participants were given 2 months
to respond to the survey, and e-mail reminders were sent bimonthly. To motivate survey participation, participants received
a $5 gift card for completing the LNAS. Survey responses were
deidentified. We administered all surveys through RED Cap, a
secure online data repository (REDCap; Vanderbilt University,
Nashville, TN). Data were analyzed using JMP Pro 11 (SAS
Inc.; Cary, NC) and Microsoft Excel (Microsoft Inc.; Redmond,
WA). We summarized data by count and percentage for categorical outcomes and used the Fisher’s exact test to compare
the perceived need for leadership training among subgroups of
residents. This study was deemed exempt by our institution’s
institutional review board.
From the Department of Medicine (Fraser, Blumenthal, Iyasere), Division of
Cardiology (Blumenthal), and Department of Emergency Medicine (Bernard),
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Corresponding author: Traci Fraser, MD, Massachusetts General Hospital,
55 Fruit Street, GRB 740, Boston, MA 02114 (e-mail: [email protected]).
317
Table 1. Characteristics of 55 survey participants at
Massachusetts General Hospital in 2013 and 2014
Characteristic
Gender
Male
Female
Residency program
Primary care
Categorical
Medicine-pediatrics
Marital status
Single
Married
Time offa
Advanced degree
MBA or MPH
MPP
PhD
Military training
Prior leadership trainingb
Through employer
During medical school
Through college
Through extracurricular organization
Prior leadership experienceb
During medical school
During college
Led a team
Career plansc
Basic science
Clinical research
Clinical fellowship
General medical fellowship
Health care administration
Health policy fellowship
Hospitalist
Primary care
Private industry
Translational research
Undecided
2013–14 2014–15
interns
interns
Total
Characteristic
13 (48%) 16 (57%) 29 (53%)
14 (52%) 12 (43%) 26 (47%)
I have a need for training in leadership competencies.
2013–14
interns
2014–15
interns
Total
22 (81%)
22 (79%)
44 (80%)
I would like training in the following competencies:
5 (19%) 7 (25%) 12 (22%)
20 (74%) 19 (68%) 39 (71%)
2 (7%)
2 (7%)
4 (7%)
18 (67%)
9 (33%)
13 (48%)
3 (11%)
0
3 (11%)
0
0
10 (37%)
3 (11%)
3 (11%)
5 (19%)
3 (11%)
22 (81%)
18 (67%)
19 (70%)
20 (74%)
17 (61%)
11 (39%)
16 (57%)
4 (14%)
0
3 (11%)
1 (4%)
0
9 (32%)
3 (11%)
3 (11%)
4 (14%)
4 (14%)
23 (82%)
21 (75%)
20 (71%)
22 (79%)
35 (64%)
20 (36%)
29 (53%)
7 (13%)
0
6 (11%)
1 (2%)
0
19 (35%)
6 (11%)
6 (11%)
9 (16%)
7 (13%)
45 (82%)
39 (71%)
39 (71%)
42 (76%)
4 (15%) 4 (14%) 8 (15%)
8 (30%) 6 (21%) 14 (25%)
19 (70%) 20 (71%) 39 (71%)
4 (15%) 7 (25%) 11 (20%)
2 (7%)
7 (25%) 9 (16%)
4 (15%) 9 (32%) 13 (24%)
6 (22%) 5 (18%) 11 (20%)
5 (19%) 5 (18%) 10 (18%)
1 (4%)
6 (21%) 6 (11%)
2 (7%)
5 (18%) 7 (13%)
3 (11%) 3 (11%) 6 (11%)
a Time
off indicates residents who took at least 1 year off between medical school and
residency.
b Respondents could check off more than one type of leadership training or experience.
The numbers and percentages in “prior leadership training” and “prior leadership experience” rows correspond to the total number of respondents who reported any kind of
leadership training or experience.
c Respondents were asked to check off all potential career options that they planned to
pursue, and many respondents checked more than one response.
RESULTS
Fifty-five of 113 eligible residents (49%) completed the
survey. While 45 survey respondents (82%) had prior leadership experience, only 6 (11%) had received focused leader318
Table 2. Characteristics of leadership training desired by the
55 survey participants at Massachusetts General Hospital in
2013 and 2014
Leading with purpose
26 (96%)
25 (89%)
51 (93%)
Problem solving
27 (100%) 25 (89%)
52 (95%)
Coaching others
27 (100%) 24 (86%)
51 (93%)
Leading a team
27 (100%) 27 (96%)
54 (98%)
Confronting problem employees
25 (93%)
51 (93%)
26 (93%)
If I were to go through leadership training, I would want the training to occur
in the following location:
Workplace
24 (89%)
28 (100%) 52 (95%)
Medical school
1 (4%)
4 (14%)
5 (9%)
University
4 (15%)
5 (18%)
9 (16%)
If I were to go through leadership training during residency, I would want the
training to occur over the following time period:
Intern year
Second year
8 (30%)
7 (25%)
15 (27%)
15 (56%)
16 (57%)
31 (56%)
Third year
1 (4%)
2 (7%)
3 (5%)
Any time during residency
2 (7%)
2 (7%)
4 (7%)
If I were to go through leadership training, I would want to be taught by the
following people:
Physician
24 (89%)
26 (93%)
50 (91%)
Business school professor
11 (41%)
20 (71%)
31 (56%)
Hospital manager
6 (22%)
13 (46%)
19 (35%)
Private industry leader
4 (15%)
13 (46%)
17 (31%)
If I were to go through leadership training, I would want to be taught using
the following methods:
Health care case discussion
14 (52%)
19 (68%)
33 (60%)
9 (33%)
13 (46%)
22 (40%)
12 (44%)
10 (36%)
22 (40%)
Large group discussion
9 (33%)
14 (50%)
23 (42%)
Small group discussion
20 (74%)
22 (79%)
42 (76%)
Simulation
15 (56%)
20 (71%)
35 (64%)
Role play
6 (22%)
8 (29%)
14 (25%)
Web training
7 (25%)
10 (36%)
17 (31%)
Non–health care case discussion
Lectures
ship training in either medical school or residency (Table 1).
Forty-eight residents (87%) somewhat or strongly agreed that
the quality of clinical leadership impacts the care they deliver,
and 44 survey participants (80%) agreed that there is a need
for additional formal leadership training. Residents’ perceived
need for additional formal leadership training did not vary by
gender (P = 0.74), residency track (P = 0.48), receipt of prior
leadership training (P = 0.73), or prior leadership experience
(P = 0.59).
Volume 28, Number 3
Figure 1. Internal medicine residents’ self-reported leadership skill needs.
Residents believed that they would benefit from additional
training to develop a number of specific leadership skills, including leading a team (98% of residents), coaching and developing others (93%), confronting problem employees (93%),
self-management (84%), resolving interpersonal conflict (84%),
and understanding different leadership styles (84%) (Figure 1).
Respondents preferred a multimodal approach to leadership
training that included teaching methods such as small group
discussion, case studies, and simulations (Table 2). Over 90%
of respondents wanted leadership training to take place in an
environment that was convenient to access from work and for
sessions to be taught by a physician rather than a business school
professor, hospital manager, or private industry leader. Fifty-six
percent of residents preferred to go through leadership training
during the second year of residency, while 15% wanted training
to occur during internship.
DISCUSSION
To our knowledge, ours is the first published documentation of US IM residents’ leadership training needs. Most survey
respondents agreed that the quality of clinical leadership impacts
clinical care quality and affirmed a need for additional formal
leadership training during residency. A review of the literature
indicates that this need is not met by traditional teaching methods at our institution or by the majority of medical schools or
residency programs around the country (2).
Our results also indicated that leadership experiences and
formal leadership training prior to entering residency may not
obviate IM residents’ needs for leadership training and may
not adequately prepare them for the leadership roles that they
assume as practicing clinicians. For example, while IM residents
in most training programs, including ours, lead clinical teams,
98% of residents surveyed reported a need for focused team
leadership training. This result raises questions about whether
July 2015
or not trainees have been equipped with the nonclinical (i.e.,
managerial) skills necessary to effectively lead clinical teams.
Survey respondents may have been more interested in learning about leadership from physicians—rather than from business school professors (content experts) or managers of hospitals
or private corporations—for a few reasons. First, physicians may
better understand the particular leadership challenges faced by
IM trainees and are more likely to have the clinical experience
necessary to teach residents to apply leadership skills in clinical
settings. Second, residents may feel more comfortable around,
and learning from, other physicians.
Our findings also have significant implications for the design
of effective leadership development interventions. For example,
while residents may prefer to learn about leadership from other
physicians, many physicians lack experience teaching leadership, so curriculum development may require collaboration
with content experts. In addition, IM residents appear to prefer
that leadership training take place during the second year of
residency and in an environment that is convenient to access
from work. Successful implementation of leadership training
programs therefore requires a commitment from residency program administrators in order to coordinate residents’ schedules
and meeting locations.
This analysis has a number of limitations. Our analysis
may have been underpowered to identify associations between
resident characteristics and specific leadership training needs.
Selection bias may have been introduced by the low response
rate, as residents who were more interested in leadership training
may have been more likely to complete the survey. Moreover,
our findings may not be generalizable to attending physicians,
residents at other institutions, or specialties other than IM.
While our survey was determined to have good content and
face validity, it has not undergone assessments of criterion or
content validity.
Assessment of leadership training needs of internal medicine residents at the Massachusetts General Hospital
319
Bohmer RMJ. Designing Care. Boston: Harvard Business Press, 2009:22–
23, 173–174.
2. Blumenthal DM, Bernard K, Bohnen J, Bohmer R. Addressing the leadership gap in medicine: residents’ need for systematic leadership development training. Acad Med 2012;87(4):513–522.
3. Donnithorne LR. The West Point Way of Leadership: From Learning
Principled Leadership to Practicing It. New York: Doubleday, 1993:
1–85.
4. Snook SA. Leader(ship) Development. Boston: Harvard Business School
Publishing, 2008.
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Ackerly DC, Sangvai DG, Udayakumar K, Shah BR, Kalman NS, Cho
AH, Schulman KA, Fulkerson WJ Jr, Dzau VJ. Training the next generation of physician-executives: an innovative residency pathway in management and leadership. Acad Med 2011;86(5):575–579.
Brouns JW, Berkenbosch L, Ploemen-Suijker FD, Heyligers I, Busari
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Avocations
Easter lily. Photo copyright © Rolando M. Solis, MD. Dr. Solis (e-mail: [email protected]) is an interventional cardiologist with Baylor Scott and White Health and
practices at Baylor Medical Center at Garland and The Heart Hospital Baylor Plano.
320
Volume 28, Number 3
Abstracts from the First Annual Scholarly Day
The Department of Medical Education at Baylor University Medical Center
at Dallas hosted its first annual Scholarly Day to showcase the research
efforts of medical students, residents, and fellows. Hania Wehbe-Janek,
PhD, vice president for academic research integration for Baylor Scott
and White Health Central Texas, shared the plenary session, “Building a
Culture of Research at Academic Medical Centers: Impact on Medical
Education and Recommended Practices.” Stuart Black, MD, John Fordtran,
MD, Ronald C. Jones, MD, Michael A. Ramsay, MD, William C. Roberts,
MD, and Hania Wehbe-Janek, PhD, served as judges of the posters and
the oral presentations. Winners in each category were as follows: best fellow poster, “Diet pattern and cardiovascular disease among women with
type 2 diabetes mellitus,” by Hyun Joon Shin, MD; best resident poster,
“Oral squamous cell carcinoma: current concepts in imaging, staging, and
fibular osteocutaneous free-flap reconstruction,” by R. Evans Heithaus, MD;
best medical student poster, “Neuromyelitis optica,” by Elizabeth Coffee;
and best oral presentation, “Transarterial chemoembolization with smaller
beads: midterm clinical outcomes,” by R. Evans Heithaus, MD. Overall,
participants in the inaugural event presented more than 40 posters and
six oral presentations. This article reprints a selection of the abstracts.
Cutaneous metastasis from hepatocellular carcinoma to the
abdomen
Jamil Alsahhar, MD (e-mail: [email protected])
Hepatocellular carcinoma (HCC) is the sixth most prevalent
cancer and the third leading cause of cancer mortality worldwide.
Patients with cirrhosis are at highest risk of developing this malignant disease. Metastases are most commonly seen in the lung, abdominal lymph nodes, and bones. Cutaneous metastases of HCC
are uncommon. We report a case of a 54-year-old Caucasian man
with a history of HCC treated with six rounds of transarterial
chemoembolization followed by CyberKnife therapy, as well
as a history of hepatitis C cirrhosis and diabetes mellitus, who
presented with complaints of abdominal rash and pain. Examination revealed multiple erythematous, firm, well-circumscribed,
dry, subcutaneous nodules surrounding the umbilicus and left
abdomen. The nodules were tender to palpation. The patient
was initially started on antibiotics, as the rash was concerning
for cellulitis. A histopathological analysis of the nodules was
consistent with high-grade adenocarcinoma of hepatobiliary
origin. Electron beam therapy was utilized for palliation. HCC
often metastasizes to the lungs, abdominal lymph nodes, and
bones. A literature review showed that cutaneous metastasis of
HCC to the abdomen is rare, with most cases occurring at sites of
previous biliary drains or biopsies. Cutaneous nodules presenting
in patients with HCC or hepatobiliary malignancies should be
biopsied to assess for possible metastases.
Formalized resident training in code blue execution in a
simulation lab improves immediate post-code survival
Adan Mora Jr., MD, Benjamin Bijas, MD, Britton Smialek, MD, Bradley
Christensen,* Jennifer Duewall, MD, and Cristie Columbus, MD (*e-mail:
[email protected])
Although residents complete advance cardiac life support
(ACLS) training, they rarely receive formal instruction in the
practical elements of leading and executing a code blue in a
hospital setting. This study tested whether code simulation
could facilitate residents’ formal training and improve code
blue execution and postcode outcomes. Internal medicine residents at Baylor University Medical Center were trained for a
10-month period in a simulation lab on a 3G version SimMan.
Residents were exposed to progressively more challenging arrhythmias and code scenarios in which ACLS was implemented
and were observed by internal medicine and critical care faculty.
The hospital’s code blue data for a 12-month historical period
were then compared with the 10-month intervention period
during which simulation training was implemented. There were
107 codes (an average of 8.9 per month) during the historical
control period, with immediate postcode survival noted in 72
codes (67.3%), and 180 codes (an average of 16.4 per month)
during the intervention period, with immediate postcode survival noted in 128 codes (71.1%). The hospital census during
the 22-month study period was stable. Twenty-five patients
(23.4%) survived to discharge in the control period, compared
with 40 patients (22.2%) in the intervention period (P = .82;
NS). While formal resident training in code execution in a
simulation lab may improve immediate postcode survival in
hospitalized patients, the trend seen in immediate postcode
survival did not translate to discharge. This may be a result
of improved ACLS execution of patients in whom successful
resuscitation would not have previously been achieved. Further
study is needed to determine whether or not the observed trend
in immediate postcode survival is significant.
321
Neuromyelitis optica heralded by intractable hiccups, nausea,
and vomiting
Elizabeth Coffee* and Chaouki Khoury, MD (*e-mail: coffee@medicine.
tamhsc.edu)
A 19-year-old woman presented to the emergency department with vertigo, dysphonia, dysphagia, right tongue deviation,
left hemiataxia, left hemiparesis, and vertical oscillopsia. Upon
further questioning, it was revealed that the patient had experienced intractable hiccups, nausea, and vomiting (IHN) 3 weeks
earlier that was treated as an acute gastroenteritis. She then developed wheezing, which was treated as reactive airways disease,
and progressed to the previously listed symptoms. On admission
she was found to have a single right dorsal medullary lesion on
magnetic resonance imaging (MRI) and was later determined to
be seropositive for aquaporin-4 antibody. Thus, a diagnosis of
neuromyelitis optica (NMO) was made. NMO is a rare inflammatory demyelinating disease of the central nervous system. Current diagnostic criteria for NMO require both optic neuritis and
acute myelitis and at least two of the following: contiguous spinal
cord lesion, MRI that does not meet criteria for multiple sclerosis, and seropositive NMO IgG. However, IHN is increasingly
recognized as an early presentation of NMO that distinguishes
it from multiple sclerosis. This distinction is crucial in order to
avoid potentially harmful treatments for patients with NMO
mistaken for multiple sclerosis. This report suggests that an indepth assessment of IHN, including a brain MRI, is needed for
a prompt and accurate diagnosis of NMO.
Continuous renal replacement therapy to treat severe
metformin-induced lactic acidosis
Jeffrey Klein, MD,* and Harold Szerlip, MD (*e-mail: Jeffrey.Klein@
baylorhealth.edu)
Chronic metformin ingestion rarely causes lactic acidosis,
but the risk is increased in chronic kidney disease. We present
a case of severe lactic acidosis in a patient with diabetes treated
with metformin, complicated by acute on chronic renal failure.
A 54-year-old African American man with hypertension, insulindependent diabetes mellitus, chronic kidney disease (serum creatinine 1.5 mg/dL), and bilateral above-the-knee amputations
presented to the emergency department with a 3-day history of
lethargy and pruritus. The patient was taking insulin, simvastatin,
and metformin (500 mg twice a day). Initial laboratory evaluation revealed leukocytosis (11,000/mm3) and severe renal failure
(blood urea nitrogen 89 mg/dL; creatinine, 10.2 mg/dL), as well
as a potassium level of 6.2 mmol/L, anion gap of 24, and glucose
of 198 mg/dL. His lactate was 11 mmol/L with an arterial blood
gas of pH 6.5 and CO2 <5. Since there was no clear source of
infection, suspicion was raised for metformin-associated lactic
acidosis (MALA). The patient required emergent hemodialysis
due to profound metabolic acidosis and electrocardiographic
changes. Marked hypotension ensued within minutes on conventional hemodialysis and required dual vasopressor support. After
3.5 hours of hemodialysis, his lactate level was 17.5 mmol/L, and
continuous venovenous hemodialysis (CVVHD) was initiated
for ongoing clearance of lactatemia and metformin. Dialysate
322
ran at 30 mL/kg/h with bicarbonate 35 mEq/L, and vasopressor
support was weaned. His lactate reduced to 3.2 mmol/L after
24 hours of CVVHD. Ultrafiltration increased to 250 mL/h on
the second day of CVVHD and was transitioned off after 4 days.
Two additional intermittent conventional hemodialysis sessions
were required. His creatinine was 2.3 mg/dL upon discharge and
1.4 two weeks later. His metformin level was 38 mcg/mL (therapeutic level 1–2) upon admission and 8.6 mcg/mL after 10 hours
of continuous replacement therapy. Our patient had findings
consistent with MALA. Continuous renal replacement therapy
effectively cleared both lactate and metformin. Early initiation
of continuous renal replacement therapy should be considered
in the setting of suspected severe MALA.
Acute coronary syndrome and androgenic anabolic steroids
Rosemary Nustas, MD,* and Stuart Lander, MD (*e-mail: Rosemary.Nustas@
baylorhealth.edu)
Many side effects of androgenic anabolic steroids (AAS) are
well reported. This report highlights the cardiovascular consequences of abusing AAS on healthy adults and presents the effect
of a proper medical intervention. A 55-year-old man who was an
active body builder for over 20 years presented to a local emergency department with severe chest pain that started during his
routine gym workout. He was found to have marked ST segment
elevations in the inferior leads and was transferred to our center
for urgent cardiac catheterization. En route, he received aspirin,
heparin, and clopidogrel. His history was significant for controlled
hypertension but no previous angina symptoms or family history
of cardiac disease. He never consumed alcohol or used tobacco.
He was on a high-protein diet and performed regular endurance
exercise to participate in weight-lifting tournaments. Upon further
questioning, he revealed consistent use of injectable testosterone
derivatives for performance enhancement. His physical exam
was remarkable for a generalized muscular appearance, baldness,
and small testicular size. The rest of his exam was unremarkable.
Laboratory results showed very low high-density lipoprotein and
slightly elevated low-density lipoprotein. Echocardiogram demonstrated depressed systolic function. Percutaneous coronary intervention revealed multiple lesions and stenosis, necessitating stent
placement in the right coronary artery. The patient tolerated the
procedure and remained symptom-free. He was discharged the
next day on dual antiplatelet therapy, appropriate medications, and
a follow-up appointment after intensive counseling on abstaining
from further steroid use. A follow-up echocardiogram at 3 months
showed improved left ventricular function. This case illustrates
that the widely used AAS are becoming a public health issue,
calling for increased awareness of the evidence implicating their
life-threatening dyslipidemia and cardiovascular effects.
A rapidly fatal case of acute myeloid leukemia
Jacque Rampy, MD (e-mail: [email protected])
Acute myeloid leukemia (AML) is the most common acute
leukemia in adults. This case describes a patient who presented with
newly diagnosed AML with hyperleukocytosis and shortness of
breath. A 55-year-old Caucasian woman with a past medical history
Volume 28, Number 3
of multiple deep vein thromboses and pulmonary embolisms dating back to 1996 was transferred to Baylor University Medical
Center via air ambulance with newly diagnosed acute leukemia.
One week prior to admission, she presented to her primary care
physician with a painful and swollen left leg and was told all of
her labs were “normal” and no further testing was performed. Two
days prior to admission, she developed severe dyspnea. Computed
tomographic angiogram of the chest at an outside hospital showed
bilateral emboli in the proximal pulmonary arteries, and Doppler
ultrasound showed deep vein thromboses in the bilateral lower
extremities. Laboratory tests showed a white blood cell count of
190,000/μL with 91% blasts. Heparin was started, and she was
transferred to Baylor Dallas. She was admitted with disseminated
intravascular coagulation and bilateral pulmonary embolisms and
the plan was to start hydroxyurea and stabilize her for leukapheresis.
Shortly after admission, she became acutely short of breath and
required emergent intubation. She then suffered bradycardiac arrest
and code blue was called. Throughout the code she had pulseless
electrical activity, with only brief periods of a thready pulse. Venous
blood gas showed an oxygen partial pressure of 28 and saturation
of 19. The patient died shortly after. An autopsy revealed deep leg
vein thrombosis and massive pulmonary thromboembolism as
well as extensive leukemic infiltrates in the lungs, kidneys, peripheral nerves, and muscles. In conclusion, leukostasis (symptomatic
hyperleukocytosis) is a medical emergency with a high mortality
rate within the first week of presentation if not treated. Treatment
includes cytoreduction through the use of chemotherapy and leukapheresis.
Is there a relationship between psoas impingement and
increased trochanteric retroversion?
Manoj Reddy,* Juan Gomez-Hoyos, Ricardo Schroder, Ian J. Palmer, Anthony
Khoury, and Hal David Martin, DO (*e-mail: [email protected])
Iliopsoas impingement refers to an anterior labral injury due
to the direct contact by the iliopsoas tendon at the nonarticular
side. Although a tight psoas is a common finding during hip arthroscopy in patients with symptomatic psoas impingement, the
cause of the tightening has not yet been explored. Previous studies
of iliopsoas impingement have found inferior clinical outcomes in
patients with increased femoral neck version (FNV); however, lesser
trochanteric version (LTV) was not assessed. This study assessed the
amount of LTV in patients with symptomatic psoas impingement
and compared that to patients with asymptomatic hips. The FNV
and LTV were evaluated on axial magnetic resonance imaging, as
well as the angle between LTV and FNV. Data from 12 symptomatic patients and 250 asymptomatic patients were analyzed. The
mean, range, and standard deviations were calculated. Independent
t tests were used to determine differences between groups. The lesser
trochanteric retroversion was significantly increased in patients
with psoas impingement compared with asymptomatic patients
in degrees (–31.1 ± 6.5 vs –24.2 ± 11.5, P < 0.05). The FNV (9 ±
8.8 vs 14.1 ± 10.7, P > 0.05) and the angle between FNV and LTV
(40.2 ± 9.7 vs 38.3 ± 9.6, P > 0.05) were not significantly different
between groups. In conclusion, the lesser trochanteric retroversion is significantly increased in patients with psoas impingement
compared with patients with asymptomatic hips.
July 2015
Beyond Typhoid Mary: the sophistication of Salmonella typhi
Charis Santini,* Curtis R, Mirkes, DO, and Cedric Spak, MD (*e-mail: santini@
medicine.tamhsc.edu)
As resistant strains of Salmonella typhi are increasing worldwide, a clinician in the United States may find it more difficult to
treat typhoid fever in returning travelers. This case demonstrates
the variability within which typhoid fever can present. A 20-yearold formerly healthy man presented with an 18-day history of
intermittent fever and myalgia. The fever spiked to approximately
104°F in the late afternoons. Associated symptoms included chills,
headache, weakness, nausea/vomiting, and occasional loose stools.
The patient returned from Bangladesh 5 days prior to symptom
onset. He denied contact with contaminated food, sick contacts,
bloody diarrhea, constipation, or rashes. His laboratory results
were significant for a white blood cell count of 4.7 × 109/L with
37% bands, thrombocytopenia (109 × 109/L), hyponatremia
(129 mmol/L), and elevated transaminases (aspartate transaminase [AST] and alanine transaminase [ALT], 157 and 138 U/L).
Cultures were obtained and the patient was placed empirically on
vancomycin and piperacillin/tazobactam. Serum cultures were positive after 48 h for gram-negative rods. After 3 days of treatment,
the patient’s symptoms did not improve. His liver transaminases
continued to increase to a maximum AST/ALT of 301/245 U/L.
Also, his hemoglobin and hematocrit levels dropped, with laboratory values consistent with intravascular hemolysis. The patient
improved on ceftriaxone. Culture growth further revealed S. typhi
group D with intermediate sensitivity to ciprofloxacin. He was
discharged on oral antibiotics. This case of typhoid fever was not the
straightforward picture of enteritis, bloody diarrhea/constipation,
and salmon-colored macules. Once typhoid fever is diagnosed, a
new difficulty arises with the changing resistance patterns; selecting appropriate antibiotic therapy is of the utmost importance.
Fluoroquinolones for 7 to 10 days is the recommended treatment.
However, in certain regions, including South Asia, fluoroquinolone resistance is becoming more prevalent. Therefore, in cases of
known fluoroquinolone resistance, recommendations promote the
use of a third-generation cephalosporin or azithromycin. Delaying
appropriate therapy increases the risk of relapse and can result in a
mortality rate of 10% to 20%.
Acute enlargement and dysfunction of the exocrine glands of
the head
Avery Smith, MD,* and Alan Hise (*e-mail: [email protected])
We present a case of immunoglobulin G4-related disease
(IgG4-RD), a recently recognized syndrome. Diagnosis generally requires elevated serum IgG4 levels, biopsy-proven elevation
in IgG4, and a rapid response to steroid treatment. A 23-yearold Ethiopian man presented with 2 weeks of facial swelling of
his upper eyelids, submandibular area, and cheeks. He endorsed
visual impairment, nasal stuffiness, dry mouth/eyes, and odynophagia. Laboratory values were normal except for eosinophilia. Magnetic resonance imaging of the head demonstrated
significant bilateral lacrimal gland swelling and buccal lymphadenopathy. The patient began to have a sensation that his throat was
“closing up” so was given high-dose intravenous dexamethasone.
Abstracts from the First Annual Scholarly Day
323
Subsequently, he had dramatic improvement. A bilateral lacrimal
gland biopsy showed many B and T lymphocytes mixed with
eosinophils. The lymphocytes were prominently positive for IgG.
Only 1% of the lymphocytes were positive for IgG4, but his
serum IgG4 level was slightly elevated at 97 mg/dL. He was transitioned to oral prednisone. After completing the steroid taper,
his facial features were normal, eosinophilia resolved, and he was
asymptomatic. He has not had a relapse to date. Enlargement of
the lacrimal and salivary glands, known as Mikulicz’s disease, was
once considered a subtype of Sjögren syndrome. This disease has
since been reclassified as falling within the IgG4-RD spectrum.
This case had many features of IgG4-RD but did not meet strict
diagnostic criteria. However, suspicion for IgG4-RD remains high
based upon his presentation, response to treatment, and exclusion
of other diagnoses. Antinuclear antibody and anti-Ro/SSA and
anti-La/SSB antibodies were negative. The marked peripheral
eosinophilia and prominent eosinophils in his lacrimal gland
biopsy suggested an allergic etiology. However, serum IgE levels
were normal. Thus, his peripheral and biopsy-proven eosinophilia
was attributed to a reactive process secondary to the recruitment
of T lymphocytes, a well-recognized feature of IgG4-RD. The
patient’s dramatic response to dexamethasone and the eventual
resolution of his dry eyes/mouth support IgG4-RD over Sjögren
syndrome. Thus, it appears that intensive steroid treatment can
markedly decrease peripheral and glandular IgG4 levels, and this
may have accounted for his negative results.
A rare case of recurrent focal myositis and an associated
coagulopathy
Avery Smith, MD,* and Carolyn Quan, MD (*e-mail: Avery.Smith@
baylorhealth.edu)
Focal myositis is a rare disorder with less than 50 cases reported to date. It typically presents as localized swelling, pain,
and skin discoloration over a muscle group of an extremity.
We present a case of recurring focal myositis complicated by
an autoimmune coagulopathy. A 74-year-old African American man presented to the emergency department with a 3-day
history of right calf swelling, dark discoloration, and pain,
which started abruptly without inciting trauma. He denied
fever, chills, or night sweats, but did note a similar presentation 2 months earlier in his left upper extremity. Based on
magnetic resonance imaging, myositis was diagnosed, and the
patient was treated with antibiotics despite negative cultures.
He improved but then returned with the right calf pain. Laboratory results showed markedly positive antinuclear antibody,
positive anti-centromere antibody, and an elevated erythrocyte
sedimentation rate/C-reactive protein. Surgical muscle biopsy
showed necrosis and muscle regeneration but no infection,
dermatomyositis, polymyositis, or inclusion body myositis.
The procedure was complicated by significant bleeding. Studies
showed an isolated prolongation of the partial thromboplastin
time, which led to the diagnosis of a factor VIII inhibitor.
324
Electromyography performed to evaluate for subclinical weakness had unremarkable results. However, his myositis recurred
at the electromyography insertion sites. He was then treated
with high-dose prednisone, rituximab, and cyclophosphamide.
He improved without further bleeding or recurrence of his
myositis. This case is unique because the patient experienced
recurrent focal myositis as well as the development of a rare
autoimmune-driven coagulopathy. Heffner’s theory regarding micro-trauma as an inciting factor was supported by this
patient’s recurrent myositis following the electromyography
study. Focal myositis is an atypical, rheumatologic syndrome
that can mimic infections of other rheumatologic entities. It
is presumably secondary to an autoimmune response against a
muscular antigen, but the specific antibody remains unknown,
with negative myositis panels, antistriated muscle antibody, and
paraneoplastic panel.
Delayed treatment for herpes zoster resulting in disabling
plexopathy in the immunosuppressed patient
Anwar Y. Zaman, MD,* Sridevi Mukkamala, MD, and Matt Bayazitoglu, MD
(*e-mail: [email protected])
Here we report two cases of adults on chronic immunosuppressive therapy who were diagnosed with herpes zoster and
treated with oral steroids alone. Both patients developed focal
weakness in the affected limb. A 63-year-old man on chronic
immunosuppression after liver transplantation presented to his
primary care physician with a left lower extremity vesicular
rash and pain. He was initially started on oral steroids and
within 5 weeks developed left lower extremity weakness with
foot drop. He subsequently was admitted to the hospital and
started on antiviral treatment. The second patient was a 66-yearold man with rheumatoid arthritis on chronic immunosuppression who presented to his primary care physician with a right
thigh vesicular rash and pain. He was started on oral steroids
and 1 month later developed progressive right lower extremity weakness. Nerve conduction studies and electromyography
were performed on the patients more than a month after onset
of symptoms. Each patient had electrodiagnostic evidence of
lumbosacral plexopathy with significant motor denervations
that matched clinical findings. Lumbosacral plexopathy with
motor involvement occurring in the context of herpes zoster is
rare and underrecognized. The patients each developed severe
weakness with minimal recovery at 2-month follow-up. The
patients did not receive antiviral treatment at the time of initial
rash presentation. The delay in antiviral treatment may have
contributed to dissemination of the infection and extensive
motor involvement. In conclusion, patients on chronic immunosuppressive therapy can be at higher risk of developing
plexopathy or polyradiculopathy secondary to herpes zoster. In
this patient population, early disease recognition and treatment
with antiviral medication may help prevent plexopathy and
subsequent disability.
Volume 28, Number 3
Uses, limitations, and complications of endobronchial
ultrasound
Bilal A. Jalil, MD, Kazuhiro Yasufuku, MD, PhD, and Amir Maqbul Khan, MD, MSc
Endobronchial ultrasound (EBUS) plays a pivotal role in the minimally
invasive staging of non–small cell lung cancer. The role of EBUS is progressively expanding to include the evaluation of peribronchial lesions,
pulmonary nodules, and other mediastinal abnormalities. Recently, EBUS
has assisted in the diagnosis of many other disease entities, including
malignancies and various infections such as tuberculosis and sarcoidosis.
This article reviews the indications and contraindications of EBUS, with
emphasis on the technique and complications encountered during the
procedure.
E
ndobronchial ultrasound (EBUS) combines bronchoscopy with ultrasound to enhance the definition
of mediastinal structures and aid in visualization of
parabronchial anatomy, reducing biopsy sampling
errors due to superior site selection for transbronchial sampling (1). Over the last two decades, EBUS has emerged as a
highly effective and minimally invasive technique for sampling
peribronchial, mediastinal, and lung masses for pathologic
examination. EBUS may provide rapid on-site results with
relatively less expertise and has a very safe profile. It has been
shown to be significantly cost-effective compared with prior
gold standard techniques (2).
EBUS plays a role in the staging of non–small cell lung
cancer (NSCLC) and the diagnostic evaluation of endobronchial lesions, peripheral pulmonary nodules, and mediastinal
abnormalities (3, 4). Recently, use of EBUS has expanded for
patients with sarcoidosis, tuberculosis, and lymphoma and in
the workup of nonspecific mediastinal adenopathy (5–7). As
chest computed tomography (CT) scans are being performed
much more frequently than before, benign diseases and incidentalomas are being detected as well as early stage lung cancer (8).
Benign diseases warrant the need for the least invasive technique
of obtaining histologic diagnosis. For this reason, EBUS has
become the staging tool of choice for mediastinal NSCLC and
is currently being explored for many other disease entities. As
medical diagnosis and therapy move towards less-invasive procedures that provide results equal or superior to those of more
invasive procedures, additional uses of EBUS are emerging on a
daily basis. EBUS can be used to characterize suspicious mucosal
lesions, determine the extension of early lung cancer, and assess
the involvement of the tracheobronchial wall or mediastinum
in cases of advanced malignancy.
TECHNIQUE
EBUS may be performed under conscious sedation or general anesthesia depending on the anticipated length of the procedure. Local anesthetic may be administered to minimize cough,
and the flexible bronchoscope is advanced for an initial airway
exam. Bronchial segments and subsegments are identified, secretions are suctioned, and 1% to 2% lidocaine is administered to
further minimize cough.
After initial airway examination, the flexible bronchoscope
is removed and the EBUS bronchoscope is advanced. While
EBUS is performed, the bronchoscopist simultaneously visualizes the ultrasonic and bronchoscopic views on display. EBUS
can help differentiate normal parenchyma from malignant tissue
by its sonographic appearance. The sonographic visualization of
normal alveolar tissue is described as a “snowstorm” appearance
(Figure 1). Figure 2a is a sonographic view of the peripheral
pulmonary nodule visualized on the CT scan in Figure 2b.
After sonographic confirmation of the biopsy site, the transbronchial needle aspiration (TBNA) needle is advanced through
a 2.2 mm working channel on the bronchoscope (Figure 3a).
This needle may be 21 or 22 gauge and can be advanced up to
40 mm. A stylet or wire is present in the needle at the time of
insertion to clear tissue that may have collected while crossing
the bronchial or tracheal wall. The distal end of the needle is
grooved, rendering it hyperechoic and improving ultrasound
visualization (Figure 3b). After the lymph node or tumor is
punctured, the needle is connected to suction and excursions
are made in the lymph node. Multiple punctures have been
recommended to decrease sampling error.
The samples obtained can either be analyzed on site by the
use of rapid on-site evaluation (ROSE) or collected in saline or
cell culture media. The application of ROSE has been shown to
significantly lower the need for additional bronchoscopic proceFrom the Department of Pulmonary and Critical Care Medicine, Baylor Scott and
White Medical Center, Waxahachie, Texas (Jalil, Khan), and Interventional Thoracic
Surgery, University of Toronto, Canada (Yasufuku).
Corresponding author: Amir Maqbul Khan, MD, MSc, 1328 West Highway 287
Bypass, Waxahachie, TX 75165 (e-mail: [email protected]).
325
tage of EBUS is the accessibility of stations 10R, 10L, 11R, and
11L, which are inaccessible by other invasive techniques (10).
Endoscopic ultrasound (EUS) also provides access to 7, but in
addition lymph node stations 8 and 9 can be accessed. EBUS
may be performed safely in a single session alongside EUS (11,
12). Lymph node stations not accessible by EBUS are shown
in Figure 4b. EBUS is preferred as a primary procedure when
EUS is performed in the same session (13).
INDICATIONS
The role of diagnostic bronchoscopy has expanded with
the introduction and rapid institution of ultrasound, giving the
bronchologist vision beyond what the bronchoscope can see.
EBUS was initially developed for the diagnosis and staging of
NSCLC but is increasingly involved in nononcologic pulmonary disease states. The following are some of the indications
and applications of EBUS.
Figure 1. Endobronchial ultrasound of normal alveolar tissue described as a
“snowstorm” appearance.
dures and puncture number (9). ROSE is particularly beneficial
when performing EBUS in the operating room with an expected need for further invasive exploration or surgical resection.
Procedure length varies by the number of lymph node stations
sampled. When EBUS is performed in the outpatient setting,
patients can be discharged home after they regain their gag reflex.
The anatomical lymph node stations that are accessible via
EBUS are 2R, 2L, 3P, 4R, 4L and 7 (Figure 4a). A unique advana
Diagnosis, staging, and restaging of lung cancer
Mediastinoscopy has been the historic gold standard in lung
cancer staging. Lung cancer staging has progressed from mediastinoscopy in the early 1950s to video-assisted thoracic surgery,
video-assisted mediastinal lymphadenectomy, transcervical extended mediastinal lymphadenectomy, and TBNA (14). The
introduction of EBUS improves the sensitivity and reliability
of TBNA in the staging of lung cancer (1).
Appropriate staging of lung cancer is of utmost importance
before initiation of treatment. Computed tomography (CT) and
positron emission tomography (PET) have been inconsistent
at accurately staging the mediastinum (15). Identification of
suspicious mediastinal metastases by CT or PET should always
b
Figure 2. (a) Imaging of a pulmonary nodule through endobronchial ultrasound, with a so-called “blizzard” appearance. (b) Axial CT of the lung nodule (arrow).
326
Volume 28, Number 3
a
c
b
Figure 3. Endobronchial ultrasound (EBUS) bronchoscope. (a) The inflated balloon over the ultrasound transducer and a protracted biopsy needle through the EBUS
working channel. (b) An EBUS biopsy needle with dimples for better sonographic visualization (arrow). (c) Real-time visualization of EBUS transbronchial aspiration
needle advancement into the lymph node.
a
b
Figure 4. Anatomical depiction of lymph node stations (a) accessible by EBUS and (b) not accessible by EBUS. Reproduced with permission from the American
College of Chest Physicians via the Copyright Clearance Center: Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest
1997;111:1718–1723.
July 2015
Uses, limitations, and complications of endobronchial ultrasound
327
be followed by histologic assessment of mediastinal and hilar
lymph nodes for accurate staging. Minimally invasive modalities
are preferred over more invasive modalities for the initial biopsy.
However, sometimes more than one procedure will be necessary,
particularly when initial tissue sampling provides inconclusive
results or is insufficient for molecular characterization.
Histologic diagnosis is prudent in the diagnosis of NSCLC,
as is disease staging, as therapy depends on the stage. In the
absence of obvious metastatic disease, it may be important to
biopsy mediastinal lymph nodes to accurately determine node
status. The 5-year survival rate of 16% for bronchogenic carcinoma with lymph node metastases is very low compared to
the rate of 49% in lung cancer without lymph node involvement (16).
Randomized trials have reported a low prevalence of metastatic disease in patients with suspected stage 1A NSCLC with
peripheral tumors <3 cm. These patients may undergo primary tumor resection, and the need for preoperative mediastinal
sampling is not well defined (17–20). Patients with suspected
NSCLC stages IB, II, and III should undergo mediastinal sampling, the timing of which should be individualized according
to patient characteristics and radiographic stage.
EBUS-TBNA is the preferred first step for large, centrally
located tumors and for suspicious nodal involvement in the
mediastinum. The most recent American College of Chest Physicians guidelines on the management and treatment of lung
cancer recommend EBUS as the initial step in the diagnostic
staging of lung cancer (21). The European Society of Thoracic
Surgeons also recommends EBUS as a first choice for mediastinal staging in patients with NSCLC (14).
EBUS-TBNA has a reported high sensitivity to stage and
diagnose NSCLC and is able to access more nodal stations than
the prior gold standard, cervical mediastinoscopy (22). EBUS
cannot sample all mediastinal lymph node stations and is usually
combined with EUS for a more thorough and systematic sampling of the mediastinum. EBUS can access the anterosuperior
mediastinum while EUS can access the posteroinferior mediastinum (23). Prior to the development of EBUS, mediastinoscopy
was used to sample the mediastinum. Mediastinoscopy is an
invasive procedure requiring general anesthesia, while EBUS
can be performed as an outpatient procedure with conscious
sedation and usually does not require postprocedure hospitalization. EBUS combined with EUS is essentially a less-invasive
alternative to mediastinoscopy.
The mediastinum is restaged after induction therapy in
patients with stage III NSCLC, as those with persistent mediastinal involvement have a worse prognosis than those with
proven mediastinal downstaging. In the absence of an experienced surgeon, it is technically challenging and difficult to
restage the mediastinum with mediastinoscopy in patients who
had undergone a prior mediastinoscopy, as tissue planes are
obliterated by fibrosis. EBUS is less invasive, more accurate,
and can be performed time and time again without the limitations that prevent mediastinal restaging by mediastinoscopy.
EBUS-TBNA is highly specific and sensitive in restaging the
mediastinum after neoadjuvant chemotherapy.
328
EBUS is also able to obtain adequate samples to run immunohistochemistry and DNA analysis on the tissue obtained.
There is a need to further subclassify cancer by driving mutations. Anaplastic lymphoma tyrosine kinase (ALK) and c-ros
oncogene 1 receptor kinase (ROS1) are examples that can be specifically treated with targeted agents. Flow-cytometric analysis,
DNA point mutations, and RNA analysis can be run on tissue
specimens obtained by EBUS sampling to help individualize
therapy for lung cancer with genetically based chemotherapy
regimens (24).
Endobronchial lesions
EBUS allows for diagnosis and treatment as well as surveillance follow-up of pathologic processes. It extends the endoscopist’s vision to allow evaluation of the tracheobronchial
wall and parabronchial anatomy. Radiographically inapparent
endobronchial lesions may be detected during bronchoscopy or
by newer methods being developed to screen high-risk patients
for lung cancer, such as autofluorescence bronchoscopy and
confocal microscopic bronchoscopy (25, 26). EBUS has been
shown to more accurately predict malignancy in endobronchial
lesions. In a trial of 105 patients with central thoracic malignancies, EBUS was superior to chest CT in differentiating tumor
invasion of the airway from tumor compression (25). EBUS not
only provides a more accurate classification of mucosal lesions,
but also contributes to therapy decisions (16).
Mediastinal and hilar lymphadenopathy
The most common indication for hilar or mediastinal lymph
node sampling is as previously described: to assess lymph node
involvement in lung cancer. There are many infectious, noninfectious, and malignant causes of hilar and mediastinal lymphadenopathy, such as sarcoidosis, reactive lymphadenopathy,
and tuberculosis. Metastatic primary cancers, thymomas, and
lymphoma are some malignant causes of hilar and mediastinal
lymphadenopathy.
The incidence of sarcoidosis in the United States is high, and
sarcoidosis-related mortality is increasing (27, 28). Currently,
conventional bronchoscopy is regarded as the standard to demonstrate noncaseating granulomas in patients with suspected sarcoidosis. EBUS-TBNA has been used in patients with suspected
sarcoidosis to obtain tissue diagnosis as well as exclude other
pathologies such as tuberculosis and malignancy. Studies have
shown a higher diagnostic yield and a lower complication rate in
favor of EBUS-TBNA. It has also been shown that use of EBUSTBNA can avoid further invasive procedures in patients with
suspected sarcoidosis (29). EBUS-TBNA is critical in confirming
a diagnosis of sarcoidosis as well as excluding other pathology
that may require prompt initiation of therapy. Compared with
conventional transbronchial biopsy, the use of EBUS has also
resulted in greater diagnostic yield (30). EBUS-TBNA is a safe
procedure with a high yield for the diagnosis of sarcoidosis (31).
Lymphoma
Mediastinoscopies or thoracotomies have been performed
as the standard procedure to obtain a histologic diagnosis in
Volume 28, Number 3
patients with mediastinal lymphadenopathy and suspected
lymphoma. These procedures require general anesthesia and
carry immense risks. Mediastinoscopy also has limited access to
perihilar lymph nodes. Conventional TBNA, though superior
to mediastinoscopy, has been shown to be inferior to EBUSTBNA due to a lower specificity and sensitivity (5). EBUS can
be performed for a histologic diagnosis in suspected lymphoma,
and fluorescence in situ hybridization can also be done on the
samples obtained by EBUS to further characterize lymphoma
subtypes (32).
LIMITATIONS OF EBUS
As with all medical technologic advances, EBUS has its
limitations. In the instance of mediastinal staging in lung cancer, EBUS is not able to stage the entire mediastinum. EBUS
is limited to the anterosuperior mediastinum, and EUS is often
utilized to sample the posteroinferior mediastinum. EBUS and
EUS can often be performed in the same session consecutively.
EBUS is technically difficult to perform in some anatomic locations, such as the upper lobes, as scope angulation is required.
Multiple studies have reported a good experience with the use
of electromagnetic navigational bronchoscopy with EBUS in
upper lobe lesions (33, 34).
Needle puncture can be technically difficult, specifically
in the elderly who have narrow intercartilaginous spaces and
cartilage calcification. A significant cough can limit the success
of the procedure in patients undergoing bronchoscopy under
conscious sedation.
With the growing development and application of EBUS,
many chest physicians lack adequate training and experience.
This may be influenced by the fact that a fully equipped EBUS
bronchoscopy suite may cost several thousand dollars to establish. For this fairly large investment, there is minimal additional
professional fee reimbursement and no additional facility fee
reimbursement above standard bronchoscopy (35).
CONTRAINDICATIONS
Contraindications to EBUS are similar to those of bronchoscopy in general. Recent myocardial infarction or ischemia,
poorly controlled heart failure, significant hemodynamic instability, chronic obstructive pulmonary disease or asthma exacerbations, or life-threatening cardiac dysrhythmias should delay
an endobronchial procedure. Contraindications particular to
EBUS-TBNA are related to coagulopathies (medication induced or inherent). The recommendation is to hold antiplatelet
and anticoagulation agents prior to endoscopy to reduce bleeding risk (36).
COMPLICATIONS
Bronchoscopy is generally a safe procedure with a reported
low complication rate (37–39). Complications related to the
bronchoscopy procedure can be related to sedation for the
procedure or directly from the bronchoscope. Complications
related to sedation are hypoxemia and hypotension, while those
related to bronchoscopy are bronchospasm, laryngospasm, nausea, vomiting, bleeding due to scope trauma, cardiac arrhythJuly 2015
mias, and vasovagal syncope. Complications specifically related
to EBUS-TBNA are pneumothorax and bleeding. There has
been a single reported case of EBUS-TBNA needle breakage
without event (40).
In summary, EBUS has become the standard of care and has
rapidly attained a key status in the diagnosis and staging of various
lung cancers, but in addition is also aiding and helping manage
other pulmonary pathologies such as sarcoidosis, lymphoma,
and in situ endobronchial lesions. The ability of EBUS to help
perform mediastinal and transbronchial biopsies less invasively
and with better sensitivity and specificity makes it more favorable
than mediastinoscopy. EBUS and EBUS-TBNA, with convex
probe or radial probe, have galvanized pulmonologists further
into the care of thoracic malignancies, improving treatment selection based on genetics and helping stage the mediastinum in a
minimally invasive, safer, and more effective fashion.
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differentiates between airway infiltration and compression by tumor. Chest
2003;123(2):458–462.
26. Chhajed PN, Shibuya K, Hoshino H, Chiyo M, Yasufuku K, Hiroshima
K, Fujisawa T. A comparison of video and autofluorescence bronchoscopy
in patients at high risk of lung cancer. Eur Respir J 2005;25(6):951–955.
27. Iannuzzi MC, Fontana JR. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA 2011;305(4):391–399.
28. Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger
D, Brown KK. Sarcoidosis-related mortality in the United States from
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29. Oki M, Saka H, Kitagawa C, Kogure Y, Murata N, Ichihara S, Moritani
S. Prospective study of endobronchial ultrasound-guided transbronchial
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T, Hiroshima K, Lam WK, Fujisawa T. Endobronchial ultrasound: new
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32. Nunez AL, Jhala NC, Carroll AJ, Mikhail FM, Reddy VV, Xian RR,
Jhala DN. Endoscopic ultrasound and endobronchial ultrasound-guided
fine-needle aspiration of deep-seated lymphadenopathy: Analysis of 1338
cases. Cytojournal 2012;9:14.
33. Kang HJ, Hwangbo B. Technical aspects of endobronchial ultrasoundguided transbronchial needle aspiration. Tuberc Respir Dis (Seoul)
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Volume 28, Number 3
Recurrent hospitalization for self-injuries and suicide
attempts: case study of a super-utilizer
Jacob W. Roden-Foreman, Ann Marie Warren, PhD, Megan Reynolds, MS, and Michael L. Foreman, MD
Super-utilizers, patients who amass disproportionately large occurrences
of emergency department visits and hospital admissions, are increasingly recognized as a significant and potentially preventable resource
consumer. A comprehensive understanding of these individuals and their
situations may prove useful in preventing unnecessary admissions and
improving patient care and outcomes. While most super-utilizers suffer
from chronic medical issues, this patient is an unusual variant, as his
super-utilization stemmed from mental health problems leading to serial self-injury. Between January 2010 and October 2014, the patient
performed 49 acts of self-harm resulting in 27 acute hospital admissions
and 17 additional admissions secondary to complications. In addition
to documented injuries, he and his family reported up to 50 additional
self-injuries since his first episode 34 years earlier. It was concluded that
the patient’s pattern of self-injury resulted from a combination of factors,
including underlying psychiatric conditions, chronic noncompliance with
medications, and potentially unavoidable behavioral reinforcement from
health care professionals.
A
ccording to the Centers for Disease Control and Prevention, in 2010 suicide was the 10th leading cause of
death among all ages in the United States, with more
than 38,000 fatalities. More than 1 million people reported attempting suicide in the past year, and twice as many
adults reported making plans to commit suicide within the
past year (1). Between 2005 and 2009, the greatest percentage
of fatal self-harm injuries occurred by firearm (47%), while
self-inflicted abdominal stabbings accounted for a very small
fraction of injuries (2). Among patients with intentional selfinflicted abdominal stab wounds, 70% were adult men, 74%
had a psychiatric history, and 41% had prior suicide attempts
(3, 4). Therefore, it is likely that many of these individuals have
been admitted to hospitals multiple times and are potential
“super-utilizers” of health care resources, patients who amass
disproportionately large occurrences of emergency department
visits and hospital admissions (5). The present case describes one
such super-utilizer, a 51-year-old divorced Caucasian man with
a pattern of serial self-injurious behavior and suicide attempts,
which required multiple hospitalizations and operations.
After obtaining the patient’s consent for multi-institutional
release of information from area hospitals where he received care,
records were obtained for all hospital admissions from 2001 to
October 2014. Charts were reviewed and demographic information, hospital charges, psychiatric diagnoses and interventions,
substance use, circumstantial aspects of the injury resulting in
hospital admission, and discharge disposition were recorded.
CASE DESCRIPTION
Since 2010, the patient performed 49 documented acts
of self-harm resulting in 27 acute hospital admissions. These
admissions included three overdoses, one episode of jumping
from a moving car, two episodes of cutting at his wound site,
three lacerations to his neck, three stab wounds to his chest,
and 37 stab wounds to his abdomen. In addition to these documented injuries, the patient and his family reported as many
as 50 additional self-injuries since his initial episode of selfinjury at age 17. These documented admissions and reported
self-injuries are detailed in Table 1. As an indicator of his level
of super-utilizing, charges of nearly $1 million were incurred
at a single hospital between 2011 and 2012, which was one of
his less active periods.
The patient reported beginning his pattern of self-harm at
age 17 when, following a breakup with his girlfriend, he shot
himself in the right shoulder. His self-injurious behavior continued and usually began with an emotional trigger that led to a
pattern of increased anxiety, manic behavior, and insomnia and
ended with an act of self-injury, most commonly by stabbing
himself one or more times in the abdomen and characteristically
leaving the object in place. However, the impetus and mechanism of self-harm varied. In one episode, the patient reportedly
slit both wrists after his grandfather died; on other occasions,
he attempted an overdose. Additionally, in several of his more
recent episodes of self-harm, he reported auditory hallucinations
of voices he believed were trying to harm him and explained
that he acted to harm himself before the voices could do so. In
nearly every occurrence, his chronic and recurrent noncompliance with his psychiatric medications was a factor.
From the Division of Trauma, Critical Care, and Acute Care Surgery, Baylor
University Medical Center at Dallas, Texas.
Corresponding author: Michael L. Foreman, MD, Chief, Division of Trauma,
Critical Care, and Acute Care Surgery, Baylor University Medical Center, 3500
Gaston Avenue, Dallas, TX 75246 (e-mail: [email protected]).
331
Table 1. Self-injuries by region
Purported
injuries
Documented
injuries*
Per region
total
Right neck
0
2
2
Left neck
0
1
1
Right shoulder
0
1
1
Mid, upper thorax
0
2
2
Epigastrium
0
3
3
Umbilical region
0
24
24
Region
Hypogastrium
0
3
3
Abdomen, unspecified
47
9
56
Total, abdomen
47
37
84
Other or general
3†
4‡
7
Total self-injuries
50
49
99
*Over the course of 27 acute admissions from January 2010 to October 2014.
†Slit both wrists and cut himself in an unspecified location.
‡Jumped from a car and three overdoses.
With repeated injury and repair, medical management of his
injuries became increasingly difficult, and it is now considered
impossible to surgically address his abdominal injuries due to
the degree of scarring and adhesions caused by repeated injury,
exploration, and complications, including wound infections and
multiple enterocutaneous fistulas. Therefore, his more recent
stab wounds have been managed nonoperatively, despite almost
certain visceral injuries (Figure 1). In addition to his abdomen
being regarded as inoperable, the patient has also been deemed
psychiatrically futile (i.e., further treatment will not improve
his underlying psychiatric condition and will be of little if any
benefit to him).
During his hospitalizations, a psychologist or psychiatrist
typically assessed him to determine his level of functioning
and identify stressors that led to the self-harm. Typically, he
denied suicidal or homicidal ideations and voiced that he used
self-injury as a coping mechanism. In one interview, he stated
that, after an argument with his then wife, he stabbed himself to
“relieve the pressure in my life.” On another occasion, he stated
that his self-stabbing was not a suicide attempt but that “it’s just
something I do to release the tension, like other people make
little cuts on themselves.” Such statements are congruent with
the reasons that people give for engaging in nonsuicidal selfinjury behaviors such as cutting one’s arms or inner thighs (6).
He also occasionally cited an inability to live with his chronic
pain, both physical and emotional, as a reason to end his life.
However, regardless of any suicidal intent, the patient always
expressed regret over harming himself and voiced his sons as
important reasons to continue living. The psychologist or psychiatrist then provided the patient with other methods of coping
to replace his current, maladaptive one and reminded him of the
importance of maintaining his medication schedule. Based on
the recommendations of the psychologist or psychiatrist, he was
commonly transferred to an inpatient psychiatric hospital for
ongoing mental health care or occasionally to a skilled nursing
facility for continued wound care.
DISCUSSION
The patient had received multiple psychiatric diagnoses
throughout his life, including bipolar disorder, posttraumatic
stress disorder, borderline personality disorder, schizophrenia,
schizoaffective disorder, REM sleep behavior disorder with comorbid narcolepsy, and dissociative identity disorder. The last
two diagnoses were thought to explain his occasional amnesia
and vehement denial of having stabbed himself; however, posttraumatic retrograde amnesia or amnesia related to his other
diagnoses seem to be more likely explanations. This is because
there was no evidence to suggest the patient was sleeping prior
to or during his self-harm, nor was there evidence of multiple
distinct personality states or dissociative fugues occurring separately from the self-harm episodes reported by him or his family.
Beyond these diagnoses, he reported a history of physical and
emotional abuse from his father as a child, and an unspecified
psychiatric disorder in his mother.
Figure 1. Lateral and anterior CT images of self-inflicted stab wound.
332
Volume 28, Number 3
In addition to reinforcing his self-harm behavior by temporarily substituting acute injury for his chronic mental and
physical pain, his behaviors were likely secondarily reinforced,
albeit unintentionally. Given his increased social isolation, the
attention he received from caregivers during his hospitalizations
may have positively reinforced his self-injurious behaviors, as
the caregivers were one of his only sources of support.
Despite ongoing outpatient counseling and multiple
inpatient stays at psychiatric facilities—both voluntary and
involuntary—recurrent noncompliance with his psychiatric
mediations may be the most important and potentially modifiable contributor to the patient’s recurring behavior pattern.
While this issue comes in part from financial difficulties and
from his increasing isolation, attempts at providing him with
medications and visiting care providers have not been successful. While the patient clearly remains a hazard to himself,
the very limited availability of inpatient long-term psychiatric
placement, both voluntary and involuntary, has made this
alternative effectively impossible.
Given the complexity and long-term, recurrent nature of
this case, it is perhaps not surprising that health care professionals have been largely unsuccessful in modifying the patient’s
behavior. A primary constraint is the limited availability of extended mental health care secondary to monetary and statutory
restrictions. While the legal issues relating to the availability
of chronic mental health placements are beyond the scope of
July 2015
this manuscript, the financial costs of institutionalization or
other creative care options are likely to be favorable compared
to the funds that continue to be expended in multiple acute
hospitalizations, not to mention the likely improvement in
his quality of life. Ultimately, while it might seem obvious,
mental and behavioral pathology can have profound influences
on super-utilizer encounters for physical illnesses and must be
addressed as part of their overall treatment plans and when
designing programs specifically to reduce their admissions.
1.
2.
3.
4.
5.
6.
Centers for Disease Control and Prevention. Suicide: Facts at a Glance
2012. Available at http://www.cdc.gov/violenceprevention/pdf/suicide_
datasheet_2012-a.pdf; accessed June 9, 2014.
Centers for Disease Control and Prevention. Web-Based Injury Statistics
Query and Reporting System (WISQARS): Fatal Injury Reports and Nonfatal
Injury Reports. Atlanta, GA: National Center for Injury Prevention and
Control. Available at http://www.cdc.gov/injury/wisqars/index.html. Last
accessed March 09, 2014
Abdullah F, Nuernberg A, Rabinovici R. Self-inflicted abdominal stab
wounds. Injury 2003;34(1):35–39.
Badger JM, Gregg SC, Adams CA Jr. Non-fatal suicide attempt by intentional stab wound: Clinical management, psychiatric assessment, and multidisciplinary considerations. J Emerg Trauma Shock 2012;5(3):228–232.
Gawande A. The hot spotters. The New Yorker, January 24, 2011. Available
at http://www.newyorker.com/magazine/2011/01/24/the-hot-spotters;
accessed August 20, 2014.
Klonsky ED. The functions of deliberate self-injury: a review of the evidence. Clin Psychol Rev 2007;27(2):226–239.
Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer
333
Radiographic findings in the nail-patella syndrome
James A. West, MD, and Thomas H. Louis, MD
Nail-patella syndrome is a rare disorder characterized classically by
the tetrad of nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns. Iliac horns are
considered pathognomonic, and the presence of hypoplastic or aplastic
patellae in conjunction with nail abnormalities is a cardinal feature of
diagnosis. Elbow dysplasia is present in most cases and can exhibit
features typical of the syndrome. Herein we present the radiographic
findings of the elbows, knees, and pelvis of a woman with nail-patella
syndrome.
N
ail-patella syndrome (NPS), a hereditary disorder
that occurs in approximately 1 in 50,000 newborns
(1), is known by many other names, including hereditary onycho-osteodysplasia (HOOD), TurnerKeiser syndrome, and Fong disease (2). It is characterized
by nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns (2).
The earliest description of a nail dysplasia being associated with knee and elbow dysplasia dates back to 1820
by Chatelain (3). The familial and hereditary nature of
the disorder was recognized by Pye-Smith and Little in
1883 and 1897, respectively (4). A few years after Fong
described the incidental finding of “iliac horns” in 1946
during a routine pyelogram, they became associated with
the syndrome and are now considered pathognomonic (4,
5). Identifying the common radiographic manifestations
of the pelvis, knees, and elbows can aid in establishing the
diagnosis of NPS.
CASE STUDY
A 70-year-old woman presented to the emergency department complaining of hip pain. An anteroposterior radiograph of
the pelvis was obtained and demonstrated no acute abnormality
and only mild osteoarthritic degenerative changes of the hips bilaterally. Incidentally, there were bilateral, triangular osseous excrescences extending from the posterior aspect of the ilia (Figure
1a). Review of the patient’s prior imaging studies revealed multiple musculoskeletal studies in addition to computed tomography (CT) of the abdomen and pelvis. CT of the abdomen and
pelvis showed the bilateral posterior iliac osseous excrescences to
334
involve the origin of the gluteus medius muscles (Figure 1b). An
anteroposterior view of the bilateral femurs demonstrated both
patellae to be hypoplastic (Figure 2). Anteroposterior and lateral
radiographs of the right elbow showed an abnormal configuration of the capitulum, lateral epicondyle, and radial head as well
as posterior inferior dislocation of the radial head (Figure 3).
Radiographic features of the left elbow were similar though less
pronounced, and the left radial head was also posteriorly and
inferiorly dislocated. Review of the patient’s records revealed a
standing diagnosis of NPS.
DISCUSSION
NPS exhibits full genetic penetrance but an unpredictable
degree of expression, even within families (1, 6). No clinical
diagnostic criteria exist for NPS; however, a combination of
clinical and imaging features seen with this condition are characteristic (6). Genetic testing can be performed if findings are
ambiguous (6). NPS results from loss of function mutations of
transcription factor LMX1B located on chromosome 9, which
is a member of the LIM-homeodomain family of transcription
factors involved in ventral-dorsal body-pattern formation during development (7).
Nail dysplasia and patellar aplasia or hypoplasia are cardinal
features in the diagnosis of NPS (4). Nail anomalies predominantly involve the fingernails, with the thumbs most severely
affected. The toenails are rarely involved and the presence of
triangular nail lunulae is considered pathognomonic (4). The
nails may be absent, hypoplastic, or dystrophic, with some of
the various nail dysplasia including horizontal or longitudinal
ridging, pitting, or the presence of a longitudinal cleft that
separates them in half.
Patellar abnormalities are present in >90% of cases and include aplasia or, more frequently, patellar hypoplasia (4). Recurrent superolateral subluxation or dislocation is common.
Even when not displaced, the hypoplastic patellae tend to be
positioned more superolateral than normal (6). There can also
From the Department of Diagnostic Radiology, Baylor University Medical Center
at Dallas, Dallas, Texas.
Corresponding author: James A. West, MD, Department of Diagnostic Radiology,
Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246
a
b
Figure 1. Imaging of the pelvis. (a) Radiograph of the anteroposterior pelvis demonstrates the presence of bilateral triangular osseous excrescences from the posterior
aspect of the ilia, known as iliac horns (arrows). (b) CT of the pelvis shows the bilateral iliac osseous excrescences (arrows) to emanate from the posterior body of
the ilia at the origin of the gluteus medius muscles.
Figure 2. Anteroposterior radiograph of the bilateral femurs shows both patellae
to be hypoplastic (arrows).
July 2015
be hypoplasia of the lateral femoral condyle resulting in a genu
valgus deformity.
Elbow dysplasia is also frequently encountered in NPS, having been described in >90% of patients (4). Most frequently the
radial heads, lateral epicondyles, and capitula are dysplastic with
recurrent, typically posterolateral, displacement of the radial
heads occurring in 61% of patients (4). Pterygia (webbing) may
also occur across the elbow.
Iliac horns, which are pathognomonic for NPS, only occur
in 70% to 80% of patients (2, 5). They are most often bilateral,
conical osseous excrescences that typically project dorsolaterally
from the posterior ilia and serve as the origin of the gluteus
medius muscles (5). On physical exam, these processes may be
palpable, although they are typically asymptomatic and have
no effect on gait (4). They can be identified as early as the third
trimester on a fetal ultrasound (6).
Other frequently encountered orthopedic features of NPS
that do not contribute to the diagnosis are shoulder girdle dysplasia, short stature, talipes equinovarus (club foot), calcaneovalgus feet, dislocation of the hips, Madelung’s deformity, and
large joint contractures.
Besides physical manifestations, there is also a strong
association with open-angle glaucoma and progressive
nephropathy (7). Nephropathy is reported to be present in
30% to 60% of patients, with progression to nephrotic syndrome in 20% and renal failure requiring dialysis and/or
transplant in approximately 10% (8). Open-angle glaucoma
occurs in 10% and ocular hypertension in 7% (4). There is
no cure for NPS, and treatment is directed towards addressing
the various orthopedic and nonorthopedic manifestations of
the disorder.
Radiographic findings in the nail-patella syndrome
335
a
b
Figure 3. Radiograph of the right elbow. (a) Anteroposterior radiograph demonstrates
dysplasia of the radial head (arrow), capitulum (asterisk), and lateral epicondyle
(arrowhead). (b) Lateral radiograph shows the radial head (arrow) to be inferiorly and
posteriorly dislocated.
1. Levy M, Feingold J. Estimating prevalence in single-gene kidney
diseases progressing to renal failure. Kidney Int 2000;58(3):925–943.
2. Mankin H. Nail-patella syndrome: hereditary onycho-osteodysplasia.
In Mankin H, ed. Pathophysiology of Orthopaedic Diseases. Rosemont,
IL: American Academy of Orthopaedic Surgeons, 2009:191–196.
3. Thompson EA, Walker ET, Weens HS. Iliac horns: an osseous manifestation of hereditary arthrodysplasia associated with dystrophy of the
fingernails. Radiology 1949;53(1):88–92.
4. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome.
Overview on clinical and molecular findings. Pediatr Nephrol
2002;17(9):703–712.
5. Fong EE. Iliac horns (symmetrical bilateral central posterior iliac processes). Radiology 1946;47(5):517.
336
6. Sweeney E, Hoover-Fong JE, McIntosh I. Nail-patella syndrome.
2003 [updated 2014 Nov 13]. In Pagon RA, Adam MP, Ardinger HH,
Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT,
Smith RJH, Stephens K, eds. GeneReviews® [Internet]. Seattle, WA:
University of Washington, 1993-2015. Available at http://www.ncbi.
nlm.nih.gov/books/NBK1132/
7. McIntosh I, Dunston JA, Liu L, Hoover-Fong JE, Sweeney E. Nail
patella syndrome revisited: 50 years after linkage. Ann Hum Genet
2005;69(Pt 4):349–363.
8. Granata A, Nori G, Ravazzolo R, Marini M, Castellino S, Sicurezza
E, Fiore CE, Mignani R. Nail-patella syndrome and renal involvement. Description of three cases and literature review. Clin Nephrol
2008;69(5):377–382.
Volume 28, Number 3
Solitary supratentorial Listeria monocytogenes brain abscess
in an immunocompromised patient
James A. West, MD, Anthony R. Onofrio, MD, Lauren C. Martinez, MD, Michael J. Opatowsky, MD, MBA, Cedric W. Spak,
MD, MPH, and Kennith F. Layton, MD, MS
We describe an 81-year-old man receiving azacitidine monotherapy for
myelodysplastic syndrome who was improving from Listeria monocytogenes bacteremia after receiving antibiotic therapy during an earlier
hospital admission. Shortly after discharge he developed new-onset
seizure activity, with brain imaging on subsequent admissions demonstrating a posterior right frontal lobe mass. Specimen cultures after
resection of the mass revealed this to be a cerebral abscess related to
L. monocytogenes. Brain abscesses related to this organism are rare.
L
isteria monocytogenes is a ubiquitous, opportunistic pathogen that rarely causes illness in healthy individuals. The
immunocompromised and those with underlying illness
are at greater risk for serious and potentially fatal infection. Approximately 20% of all listeriosis patients succumb to
infection despite early aggressive treatment, with particularly
elevated case fatality rates in those with comorbid illnesses and
in immunocompromised states (1–4). While L. monocytogenes
is a well-known cause of meningitis and encephalitis, brain abscesses related to this organism are rare and reported to occur in
only 10% of all Listeria central nervous system (CNS) infections
(4). Here we present the case of an immunocompromised man
who developed L. monocytogenes bacteremia and a subsequent
single supratentorial brain abscess.
CASE DESCRIPTION
An 81-year-old man with myelodysplastic syndrome was being treated with azacitidine monotherapy. He also had a remote
history of acute myelogenous leukemia in remission, medically
controlled atrial fibrillation, basal cell skin carcinoma resection,
and treated prostate cancer. For 1 week, the patient complained
only of intermittent fevers, reaching a maximum temperature
of 102.4°F, and mild fatigue. Four days after the onset of fevers,
blood cultures were drawn and he was started on levofloxacin
and later on amoxicillin clavulanate once Gram-positive rods
were isolated. Blood cultures grew L. monocytogenes, and the
patient was hospitalized.
He received intravenous piperacillin-tazobactam for 2 days.
When sensitivity tests revealed susceptibility to ampicillin, penicillin G, and trimethoprim sulfamethoxazole, the treatment
was changed to intravenous ampicillin, which continued for
his remaining 2 days in the hospital. Repeat blood cultures
were negative at the time of discharge and he was afebrile. The
patient was discharged home on continuous intravenous penicillin infusion. During the hospital admission there were no
specific neurologic complaints, headaches, or altered sensorium.
The morning after discharge, the patient had generalized
jerking movements and left facial droop that lasted approximately 10 minutes while he remained lucid. Two additional
seizure-like episodes occurred during transport to the emergency department. Noncontrast head computed tomography
(CT) demonstrated a mass in the right frontoparietal region.
Treatment with lorazepam and dexamethasone was initiated.
Subsequent contrast-enhanced magnetic resonance imaging
(MRI) of the brain showed a 2.2 cm rim-enhancing mass within
the posterior right frontal lobe with mild surrounding edema
(Figure 1). Intravenous ampicillin was restarted and levetiracetam treatment initiated. A 2-day posttreatment contrast-enhanced brain MRI demonstrated a slightly decreased volume of
the mass, a similar degree of edema, and imaging characteristics
most suggestive of an isolated cerebral abscess.
A right frontal craniotomy was performed and a purulent
cavity in the posterior right frontal lobe was resected. Specimens
revealed acute inflammation consistent with cerebritis/abscess,
although no organisms were identified by microscopy. Cultures
of the abscess fluid were positive for L. monocytogenes susceptible
to ampicillin, penicillin G, and trimethoprim sulfamethoxazole.
No additional seizures occurred, and the patient was discharged
on long-term intravenous ampicillin therapy, with surveillance
imaging 7 days after the abscess was resected.
DISCUSSION
L. monocytogenes is a ubiquitous, Gram-positive, facultative
intracellular bacterium that is typically acquired via food contamination (4). The groups considered at risk for listeriosis are pregnant
women and neonates, the elderly, and immunocompromised or
From the Department of Diagnostic Radiology (West, Onofrio, Opatowsky, Layton),
the Department of Internal Medicine (Martinez), and the Division of Infectious
Diseases (Spak), Baylor University Medical Center at Dallas.
Corresponding author: James A. West, MD, Department of Diagnostic Radiology,
Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246
337
a
b
c
Figure 1. Baseline contrast-enhanced brain MRI. (a) T1 post-gadolinium image shows a 2.2 cm rim-enhancing mass within the posterior right frontal lobe (arrow)
with surrounding edema. (b) Fluid-attenuated inversion recovery (FLAIR) image shows the rim of the mass to be hypointense (arrow) with a central core of heterogeneous signal. Increased signal within the subcortical white matter surrounding the mass reflects reactive vasogenic edema (arrowhead) that contributes to mild
local mass effect with partial sulcul effacement. (c) Diffusion-weighted imaging reveals restricted diffusion predominantly within the rim of the mass (arrow), with
less pronounced heterogeneous central diffusion restriction. (The confirmatory apparent diffusion coefficient [ADC] map is not shown.)
debilitated adults with underlying diseases (5). In nonpregnant
adults, most cases have been associated with solid and hematologic
malignancies, antineoplastic chemotherapy, immunosuppressant
therapy, chronic liver disease, kidney disease, diabetes, collagen
diseases, and HIV infection (5).
In the immunocompetent, gastrointestinal exposure to a
high inoculum of L. monocytogenes can result in a self-limited,
febrile diarrheal gastroenteritis with a median duration of
27 to 42 hours (6). In the immunocompromised, gastrointestinal invasion can lead to bacteremia and seeding to
various organs, with a particular predilection and invasive
efficiency for the CNS, where it can cause meningitis, meningoencephalitis, rhombencephalitis, or, much less commonly,
brain abscesses (5).
Brain abscesses constitute approximately 10% of all L.
monocytogenes CNS infections (4). Bacteremia is almost always
present, and concomitant meningitis with isolation of L. monocytogenes from the cerebrospinal fluid occurs in 25% to 40% of
brain abscess cases (4). Little information was available regarding the relative incidence of L. monocytogenes as the causative
bacterium of cerebral abscesses in general. In an 8-year prospective multiinstitutional study by Prasad et al, L. monocytogenes
was isolated from 0.8% of brain abscesses; however, this study
did not include an organ transplant population, which could
potentially constitute a significant number of patients who acquire Listeria brain abscesses (7). A retrospective study by Tattevin et al showed that L. monocytogenes accounted for 9% of
brain abscesses in patients admitted to the intensive care unit,
although patients with HIV were excluded from this study (8).
While L. monocytogenes is not the most common cause of
CNS infections, an epidemiologic study of bacterial meningitis
in the US in 1995 found that it is nearly 10-fold more efficient
than other neuroinvasive Gram-positive bacteria at invading
338
the CNS (9, 10). L. monocytogenes gains access to the CNS
by transporting across the blood-brain or blood-choroid barriers within circulating leukocytes by a phagocyte-facilitated
(Trojan horse) mechanism, direct invasion of blood-brain or
blood-choroid endothelial cells by extracellular blood-borne
bacteria, or retrograde migration into the brain within the axons
of cranial nerves (9).
Approximately 20% of all listeriosis patients succumb to
infection despite early aggressive treatment, with particularly elevated case fatality rates in those who are immunocompromised
or have an underlying illness or malignancy (1–4). Skogberg et al
demonstrated a 32% mortality in those with underlying disease
or in those receiving immunosuppressant medication, while no
deaths were observed in healthy patients (3). Goulet et al demonstrated up to 40% mortality among those with L. monocytogenes
bacteremia complicating a malignancy, with the highest incidence
of infection occurring in patients with chronic lymphocytic leukemia and liver cancer and the highest case fatality rate in those
with lung and pancreatic cancers (1). This high mortality rate
is at least in part due to L. monocytogenes being a facultative intracellular pathogen with the capability to infect adjacent cells
by direct extension through filopodia formation within the host
cell, allowing the bacterium to circumvent extended exposure to
the humoral immune response (9). This leaves the critical role
of pathogen elimination to T lymphocyte–mediated cytotoxicity, which is typically impaired in various physiologically and
pathologically immunocompromised states (9).
There are currently no large controlled trials comparing
treatments for listeriosis. Generally, ampicillin is considered the
treatment of choice (4). Gentamicin is often added to ampicillin
due to synergy that has been observed in vitro and in animal
models; however, its use in clinical practice is often debated (11).
In those with a penicillin allergy, trimethoprim sulfamethoxazole
Volume 28, Number 3
is considered an acceptable second-line treatment (12). Listeria is
often in part or fully resistant to cephalosporins, so they are
not typically recommended (13). Patients with a Listeria brain
abscess should receive treatment for at least 6 weeks and be followed by serial neurological imaging, with MRI as the preferred
modality (4).
6.
7.
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2.
3.
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Goulet V, Hebert M, Hedberg C, Laurent E, Vaillant V, De Valk H,
Desenclos JC. Incidence of listeriosis and related mortality among groups
at risk of acquiring listeriosis. Clin Infect Dis 2012;54(5):652–660.
Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system
infection with Listeria monocytogenes. 33 years’ experience at a general
hospital and review of 776 episodes from the literature. Medicine (Baltimore) 1998;77(5):313–336.
Skogberg K, Syrjänen J, Jahkola M, Renkonen OV, Paavonen J, Ahonen
J, Kontiainen S, Ruutu P, Valtonen V. Clinical presentation and outcome
of listeriosis in patients with and without immunosuppressive therapy.
Clin Infect Dis 1992;14(4):815–821.
Lorber B. Listeria monocytogenes. In Bennett J, Dolin R, Blaser M, eds.
Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases,
8th ed. Philadelphia, PA: Elsevier/Saunders, 2015:2383–2390.
Vázquez-Boland JA, Kuhn M, Berche P, Chakraborty T, DomínguezBernal G, Goebel W, González-Zorn B, Wehland J, Kreft J. Listeria
pathogenesis and molecular virulence determinants. Clin Microbiol Rev
2001;14(3):584–640.
July 2015
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Dalton CB, Austin CC, Sobel J, Hayes PS, Bibb WF, Graves LM,
Swaminathan B, Proctor ME, Griffin PM. An outbreak of gastroenteritis and fever due to Listeria monocytogenes in milk. N Engl J Med
1997;336(2):100–105.
Prasad KN, Mishra AM, Gupta D, Husain N, Husain M, Gupta RK.
Analysis of microbial etiology and mortality in patients with brain abscess.
J Infect 2006;53(4):221–227.
Tattevin P, Bruneel F, Clair B, Lellouche F, de Broucker T, Chevret S,
Bédos JP, Wolff M, Régnier B. Bacterial brain abscesses: a retrospective
study of 94 patients admitted to an intensive care unit (1980 to 1999).
Am J Med 2003;115(2):143–146.
Drevets DA, Bronze MS. Listeria monocytogenes: epidemiology, human
disease, and mechanisms of brain invasion. FEMS Immunol Med Microbiol
2008;53(2):151–165.
Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M,
Reingold AL, Lefkowitz L, Perkins BA; Active Surveillance Team.
Bacterial meningitis in the United States in 1995. N Engl J Med 1997;
337(14):970–976.
Edmiston CE Jr, Gordon RC. Evaluation of gentamicin and penicillin as
a synergistic combination in experimental murine listeriosis. Antimicrob
Agents Chemother 1979;16(6):862–863.
Michelet C, Avril JL, Cartier F, Berche P. Inhibition of intracellular growth
of Listeria monocytogenes by antibiotics. Antimicrob Agents Chemother
1994;38(3):438–446.
Hof H, Nichterlein T, Kretschmar M. Management of listeriosis. Clin
Microbiol Rev 1997;10(2):345–357.
Solitary supratentorial Listeria monocytogenes brain abscess in an immunocompromised patient
339
Asplenia and fever
Mitchell L. Huebner, MD, and Kristin A. Milota, RN, MSN
A 45-year-old-man presented with the abrupt onset of a fever over 30
years after surgical splenectomy. He presented with symptoms and
findings that seemed consistent with influenza. He rapidly developed
fulminant meningitis that resulted in his death.
P
neumococcal meningitis remains a devastating illness
with high mortality and morbidity despite all of the
advances in medical care. Pneumococcal meningitis has
been found in some studies to be over four times deadlier than other causes of bacterial meningitis in adults, and over
six times more likely to cause other poor outcomes (1). Survivors
of meningitis frequently are left with chronic neurologic deficits.
Streptococcus pneumoniae, otherwise known as pneumococcus,
is an encapsulated bacterial organism. Individuals who lack a
functional spleen are at higher risk for infection from encapsulated organisms. A person without a functional spleen is at risk
for postsplenectomy sepsis (PSS) and overwhelming infection,
including pneumococcal meningitis. They are also more likely
to have a devastating outcome despite current treatment options. Physicians and caregivers in the outpatient clinic setting
will rarely, if ever, see a patient presenting with PSS. As such,
primary caregivers are less familiar with the best practice guidelines associated with PSS than caregivers in the hospital setting.
CASE DESCRIPTION
A 45-year-old man who had a history of a splenectomy at
age 13 secondary to idiopathic thrombocytopenic purpura presented with the abrupt onset of a high fever, myalgias, fatigue,
loose stools, and headache. He had received an influenza vaccine
about 2 months earlier. His temperature was 102.3°F and blood
pressure, 110/74 mm Hg. He appeared sick, answered questions
appropriately, and had no nuchal rigidity; head, ear, eye, nose,
or throat abnormalities; rales or rhonchi; abdominal abnormalities; or evidence of dermal cellulitis. A rapid influenza test was
negative. He was sent home on oseltamivir with instructions
to call back if his clinical situation changed. The next day his
temperature was 99.4°F. He still had myalgias and mild diarrhea
and had developed a “puffiness” in his hands.
He became confused that night at home and was taken to the
emergency department. His blood pressure was 129/80 mm Hg
340
and heart rate, 76 beats per minute. He was in distress, moaning, combative, and not following commands, but had reactive
pupils, a supple neck, and no other abnormalities. Computed tomographic scan of the head revealed no apparent disease. A lumbar puncture was described by the emergency room physician as
having high opening pressure with cloudy fluid, and specifically
that the cerebrospinal fluid (CSF) “flew 3 feet with patient lying
on side.” The CSF had a protein of 425 mg/dL and a glucose
of <5 mg/dL. Gram stain revealed Gram-positive cocci in pairs.
Pneumococcal antigen was present.
Intravenous antibiotics (vancomycin and cephtriaxone) were
immediately started. He experienced respiratory arrest nearly
6 hours after arrival to the emergency department. He was intubated and ventilated, but cardiac arrest occurred. After several
rounds of cardiopulmonary resuscitation and the addition of
multiple cardiac vasopressor medications, his pulse was stable.
He was given ventilator support and intensive therapy, but never
regained consciousness and died 3 days later.
DISCUSSION
Streptococcus pneumoniae is the most common bacteria implicated in overwhelming PSS. Some studies have suggested it
might be responsible for as many as 90% of these devastating
infections (2). The initial infection leading to pneumococcal
meningitis usually presents with vague symptoms such as fever,
chills, malaise, headache, and various gastrointestinal symptoms. Bacterial meningitis often presents with only one of the
classic meningitis triad: a) fever, b) neck stiffness (i.e., nuchal
rigidity), and c) altered mental status. A delay in diagnosis and
treatment of meningitis can be devastating and fatal. Studies
have shown a triphasic progression to bacterial meningitis:
from a nonspecific illness phase to a bacteremic phase to finally
bacteremic seeding of the CNS and the meningitic phase (3).
Bonadio explained:
Symptoms characterizing each phase can be heterogenous, can
vary in type and duration, and are often of a ‘nonspecific’ nature
From Dallas Diagnostic Association Park Cities, Dallas, Texas (Huebner) and the
Department of Critical Care Services, Children’s Health System, Dallas, Texas (Milota).
Corresponding author: Mitchell L. Huebner, MD, Dallas Diagnostic Association
Park Cities, Health Texas Provider Network, 9101 N. Central Expressway, Suite
300, Dallas, TX 75231 (e-mail: [email protected]).
(e.g. fever, vomiting, alterations in behavior and activity) that
can mimic those indicative of less serious, nonmeningitic illnesses. The relatively more ‘specific’ symptoms of meningitis
(e.g. nuchal rigidity, bulging fontanelle, altered mental status/
neurologic deficit) are not invariably present, especially early
in the course of the infection (3).
These phases can progress more rapidly in patients without
a functional spleen, sometimes over the course of a few hours
rather than days. Our patient presented with only one symptom
of the classic meningitis triad (fever). He began showing mental
status changes about 36 hours after initial presentation. He was
never reported to have nuchal rigidity.
The patient was initially thought to have influenza. The
presentation of a variety of infections can mimic influenza,
especially in early phases. If the patient has not received an
influenza vaccine or has a positive rapid influenza test, one can
be more confident of the diagnosis; however, the absence of
either of these two does not rule out influenza as the causative
agent. The influenza vaccine’s effectiveness against influenza A
and B varies from 50% to 90%. The rapid influenza antigen
tests that are used in most primary care offices range in sensitivity from 10% to 70%. The Centers for Disease Control and
Prevention stated:
Negative results of [rapid influenza diagnostic tests] do not
exclude influenza virus infection in patients with signs and
symptoms suggestive of influenza. Therefore, antiviral treatment should not be withheld from patients with suspected
influenza, even if they test negative. While influenza vaccine
is the best way to prevent influenza, a history of influenza
vaccination does not rule out influenza virus infection in an
ill patient with clinical signs and symptoms compatible with
influenza (4).
Our patient had a splenectomy as a child, increasing his
risk of serious infection in the setting of a febrile illness. PSS
is most common in the first few years after a splenectomy,
but may appear even decades later. Current recommendations
for vaccines prior to a splenectomy call for a patient to receive a 13-valent pneumococcal conjugate vaccine (PCV13)
8 weeks prior, and then a pneumococcal polysaccharide vaccine
(PPSV23) at least 14 days prior to the surgery. A Haemophilus
influenza type b vaccine (Hib) and a quadrivalent meningococcal conjugate vaccine (MenACWY) should be given at least 14
days prior to the procedure in those who have not previously
been vaccinated for either of these organisms. It is also recommended that both children and adults without a functional
spleen be reimmunized 5 years after their initial vaccination
with a PPSV23, and again at the age of 65 (5). The MenACWY
should be repeated every 5 years after the splenectomy (5).
Yearly influenza immunizations are recommended. Asplenic
adults are not recommended to take prophylactic antibiotics,
but should have antibiotics available to them to “be taken at
the first sign of infection (increase in body temperature, malaise
or shivering) if the patient is unable to obtain prompt medical
attention. However, in such situations medical help should still
July 2015
be sought without delay” (6). “Prompt” medical attention is
defined as less than 2 hours (5).
In an emergency room or hospital setting, appropriate
evaluation and treatment for an asplenic febrile patient should
include a complete blood count with differential, blood culture
with Gram stain, arterial blood gas analysis, chest x-ray, and
consideration for lumbar puncture with CSF studies. None
of these evaluations should delay the initiation of appropriate
broad-spectrum intravenous antibiotics. The Surviving Sepsis
Campaign guidelines state that antibiotics should be administered in a patient suspected of sepsis within 1 hour of presentation (7). Delay in starting antibiotics for any reason is associated
with a poor outcome.
There is fairly clear understanding of the risks to asplenic
patients and of PSS among hospital specialists and hospitalbased physicians, most likely because of the frequency with
which they encounter these patients. Conversely, in the primary
care setting, experience and familiarity with these patients is
lower. A study published in the Journal of Clinical Pathology
“suggests a continuing broad failure to attain currently accepted
best practice in the management of asplenic patients” (8). Primary care literature has published very few articles reviewing the
risks to asplenic patients and of PSS. A review of the New England Journal of Medicine and the Journal of the American Medical
Association found only two articles related to PSS published in
the last 10 years (5, 9). The overwhelming majority of articles
related to these topics are published in surgical or specialty
literature. In this time of avoiding the overuse of antibiotics
due to the development of resistance, it is important to know
this important exception.
1.
2.
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M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351(18):1849–1859.
Moffett SL. Overwhelming postsplenectomy infection: managing patients
at risk. JAAPA 2009;22(7):36–39, 45.
Bonadio WA. Medical-legal considerations related to symptom duration and patient outcome after bacterial meningitis. Am J Emerg Med
1997;15(4):420–423.
Centers for Disease Control and Prevention. Notice to Clinicians: Early
Reports of pH1N1-Associated Illnesses for the 2013-14 Influenza Season.
CDC Health Alert Network, December 24, 2013. Available at http://
emergency.cdc.gov/han/han00359.asp; accessed April 27, 2015.
Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient.
N Engl J Med 2014;371(4):349–356.
Melles DC, de Marie S. Prevention of infections in hyposplenic and
asplenic patients: an update. Neth J Med 2004;62(2):45–52.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM,
Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally
ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman
CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL,
Moreno R; Surviving Sepsis Campaign Guidelines Committee including
the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care
Med 2013;41(2):580–637.
Waghorn DJ. Overwhelming infection in asplenic patients: current
best practice prevention measures are not being followed. J Clin Pathol
2001;54(3):214–218.
Gandhi TK, Zuccotti G, Lee TH. Incomplete care—on the trail of flaws
in the system. N Engl J Med 2011;365(6):486–488.
Asplenia and fever
341
Myroides odoratimimus bacteremia in a diabetic patient
Tiana R. Endicott-Yazdani, Neelam Dhiman, PhD, Raul Benavides, MD, and Cedric W. Spak, MD, MPH
Myroides species are a rare source of human infection. Though not part
of the human microbiota, Myroides species are commonly found in the
environment. Myroides infections are typically attributed to contact with
contaminated water; the most common presentation is in immunocompromised patients. We present a patient with a diabetic foot ulcer who subsequently developed Myroides odoratimimus bacteremia and bone abscess.
M
yroides odoratum and odoratimimus are gram-negative, nonmotile, obligate aerobic bacilli with yellow
pigmentation and a distinct fruity odor (1). Myroides species infect primarily immunocompromised
patients, often with diabetes mellitus, cirrhosis, chronic obstructive pulmonary disease, or prolonged corticosteroid therapy
(2–6); they are infrequent sources of bloodstream infections
(1, 7). This case describes Myroides odoratimimus bloodstream
infection in a patient with a chronic diabetic foot ulcer who
was exposed to freshwater sources.
CLINICAL PRESENTATION
A 75-year-old white man presented to the emergency department with a 2-day history of fever, chills, and concern of an
infected wound on his arm. The patient had taken a recent trip
to Colorado, where he went whitewater rafting and spent time
in a mineral spa. During the trip he slipped on a rock and fell
on his arm, causing an abrasion. Five days later, after returning
home, he developed a fever (up to 102°F), fatigue, and malaise,
treated with acetaminophen. He became concerned that his
arm could be the source of his infection. His temperature was
98.8°F; blood pressure, 118/57 mm Hg (sitting); heart rate,
62 beats/minute; and respiratory rate, 18 breaths/minute. Physical exam revealed a 3 cm abrasion on the right forearm with
mild erythema, minimal warmth, and no swelling or exudate
and a nontender ulcerated lesion on the right second toe with no
exudate. His white blood cell count was 12.5 K/µl. He received a
1 L 0.9% saline bolus, and blood cultures were collected. Lactate
results were initially 3.0 mmol/L and decreased to 2.0 mmol/L
when redrawn following the fluid bolus. He was discharged
with directions to follow up with his primary care physician.
Two days after discharge from the emergency department,
the blood cultures demonstrated gram-negative rods. The initial
342
identification of the culture revealed Myroides species. The patient was contacted and instructed to return to the hospital.
He was started on intravenous meropenem 500 mg every 6
hours and vancomycin 1500 mg every 12 hours. The patient
improved on the antibiotic regimen. He was also found to have
a chronic, nonhealing ulcer on his left second toe. The toe was
excised prior to discharge and cultures showed polymicrobial
growth of Myroides species along with multiple morphotypes
of coagulase-negative Staphylococcus species. He was discharged
2 days following his toe amputation.
Initial identification of Myroides species was performed using Matrix-assisted laser desorption ionization time-of-flight
(MALDI-TOF) on a VITEK MS system (bioMerieux, Nürtingen, Germany). Briefly, isolated bacterial colonies from blood
agar plates were smeared on the VITEK MS-DS target slide. The
smear was overlaid with 1 µL matrix solution and allowed to air
dry completely. Composite mass spectra of over 100 spectral
profiles were generated within the range of 2 to 20 kilodaltons
and probed using the Research-Use Only version of the VITEK
MS Plus database (SARAMISTM Knowledge Base v4.12) that
includes M. odoratimimus and M. odoratus. Species-level–only
identification was obtained at a 92.8% to 99.9% confidence
level at four different attempts. Definitive identification of M.
odoratimimus was accomplished via 16S rRNA sequencing using
subcultured isolates from the same plate at the reference testing
facility (ARUP Laboratories, Salt Lake City, UT).
DISCUSSION
The two most common Myroides species seen in humans
are odoratus and odoratimimus (8). The most common clinical
presentations are bacteremia, cellulitis, and isolated outbreaks
of urinary tract infections following exposure to a contaminated
water source or in the setting of trauma (8, 9). Infections are
rare but can occasionally be life-threatening (8). The less common Myroides species pelagicus, profundi, and marinus have been
From the Department of Internal Medicine (Endicott-Yazdani), the Department
of Pathology (Benavides), and the Division of Infectious Diseases (Spak), Baylor
University Medical Center at Dallas; and med fusion and ClearPoint Diagnostic
Laboratories, Lewisville, Texas (Dhiman, Benavides).
Corresponding author: Cedric W. Spak, MD, MPH, 3409 Worth Street, Suite
600, Dallas, TX 75246 (e-mail: [email protected]).
isolated from various seawater sources but have not to date been
documented as a source of infections in humans (10–12).
The traditional epidemiology of Myroides involves infection
of an immunocompromised host. While our patient appeared
clinically well, patients with diabetes are well documented to
be relatively immunocompromised compared with nondiabetic patients. The most common types of patients infected
with Myroides species (M. odoratus and odoratimimus) are immunocompromised or have end-stage renal disease, cirrhosis,
chronic obstructive pulmonary disease, neoplasms, or heart
diseases (4–7, 9, 13–16). While M. odoratus infections in diabetics have been documented, to our knowledge, ours is the
first documented case of M. odoratimimus in a diabetic patient
(14, 16). Of the five documented reports of M. odoratimimus
infections, two involved nosocomial outbreaks of urinary tract
infections in the setting of urinary stones or cancer (9, 17).
Another report documented bacteremia and cellulitis in a patient with alcoholic cirrhosis (13). The next report involved an
otherwise healthy elderly man who experienced severe trauma
from a farming accident that caused septic shock, pneumonia,
and soft tissue infection (8). The last report was of a child who
suffered a pig bite and subsequently developed cellulitis (1). In
our case, the primary portal of entry and source of infection
was felt to be the second left toe, after exposure of that open
wound to a presumably contaminated water source, either the
natural thermal mineral spa or the river. Subsequently, there
was hematogenous spread of M. odoratimimus from the infected
nonhealing chronic ulcer.
Although antibiotics appeared to clinically resolve the
Myroides bloodstream infection, the patient’s left second toe
was still amputated due to a chronic nonhealing ulcer that was
felt to pose a risk for future infections. Cultures of the left
toe revealed Staphylococcus epidermidis in the bone as well as
coagulase-negative Staphylococcus and Myroides spp. from an
abscess in the toe. While the patient was initially concerned that
the arm abrasion was the cause of infection, that was unlikely
given the Myroides abscess found in the left second toe.
1.
Maraki S, Sarchianaki E, Barbagadakis S. Myroides odoratimimus soft tissue
infection in an immunocompetent child following a pig bite: case report
and literature review. Braz J Infect Dis 2012;16(4):390–392.
July 2015
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Holmes B, Snell JJ, Lapage SP. Flavobacterium odoratum: a species
resistant to a wide range of antimicrobial agents. J Clin Pathol
1979;32(1):73–77.
Winn WC, Koneman EW, Allen SD, Procop GW, Janda WM,
Schreckenberger PC. The nonfermentative gram-negative bacilli.
In Koneman’s Colour Atlas and Textbook of Diagnostic Microbiology.
Philadelphia: Lippincott Williams and Wilkins, 2006:304–391.
Hsueh PR, Wu JJ, Hsiue TR, Hsieh WC. Bacteremic necrotizing fasciitis
due to Flavobacterium odoratum. Clin Infect Dis 1995;21(5):1337–1338.
Bachman KH, Sewell DL, Strausbaugh LJ. Recurrent cellulitis and bacteremia caused by Flavobacterium odoratum. Clin Infect Dis 1996;22(6):1112–
1113.
Green BT, Green K, Nolan PE. Myroides odoratus cellulitis and bacteremia:
case report and review. Scand J Infect Dis 2001;33(12):932–934.
Ferrer C, Jakob E, Pastorino G, Juncos LI. Right-sided bacterial endocarditis due to Flavobacterium odoratum in a patient on chronic hemodialysis.
Am J Nephrol 1995;15(1):82–84.
Benedetti P, Rassu M, Pavan G, Sefton A, Pellizzer G. Septic shock, pneumonia, and soft tissue infection due to Myroides odoratimimus: report of
a case and review of Myroides infections. Infection 2011;39(2):161–165.
Yağci A, Cerikçioğlu N, Kaufmann ME, Malnick H, Söyletir G, Babacan F, Pitt TL. Molecular typing of Myroides odoratimimus (Flavobacterium odoratum) urinary tract infections in a Turkish hospital. Eur J Clin
Microbiol Infect Dis 2000;19(9):731–732.
Yoon J, Maneerat S, Kawai F, Yokota A. Myroides pelagicus sp.
nov., isolated from seawater in Thailand. Int J Syst Evol Microbiol
2006;56(Pt 8):1917–1920.
Zhang XY, Zhang YJ, Chen XL, Qin QL, Zhao DL, Li TG, Dang HY,
Zhang YZ. Myroides profundi sp. nov., isolated from deep-sea sediment of
the southern Okinawa Trough. FEMS Microbiol Lett 2008;287(1):108–
112.
Cho SH, Chae SH, Im WT, Kim SB. Myroides marinus sp. nov., a member of the family Flavobacteriaceae, isolated from seawater. Int J Syst Evol
Microbiol 2011;61(Pt 4):938–941.
Bachmeyer C, Entressengle H, Khosrotehrani K, Goldman G, Delisle F,
Arlet G, Grateau G. Cellulitis due to Myroides odoratimimus in a patient
with alcoholic cirrhosis. Clin Exp Dermatol 2008;33(1):97–98.
Motwani B, Krezolek D, Symeonides S, Khayr W. Myroides odoratum
cellulitis and bacteremia: a case report. Infect Dis Clin Pract 2004;
12(6):343–344.
Spanik S, Trupl J, Krcmery V. Nosocomial catheter-associated Flavobacterium odoratum bacteraemia in cancer patients. J Med Microbiol
1998;47(2):183.
Prieur D, Colombani JC, Michelon G. Bacteriemie a Flavobacterium
odoratum. Med Mal Infect 1988;18(10):466–467.
Ktari S, Mnif B, Koubaa M, Mahjoubi F, Ben Jemaa M, Mhiri MN,
Hammami A. Nosocomial outbreak of Myroides odoratimimus urinary
tract infection in a Tunisian hospital. J Hosp Infect 2012;80(1):77–81.
Myroides odoratimimus bacteremia in a diabetic patient
343
Right-sided hydropneumothorax as a presenting symptom
of Boerhaave’s syndrome (spontaneous esophageal rupture)
Supannee Rassameehiran, MD, Saranapoom Klomjit, MD, and Kenneth Nugent, MD
Boerhaave’s syndrome, or spontaneous esophageal rupture, is a rare
condition that classically presents with Mackler’s triad of vomiting, subcutaneous emphysema, and severe sudden onset of chest pain and
requires immediate medical attention. Approximately 90% of the perforations occur at the left lateral aspect of the distal esophagus, causing
a left-sided pleural effusion. Less than 10% of patients have bilateral
effusions, and few patients have a right-sided pleural effusion only. We
present the case of a 59-year-old man with spontaneous esophageal
rupture. His clinical presentation is of interest since he had no inciting
event for spontaneous esophageal rupture and had a delayed presentation with a right-sided hydropneumothorax.
B
oerhaave’s syndrome, or spontaneous esophageal rupture, is a life-threatening condition that requires prompt
diagnosis and treatment. Delayed diagnosis may result
in serious complications, including mediastinitis, pneumonitis, pericarditis, empyema, and death. We report an atypical presentation of Boerhaave’s syndrome with no vomiting,
with progressive right-sided chest pain and shortness of breath of
2 weeks’ duration, and with a right-sided hydropneumothorax.
CASE REPORT
A 59-year-old man with a history of hypertension presented with worsening right-sided chest pain and progressive
shortness of breath of 2 weeks’ duration. The patient had
reported mild constant right-sided chest pain over the past
year. The chest pain was pleuritic in nature. He denied fevers,
chills, productive cough, nausea, and vomiting. The patient
had a history of upper gastrointestinal bleeding 4 months
prior to presentation while taking meloxicam. He underwent
esophagogastroduodenoscopy, which showed benign esophageal ulcers in the middle thoracic esophagus from 26 to 29 cm
and in the distal esophagus from 33 to 36 cm, as well as
chronic gastritis. He took oral omeprazole 20 mg twice a day
and stopped taking meloxicam. He started to take one or
two 7.5 mg tablets of meloxicam a day to relieve the chest
pain without taking omeprazole for 1 week before his current
presentation. He denied reflux symptoms, a history of heavy
lifting or straining, a history of chest trauma, peptic ulcer
disease, or alcohol or steroid use.
344
His blood pressure was 114/66 mm Hg; heart rate, 123 beats/
min; respiratory rate, 21 breaths/min; and temperature, 36.7°C
(98°F). His body mass index was 20.3 kg/m2. The jugular veins
were not distended. Breath sounds were decreased in the right
lower field, with corresponding dullness on percussion. There was
no murmur, subcutaneous emphysema, or Hamman’s crunch.
The abdomen was soft without tenderness. The bowel sounds
were normal. Initial laboratory tests revealed the following: white
blood cell count, 26,570/μL with 95% polymorphonuclear cells;
hemoglobin, 10.7 g/dL; blood urea nitrogen, 31 mg/dL; creatinine, 0.9 mg/dL; and albumin, 2.7 g/dL. All other laboratory
results were unremarkable. His initial chest radiograph revealed
a right-sided hydropneumothorax (Figure 1).
A thoracostomy tube was placed into the right chest, resulting in the drainage of 1 L of brownish purulent material. Pleural
fluid analysis showed a pH of 7.2. Gram stain of the pleural
fluid showed a few white blood cells; many Gram-positive cocci
in pairs, chains, and clusters; moderate Gram-positive rods;
few Gram-negative rods; and few yeast. Computed tomography (CT) of the chest revealed moderate right pleural effusion,
small right pneumothorax, consolidation/atelectasis in the right
lower lobe with air bronchograms, and thickening of the distal
esophagus and gastroesophageal junction.
The patient had video-assisted thorascopic surgery 2 days
after admission. Gastrointestinal contents were found in the
pleural cavity. At this point, the diagnosis of Boerhaave’s syndrome was suspected, and the procedure was converted to an
open thoracotomy. The patient had a hiatal hernia and a distal
esophagus perforation measuring approximately 2.5 cm. A distal esophageal resection and gastrostomy tube placement were
performed. The biopsy report of the distal esophagus showed
intestinal metaplasia and ulcer without dysplasia or malignancy.
The patient’s postoperative course was complicated by sepsis
and acute renal failure. The pleural culture grew Citrobacter
freundii; blood cultures were negative. He was continued on
meropenem and fluconazole. His renal function returned to
From the Department of Internal Medicine, Texas Tech University Health Science
Center, Lubbock, Texas.
Corresponding author: Supannee Rassameehiran, MD, Department of Internal
Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock,
TX 79430 (e-mail: [email protected]).
Figure 1. Chest radiograph demonstrates right hydropneumothorax.
normal. The chest tubes, drains, and gastrostomy tube were
discontinued, and the patient was discharged on day 19 of
admission.
DISCUSSION
Boerhaave’s syndrome is a rare condition, with an incidence
of 7.4 per 10 million per year (1). It is associated with substantial morbidity and has a mortality rate of at least 20% (1–3).
This condition is caused by an acute increase in intraluminal
esophageal pressure as the result of retching or vomiting causing
perforation at the weak point of the esophageal wall, which is
the left posterolateral wall of the distal esophagus (4). There are
anatomical reasons to explain this location, including thinning
of the muscle in the distal esophagus, weakening of its wall as
a result of vessels and nerves entering it, anterior angulation
at the left diaphragmatic crus, and lack of adjacent support-
ing structures (5). The classical clinical presentation, Meckler’s
triad, is severe vomiting and retching followed by severe sudden
onset of chest pain and subcutaneous emphysema (6). However,
some reviews point out that the presence of the entire triad is
rare, and reliance on a classic presentation may lead to delayed
diagnosis, resulting in mediastinitis, pneumonitis, pericarditis,
empyema, and increased mortality (5, 7).
Mediastinal pleura rupture from acute intraabdominal
pressure elevation or digestion by gastric contents will lead to
leakage of air and fluid into the pleural space, causing pleural
effusion, pneumothorax, or hydropneumothorax. Approximately 90% of patients have left-sided pleural effusions, 5%
to 10% of patients have bilateral effusions, and few patients
have an effusion on the right side only (8). Only five cases
have been reported to present with right-sided effusions in the
past 10 years (Table 1) (9–12).
Table 1. Patients with spontaneous esophageal perforation who presented with right-sided pleural effusions, 2005 to 2015
First author,
year of
publication (ref)
Age
(years) Gender
Underlying disease
Vomiting
Days from
prior to
Perforation presentation
presentation
length
to diagnosis
Treatment
Outcome
Rokszin, 2011 (9)
53
Male
GERD, BE, rectal cancer
Yes
5–7 mm
–
Endoscopic closure
Survived
Hingston, 2010 (10)
84
Female
Osteopenia treated with
alendronic acid 5 h before
presentation
Yes
6 cm
3
Gastric port and bilateral
chest tube drainage
Survived
Cascio, 2010 (11)
45
Female
Alcoholism, pregnancy
No
–
8
Right chest tube drainage;
Died
primary repair of esophagus
Khan, 2005 (12)
61
Male
Spontaneous esophageal
rupture 26 mo earlier, BE
Yes
2 cm
–
Primary repair of esophagus Survived
Khan, 2005 (12)
51
Male
Spontaneous esophageal
rupture 27 mo earlier, BE
Yes
3 cm
–
Conservative treatment
Survived
BE indicates Barrett esophagus; GE, gastroesophageal; GERD, gastroesophageal reflux disease; –, no information available.
July 2015
Right-sided hydropneumothorax as a presenting symptom of Boerhaave’s syndrome
345
The diagnosis of Boerhaave’s syndrome is made primarily
from clinical presentation and radiographic evidence. A posteroanterior and lateral chest radiograph is the best method to
see indirect signs of esophageal perforation, since up to 90% of
patients have abnormal chest x-ray findings, including pleural
effusion, pneumothorax, hydropneumothorax, pneumomediastinum, widening mediastinum, and subcutaneous emphysema.
However, an immediate chest x-ray after esophageal perforation
may be normal, as a pneumomediastinum will take at least an
hour to develop and a pleural effusion may take several hours
to become discernable (13). A water-soluble contrast swallow
study is recommended to confirm the diagnosis by showing
leakage of contrast into the mediastinum and/or pleural cavity
and to identify the anatomical site of perforation. CT of the
chest and upper abdomen with oral contrast can also show
the site of perforation and the degree of contamination. Given
current access to CT and oral contrast studies, the diagnosis of
esophageal rupture was missed and found only at autopsy in
only 17% of patients in a recent study (1).
Early recognition and operative repair are the mainstays of
treatment and provide better outcomes. Dasari and colleagues
summarized 27 case series using esophageal stents in patients
with esophageal anastomotic leaks and benign perforations.
These series included 340 patients, and technical and clinical
success rates with stenting were 91% and 81%, respectively.
However, 187 patients required thoracotomy procedures, including chest tubes and surgery (14). Salo reported his experience with Boerhaave’s syndrome over a three-decade period. His
approach includes early antibiotics, a CT study of the thorax
and upper abdomen, emergency endoscopy to evaluate the
rupture and tissue vitality, and primary esophageal repair with
fundic reinforcement when possible. Mortality has fallen from
50% to 5%; all aspects of current management appear to have
contributed to this improvement (15). Conservative treatment
can be an option for selected patients with small and contained
intrathoracic esophageal ruptures (16). Unusual presentations
should be kept in mind while evaluating patients with hydropneumothorax, even on the right side.
The only risk factor that might explain esophageal rupture
in our patient is nonsteroidal antiinflammatory drug use with a
history of esophageal ulcer when he was taking this drug in the
346
past. Our patient had a delayed presentation with a right-sided
hydropneumothorax, required surgery, and had a prolonged
19-day hospital course.
1.
2.
3.
4.
5.
6.
7.
8.
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Vidarsdottir H, Blondal S, Alfredsson H, Geirsson A, Gudbjartsson
T. Oesophageal perforations in Iceland: a whole population study on
incidence, aetiology and surgical outcome. Thorac Cardiovasc Surg
2010;58(8):476–480.
Ryom P, Ravn JB, Penninga L, Schmidt S, Iversen MG, Skov-Olsen P,
Kehlet H. Aetiology, treatment and mortality after oesophageal perforation
in Denmark. Dan Med Bull 2011;58(5):A4267.
Bhatia P, Fortin D, Inculet RI, Malthaner RA. Current concepts in the
management of esophageal perforations: a twenty-seven year Canadian
experience. Ann Thorac Surg 2011;92(1):209–215.
Garas G, Zarogoulidis P, Efthymiou A, Athanasiou T, Tsakiridis K,
Mpaka S, Zacharakis E. Spontaneous esophageal rupture as the underlying cause of pneumothorax: early recognition is crucial. J Thorac Dis
2014;6(12):1655–1658.
Jagminas L, Silverman RA. Boerhaave’s syndrome presenting with abdominal
pain and right hydropneumothorax. Am J Emerg Med 1996;14(1):53–56.
Curci JJ, Horman MJ. Boerhaave’s syndrome: the importance of early
diagnosis and treatment. Ann Surg 1976;183(4):401–408.
Jones WG 2nd, Ginsberg RJ. Esophageal perforation: a continuing challenge. Ann Thorac Surg 1992;53(3):534–543.
Janjua KJ. Boerhaave’s syndrome. Postgrad Med J 1997;73(859):265–270.
Rokszin R, Simonka Z, Paszt A, Szepes A, Kucsa K, Lazar G. Successful
endoscopic clipping in the early treatment of spontaneous esophageal
perforation. Surg Laparosc Endosc Percutan Tech 2011;21(6):e311–312.
Hingston CD, Saayman AG, Frost PJ, Wise MP. Boerhaave’s syndrome—
rapidly evolving pleural effusion: a radiographic clue. Minerva Anestesiol
2010;76(10):865–867.
Cascio A, Barone M, Micali V, Iaria C, Delfino D, David A, Monaco
M, Monaco F. On a fatal case of Candida krusei pleural empyema in a
pregnant woman with spontaneous esophagus perforation. Mycopathologia
2010;169(6):451–455.
Khan OA, Barlow CW, Weeden DF, Amer KM. Recurrent spontaneous
esophageal rupture. Eur J Cardiothorac Surg 2005;28(1):178–179.
Wu JT, Mattox KL, Wall MJ Jr. Esophageal perforations: new perspectives
and treatment paradigms. J Trauma 2007;63(5):1173–1184.
Dasari BV, Neely D, Kennedy A, Spence G, Rice P, Mackle E, Epanomeritakis E. The role of esophageal stents in the management of esophageal anastomotic leaks and benign esophageal perforations. Ann Surg
2014;259(5):852–860.
Salo J, Sihvo E, Kauppi J, Rasanen J. Boerhaave’s syndrome: lessons learned
from 83 cases over three decades. Scand J Surg 2013;102(4):271–273.
Cameron JL, Kieffer RF, Hendrix TR, Mehigan DG, Baker RR. Selective
nonoperative management of contained intrathoracic esophageal disruptions. Ann Thorac Surg 1979;27(5):404–408.
Volume 28, Number 3
Pneumomediastinum in inflammatory bowel disease
Nino Mihatov, MD, and Andrew Z. Fenves, MD
A 28-year-old man with a history of inflammatory bowel disease (IBD)
developed sudden-onset chest pain and dyspnea 9 days after esophagogastroduodenoscopy and colonoscopy. A chest radiograph demonstrated
pneumomediastinum tracking along the left heart border. The spontaneous
pneumomediastinum was presumed to be a complication of his severe colitis. The severity of our patient’s symptoms ultimately necessitated a subtotal
colectomy, a decision unrelated to the pneumomediastinum. IBD-associated
pneumomediastinum can be attributed to retroperitoneal air leakage from
severe colitis and usually resolves with conservative management.
P
neumomediastinum, often associated with diseases of
or traumatic injury to the airway, is a rare complication
of inflammatory bowel disease (IBD). In IBD, pneumomediastinum is most frequently a procedural complication associated with esophageal microperforation during
esophagogastroduodenoscopy or colonic perforation during
colonoscopy (1). We present a patient with severe IBD who
developed spontaneous pneumomediastinum.
CASE REPORT
A 28-year-old man with an 11-month history of IBD presented
to an outside hospital with 6 weeks of fatigue, severe abdominal
pain, diarrhea, and hematochezia. He was treated for an IBD flare
with corticosteroids, mesalamine, and infliximab. He underwent
a flexible sigmoidoscopy that demonstrated extensive rectal inflammation and ulceration suggestive of ulcerative colitis. After 3
weeks of persistent symptoms, he was transferred to our hospital
for further management and surgical evaluation. Prior to his admission, he was taking mesalamine, prednisone, and hydrocortisone
enemas. He was a graduate student who occasionally drank alcohol
but had never smoked or used illicit substances. He had no known
drug allergies. His family history was notable for colon cancer in
his paternal grandfather and liver cancer in his maternal uncle.
On admission to our hospital, he was afebrile, with a heart
rate of 84 beats/minute, blood pressure of 100/60 mm Hg, and
oxygen saturation of 94% on room air. He appeared uncomfortable and was vomiting. His cardiopulmonary examination disclosed no abnormalities. His abdomen was mildly distended and
tender to palpation without organomegaly. Rectal examination
revealed few external hemorrhoids without fissures or masses.
The patient’s hemoglobin was 8.1 g/dL and the hematocrit
was 24.5%. His white blood cell count, platelet count, basic
chemistries, prothrombin time, and partial thromboplastin time
were normal. The serum albumin was 2.5 g/dL. The serum iron
was 17 mcg/dL, iron binding capacity was 212 mcg/dL, and
ferritin was 16 ng/mL. A chest radiograph was normal.
On hospital day 2, the patient underwent an esophagogastroduodenoscopy that demonstrated a normal esophagus,
stomach, and duodenum. Colonoscopy with biopsy revealed
severe inflammation from the rectum to the transverse colon
and discontinuously in the cecum in a pattern suggestive of
Crohn’s disease. Corticosteroids and infliximab were continued.
On day 11 of hospitalization, 9 days after the procedure, the
patient developed sudden-onset chest pain and dyspnea. He was
no longer vomiting and had not been retching or coughing. The
chest pain worsened with positional changes and inspiration.
He remained hemodynamically stable. Examination of the chest
revealed palpable subcutaneous crepitus over both sternoclavicular joints. Lungs were clear to auscultation bilaterally. An
anteroposterior chest radiograph showed pneumomediastinum
tracking along the left cardiac border and superiorly in the bilateral soft tissues of the upper mediastinum and neck (Figure 1a).
A barium swallow study revealed a normally distensible
esophagus with no areas of abnormal contrast retention or
extravasation (Figure 2). Computed tomography (CT) of the
chest with oral contrast demonstrated contrast in the esophagus
without obvious defect of the esophageal wall or extravasation
of esophageal contrast (Figure 3). Further CT of the abdomen
with oral and intravenous contrast demonstrated mild wall
thickening of the distal descending and rectosigmoid colon
with pericolonic stranding consistent with inflammatory bowel
disease. The small bowel was normal. There was no evidence of
toxic megacolon or retroperitoneal free air.
With cessation of oral intake and intravenous broadspectrum antibiotics, the chest pain and dyspnea decreased.
Radiographically, the patient had progressive reduction in the
From the Department of Medicine, Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts.
Corresponding author: Nino Mihatov, MD, Massachusetts General Hospital,
Harvard Medical School, Department of Medicine, 55 Fruit Street, GRB 740,
Boston, MA 02114 (e-mail: [email protected]).
347
a
b
Figure 1. Chest radiograph (a) at the onset of symptoms, with mediastinal air (white arrows) evident along the left heart border and upper mediastinum, and
(b) 9 days later, with resolution of the previously demonstrated pneumomediastinum.
degree of mediastinal air with resolution by day 9 following the
onset of symptoms (Figure 1b).
The patient continued to have abdominal pain refractory to
medical therapy. A repeat flexible sigmoidoscopy demonstrated worse
colitis compared to the prior colonoscopy. The patient underwent
an uncomplicated laparoscopic subtotal colectomy with ileostomy
on hospital day 16. He was discharged on day 21. Pathology of the
excised colon revealed severely active chronic colitis without dysplasia
or granulomas. There was no evidence of colonic perforation.
Figure 2. Barium swallow study at the time of symptom onset demonstrating
contrast in the esophagus and gastric fundus without evidence of contrast extravasation or esophageal wall defect.
348
DISCUSSION
Pneumomediastinum is an overall rare finding characterized by free air within the mediastinum. Some principal causes
include 1) blunt trauma to the chest; 2) increased alveolar
pressure and rupture from coughing, straining, emesis, or
positive pressure ventilation; 3) gas-forming organisms driving
an infectious process in the neck, chest, or oropharynx; and 4) a
complication from esophageal or colonic instrumentation and
subsequent perforation (1–4).
Spontaneous pneumomediastinum is defined by the absence
of a clear inciting cause for mediastinal air accumulation. There
are nine reported cases of spontaneous pneumomediastinum in
association with inflammatory bowel disease, most commonly
ulcerative colitis, and in the absence of evidence of perforation (5–12). In our patient who was not coughing or actively
vomiting and had no underlying lung disease or perforation of
a viscous, the spontaneous pneumomediastinum was thought
to be a complication of his severe colitis.
Symptoms of pneumomediastinum include dyspnea, chest
pain, and neck pain. Examination often reveals subcutaneous
crackling in the neck and cervical soft tissue reflective of free air
(13). Pneumomediastinum can be diagnosed with plain chest
radiographs and confirmatory CT. Identifying the cause of the
pneumomediastinum can prove difficult.
In IBD, severe inflammation facilitates forcible herniation
of colonic mucosa, allowing microscopic perforations to develop
that are permeable to air (7). The risk of colonic perforation in
patients with ulcerative colitis, in particular, has been correlated
to the severity of symptoms (14).
The retroperitoneum communicates with the mediastinum
and subcutaneous tissue through the visceral space, one of three
described compartments of the neck (4). The visceral space follows
the trachea and esophagus into the chest and creates a tract for air
between the mediastinum and the neck. The space continues inferiorly through the diaphragmatic hiatus into the retroperitoneum.
Volume 28, Number 3
a
b
Figure 3. (a) Axial and (b) coronally reformatted CT images of the chest with intravenous contrast and oral contrast ingested at the time of image acquisition. Oral
contrast is seen in the distal esophagus with no evidence of extravasation (black arrow). Mediastinal air is seen throughout the mediastinum, particularly along the
heart border with extension to the soft tissue of the neck (white arrows).
The overall rarity of pneumomediastinum makes validating an
optimal management strategy difficult. In general, management of
pneumomediastinum requires surgical correction of any mucosal
disruption, treatment of any infectious causes, and elimination of
contributors to increased alveolar pressure such as bronchospasm
or positive-pressure ventilation (4). In spontaneous pneumomediastinum, nonoperative management is often most effective (2,
15, 16). In IBD-associated pneumomediastinum, management
of IBD symptoms has been reported to result in resolution of
mediastinal air (6, 8, 11, 12). Although the decision to pursue
surgery in this case was unrelated to the pneumomediastinum,
persistent pneumomediastinum may reflect a severe degree of
colitis that may necessitate surgical intervention.
Pneumomediastinum should be considered in a patient
with severe IBD symptoms who acutely develops pleuritic
chest pain and dyspnea. An exhaustive search for a primary
cause of pneumomediastinum, most notably colonic or esophageal perforation following instrumentation, should be undertaken. In the absence of a clear cause, pneumomediastinum
can be attributed to retroperitoneal air leakage from severe
colitis and should resolve with conservative management.
1.
2.
3.
Cappello M, Randazzo C, Peralta S, Cocorullo G. Subcutaneous emphysema, pneumomediastinum and pneumoperitoneum after diagnostic colonoscopy for ulcerative colitis: a rare but possible complication in patients
with multiple risk factors. Int J Colorectal Dis 2011;26(3):393–394.
Park NS, Choi JH, Lee DH, Kim YJ, Kim ES, Jung SW, Koo JS, Lee HS,
Lee SW. Pneumoretroperitoneum, pneumomediastinum, pneumopericardium, and subcutaneous emphysema after colonoscopic examination. Gut
Liver 2007;1(1):79–81.
Dehal A, Tessier DJ. Intraperitoneal and extraperitoneal colonic perforation following diagnostic colonoscopy. JSLS 2014;18(1):136–141.
July 2015
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in ulcerative colitis complicated by pneumomediastinum: report of two
cases. Gastroenterology 1980;79(3):559–562.
Annaházi A, Polyák I, Nagy F, Wittmann T, Molnár T. “Ulcerative
crepitus”—a case with subcutaneous emphysema and pneumomediastinum without colonic perforation or toxic megacolon in ulcerative colitis
successfully treated conservatively. J Crohns Colitis 2012;6(6):717–719.
Cohen ME, Kleinman MS. Pneumomediastinum during relapse of
ulcerative colitis. Am J Gastroenterol 1997;92(12):2306–2307.
Martín Castillo A, Pons Miñano JA, Riquelme Riquelme J, Parrilla Paricio
P. Retroperitoneal perforation, pneumomediastinum and subcutaneous emphysema in severe ulcerative colitis. Gastroenterol Hepatol 2003;26(4):275.
Badina L, Ferrara G, Guastalla P, Barbi E. A precordial rub in a boy with
a severe attack of ulcerative colitis. Pediatr Emerg Care 2014;30(4):268.
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2001;25(12):1121–1123.
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Rananavare R, Kalro RH. Retroperitoneal perforation in ulcerative colitis with mediastinal and subcutaneous emphysema. J Clin Gastroenterol
1997;25(2):453–455.
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and subcutaneous emphysema in a child with ulcerative colitis. Pediatr
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Baumann MH, Sahn SA. Hamman’s sign revisited. Pneumothorax or
pneumomediastinum? Chest 1992;102(4):1281–1282.
De Dombal FT, Watts JM, Watkinson G, Goligher JC. Intraperitoneal perforation of the colon in ulcerative colitis. Proc R Soc Med
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Pneumomediastinum in inflammatory bowel disease
349
Pulmonary veno-occlusive disease as a cause of pulmonary
arterial hypertension
Mateo Porres-Aguilar, MD, Ihsan Al-Bayati, MD, Mateo Porres-Muñoz, MD, Osvaldo Padilla, MD, Saad H. Syed, MD,
Kevin Lowder, Komola Azimova, Jerry Fan, Debabrata Mukherjee, MD, and Aamer Abbas, MD
Pulmonary veno-occlusive disease (PVOD) represents a rare form of
precapillary pulmonary arterial hypertension. We present a young patient
hospitalized with progressive dyspnea, with initial workup suggestive of
pulmonary hypertension and unexplained noncardiogenic pulmonary
edema. His subsequent clinical course was consistent with the diagnosis
of PVOD.
Pulmonary veno-occlusive disease (PVOD) represents an
uncommon form of pulmonary arterial hypertension (PAH)
characterized by progressive obliteration of the pulmonary venules, elevation of pulmonary arterial pressures, and increased
pulmonary vascular resistance, leading to right ventricular failure and death (1–3). PVOD shares similar characteristics with
idiopathic PAH, which can easily lead to misdiagnosis among
these two entities. Based on data from the French pulmonary
hypertension registry, the annual incidence of PVOD is low (4).
A less-invasive diagnostic approach utilizing high-resolution
computed tomography (CT) of the chest, arterial blood gases,
pulmonary function tests, and appropriate hemodynamic interpretation of right-sided heart catheterization could be useful
for the detection of PVOD (2).
CASE PRESENTATION
A 19-year-old man was brought to the hospital by his mother
in an acute confusional state after being found lying on the floor
and responding slowly to verbal and tactile stimuli. According
to his mother, the patient had smoked spice (herbal mixtures of
synthetic cannabinoid compounds) and complained of progressive dyspnea for the past 3 months. He smoked cigarettes, weed,
and spice and drank alcohol. On admission he was hypoxic,
with an oxygen saturation of 84% on room air. He had clubbing
of fingernails and an accentuated second pulmonic heart sound.
A chest radiograph showed enlarged pulmonary arteries and
mild interstitial prominence (early pulmonary edema). A 12lead electrocardiogram showed right axis deviation, incomplete
right bundle branch block, and right ventricular hypertrophy.
A CT scan of the chest with contrast showed diffuse bilateral
confluent ground-glass opacities, septal line thickening with
bilateral small pleural effusions, a mildly enlarged right atrium,
mildly enlarged mediastinal and hilar lymphadenopathies, and
350
a dilated pulmonary trunk (Figure 1). A transthoracic echocardiogram showed a severely dilated right atrium and ventricle, a
flattened ventricular septum, and an estimated right ventricular
systolic peak pressure of 79 mm Hg. A ventilation/perfusion
lung scan was negative for chronic thromboembolic pulmonary
hypertension. Right-sided heart catheterization showed severe
PAH with a mean pulmonary artery pressure of 56 mm Hg,
pulmonary arterial occlusion pressure measured in different
lung zones at 3 to 4 mm Hg, cardiac output of 4.2 L/min, and
calculated pulmonary vascular resistance of 13.32 Wood units
(Figure 2). The patient was discharged on oral diuretics, home
oxygen, and low-dose warfarin.
DISCUSSION
The annual incidence of PVOD is approximately 0.1 to
0.2 cases per million in the general population per year.
However, since 5% to 10% of PVOD cases are misdiagnosed
as idiopathic PAH, the actual incidence rate may be higher
(1). PVOD poses a diagnostic challenge given the overlapping
features and similarities with idiopathic PAH (Table 1).
Hemodynamic evaluation is necessary to differentiate between suspected cases of PAH and PVOD. Both of these conditions show evidence of severe PAH with an elevated resting
mean pulmonary artery pressure ≥25 mm Hg and pulmonary
artery occlusion pressure ≤15 mm Hg (2). While the right atrial
pressure is higher in idiopathic PAH, it is lower in PVOD.
Another distinguishing finding in PVOD is normal or low pulmonary artery occlusion pressure (5, 6).
The use of pulmonary vasodilators does not appear to
help in the management of PVOD or in predicting the risk
From the Department of Internal Medicine (Porres-Aguilar, Al-Bayati, Syed),
Department of Pathology (Padilla), Division of Cardiovascular Diseases
(Mukherjee, Abbas), and medical student (Lowder, Azimova, Fan), Texas Tech
University Health Sciences Center/Paul L. Foster School of Medicine, El Paso,
Texas; and Universidad Autonoma de Tamaulipas School of Medicine and Division
of General Internal Medicine, Beneficencia Española de Tampico, Tampico, Mexico
(Porres-Muñoz).
Corresponding author: Mateo Porres-Aguilar, MD, Department of Internal
Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of
Medicine, 4800 Alberta Avenue, El Paso, TX 79905 (e-mail: [email protected]).
Figure 1. CT scan of the thorax with intravenous contrast showing confluent groundglass opacities (white arrow), thickened septal lines (top black arrow), and mild
bilateral pleural effusion (bottom black arrow), which are highly suggestive of PVOD.
of pulmonary edema in the long term (7). One exception to
this may be the use of intravenous epoprostenol, which led to
significant improvements in symptoms, exercise capacity, quality
of life, cardiopulmonary hemodynamics, and survival without
significant development of pulmonary edema in a few studies
of patients with PVOD (8).
Histological analysis of lung biopsy is the “gold standard” for
definitive diagnosis of PVOD (1). However, since this invasive
procedure poses many risks, it is important to seek alternative,
less-invasive tools, such as high-resolution CT and right-sided
heart catheterization, which may be utilized to make an accurate
diagnosis and distinguish PVOD from PAH. High-resolution
CT of the chest in PVOD is characterized by 1) centrilobular ground-glass opacities, 2) septal lines, and 3) mediastinal
lymphadenopathy. In contrast, normal lung parenchyma is
noted among patients with idiopathic PAH (2, 5). The combination of these three CT findings is present in up to 75%
of histologically proven cases, with a sensitivity of 75% and
specificity of 84.6% (1). Hence, CT represents an important
diagnostic tool.
PVOD is a progressive condition that is managed symptomatically. The prognosis appears to be more dismal than for
idiopathic PAH, with a 1-year mortality rate as high as 75%
(2). Studies have shown that the average time from first symptom onset to death or lung transplantation was significantly
Figure 2. Hemodynamic tracings during right heart catheterization. (a) Pulmonary arterial occlusion pressure of 1 to 2 mm Hg. (b) Mean pulmonary arterial pressure
of 56 mm Hg.
July 2015
Pulmonary veno-occlusive disease as a cause of pulmonary arterial hypertension
351
Table 1. A comparison of selected characteristics of idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease
Characteristic
Idiopathic pulmonary arterial hypertension
Pulmonary veno-occlusive disease
Anatomic site affected
Precapillary arteriolar vascular remodeling
Postcapillary venular proliferation
Gender predominance
Female predominance
Female:Male ≈ 1:1
Tobacco exposure
Unrelated
More frequent/higher exposure
High-resolution chest computed
tomography
Normal findings
Ground-glass opacities, thickening of septal lines, mediastinal
lymphadenopathies, bilateral pleural effusions
Hemodynamics
RAP is usually high (≥10 mm Hg), PAOP is usually low
(≤15 mm Hg)
RAP is usually lower (<5 mm Hg), as is PAOP (≤5 mm Hg)
Response to pulmonary vasodilators Improves hemodynamics, functional status, and survival Increased risk of pulmonary edema
RAP indicates right atrial pressure; PAOP, pulmonary artery occlusion pressure.
lower in severe PVOD cases than in idiopathic PAH cases,
indicating that PVOD is more severe and progressive. Therapy is
primarily focused on symptomatic management due to limited
definitive treatment options for PVOD. Lung transplantation
represents the treatment of choice and is the only therapeutic
option capable of improving survival in patients with PVOD.
Single- and double-lung transplantation procedures have both
been used. Therefore, early diagnosis and lung transplantation
are key prognostic factors in PVOD.
1.
2.
3.
352
Montani D, Price LC, Dorfmuller P, Achouh L, Jaïs X, Yaïci A, Sitbon
O, Musset D, Simonneau G, Humbert M. Pulmonary veno-occlusive
disease. Eur Respir J 2009;33(1):189–200.
Huertas A, Girerd B, Dorfmuller P, O’Callaghan D, Humbert M, Montani
D. Pulmonary veno-occlusive disease: advances in clinical management
and treatments. Expert Rev Respir Med 2011;5(2):217–229.
Dai Z, Matsui Y. Pulmonary veno-occlusive disease: an 80-year-old
mystery. Respiration 2014;88(2):148–157.
4.
Montani D, Achouh L, Dorfmüller P, Le Pavec J, Sztrymf B, Tchérakian
C, Rabiller A, Haque R, Sitbon O, Jaïs X, Dartevelle P, Maître S, Capron
F, Musset D, Simonneau G, Humbert M. Pulmonary veno-occlusive
disease: clinical, functional, radiologic, and hemodynamic characteristics
and outcome of 24 cases confirmed by histology. Medicine (Baltimore)
2008;87(4):220–233.
5. Frazier AA, Franks TJ, Mohammed TL, Ozbudak IH, Galvin JR.
From the Archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Radiographics
2007;27(3):867–882.
6. El-Gabaly M, Farver CF, Budev MA, Mohammed TL. Pulmonary capillary hemangiomatosis imaging findings and literature update. J Comput
Assist Tomogr 2007;31(4):608–610.
7. Kothari SS, Jagia P, Gupta A, Singh N, Ray R. Images in cardiovascular medicine. Pulmonary capillary hemangiomatosis. Circulation
2009;120(4):352–354.
8. Montani D, O’Callaghan DS, Savale L, Jaïs X, Yaïci A, Maitre S,
Dorfmuller P, Sitbon O, Simonneau G, Humbert M. Pulmonary venoocclusive disease: recent progress and current challenges. Respir Med
2010;104(Suppl 1):S23–S32.
Volume 28, Number 3
Pulmonary artery catheter–induced perforation treated with
coil embolization
Darpan S. Kumar, MD, Christopher Trotter, MD, Douglas McDonald, MD, and Timothy A. Mixon, MD
The past 40 years have taught us much about the use of pulmonary
artery catheters and their complications. Pulmonary artery rupture carries
high morbidity and mortality, and therefore a high index of suspicion and
timely management are key to the survival of patients who suffer from
this rare complication. While surgical therapy has been considered the
mainstay of treatment, endovascular therapy is feasible when surgery is
not possible or desirable, as demonstrated in our patient. It is unknown
which approach is optimal.
W
e present a case describing the diagnosis and management of a woman who underwent diagnostic
right-sided heart catheterization resulting in iatrogenic left lower lobe pulmonary artery (PA) branch
perforation managed utilizing endovascular coil embolization.
Figure 1. Development of large left-sided hemothorax noted on fluoroscopy.
CASE HISTORY
A 74-year-old woman was admitted to the hospital with
dyspnea and volume overload, as evidenced by pulmonary vascular congestion on chest x-ray, as well as a B-type natriuretic
peptide level of 376 pg/mL and lower extremity edema on examination. She had a body mass index of 45 kg/m2 and a history
of cerebrovascular accident, coronary artery disease, and atrial
fibrillation treated with warfarin. A transthoracic echocardiogram revealed an ejection fraction of 65% with increased right
atrial and right ventricular sizes and a right ventricular peak
systolic pressure of 60 mm Hg. Despite aggressive diuresis, the
patient remained dyspneic and therefore the decision was made
to perform diagnostic heart catheterization.
The patient’s anticoagulation was discontinued and the international normalized ratio was 1.8 on the day of the procedure.
Right-sided heart catheterization via a right femoral vein approach
revealed a right atrial pressure of 29/27, right ventricle pressure of
84/17, PA systolic pressure of 78/39, and PA wedge pressure of
36 mm Hg. The PA catheter balloon was wedged in the left lobe
without incident, but it was noted upon deflation of the balloon
that the PA catheter dove deep into the left lower lobe lung field,
and this was subsequently pulled back. Given the elevated pulmonary wedge pressure in the presence of normal systolic function,
we then proceeded with left-sided heart catheterization via a right
femoral artery approach. Once the left ventricle was entered with
a pigtail catheter, we proceeded with reinflation of the PA catheter
balloon to obtain simultaneous wedge and left ventricular diastolic
pressures to evaluate for possible mitral valve disease.
At this time the patient was noted to have a small amount
of hemoptysis, which subsequently progressed to massive hemoptysis. The patient was emergently intubated with a dual
lumen endotracheal tube. Fluoroscopy of the chest wall revealed
a large left-sided hemothorax (Figure 1). Immediate administration of fresh frozen plasma and blood products was initiated.
Vasopressor support was administered with multiple rounds of
intravenous epinephrine followed by a norepinephrine infusion. Selective arteriography of the left PA revealed an actively
extravasating branch in the left lower lobe (Figure 2a). The
branch was embolized with four 5/3 0.035 Tornado Platinum
coils (Cook Medical, Bloomington, IN), which resulted in cessation of flow on postembolization arteriography (Figure 2b).
The left hemothorax was treated with fluoroscopic-guided chest
tube placement at the same time.
From the Division of Cardiology (Kumar, Trotter, Mixon) and the Department of
Radiology (McDonald), Baylor Scott & White Healthcare, Temple, Texas.
Corresponding author: Darpan S. Kumar, MD, Division of Cardiology, Baylor Scott
& White Healthcare, 2401 S. 31st Street, Temple, TX 76508 (e-mail: DKumar@
sw.org).
353
b
a
Figure 2. Arteriography images (a) showing the actively extravasating branch of the left lower lobe pulmonary artery subselected during pulmonary arteriography
and (b) after coil embolization of the previously extravasating branch of the left lower lobe pulmonary artery.
The patient was subsequently transferred to the intensive
care unit (ICU) where her stay was further complicated by the
development of loculations consisting of pus and blood in the
left lower lobe, resulting in concomitant pneumonia and acute
respiratory distress syndrome. Subsequent fiberoptic bronchoscopy with clot evacuation was then performed with placement
of a second chest tube. She remained in the ICU for approximately 7 days, after which she was successfully extubated and
transferred to the medical floor in stable condition. Although
she suffered great morbidity as a result of a rare complication
that occurred during her catheterization procedure, emergent
coil embolization saved her life and led to her eventual discharge
from the hospital on day 14.
surgical management of PA rupture utilizing lobectomy, pneumonectomy, and hilar clamping with direct arterial repair or PA
ligation are some of the options available to the surgeon (6).
More recently a less invasive option for treatment that has
emerged is transcatheter embolization utilizing steel coils, liquids (sobutyl-2-cyano-acrylate), absorbable gelatin sponges,
or detachable balloons (7). The stainless steel coil, introduced
in 1975 by Gianturco et al, was initially intended for arterial
occlusions, control of hemorrhage, and management of arteriovenous fistulas, malformations, and aneurysms (8). While
catheter-based embolization has been used extensively for these
indications, it has only recently been described for the treatment
of PA perforation (9).
DISCUSSION
The use of PA catheters to estimate right-sided heart and
PA pressures was first described in 1970 and expanded our understanding and guided our therapies of the most complex cardiovascular patients (1). Documented complications including
venous damage, valvular damage, arrhythmias, catheter knotting,
balloon rupture, pulmonary embolism, pulmonary hemorrhage,
PA rupture, bacteremia, and death usually arise either as a result of
insertion or of maintenance of the catheter (2–4). While the rate
of major/potentially life-threatening complications (ventricular
arrhythmias, endocarditis, valve rupture, septicemia, pulmonary
hemorrhage/infiltrates) and minor complications of this procedure has been reported to be as high as 23%, a retrospective
chart review involving 32,442 inpatients revealed an observed
PA rupture rate of 0.031% of catheter insertions (5, 6). The
most common risk factors leading to PA rupture, all of which
were present in our patient, include systemic anticoagulation,
pulmonary hypertension, female gender, and age >60 years. The
overall mortality rate from PA rupture approaches 70% (6). In
the intraoperative setting (e.g., coronary artery bypass surgery),
1.
354
2.
3.
4.
5.
6.
7.
8.
9.
Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D.
Catheterization of the heart in man with use of a flow-directed balloontipped catheter. N Engl J Med 1970;283(9):447–451.
Sprung CL, Elser B, Schein RM, Marcial EH, Schrager BR. Risk of right
bundle-branch block and complete heart block during pulmonary artery
catheterization. Crit Care Med 1989;17(1):1–3.
Lipp H, O’Donoghue K, Resnekov L. Intracardiac knotting of a flowdirected balloon catheter. N Engl J Med 1971;284(4):220.
Boscoe MJ, de Lange S. Damage to the tricuspid valve with a Swann-Ganz
catheter. Br Med J (Clin Res Ed) 1981;283(6287):346–347.
Boyd KD, Thomas SJ, Gold J, Boyd AD. A prospective study of complications of pulmonary artery catheterizations in 500 consecutive patients.
Chest 1983;84(3):245–249.
Kearney TJ, Shabot MM. Pulmonary artery rupture associated with the
Swan-Ganz catheter. Chest 1995;108(5):1349–1352.
Abreu AR, Campos MA, Krieger BP. Pulmonary artery rupture induced
by a pulmonary artery catheter: a case report and review of the literature.
J Intensive Care Med 2004;19(5):291–296.
Chuang VP, Wallace S, Gianturco C, Soo CS. Complications of coil
embolization: prevention and management. AJR Am J Roentgenol
1981;137(4):809–813.
Gottwalles Y, Wunschel-Joseph ME, Hanssen M. Coil embolization treatment in pulmonary artery branch rupture during Swan-Ganz catheterization. Cardiovasc Intervent Radiol 2000;23(6):477–479.
Volume 28, Number 3
A hybrid repair of a superior mesenteric artery
pseudoaneurysm using open mesenteric bypass and
endovascular exclusion
Todd A. Cumbie, MD, John C. Kedora, MD, Gregory J. Pearl, MD, and William P. Shutze, MD
Superior mesenteric artery (SMA) aneurysms and pseudoaneurysms are
uncommonly encountered in vascular surgery practice, but they typically
require repair. Historically, they have been repaired with open aneurysmorrhaphy, bypass and exclusion, or simple ligation. More recently,
endovascular repair with coil embolization and stent graft exclusion have
been advocated. We present a repair of an SMA pseudoaneurysm via
a hybrid approach with common hepatic artery to SMA bypass, exclusion of the pseudoaneurysm with ligation of the SMA proximal to the
bypass, plug occlusion of the proximal SMA, and coil embolization of
the pseudoaneurysm.
S
uperior mesenteric artery (SMA) aneurysms and pseudoaneurysms are rare entities being encountered more
frequently secondary to increased utilization of abdominal imaging (1, 2). When SMA aneurysms and pseudoaneurysms are discovered, most surgeons elect to repair them
because of the 35% mortality rate associated with rupture, acute
thrombosis, or embolization to the small bowel (3). Traditionally, repair has consisted of open SMA bypass with exclusion of
the aneurysm or aneurysmorrhaphy. There have been multiple
recent reports of endovascular repair either by stent graft exclusion or coil embolization of the aneurysm. We report a case
of a 4.5-cm mid-SMA pseudoaneurysm repaired by a hybrid
technique with open bypass and endovascular exclusion.
CASE DESCRIPTION
In 2008, a 76-year-old woman presented to an outside
hospital with ischemic colitis. At that time, she underwent a
total abdominal colectomy with end ileostomy followed by a
complicated SMA stenting procedure. The patient had a long
segment chronic dissection of the SMA that was treated with
three 6 × 20 mm balloon expandable stents from the ostium of
the SMA to mid-SMA. This procedure was complicated by the
most proximal stent being misdeployed, with half of the stent
residing outside the SMA in the aorta. Ultimately, this stent was
snared and removed via an open femoral cutdown.
The patient subsequently came under our care for right
lower extremity tissue loss in December 2011. An angiogram
was performed that incidentally demonstrated a large mesenteric
aneurysm. Computed tomography (CT) angiogram delineated
Figure 1. Preoperative CT angiogram demonstrating a 4.5-cm superior mesenteric
artery pseudoaneurysm (arrow).
the anatomy most clearly (Figure 1). An abdominal aortogram
showed the large aneurysm involving the origin of the SMA
and the stents (Figure 2).
The patient was then sent to the operating room for a hybrid
open/endovascular repair of this pseudoaneurysm. We performed
a common hepatic artery (CHA) to mid-SMA bypass with reversed greater saphenous vein. The SMA distal to the aneurysm,
but proximal to the bypass anastomosis, was ligated to occlude
the outflow of the pseudoaneurysm. The proximal SMA stent
was cannulated from a femoral approach using a renal doublecurve guiding catheter, and using the telescope technique, we
advanced the guide catheter over a glide catheter and Bentson
wire (Olympus America, Center Valley, PA) into the aneurysm.
We then deployed an 8-mm Amplatzer plug (St. Jude Medical,
St. Paul, MN) within the proximal stent after withdrawing the
guide sheath into the aorta. This effectively occluded the inflow
into the pseudoaneurysm. The exposed pseudoaneurysm was
From Waco Surgical Group, Waco, Texas (Cumbie) and the Division of Vascular
Surgery, Baylor University Medical Center at Dallas (Kedora, Pearl, Shutze).
Corresponding author: William P. Shutze, MD, Texas Vascular Associates, 621
N. Hall Street, Suite 100, Dallas, TX 75226 (e-mail: [email protected]).
355
Figure 2. Abdominal aortogram demonstrating a very large aneurysm involving
the origin of the superior mesenteric artery (SMA) and the SMA stents (arrow).
The SMA can be seen filling distal to the aneurysm.
accessed from the abdomen with a 5 French sheath and the
pseudoaneurysm was evacuated. Several intravascular coils were
deployed into the pseudoaneurysm sac through the 5 French
sheath (Boston Scientific, Marlborough, MA). The sheath was
removed and the access site oversewn with 5-0 Prolene (Ethicon
US, Somerville, NJ). The completion angiogram showed exclusion of the pseudoaneurysm sac with excellent filling of the distal
SMA via the CHA-to-SMA bypass (Figure 3).
The patient recovered uneventfully and was discharged
home on postoperative day 7. CT angiogram was performed
prior to discharge and confirmed exclusion of the pseudoaneurysm with sac shrinkage and patency of the CHA-to-SMA
bypass (Figure 4). At 3-month follow-up, the patient continued
to be asymptomatic. She died at another facility 4 months after
the procedure due to line sepsis.
DISCUSSION
SMA pseudoaneurysms and aneurysms are rarely encountered but can potentially lead to significant morbidity and mortality (4). Historically, SMA aneurysms resulted from infections.
However, more recently, atherosclerosis and collagen vascular
disease have been reported as more common etiologies. Additionally, SMA pseudoaneurysms can occur from arterial dissection, pancreatitis, trauma, and iatrogenic sources (3).
Typically, SMA aneurysms affect the proximal 5 cm of the
SMA. Approximately 90% of patients are symptomatic with
abdominal pain or nausea and vomiting. They may also present
with gastrointestinal hemorrhage. Half of patients will have a
pulsatile mass or bruit (5).
SMA aneurysms and pseudoaneurysms have usually been
repaired with aneurysmorrhaphy, exclusion, and bypass or, in
some cases, ligation. The perioperative mortality ranges from
1.3% to 5%, with morbidity rates close to 10% (6, 7). Excellent
356
Figure 3. Intraoperative completion sagittal angiogram demonstrating the proximal superior mesenteric artery (SMA) stent occluded by an Amplatzer plug (thin
white arrow), the stent within the SMA as it exits the pseudoaneurysm (thick
black arrow), the clip occluding SMA outflow (thin black arrow), and coils within
the pseudoaneurysm sac.
long-term results have been achieved, with surgical repair providing good survival rates and protection from late aneurysmrelated adverse events (6, 7). More recently, endovascular means
to treat these aneurysms have been employed, with case reports
and case series detailing both endovascular stent graft exclusion
and coil embolization (3, 7). The ability to use endovascular
techniques is limited by challenging target vessel access, arterial
tortuosity, and the necessity to preserve side branches at or near
Figure 4. Postoperative CT angiogram demonstrating the excluded superior
mesenteric artery pseudoaneurysm without flow (arrow).
Volume 28, Number 3
the repair site; therefore, only a few totally endovascular repairs
have been reported (7). Long-term follow-up in the endovascularly treated patients is not available, and the durability of these
repairs is not firmly established.
Our patient’s SMA pseudoaneurysm likely arose from previous manipulation with balloon-expandable stents within a
chronic dissection. A totally endovascular repair was considered
but abandoned due to the angulation constraints of the proximal inflow of the pseudoaneurysm and the outflow vessel. It did
not appear that the anatomy of the SMA would accommodate
a covered stent graft without causing significant kinking of the
stent graft (Figure 2). A totally open operative repair of the SMA
pseudoaneurysm was considered. However, because of the close
proximity of the SMA pseudoaneurysm to the aorta, proximal
control would have been obtained on the supraceliac aorta before
opening the aneurysm, and an aorto-mesenteric bypass would
have been necessary. Therefore, we chose a hybrid approach for
this particular anatomy. The inflow to the pseudoaneurysm was
excluded by an endovascular plug, avoiding the morbidity associated with supraceliac aortic cross-clamping. The SMA was
ligated and revascularized distally with an extra-anatomic bypass.
Coils were placed directly into the sac to ensure sac thrombosis.
Complications of endovascular therapy can lead to challenging anatomic situations. Pure endovascular or surgical rescue
July 2015
will often suffice. At times, a combination of these modalities
is the best approach, as exemplified by this case. Utilizing both
endovascular and open techniques can minimize the complexity and morbidity of the open procedure while maintaining the
durability of the pseudoaneurysm repair.
1.
2.
3.
4.
5.
6.
7.
Dasari BV, Mullan M, Lau L, Loan W, Lee B. A 6.5-cm pseudoaneurysm
of the superior mesenteric artery managed by primary surgical repair.
Vascular 2011;21(1):39–42.
Díaz E, Lozano FS, González S, Alcázar JA, Torres JA, Gónzalez-Porras JR,
Gómez-Alonso A. Open and endovascular treatment of pseudoaneurysms
of the superior mesenteric artery. Ann Vasc Surg 2010;24(5):690.e9–e12.
Stone WM, Abbas M, Cherry KJ, Fowl RJ, Gloviczki P. Superior mesenteric artery aneurysms: is presence an indication for intervention? J Vasc
Surg 2002;36(2):234–237; discussion 237.
Shrikhande GV, Khan SZ, Gallagher K, Morrissey NJ. Endovascular
management of superior mesenteric artery pseudoaneurysm. J Vasc Surg
2011;53(1):209–211.
Nosher JL, Chung J, Brevetti LS, Graham AM, Siegel RL. Visceral and
renal artery aneurysms: a pictorial essay on endovascular therapy. Radiographics 2006;26(6):1687–1704; quiz 1687.
Pulli R, Dorigo W, Troisi N, Pratesi G, Innocenti AA, Pratesi C. Surgical
treatment of visceral artery aneurysms: a 25-year experience. J Vasc Surg
2008;48(2):334–342.
Marone EM, Mascia D, Kahlberg A, Brioschi C, Tshomba Y, Chiesa R.
Is open repair still the gold standard in visceral artery aneurysm management? Ann Vasc Surg 2011;25(7):936–946.
A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion
357
Allergic acute coronary syndrome (Kounis syndrome)
Sarfaraz Memon, MD, Lovely Chhabra, MD, Shihab Masrur, MD, and Matthew W. Parker, MD
Anaphylaxis rarely manifests as a vasospastic acute coronary syndrome
with or without the presence of underlying coronary artery disease. The
variability in the underlying pathogenesis produces a wide clinical spectrum of this syndrome. We present three cases of anaphylactic acute
coronary syndrome that display different clinical variants of this phenomenon. The main pathophysiological mechanism of the allergic anginal
syndromes is the inflammatory mediators released during a hypersensitivity reaction triggered by food, insect bites, or drugs. It is important
to appropriately recognize and treat Kounis syndrome in patients with
exposure to a documented allergen.
A
cute coronary syndrome accompanying mast cell activation from allergic, hypersensitivity, or anaphylactoid
reactions was first described by Kounis and Zavras in
1991 and has been referred to as “allergic angina” or
“allergic myocardial infarction” (1, 2). The mechanism of Kounis syndrome (KS) involves release of inflammatory cytokines
through mast cell activation, which leads to coronary artery
vasospasm and/or atheromatous plaque erosion or rupture (2).
KS has been described with multiple conditions, including a
variety of environmental exposures and drugs (3). More recently,
variant presentations of allergic angina have been described. In
this case series, we describe three variable case presentations of
anaphylactic ST elevations, which include ST-elevation myocardial infarction (MI) in the presence of underlying coronary
artery disease and ST-elevation MI without underlying coronary
artery disease (pure vasospasm). We also briefly review the existing literature on KS.
CASE PRESENTATIONS
Case 1
A 64-year-old man with known peripheral arterial disease,
chronic obstructive pulmonary disease, coronary artery disease,
dyslipidemia, and hypertension presented with pruritus, chest
pain, dyspnea, and nausea immediately after having dinner at
a restaurant including pea salad. The initial electrocardiogram
demonstrated ST-segment elevations in leads II, III, and aVF
(Figure 1a). The patient had a prior known allergic reaction
(type 1) to peas and peanuts. His initial vital signs were a tem-
358
perature of 98°F, blood pressure of 81/60 mm Hg, respiration rate of 20 breaths/minute, and pulse of 91 beats/minute.
Examination disclosed wheezing, generalized erythema, and
weak peripheral pulses. His hemogram and basic chemistry
panel were unremarkable except for a white blood cell count
of 19,500/uL. Both the creatinine kinase and troponin I levels
were normal (145 U/L, normal 24–204 U/L; and <0.30 ng/
mL, normal <0.30 ng/mL, respectively).
Emergent coronary angiogram demonstrated moderate stenosis of the proximal and mid left anterior descending artery
and the right coronary artery, with evidence of improvement in
the stenosis with administration of intracoronary nitroglycerine
(Figure 2). Diagnosis of coronary vasospasm was made secondary to anaphylactic reaction from pea ingestion. Treatment for
anaphylaxis was initiated with intravenous hydrocortisone, diphenhydramine, and famotidine with improvement in pruritus,
dyspnea, and chest discomfort. The patient’s blood pressure
also improved to 120/60 mm Hg. Repeat electrocardiogram
showed resolution of ST segment elevations (Figure 1b). He
was discharged home.
Case 2
A 54-year-old man with past Lyme disease, hypertension,
hyperlipidemia, and gastroesophageal reflux disease presented
after he was stung by a bee while working in the yard. He
developed facial swelling and hypotension. Emergency medical services found him to be in respiratory distress associated
with facial swelling. He was intubated and was administered
intravenous diphenhydramine and methylprednisolone and
inhaled albuterol. The initial electrocardiogram demonstrated
ST elevations in the inferior leads (Figure 3a). The patient was
started on intravenous fluids and heparin and was transferred
to our hospital. On arrival, he was found to have transient
complete heart block, which resolved after administration of
diphenhydramine and methylprednisolone. Coronary angiography revealed severe 3-vessel disease but no acute culprit lesion
(Figure 4). Based on the clinical data, coronary vasospasm as
From the Department of Cardiovascular Medicine, Hartford Hospital, University
of Connecticut School of Medicine, Hartford, Connecticut.
Corresponding author: Sarfaraz Memon, MD, 80 Seymour Street, Hartford, CT
a
b
Figure 1. Electrocardiograms in case 1. (a) Initial electrocardiogram demonstrates an ectopic atrial rhythm with an isolated sinus beat (third beat), inferior Q
waves, and ST elevation in the inferior leads. (b) Repeat electrocardiogram shows Q waves in the inferior leads and resolution of inferior ST elevations. There
is limb lead reversal.
a
b
c
Figure 2. Coronary angiogram in case 1. (a) A left anterior oblique cranial view shows left main coronary artery (LM), left circumflex artery (LCx) and left anterior
descending artery (LAD). The arrow points to significant proximal LAD stenosis (a nonculprit lesion for the presentation). (b) The right coronary artery (RCA) shows
evidence of distal stenosis (black arrow). (c) After administration of intracoronary nitroglycerine, the RCA stenosis demonstrated resolution consistent with coronary
vasospasm (white arrow).
July 2015
359
a
b
Figure 3. Electrocardiograms in case 2. (a) Initial electrocardiogram demonstrates ST elevations in the inferior leads. (b) Repeat electrocardiogram demonstrates
resolution of ST elevations.
a
b
Figure 4. Coronary angiogram in case 2. (a) Posteroanterior caudal view shows chronic multivessel coronary artery disease of the left main (LM) coronary artery, left
anterior descending (LAD) artery, and left circumflex (LCx) artery (arrows). There was no acute culprit lesion. (b) Left anterior oblique projection of the right coronary
artery (RCA) shows focal severe stenosis in the mid and distal RCA and mild to moderate atherosclerotic disease at other locations.
360
Volume 28, Number 3
a
b
Figure 5. Electrocardiograms in case 3. (a) Initial electrocardiogram shows inferior lead ST elevations and premature ventricular complexes. (b) Repeat electrocardiogram demonstrates resolution of inferior lead ST elevations. Premature ventricular complexes and widespread T wave inversions are additional notable findings.
the likely cause was considered in retrospect. The ST elevations
resolved on a repeat electrocardiogram (Figure 3b). He was seen
by a cardiothoracic surgery team and was scheduled for elective
bypass surgery.
Case 3
A 75-year-old man with known diabetes mellitus, hypertension, hyperlipidemia, and abdominal aortic aneurysm presented
to our hospital with dysuria and fever. His urinalysis was positive for leukocyte esterase, a few red blood cells, and multiple
leucocytes. He was given intravenous ceftriaxone for suspected
urinary tract infection. After the administration of ceftriaxone,
he immediately developed a generalized erythematous macular rash, hypotension, and tachycardia followed by pulseless
electrical activity and cardiac arrest. Advanced cardiovascular
life support was employed, including the use of intravenous
July 2015
epinephrine per protocol. He had return of spontaneous circulation with complete neurological recovery. The electrocardiogram
after return of the patient’s spontaneous circulation revealed ST
segment elevations in inferior leads (II, III, and aVF) (Figure 5a),
leading to activation of the cardiac catheterization laboratory
team. The patient also received intravenous diphenhydramine,
famotidine, and methylprednisolone. Subsequent electrocardiograms taken 5 and 15 minutes later showed normalization
of ST segments (Figure 5b). His hemogram and basic chemistry panel were normal; the creatinine kinase was 145 U/L,
and troponin I, <0.30 ng/mL. The patient was admitted and
successfully extubated after a day. His urinary tract infection
resolved, and he was discharged home in a stable condition.
Prior to discharge, he underwent an elective nuclear stress test,
which showed a small fixed apical anterolateral wall defect with
no evidence of ischemia.
361
DISCUSSION
Three types of KS have been previously described (4). Type
I includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute
allergic insult leads to coronary artery spasm with normal cardiac
biomarkers or infarction with positive cardiac biomarkers. This
variant represents a manifestation of endothelial dysfunction or
microvascular angina (5). The type II variant includes patients
with culprit but inactive preexisting atheromatous disease, in
whom the allergic insult leads to plaque erosion or rupture,
leading to acute myocardial infarction or coronary vasospasm
with normal cardiac enzymes (4). The type III variant includes
coronary artery stent thrombosis secondary to allergic reaction
(4). The ischemia in allergic reaction is secondary to the release
of inflammatory mediators, including histamine, tryptase, chymase, platelet-activating factor, cytokines, and prostaglandins,
and leukotriene synthesis, which leads to coronary vasospasm (2).
Vigorito et al previously reported a paradoxical vasoconstriction
mediated by histamine-1 receptors (6). Multiple cases of KS have
been reported in the literature (7). Our first two cases were a form
of type 2 KS, and the third case represented a form of type 1 KS.
The second patient experienced transient complete heart block
with anaphylaxis and is the second such report of KS associated
with complete heart block described in the literature (8).
Our cases further support KS as a distinct phenomenon.
Some authors have argued against the vasospastic process being the dominant underlying pathophysiological explanation
for KS. It is well known that anaphylaxis causes systemic vasodilation and decreased venous return secondary to increased
vascular permeability and subsequently may lead to a depressed
cardiac output, resulting in coronary hypoperfusion and myocardial damage. Thus, differentiating primary myocardial damage secondary to mast cell activation from global myocardial
hypoperfusion can be challenging and remains an alternative
potential explanation for allergic acute coronary syndrome (elec-
362
trocardiographic ST elevations) (4). It is important to recognize
these forms of KS to provide appropriate management and care.
The diagnosis and treatment of KS can be indeed challenging,
requiring attention to both the cardiac and anaphylactic pathophysiology concurrently.
Treatment of KS requires thoughtful use of several common
drugs. Morphine, an important drug for treating acute chest
pain, should be avoided in KS, as it may potentially stimulate
histamine release and exacerbate the pathologic cascade in KS.
Beta-blockers also may potentiate coronary vasospasm if used
in an acute exacerbation of KS due to an unopposed alpha
adrenergic action. Epinephrine, which is used routinely for the
treatment of anaphylaxis, should also be used with cautionary
monitoring, as it may potentially worsen coronary vasospasm
and aggravate coronary ischemia in KS (4). The primary focus
of treatment of KS should be directed towards the allergic insult
and removal of the offending allergens.
1.
2.
3.
4.
5.
6.
7.
8.
Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the
concept of allergic angina. Br J Clin Pract 1991;45(2):121–128.
Kounis NG. Kounis syndrome (allergic angina and allergic myocardial
infarction): a natural paradigm? Int J Cardiol 2006;110(1):7–14.
Rodrigues MC, Coelho D, Granja C. Drugs that may provoke Kounis
syndrome. Braz J Anesthesiol 2013;63(5):426–428.
Kounis NG. Coronary hypersensitivity disorder: the Kounis syndrome.
Clin Ther 2013;35(5):563–571.
Nikolaidis LA, Kounis NG, Gradman AH. Allergic angina and allergic
myocardial infarction: a new twist on an old syndrome. Can J Cardiol
2002;18(5):508–511.
Vigorito C, Poto S, Picotti GB, Triggiani M, Marone G. Effect of activation of the H1 receptor on coronary hemodynamics in man. Circulation
1986;73(6):1175–1182.
Caglar FN, Caglar IM, Coskun U, Ugurlucan M, Okcun B. Kounis
syndrome: myocardial infarction secondary to an allergic insult—a rare
clinical entity. Acta Cardiol 2011;66(4):559–562.
Kounis NG. Caspofungin-induced fatal complete heart block: Another manifestation of Kounis syndrome. J Pharmacol Pharmacother
2013;4(2):161–162.
Volume 28, Number 3
Blood cyst of the anterior mitral leaflet causing severe
mitral regurgitation
Suresh Madhavan, MD, DM, K. Jayaprakash, MD, DM, N. Jayaprasad, MD, DM, Gargi Sathish, DO, MS, and
Raju George, MD, DM
We report a case of blood cyst of the anterior mitral leaflet leading to
severe mitral regurgitation and heart failure in a 70-year-old woman
with no other factors that could explain the severe mitral regurgitation.
B
lood cysts of the cardiac valves are rare. They are relatively common in newborns, but disappear spontaneously during infancy in most cases. Finding a blood
cyst on the mitral valve in an older adult prompted
this case report.
CASE REPORT
A 70-year-old woman was admitted for progressive effort
dyspnea and palpitation of 5 years’ duration and orthopnea
and paroxysmal dyspnea for 6 months. She had no history of
rheumatic fever. She had acute loss of vision in her left eye, diagnosed as retinal artery occlusion 3 weeks prior to the present
admission. On examination, she was dyspneic and tachypneic,
with a heart rate of 98 beats per minute. Her jugular venous
pressure was 8 cm above the sternal angle. Both ankles were
edematous, and her blood pressure was 100/80 mm Hg. Her
heart was enlarged, and a systolic thrill and left parasternal heave
were palpated. The first heart sound was soft, the second heart
sound was widely split with an accentuated pulmonary component, and the left ventricular third heart sound was heard over
the apex. There was a grade 4/6 pansystolic murmur at the apex,
and it radiated to the back. An electrocardiogram showed sinus
rhythm with a right axis deviation and left ventricular volume
overload pattern. A chest radiograph showed cardiomegaly with
pulmonary venous and arterial enlargement.
A transthoracic echocardiogram showed a dilated left ventricle and a left atrium with an ejection fraction of 55%. A cystic
swelling was attached to the atrial aspect of the anterior mitral
leaflet, present during both systole and diastole (Figure 1a).
The chordae and papillary muscles were normal. Severe mitral
regurgitation was observed (Figure 1b). There was no regional
wall motion abnormality or mitral annular calcium. Pulmonary
arterial hypertension was estimated to be 64 mm Hg. Transesophageal examination confirmed the cystic swelling in the
anterior mitral leaflet (Figure 1c) with severe mitral regurgitation
(Figure 1d), with no other morphological changes in the mitral
valve apparatus (Video supplement). The coronary arteries were
normal. The patient was treated with diuretics, digoxin, and
vasodilators. Intraoperatively, surgeons noted a 16 mm round,
bluish cystic swelling with a broad base attached to the atrial
aspect of the anterior mitral leaflet. The patient subsequently
underwent successful mitral valve replacement with a TTK
Chitra tilting disc prosthesis. Histopathology revealed bloodfilled space lined with a single layer of endothelium consistent
with a blood cyst. At 1-year follow up, the patient was clinically
stable.
DISCUSSION
Intracardiac blood cysts are rare. Blood cysts are lined by
flattened endothelial cells and filled with nonorganized blood
(1). Generally blood cysts are small and round, although giant
cysts have been reported. Their etiology is thought to be congenital or acquired. There are various theories regarding the
origin of intracardiac blood cysts. Boyd’s theory states that during valvular development, blood is pressed into the crevices on
the valvular surfaces of the cusps, which later gets sealed off (2).
Kantelip’s theory proposes dilatation of the normal invagination
of the valve cusp as the mechanism of genesis of the blood cyst
(3). Blood cysts may be derived from ectatic blood vessels or
angiomas. Inflammation, vagal stimulation, anoxia, and hemorrhagic diathesis could lead to sudden occlusion of small vascular
channels and lead to subsequent hematoma formation in the
subvalvular region.
Congenital blood cysts of the heart valves are mostly seen
on tricuspid and mitral valves of fetuses and infants. Autopsy
reports of fetuses and infants have shown a higher occurrence
of cardiac blood cysts (4), indicating that severe hypoxia or
inflammation may be an etiology for the appearance of this
entity. Blood cysts are often found in neonates dying of various
causes and probably have no clinical significance. Blood cysts
may persist and enlarge to form giant cysts of heart valves.
Blood cysts are usually asymptomatic in adults and have often
been discovered incidentally during routine echocardiographic
From Government Medical College, Kottayam, Kerala State, India.
Corresponding author: Suresh Madhavan, MD, DM, Government Medical
College, Kottayam, Kerala State, India 686008 (e-mail: drsureshmadhavan76@
gmail.com).
363
a
b
c
d
Figure 1. Apical four-chamber echocardiography showing (a) a blood cyst of the anterior mitral leaflet and (b) severe mitral regurgitation. Transesophageal echocardiography showing (c) a blood cyst of the anterior mitral leaflet and (d) severe mitral regurgitation.
evaluation. They can cause inflow and outflow obstruction and
valvular regurgitation due to incomplete coaptation (5). Mitral
regurgitation can also occur due to the mitral paraannular location
of the cyst (6). Cysts may be a potential source of cerebrovascular
embolism (7). There is not necessarily a correlation between the
size of the cyst and hemodynamic consequences; even giant blood
cysts can be asymptomatic and may be an incidental finding during echocardiography (8).
There is no consensus regarding the management of blood
cysts. Pelikan et al suggested that asymptomatic cysts, because
of their benign character, can be monitored with echocardiography, and resection should be reserved for cysts that interfere
with normal cardiac function (9). Paşaoğlu et al advised surgical
excision of all cystic tumors of the heart, especially in a valvular
location, because the precise diagnosis can be made only by
intraoperative examination (10).
Video supplement
Transesophageal echocardiography at 130° showing the cyst
in the atrial aspect of the anterior mitral valve leaflet (see www.
BaylorHealth.edu/Proceedings/Documents/BUMC%20Proceedings/2015%20Vol%2028/No_3/28_3_Jayaprakash.mp4).
364
Burke A, Virmani R. Tumors of the Heart and Great Vessels (Atlas of Tumor
Pathology, Third Series, Vol. 15). Washington, DC: American Registry of
Pathology, 1996:171–177.
2. Boyd TA. Blood cysts on the heart valves of infants. Am J Pathol
1949;25(4):757–759.
3. Kantelip B, Satge D, Camilleri L, Chenard MP, De Riberolles C. Valvular
cyst and atrioventricular canal in a child with trisomy 21. Ann Pathol
1994;14(2):101–107.
4. Zimmerman KG, Paplanus SH, Dong S, Nagle RB. Congenital blood
cysts of the heart valves. Hum Pathol 1983;14(8):699–703.
5. Xie SW, Lu OL, Picard MH. Blood cyst of the mitral valve: detection by
transthoracic and transesophageal echocardiography. J Am Soc Echocardiogr
1992;5(5):547–550.
6. Sekine S, Abe T, Kuribayashi R, Aida H, Seki K, Shibata Y. Mitral regurgitation caused by mitral paraannular cyst. J Heart Valve Dis 1997;6(1):67–68.
7. Kuvin J, Saha P, Rastegar H, Salomon RN, Pandian N, Denofrio D. Blood
cyst of the mitral valve apparatus in a woman with a history of orthotopic
liver transplantation. J Am Soc Echocardiogr 2004;17(5):480–482.
8. Abreu A, Galrinho A, Sá EP, Ramos S, Martins AP, Fragata J, Ferreira R.
Hamartoma of the mitral valve with blood cysts: a rare tumor detected
by echocardiography. J Am Soc Echocardiogr 1998;11(8):832–836.
9. Pelikan HM, Tsang TS, Seward JB. Giant blood cyst of the mitral valve.
J Am Soc Echocardiogr 1999;12(11):1005–1007.
10. Paşaoğlu I, Doğan R, Nazli N, Güngen Y, Bozer AY. Blood cyst originating
from tricuspid septal leaflet. J Cardiovasc Surg (Torino) 1991;32(5):589–
591.
1.
Volume 28, Number 3
Right-sided superior vena cava draining into the left
atrium in a patient with persistent left-sided superior
vena cava emptying into the right atrium diagnosed by
echocardiography
Courtney Clark, RDCS, and Lee MacDonald, MD
We present a patient with an isolated right-sided superior vena cava
draining into the left atrium with a persistent left-sided superior vena cava
emptying into the right atrium. During an agitated saline injection into
the patient’s right upper extremity intravenous line, the patient suffered
an acute transient ischemic attack. To our knowledge, this is the only
reported case of this rare anomaly incidentally uncovered during an
echocardiogram with saline contrast study.
A
nomalous systemic venous connection with the left
atrium (LA) is an unusual congenital cause of a rightto-left shunt. It is most commonly due to a persistent
left-sided superior vena cava (SVC) draining into the
LA (1). Less commonly, the right-sided SVC may drain into
the LA. This occurrence is rare in the absence of other cardiac
abnormalities (2). Here we present a rare cardiac congenital
anomaly with double SVC drainage, with a right-sided SVC
emptying into the LA and a persistent left-sided SVC emptying
into the right atrium (RA).
CASE PRESENTATION
A 65-year-old man presented to the emergency department with a sudden onset of speech disturbances and left arm
weakness. He was known to have had hypertension, pancreatitis, migraines, hyperlipidemia, and a cerebral brain abscess
drained at the age of 22, resulting in a seizure disorder. He was
not cyanotic. Due to his sudden onset of stroke symptoms, a
transthoracic echocardiogram with agitated saline was done. A
peripheral intravenous line in the patient’s right antecubital vein
was used to inject agitated saline and evaluate for intracardiac
shunting. During echocardiographic imaging, the agitated saline
immediately entered the LA, bypassing the right side of the
heart (Figure 1). Immediately following the injection of agitated
saline, the patient had a sudden onset of left-sided weakness
and speech disturbances and was ultimately diagnosed with a
transient ischemic attack. In preparation for a transesophageal
echocardiogram, an additional peripheral intravenous line was
placed in the left antecubital vein. When the agitated saline was
injected into the left arm, imaging demonstrated that it entered
into the RA normally. A computed tomographic angiogram of
the chest demonstrated a double SVC. The persistent left SVC
Figure 1. Echocardiographic apical four-chamber view. The agitated saline
completely fills the left heart chambers after right antecubital venous injection.
coursed through the left mediastinum and around the left side
of the heart, where it emptied into the coronary sinus, which
was significantly enlarged. This coronary sinus then emptied
into the RA. The right SVC drained the right subclavian vein
and coursed along the right mediastinum and emptied into the
LA, just superior to the right upper pulmonary vein, producing
a large right-to-left shunt (Figure 2). No significant connection
From Swedish Medical Center, Englewood, Colorado.
Corresponding author: Lee MacDonald, MD, Cardiac Catheterization Laboratory
Director, Cardiology Section Chair, Assistant Chair of Medicine, Swedish Medical
Center, 501 East Hampden Avenue, Englewood, CO 80113 (e-mail: Leem@
southdenver.com).
365
Figure 2. Chest computed tomography shows the right superior vena cava
draining into the left atrium, with the persistent left-sided superior vena cava
(filled with contrast) draining into the right atrium inferiorly.
or communication was noted between the persistent left SVC
and the right SVC. The patient recovered fully and was discharged after 1 week of hospitalization. Surgery was declined
by the patient.
DISCUSSION
Persistent left SVC occurs in about 0.3% of the general
population and in about 5% of patients with congenital heart
disease. It is the most common form of anomalous systemic
venous return (1). A left-sided SVC forms when the left anterior
cardinal vein is not obliterated during normal fetal development. The persistent left SVC passes anterior to the left hilum
366
and lateral to the aortic arch before rejoining the circulatory system (3). The persistent left SVC drains into the coronary sinus
or RA in 92% of patients. In the remaining 8%, the persistent
left SVC drains into the LA. A right-sided SVC is present in
82% to 90% of patients with a persistent left SVC; in about
30% of these patients, the left innominate vein is present (4).
This usually drains into the RA. A right-sided SVC that drains
into the LA is a rare congenital abnormality, and only a few
cases have been reported. In our patient, due to the injection of
agitated saline into the right antecubital vein, the agitated saline
traveled through the right SVC and then drained directly into
the LA. These saline bubbles may have acted as small air emboli,
progressing to the brain, resulting in a transient ischemic attack. If the intravenous access would have been in the left arm
during the echocardiogram with agitated saline, the anomaly
most likely would not have been identified, and the systemic
venous-arterial connection may have been missed. When an
agitated saline study was performed from the left upper extremity, transesophageal imaging demonstrated normal drainage
through the left SVC into the RA.
1.
Hulten EA, Pinto G, Weissman G, Fuisz A. Anomalous vena caval return
to the left atrium. Circulation 2012;125(13):e525–e528.
2. Baggett C, Skeen SJ, Gantt DS, Trotter BR, Birkemeier KL. Isolated right superior vena cava drainage into the left atrium diagnosed
noninvasively in the peripartum period. Tex Heart Inst J 2009;
36(6):611–614.
3. Pahwa R, Kumar A. Persistent left superior vena cava: an intensivist’s
experience and review of the literature. South Med J 2003;96(5):528–
529.
4. Pretorius PM, Gleeson FV. Case 74: right-sided superior vena cava draining into left atrium in a patient with persistent left-sided superior vena
cava. Radiology 2004;232(3):730–734.
Volume 28, Number 3
Spontaneous coronary artery dissection in a 22-year-old
man on lisdexamfetamine
Aasim M. Afzal, MD, MBA, Syed A. Sarmast, MD, Nicholas A. Weber, BA, and Jeffrey M. Schussler, MD
Spontaneous coronary artery dissection (SCAD) is a rare cause of coronary events and sudden cardiac death. SCAD can present with a wide
spectrum of clinical presentations and as an entity remains underrecognized. Several risk factors, such as female gender, peripartum and early
postpartum state, and atherosclerotic disease, have been attributed to
SCAD. Amphetamine use has been attributed to an increased risk for
coronary artery events. We present a case of a 22-year-old man on lisdexamfetamine and no other significant medical history who presented
with SCAD and was successfully treated with medical management.
S
pontaneous coronary artery dissection (SCAD) overall
remains a relatively rare cause of acute coronary syndromes and tends to affect the young healthy population, with a female preponderance. SCAD resulting in
acute coronary events has a high mortality rate, and its prompt
recognition and treatment is vital. SCAD should be included as
part of a complete differential in a population with identifiable
risk factors. Amphetamines and cocaine have been identified as
risk factors for SCAD. Lisdexamfetamine is an amphetamine
commonly prescribed for the treatment of attention-deficit/
hyperactivity disorder (ADHD). We report a case of a 22-yearold on lisdexamfetamine who presented with SCAD and was
successfully treated with medical management.
CASE PRESENTATION
A 22-year-old white man with ADHD presented to the
emergency department with severe substernal chest pain 8 out
of 10 on a pain scale with radiation to his left arm and neck
associated with dyspnea, nausea, and vomiting. The pain started
while he was bicycling and had resolved by the time he arrived at
the emergency department. His only home medication was lisdexamfetamine, which he had been taking for about 5 months.
He denied any drug or alcohol use, and his drug screen was
positive for amphetamines (his prescribed medication). The
electrocardiogram was normal and his initial troponin level was
<0.05 μg/L. An echocardiogram showed ventricular septal hypokinesis with an ejection fraction of 60%. A second troponin
test was positive at 2 μg/L and ultimately peaked at 24 μg/L.
The patient was started on heparin, aspirin, metoprolol,
and clopidogrel and was evaluated with a gated computed
tomography coronary angiogram (CTCA). The CTCA showed
a density concerning for a dissection, with intramural hematoma within the proximal left anterior descending artery (LAD)
(Figure 1a, 1b). Left-sided heart catheterization demonstrated a
hazy area in the proximal LAD, consistent with dissection and
adherent clot (Figure 1c). Intravascular ultrasound confirmed
a dissection in the proximal LAD (Figure 1d). There was TIMI
3 flow in the LAD without evidence of compromised flow.
He was medically treated with aspirin, statin, carvedilol, and
lisinopril. The lisdexamfetamine was discontinued, and he was
cautioned not to start it again. He remained symptom free and
was discharged on the above-mentioned medications. At the
1-year mark, he was symptom free and was exercising regularly.
Follow-up CTCA at 6 months showed complete resolution of
both the dissection and the hematoma.
DISCUSSION
This is the first reported case of lisdexamfetamine associated
with SCAD. It is unusual for young men to present with coronary dissection (which typically has a female predominance),
suggesting that the amphetamine derivative played a role in the
pathophysiology (1). There are isolated cases of methamphetamine causatively associated with SCAD (2). Lisdexamfetamine,
an amphetamine-derived stimulant treatment used for ADHD,
has been shown to have a safety profile similar to that of other
medications in this group, but has been associated with increased risks of cardiovascular side effects (3, 4).
Notable in this case is that CTCA was used as the initial test
in evaluating the patient, especially given the low pretest probability for the presence of coronary disease. It can be a valuable
tool in evaluating patients with SCAD (5).
In this case, as in many cases where SCAD occurs, treatment
should be individualized. Patients who are hemodynamically stable,
without active symptoms, may be best treated with medications
alone. In follow up, as in our case, many of those patients show
From the Department of Internal Medicine (Afzal) and Division of Cardiology
(Sarmast, Schussler), Baylor University Medical Center at Dallas and Baylor
Hamilton Heart and Vascular Hospital; and Texas A&M College of Medicine
(Schussler); and the University of Texas at Austin (Weber).
Corresponding author: Jeffrey M. Schussler, MD, 621 N. Hall Street, Suite 400,
Dallas, TX 75226 (e-mail: [email protected]).
367
a
b
complete angiographic resolution of
the dissection and do not need either
angioplasty or surgery (6, 7).
1.
2.
3.
4.
c
d
5.
6.
Figure 1. (a, b) Computed tomography coronary angiogram demonstrating an area of decreased density in the proximal
left anterior descending artery (LAD) concerning for dissection and intramural hematoma (arrows). (c) Coronary angiogram with hazy area in the proximal LAD, concerning for dissection with thrombus (arrow). (d) Intravascular ultrasound
confirming a proximal LAD dissection (arrows).
368
7.
Saw J. Spontaneous coronary artery dissection. Can J Cardiol 2013;29(9):1027–1033.
Kanwar M, Gill N. Spontaneous multivessel coronary artery dissection. J Invasive Cardiol 2010;22(1):E5–E6.
Weisler R, Young J, Mattingly G, Gao
J, Squires L, Adler L; 304 Study Group.
Long-term safety and effectiveness of lisdexamfetamine dimesylate in adults with
attention-deficit/hyperactivity disorder.
CNS Spectr 2009;14(10):573–585.
Adler LA, Weisler RH, Goodman DW,
Hamdani M, Niebler GE. Short-term
effects of lisdexamfetamine dimesylate
on cardiovascular parameters in a 4-week
clinical trial in adults with attentiondeficit/hyperactivity disorder. J Clin
Psychiatry 2009;70(12):1652–1661.
Schroder C, Stoler RC, Branning GB,
Choi JW. Postpartum multivessel spontaneous coronary artery dissection confirmed
by coronary CT angiography. Proc (Bayl
Univ Med Cent) 2006;19(4):338–341.
Tweet MS, Hayes SN, Pitta SR, Simari
RD, Lerman A, Lennon RJ, Gersh
BJ, Khambatta S, Best PJ, Rihal CS,
Gulati R. Clinical features, management, and prognosis of spontaneous
coronary artery dissection. Circulation
2012;126(5):579–588.
Maeder M, Ammann P, Angehrn W,
Rickli H. Idiopathic spontaneous
coronary artery dissection: incidence,
diagnosis and treatment. Int J Cardiol
2005;101(3):363–369.
Volume 28, Number 3
Worsening dyspnea in a 38-year-old woman
D. Luke Glancy, MD, Douglas K. Mendoza, MD, and Radhakrishnan G. Nair, MD
Figure 1. Electrocardiogram soon after admission showed left atrial enlargement (negative terminal P-wave deflection in lead V1 ≥ 0.1 mV and 0.04 s in duration)
(2) and right ventricular enlargement (right axis deviation of the QRS complex and R/S ratio V1 > 1.0 with a negative T V1) (3).
A
38-year-old Hispanic woman with longstanding exertional dyspnea sought medical attention because of
the recent onset of paroxysmal nocturnal dyspnea. Cardiac physical examination revealed murmurs of mitral
stenosis and regurgitation, a prominent a wave in the jugular
venous pulse, and a loud pulmonic valvular closure sound. An
electrocardiogram showed sinus rhythm, left atrial enlargement,
right axis deviation of the QRS complex, and an R/S ratio in
lead V1 > 1.0 with a negative T V1, suggesting right ventricular
hypertrophy (Figure 1).
At cardiac catheterization, the pressures (mm Hg) were
64/30 in the pulmonary artery, 65/8 in the right ventricle, a
mean of 7 in the right atrium with a waves of 10 and v waves
of 7, a mean of 26 with a waves of 17 and v waves of 38 in
the pulmonary arterial wedge position, and 96/6 in the left
ventricle. The cardiac output by thermodilution was 3.4 L/
min, which together with a 16 mm Hg mean diastolic pressure
gradient between pulmonary arterial wedge and left ventricle
gave a calculated mitral valve area of 0.7 cm2 (Figure 2). Angiocardiography revealed mild mitral regurgitation, trivial tricuspid
regurgitation, and no aortic regurgitation.
Rheumatic heart disease is the cause of mitral stenosis in
most adults. Because of the steady decrease in the incidence of
acute rheumatic fever over the past 75 years in the United States,
Figure 2. Simultaneous pulmonary arterial wedge and left ventricular pressure
tracings showing a 16 mm Hg mean diastolic pressure gradient across the mitral
valve (MVG). The pressure scale on each side of the tracing is in mm Hg. DFP
indicates diastolic filling period.
From the Sections of Cardiology, Department of Medicine, Louisiana State
University Health Sciences Center and the Interim LSU Hospital, New Orleans,
Louisiana. Currently, Dr. Mendoza is a cardiologist in Baton Rouge, Louisiana,
and Dr. Nair is a cardiologist in Plano, Texas.
Corresponding author: D. Luke Glancy, MD, 1203 West Cherry Hill Loop, Folsom,
LA 70437 (e-mail: [email protected]).
369
mitral stenosis is now uncommon here and is most often seen
in older patients and, as in this patient, in immigrants from less
developed countries (1).
Clinical evaluation is usually sufficient for making a diagnosis of mitral stenosis (1). The electrocardiogram can be
helpful in this regard, but the history, physical exam, chest
radiograph, and especially the echocardiogram are usually
more helpful. Nevertheless, electrocardiographic evidence of
left atrial enlargement and right ventricular hypertrophy in a
dyspneic young immigrant woman from an underdeveloped
country puts mitral stenosis toward the top of the list of diagnostic possibilities.
1.
2.
3.
Rahimtoola SH. Mitral stenosis. In Fuster V, Walsh RA, O’Rourke RA,
Poole-Wilson P, eds. Hurst’s The Heart, 12th ed. New York: McGraw Hill
Medical, 2008:1757–1769.
Morris JJ Jr, Estes EH Jr, Whalen RE, Thompson HK Jr, McIntosh HD.
P-wave analysis in valvular heart disease. Circulation 1964;29:242–252.
Milliken JA, Macfarlane PW, Lawrie TDV. Enlargement and hypertrophy.
In Macfarlane PW, Lawrie TDV, eds. Comprehensive Electrocardiology.
Theory and Practice in Health and Disease, Vol. 1. New York: Pergamon
Press, 1989:631–670.
Avocations
Cheetah and cub, Tanzania. Photo copyright © Jed Rosenthal, MD. Dr. Rosenthal is a cardiologist in Dallas, Texas (e-mail: [email protected]).
370
Volume 28, Number 3
Chronic pulmonary embolism in a young athletic woman
Timothy R. Larsen, DO, and Timothy C. Ball, MD, PhD
Exercise-induced dyspnea (EID) is a common complaint in young athletes. Exercise-induced bronchospasm (EIB) is the most common cause
of EID in healthy athletes, but it is important to recognize more serious
pathology. Herein we present the case of an 18-year-old woman with a
1.5-year history of EID. She had been treated for EIB without relief. Her
arterial oxygen saturation was 88% during exercise testing. Computed
tomographic angiography to assess for vascular abnormalities identified
a large thrombus in the main pulmonary trunk. Symptoms markedly
improved with therapeutic anticoagulation. Massive pulmonary embolus
is an exceedingly rare etiology of exertional dyspnea in young athletes.
Hypoxemia during exercise testing was an important clue that something
more ominous was lurking that required definitive diagnosis.
E
xercise-induced dyspnea (EID) is a common complaint
in young athletes. Exertional dyspnea in young, otherwise
healthy and active individuals can be challenging to diagnose and treat. Exercise-induced bronchospasm (EIB) is
recognized as the most common cause of EID in otherwise healthy
athletes (1). Patients with EIB typically experience wheezing, chest
tightness, coughing, and dyspnea that is due to transient narrowing
of the airways (bronchospasm) during or shortly after exercise (2).
EIB affects approximately 10% to 15% (3) of the general population. Athletes (particularly varsity and elite athletes) show a much
higher prevalence, around 40% (4, 5). The diagnosis of EIB is
often made on the basis of self-reported symptoms without objective testing. This approach is neither sensitive nor specific (6). It is
important for clinicians to recognize that EID in healthy adolescent
athletes may have causes other than asthma (7). Alternative causes
of EID should be sought when other symptoms of asthma are not
present, bronchodilators do not completely prevent or promptly
relieve EID, and baseline pulmonary function is normal (8). Correct diagnosis will not only prevent the use of medications destined
to fail but will occasionally uncover potentially life-threatening
disease. Herein we present a case of a young athlete with EID who
was initially misdiagnosed and treated empirically for EIB, which
led to delayed diagnosis of a life-threatening disease.
CASE DESCRIPTION
An 18-year-old woman presented to an outpatient cardiology
clinic for evaluation of exertional dyspnea worsening over the past
1.5 years. Her medical history was significant for the diagnosis
of exercise-induced asthma treated with as-needed short-acting
bronchodilators. Her only other medication was an oral contraceptive (desogestrel-ethinyl estradiol 0.15–30 mg–mcg). She
did not use tobacco, alcohol, or recreational or performanceenhancing drugs. She was an active athlete participating in varsity
basketball, volleyball, and track. Approximately 1.5 years prior
to presentation, she developed sudden worsening dyspnea with
minimal exertion and associated presyncope. Symptoms were provoked by 5 minutes of aerobic exertion and relieved with <5 minutes of rest. She did not experience wheezing, and albuterol did
not provide relief. Her blood pressure was 102/56 mm Hg; heart
rate, 52 beats/minute; respiratory rate, 18 breaths/minute; resting
oxygen saturation, 99% breathing ambient air; and body mass
index, 21.3 kg/m2. She was physically fit, in no distress, and had
no conversational dyspnea. Cardiac and pulmonary exams were
normal. Her abdomen was soft, nontender, nondistended, and
without masses or organomegaly. There was no peripheral edema;
peripheral pulses were full and equal bilaterally. Further, there was
no calf tenderness, and Homman’s sign was absent.
Initial laboratory data revealed normal serum electrolytes, blood counts, and renal and liver function. Quantitative
D-dimer was 0.42 ug FEU/mL (normal <0.48 ug FEU/mL).
Chest x-ray showed subtle findings, including elevation of
the left hemidiaphragm and a Westermark sign (cutoff of the
left main pulmonary artery) (Figure 1). An electrocardiogram
showed sinus bradycardia, normal intervals and voltage, and
no ST segment abnormalities (Figure 2). Pulmonary function
testing showed normal spirometry, lung volumes, and diffusing capacity; there was no change with bronchodilator. Resting transthoracic echocardiogram showed the left ventricular
ejection fraction to be 60% to 65%. There was mild tricuspid
regurgitation (maximum regurgitant velocity of 2.26 m/s), and
the estimated pulmonary artery systolic pressure was 25 mm Hg.
Right ventricular basal diameter was 42 mm (normal ≤ 42 mm);
From the Section of Cardiology, Department of Internal Medicine, Virginia TechCarilion School of Medicine, Roanoke, Virginia.
Corresponding author: Timothy R. Larsen, DO, Section of Cardiology, Department
of Internal Medicine, Carilion Clinic, Virginia Tech Carilion School of Medicine,
2001 Crystal Spring Avenue, Suite 203, Roanoke, VA 24014 (e-mail: tlarsen17@
gmail.com).
371
was 170 beats/min (84% of her age-predicted maximum).
Arterial oxygen saturation was 88% at peak exercise. Computed tomography (CT) angiogram of the chest showed a large
intraluminal thrombus within the left main pulmonary artery
extending into the right and left pulmonary arteries (Figure 4).
The left pulmonary artery was completely occluded (Figure 5).
Protein C activity was 116% (normal 70%–130%), protein S
activity was 70% (normal 55%–123%), and antithrombin III
activity was 92% (normal 80%–120%). Assays for cardiolipin
IgG, IgM, and IgA were within the normal range. Two tests for
lupus anticoagulant were negative (DRVVT screen and PTTLupus reagent). There was no evidence of activated protein C
resistance. DNA testing for Factor V Leiden and prothrombin
II gene mutations were negative.
Therapeutic anticoagulation was started with warfarin. After
6 weeks of anticoagulation, she noted marked improvement in
functional capacity, nearly back to previous baseline. A followup CT angiogram at 8 weeks showed marked improvement in
thrombus burden.
Figure 1. Chest x-ray showing cutoff of the left pulmonary artery, Westermark
sign (arrow), and elevation of the left hemidiaphragm.
mid ventricle, 32 mm (normal ≤ 35 mm); and longitudinal
length, 56 mm (normal ≤ 86 mm) (Figure 3). Tricuspid annular plane systolic excursion (TAPSE) was 16.4 mm (abnormal
≤ 16 mm), and systolic excursion velocity was 10.57 cm/s
(abnormal ≤ 10 cm/s).
The patient exercised for 5:32 minutes on a Bruce treadmill protocol (maximum speed 3.4 mph, 14% grade). She
reached 6.2 metabolic equivalents. Her maximum heart rate
DISCUSSION
Massive pulmonary embolus (PE) is an exceedingly rare
etiology for exertional dyspnea in young athletes. Young athletes often do not present with classic symptoms associated
with PE; thus, these patients are often treated for a number
of other conditions before the correct diagnosis is reached
(9). Hypoxemia during exercise testing was an important
clue that something more ominous was lurking. Normal
pulmonary function testing (spirometry, lung volumes, and
diffusing capacity) make primary lung pathology less likely.
Figure 2. Electrocardiogram demonstrating sinus bradycardia (heart rate 56 bpm), normal intervals and voltage, and no ST segment or T wave abnormalities.
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Volume 28, Number 3
Figure 5. CT angiogram with three-dimensional volume rendering in the anterior
and posterior view demonstrating the absence of left pulmonary artery (PA)
circulation.
Figure 3. Transthoracic echocardiogram with an apical four-chamber view at
end diastole demonstrating right ventricle (RV) dimensions at the upper limit of
normal; an RV diameter at the base of 42 mm; mid ventricle 32 mm; and long
axis 56 mm. The function of the left ventricle (LV) was normal.
Causes of exertional dyspnea with hypoxia in a young athlete
(with healthy lungs) are typically related to vascular abnormalities usually resulting in right-to-left shunting or large
ventilation-perfusion defects (functional right-to-left shunt).
Important considerations include anomalous venous return
(10), intrapulmonary arteriovenous malformations (11), and
intravascular obstruction (such as PE). Large occlusive PEs
cause a functional right-to-left shunt. Shunting occurs due
to severe ventilation-perfusion mismatch, which results in a
large increase in total dead space with adjacent areas of excess
perfusion (12). Shunting is more pronounced in the presence
of an atrial septal defect or patent ductus arteriosus as pulmonary pressure increases (due to increased pulmonary vascular
resistance) flow through the defect increases.
Figure 4. CT angiogram demonstrating a large intraluminal filling defect in the
main pulmonary trunk (arrow) extending into both the right and left pulmonary
arteries. Note the paucity of vascular markings over the left lung field.
July 2015
The test of choice for the diagnosis of pulmonary vascular
disorders is pulmonary angiography and chest CT (13, 14).
Once PE has been confirmed, interventions are targeted at disruption of the coagulation cascade to minimize ongoing thrombosis. Therapeutic anticoagulation is the mainstay of therapy. In
patients with high-risk PEs (particularly cardiogenic shock and/
or persistent arterial hypotension), thrombolysis, percutaneous catheter embolectomy and fragmentation, and/or surgical
embolectomy should be considered. A major clinical decision
in our patient is the duration of anticoagulation. Indefinite
anticoagulation reduces the risk of subsequent venous thromboembolism by approximately 90%; the major disadvantages are
increased risk of bleeding and the inconvenience of anticoagulation over the lifetime of our young patient (15, 16).
Plasma levels of D-dimer increase in the presence of acute
thrombi. D-dimer has a low positive predictive value but a high
negative predictive value. Barring laboratory error, our patient’s
negative D-dimer may be due to chronic organized thrombus
or may simply be a false negative.
Our patient was investigated for hypercoagulable conditions with entirely normal results. The only identifiable risk
factor for thromboembolism was the use of a combined oral
contraceptive preparation. She had been taking an oral contraceptive prior to symptom onset and continued it until the
time of diagnosis. While oral contraceptives increase the risk of
venous thromboembolic disease by about 3 to 6 times that of
similar patients not taking them, the absolute risk is still quite
low, at 3 to 4 per 10,000 woman-years (17). The relative risk
of thromboembolism in patients using oral contraceptives is
about half that of pregnancy (18). A progestin-only preparation
would be an appropriate substitution for future contraception
while minimizing the risk of recurrent thromboembolism in a
patient such as ours. (Our patient opted to forego hormonal
prophylaxis.)
While EIB is the most common cause of EID in young athletes, it is imperative that physicians recognize alarming features
that may suggest more serious underlying pathology. Massive PE
Chronic pulmonary embolism in a young athletic woman
373
is an exceedingly rare etiology of exertional dyspnea in otherwise
healthy young athletes. Appropriate and timely intervention can
prevent serious morbidity and mortality.
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374
Koehle M, Lloyd-Smith DR, McKenzie DC. Exertional dyspnea in athletes. Br Columbia Med J 2003;45(10):508–514.
Godfrey S, Anderson SD, Silverman M. Physiologic aspects of exerciseinduced asthma. Chest 1973,63(Suppl):365–375.
Seear M, Wensley D, West N. How accurate is the diagnosis of exercise induced asthma among Vancouver schoolchildren? Arch Dis Child
2005;90(9):898–902.
Feinstein RA, LaRussa J, Wang-Dohlman A, Bartolucci AA. Screening adolescent athletes for exercise-induced asthma. Clin J Sport Med
1996;6(2):119–123.
Parsons JP, Kaeding C, Phillips G, Jarjoura D, Wadley G, Mastronarde
JG. Prevalence of exercise-induced bronchospasm in a cohort of varsity
college athletes. Med Sci Sports Exerc 2007;39(9):1487–1492.
Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR.
Self-reported symptoms and exercise-induced asthma in the elite athlete.
Med Sci Sports Exerc 2001;33(2):208–213.
Löwhagen O, Arvidsson M, Bjärneman P, Jörgensen N. Exercise-induced
respiratory symptoms are not always asthma. Respir Med 1999;93(10):734–
738.
Abu-Hasan M, Tannous B, Weinberger M. Exercise-induced dyspnea in
children and adolescents: if not asthma then what? Ann Allergy Asthma
Immunol 2005;94(3):366–371.
Koehle M, Lloyd-Smith DR, McKenzie DC. Exertional dyspnea in
athletes. Br Columbia Med J 2003;45(10):508–514.
10. Valencia PA, Oeckler RA, Taggart NW, Bonnichsen CR. Levoatriocardinal
vein: an unusual cause of hypoxemia in the intensive care unit. Am J Respir
Crit Care Med 2014;A4842.
11. Weiss P, Rundell KW. Imitators of exercise-induced bronchoconstriction.
Allergy Asthma Clin Immunol 2009;5(1):7–15.
12. Goldhaber SZ, Elliott CG. Acute pulmonary embolism: part I: epidemiology, pathophysiology, and diagnosis. Circulation 2003;108(22):2726–
2729.
13. Remy J, Remy-Jardin M, Giraud F, Wattinne L. Angioarchitecture of pulmonary arteriovenous malformations: clinical utility of three-dimensional
helical CT. Radiology 1994;191(3):657–664.
14. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk
P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E,
Remy-Jardin M, Bassand JP; ESC Committee for Practice Guidelines
(CPG). Guidelines on the diagnosis and management of acute pulmonary
embolism: the Task Force for the Diagnosis and Management of Acute
Pulmonary Embolism of the European Society of Cardiology (ESC). Eur
Heart J 2008;29(18):2276–2315.
15. Research Committee of the British Thoracic Society. Optimum duration
of anticoagulation for deep-vein thrombosis and pulmonary embolism.
Lancet 1992;340(8824):873–876.
16. Schulman S; Duration of Anticoagulation Study Group. The effect of the
duration of anticoagulation and other risk factors on the recurrence of
venous thromboembolisms. Wien Med Wochenschr 1999;149(2–4):66–69.
17. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk
of venous thrombosis. N Engl J Med 2001;344(20):1527–1535.
18. Weiss G. Risk of venous thromboembolism with third-generation oral
contraceptives: A review. Am J Obstet Gynecol 1999;180(2 Pt 2):295–301.
Volume 28, Number 3
Nonhepatic hyperammonemic encephalopathy
due to undiagnosed urea cycle disorder
Tashfeen Mahmood, MD, and Kenneth Nugent, MD
Ornithine transcarbamoylase deficiency is the most common inherited
urea cycle disorder. In adults, its phenotypes are diverse. In asymptomatic
patients with late presentations, symptom onset is often associated with
a precipitating factor. We present a case of a woman with urea cycle
disorder diagnosed after an acute peptic ulcer bleed and fasting.
U
rea cycle disorders are commonly seen in the pediatric
population. Several enzymes are involved in this cycle,
and a defect in any of them can lead to specific laboratory abnormalities and variable clinical presentations.
Deficiency of the enzyme ornithine transcarbamoylase (OTC)
is the most common inherited urea cycle disorder. In adults, its
phenotypes range from severe encephalopathy to subtle psychiatric manifestations to apparently asymptomatic states. Among
asymptomatic patients with late presentations, symptom onset
may be associated with a precipitating factor, such as trauma,
surgery, infection, and/or increased protein intake. We present
a case of a woman who had undiagnosed urea cycle disorder
that was unmasked by an acute peptic ulcer bleed and fasting
for several days.
CASE REPORT
A 35-year-old white woman with prior peptic ulcer disease
and menorrhagia was taken to a local emergency department for
an altered level of consciousness and transferred to our medical
intensive care unit. She had been alone for 5 days when her
family found her lethargic, confused, and minimally responsive.
The patient apparently had been withdrawn for 1 year with low
self-esteem, occasionally stating that she wished she were dead.
Home medications included pantoprazole and norgestimate/
ethinyl estradiol. She was currently single and unemployed
and had few friends and no children. Examination disclosed
normal vital signs. Neurological examination revealed a minimally responsive woman without apparent focal deficits and
normal reflexes. She had no nuchal rigidity. Initial laboratory
work showed a normal metabolic panel, thyroid function tests,
and liver function tests, including aminotransferases, albumin,
bilirubin, and prothrombin time. She had anemia with a hemoglobin of 8.1 g/dL, a guaiac-positive stool, and a ferritin level of
8 ng/mL (reference range, 12–150 ng/mL). A urine drug screen
was negative; acetaminophen, alcohol, and salicylate levels were
undetectable. Computed tomography (CT) and magnetic resonance images of the head were within normal limits.
On the night of admission, the patient had an episode of
hematemesis, and her hemoglobin dropped to 6.6 g/dL. The
next morning she had decerebrate posturing to pain, a decline
in responsiveness, twitching movements in her left leg, and
plantar flexion of both feet. A repeat CT scan was normal, and
electroencephalography did not reveal any subclinical epileptiform discharges. She was intubated, and an esophagogastroduodenoscopy showed an actively bleeding duodenal ulcer that
was cauterized.
Her ammonia level was 593 mcg/dL (reference range,
15–45 mcg/dL). The patient was started on lactulose, rifaximin, and a low-protein diet. Her subsequent ammonia level
in 4 hours dropped to 266 mcg/dL, which continued to improve over the next few hours. A liver ultrasound was within
normal limits, and her liver enzymes were normal throughout
her hospitalization. She gradually improved, with her ammonia level returning toward normal over the next several days.
She had a plasma citrulline of 20 nmol/mL (reference range,
30–45 nmol/mL) and a urine orotic acid level of 1.8 mmol/
mol creatinine (reference range, 0.4–1.2 mmol/mol creatinine),
levels consistent with OTC deficiency. She was discharged home
on lactulose and a low-protein diet.
DISCUSSION
The urea cycle is the metabolic pathway that converts nitrogen to urea for excretion from the body (Figure 1). A deficiency in one of the enzymes in this pathway causes a urea cycle
disorder (1), and all deficiencies except arginase cause severe
hyperammonemia. The amino acid products of endogenous
and exogenous protein digestion are degraded by hepatic transamination and oxidative deamination to produce ammonia,
which is then converted to urea via the six enzymes of the urea
cycle (Table) and excreted by the kidneys (2). The most common genetic disorder of the urea cycle is a deficiency in OTC
From the Department of Internal Medicine, Texas Tech University Health Science
Center, Lubbock, Texas.
Corresponding author: Tashfeen Mahmood, MD, 3601 4th Street, Lubbock, TX
375
Figure 1. Urea cycle disorders. ARG indicates arginase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; CPS1, carbamoylphosphate synthetase 1;
ORNT1, ornithine transporter 1; OTC, ornithine transcarbamoylase.
(3). Partial OTC deficiency has a variable presentation (4), but
its symptoms are caused by hyperammonemia secondary to
accumulation of precursors of urea, primarily ammonia and
glutamine (2). The clinical presentation of hyperammonemia
caused by OTC deficiency varies with the age of the patient. In
infants, hyperammonemia is associated with lethargy, poor sucking response, vomiting, hypotonia, and seizures (5). In adults, its
phenotypes are diverse, ranging from severe encephalopathy to
apparently asymptomatic states (6). The OTC gene is encoded
on the X chromosome and is expressed in the mitochondrial
matrix of the small intestine and liver, where it catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine (2).
OTC deficiency has an estimated incidence of 1 in 82,000
live births in the USA and is the only X-linked urea cycle disorder (2). The biochemical and molecular bases of OTC deficiency
have a wide spectrum of genetic defects, resulting in different
Table. Urea cycle defects
Enzyme deficiency
Location
Incidence
Genetics
Presentation
↑↑NH3 in newborns
Distinct labs
+NH3, low CIT, low ARG, normal urine OA
1. CPS1: Carbamoyl phosphate synthetase Mitochondria
1:1,300,000 AR
2. OTC: Ornithine transcarbamylase
Mitochondria
1:56,500
0–30% EA
X-linked Risk of ↑NH3 high in
dominant pregnancy
+OR, +UR, +UOA, low plasma CIT
3. ASS: Argininosuccinic acid synthetase
(citrullinemia)
Cytosol
1:250,000
AR
Some nitrogen incorp
in UC
++CIT, absent AS, fibroblast EA
4. ASL: Argininosuccinate lyase
(argininosuccinic aciduria)
Cytosol
1:218,750
AR
Rap in infants, Rx ARG
+CIT, +ASA
5. ARG: Arginase (hyperargininemia)
Cytosol
1:950,000
AR
Often normal NH3,
spasticity, ataxia
+ARG
7. NAGS: N-acetylglutamate synthetase
Mitochondria
1:2,000,000 AR
8. ORNT1: Ornithine transporter
Gene mutation
↑NH3 may respond to NAG +NH3
Membrane transporter
+NH3,+OR, +homocitrulline
AR indicates autosomal recessive; ARG, arginine; AS, argininosuccinate; ASA, argininosuccinate acid; CIT, citrulline; EA, enzyme assay; NAG, N-acetylglutamate; NH3, ammonia;
OA, orotic acid; OR, ornithine; UC, urea cycle; UOA, urine orotic acid; UR, uracil.
376
Volume 28, Number 3
phenotypes (7). Mutations that abolish all enzyme activity are
found in the neonatal-onset group; mutations causing partial
enzyme deficiency are found in the late-onset group (8). Among
asymptomatic patients with late presentation, symptom onset
is often associated with a precipitating factor, such as infection,
trauma, medications (sodium valproate), surgery, pregnancy,
excess protein intake, and physiological stress (9, 10). Patients
with partial urea cycle disorders may exhibit psychological
or cognitive difficulties, presumably due to chronic low-level
hyperammonemia, before their presentation with a hyperammonemic crisis (11, 12). Some patients report self-selection of
vegetarian diets, stating that high protein intake makes them
sick (11). Due to its diverse phenotypic presentations and rarity in the adult population, hyperammonemic crisis resulting
from a partial urea cycle disorder is probably underdiagnosed.
An elevated serum ammonia level, particularly with normal
liver enzymes and the absence of relevant medications, should
suggest an inborn error of metabolism and prompt treatment of
the hyperammonemic state followed by measurement of plasma
amino acid and urine orotic acid levels.
There are case reports in which neuropsychiatric and/or neurodevelopmental disturbances represented the initial manifestations and main clinical signs of the disease. Mental retardation,
attention-deficit hyperactivity disorder, oppositional defiant disorder, and problems in communication, such as autistic-like behavior, have been reported. Delirium, confusion, and incoherent
speech can occur. Moreover, episodes of depressed consciousness
were misdiagnosed in one series and erroneously interpreted as
psychiatric disorders. These patients responded well to dietary
modifications and ammonia-lowering therapy (13). Our patient
had recent neuropsychiatric problems, including regression, lack
of attention leading to job loss, and introverted behavior, but a
formal psychiatric diagnosis was not available.
Due to the rarity of these disorders, most physicians have
relatively little experience with management. Treatment for
acute hyperammonemia should be started before the precise
diagnosis is made to reduce production of nitrogenous waste
and to lower plasma ammonia levels quickly. This is achieved
by withdrawing all protein for 24 to 48 hours, supplying a
hypercaloric, protein-free solution with insulin to enhance
anabolism (14), infusing arginine, and exploiting alternative
pathways for excretion of waste nitrogen. A loading dose of Larginine hydrochloride, sodium benzoate, and sodium phenyl
July 2015
acetate is given intravenously over 90 minutes, followed by
sustained infusion over 24 hours until the patient is no longer
hyperammonemic and oral therapy can be tolerated. Hemodialysis should be considered in patients with persistently high
ammonia levels (15).
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University of Washington, Seattle, 1993–2015. Available at http://www.
ncbi.nlm.nih.gov/books/NBK1217/; accessed April 8, 2015.
Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996;43:127–170.
Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 2000;105(1):e10.
Tuchman M, Jaleel N, Morizono H, Sheehy L, Lynch MG. Mutations
and polymorphisms in the human ornithine transcarbamylase gene. Hum
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in the newborn infant. J Pediatr 1973;82(4):642–649.
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Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J
Med Genet 2000;93(4):313–319.
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Tuchman M, Morizono H, Rajagopal BS, Plante RJ, Allewell NM. The
biochemical and molecular spectrum of ornithine transcarbamylase deficiency. J Inherit Metab Dis 1998;21(Suppl 1):40–58.
Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect.
Eur J Paediatr Neurol 2003;7(3):115–121.
Ellaway CJ, Bennetts B, Tuck RR, Wilcken B. Clumsiness, confusion,
coma, and valproate. Lancet 1999;353(9162):1408.
Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ,
Sniderman King L, Christman BW. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005;21(4 Suppl):S1–S8.
Lien J, Nyhan WL, Barshop BA. Fatal initial adult-onset presentation of
urea cycle defect. Arch Neurol 2007;64(12):1777–1779.
Serrano M, Martins C, Pérez-Dueñas B, Gómez-López L, Murgui E, Fons
C, García-Cazorla A, Artuch R, Jara F, Arranz JA, Häberle J, Briones P,
Campistol J, Pineda M, Vilaseca MA. Neuropsychiatric manifestations in
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Singh RH. Nutritional management of patients with urea cycle disorders.
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Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A.
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Nonhepatic hyperammonemic encephalopathy due to undiagnosed urea cycle disorder
377
Anaplastic large-cell lymphoma in AIDS
Michael L. Krol, MD, Varsha Podduturi, MD, Abdulla Majid-Moosa, MD, John R. Krause, MD, and Adan Mora Jr., MD
AIDS-related malignancies may alter clinical courses and result in death
in critically ill patients. We present a case of a newly diagnosed AIDS
patient with Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and
cytomegalovirus infections who was found to have widely metastatic
kinase-negative anaplastic large-cell lymphoma. This case demonstrates
the diversity in the malignant presentation of HIV-infected patients, outside of the more commonly observed non-Hodgkin lymphomas.
A
naplastic large-cell lymphoma (ALCL) is rarely associated with HIV-infected patients. We describe a case of
a newly diagnosed HIV-positive man with pathologyconfirmed ALCL and a co-occurring Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus
infection.
CASE PRESENTATION
A 55-year-old man with newly diagnosed HIV presented to
the hospital for a recent onset of fever and a 1-month history
of shortness of breath, fatigue, nonproductive cough, night
sweats, dysphagia, and a 20-lb unintentional weight loss. He
had only received 2 days of highly active antiretroviral therapy
prior to presentation. His CD4 cell count was 5/mm3, with a
viral load of 609,639 copies/mL on admission. On physical
exam, the patient was tachypneic, with evidence of thrush but
no lymphadenopathy or splenomegaly initially noted. He was
pancytopenic; his white blood cell count was 4.3 K/uL, with
77% neutrophils and 12% monocytes, his hemoglobin level was
8.7 g/dL, and his platelet count was 124/mcL. He had a lactate
of 4.3 mmol/L and an elevated lactate dehydrogenase (LDH)
of 900 IU/L and was hypoxic, with arterial oxygen of 40 mm
Hg. On admission, a two-view chest x-ray showed a subtle increased density in the right infrahilar region, with no evidence
of pleural effusion, adenopathy, or consolidation (Figure 1a).
The patient was initially treated for P. jiroveci pneumonia with
steroids, Bactrim, and then with addition of pentamidine after
limited clinical improvement and persistent elevation in LDH,
bandemia, and ongoing lactic acidosis.
Over the next few days, he made modest improvement in
respiratory function and was able to be weaned from bilevel
positive airway pressure to high-flow nasal canula. A cytomega378
lovirus PCR test was positive, and he was started on valganciclovir. On hospital day 10, the patient had an acute worsening
hypoxia and became tachycardic and febrile, requiring emergent intubation. He also had a new finding of enlarged inguinal
lymph nodes. He was more edematous, precluding appreciation
of any additional lymphadenopathy. Abdominal ultrasound at
that time showed two hepatic masses and splenomegaly. The
patient continued a rapidly progressive decline, with worsening multiorgan failure attributed to sepsis despite negative
cultures and precluding additional diagnostic studies due to
his hemodynamic instability. All blood cultures obtained had
no bacterial growth. He died on hospital day 14. An autopsy
was performed.
At autopsy, the right and left lungs weighed 1475 and
1175 g, respectively. The lung parenchyma was diffusely consolidated. The pleural surfaces were indurated, with nodules
averaging 0.5 cm in diameter. There was splenomegaly (1050 g),
hepatomegaly (2000 g), and widespread lymphadenopathy
within the chest and abdomen (up to 4.0 cm in greatest diameter). Microscopic evaluations of the lymph nodes revealed
architectural effacement, composed of large, atypical lymphoid
cells, with prominent nucleoli. Tumor cells were also present
in the large upper lobe nodule and the smaller blood vessels
throughout the lungs and pleural space (Figure 1b). The bone
marrow was devoid of neoplastic cells.
Neoplastic lymphoid cells were diffusely immunohistochemically positive for CD30 and focally positive for CD3
(a T-cell marker) and epithelial membrane antigen. Cells were
strongly positive by Epstein-Barr virus–encoded RNA (EBER)
in situ hybridization. The tumor cells were negative for anaplastic lymphoma kinase (ALK) protein, B-cell markers (BCL6
and CD20), T-cell markers (CD56, TIA-1, CD4, CD5, CD7,
CD43), and HHV-8, PAX5, and CD10. Mitotic activity, or
Ki-67, measured 20% to 25%, with focal areas of 60% to 65%.
T-cell receptor gamma gene rearrangement and IgH receptor
From the Department of Internal Medicine (Krol, Majid-Moosa), Department of
Pathology (Podduturi, Krause), and Division of Pulmonary Disease (Mora), Baylor
University Medical Center at Dallas.
Corresponding author: Adan Mora Jr., MD, Division of Pulmonary Disease,
Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX
a
c
b
Figure 1. (a) Posterioanterior chest x-ray showing subtle increased density in the right infrahilar region, with no evidence of pleural effusion, adenopathy, or consolidation. (b) Anaplastic large-cell lymphoma, hematoxylin and eosin, 400×. (c) Pneumocystis jiroveci, Gomori methenamine silver stain, 1000×. Special thanks to
Joseph Manuel Guileyardo, MD, for providing the autopsy images.
gene rearrangement were unable to yield results due to the poor
quality of DNA present in the sample.
The final diagnosis was ALK-negative ALCL arising in a setting of HIV. There was widespread lymphomatous involvement
of liver, gallbladder, spleen, kidney, lung, stomach, and heart.
Other findings included right and left ventricular dilatation,
Pneumocystis pneumonia (Figure 1a), bilateral cytomegalovirus
adrenalitis, and an incidental appendiceal carcinoid tumor. Postmortem blood cultures were positive for vancomycin-resistant
Enterococcus spp.
DISCUSSION
The World Health Organization (WHO) classification
scheme classifies lymphoid neoplasms based on their cell of
origin. Peripheral T-cell lymphoma (PTCL) arises from and
resembles the phenotype of a mature T cell (1). PTCL accounts
for about 5% to 10% of non-Hodgkin lymphomas in the general US population, with an incidence of <1 per 100,000 people
(2, 3). PTCL is further subdivided into nodal, extranodal, and
leukemic subgroups. ALCL is the least common subtype within
the nodal subgroup, representing 12% of the PTCL cases worldwide (4, 5). ALCL is distinguishable based on the strong and
diffuse CD30-positive staining of the malignant cells compared
to scattered CD30 staining in the more commonly identified
PTCL-not otherwise specified (25.9% of PTCL cases).
In 2008, the WHO classification further subdivided ALCL
based on the presence or absence of an ALK protein (1). On
presentation, ALK-negative ALCL is more likely than ALKpositive tumors to be found in older patients, with more advanced (stage 3 or 4) disease and with increased involvement of
extranodal sites, including lung, liver, and skin. ALK-negative
ALCL is a more aggressive and less responsive disease, with
studies suggesting 5-year overall survival rates of 49% vs. 70%
for ALK-positive ALCLs (4).
In HIV-infected patients, non-Hodgkin lymphoma is the
most prevalent malignancy. PTCL is less common, occurring
in only 12% to 15% of HIV-affected individuals with lymphoma, of which ALCL only accounts for 28% of cases (6, 7).
Thus, with the limited available data, most of our knowledge
on ALCL in the HIV patient population is based on a comprehensive review of 37 HIV-associated ALCL patients. This
case review demonstrated that ALCL was predominantly ALK
July 2015
negative, with an average patient age of 38 years and a mean
CD4 count of 83 cells/mm3. Among the cases studied, onethird were EBER positive and 78% of patients presented with
advanced lymphoma (stage 3/4), with all showing extranodal
involvement including lungs, liver, bone marrow, spleen, and
myocardium.
The present case furthers the knowledge of HIV-associated
ALCL. The patient had a unique presentation, including newly
diagnosed HIV. He also had an AIDS-defining illness of P.
jiroveci pneumonia on the onset of presentation, along with
cytomegalovirus infection and Epstein-Barr virus. In Perez and
colleagues’ (2010) review, they found that only 11 of the 37
case reports of ALCL in HIV patients had another underlying
AIDS-defining illness.
Regarding treatment, chemotherapy options are usually
based around CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like therapies. For relapsed/
refractory T-cell lymphomas, preliminary data support the use
of autologous stem-cell transplantation to increase progressionfree survival (8). Additional promising research is focused on
anti-CD30 monoclonal antibodies, with positive preliminary
response in previously treated ALK-negative patients (9, 10).
Undoubtedly, the emergence of novel and targeted therapies will
increase our ability to treat and manage ALCL in the future.
1.
2.
3.
4.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele
J, Vardiman JW. WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues, 4th ed. Lyon, France: International Agency for Research
on Cancer Press, 2008:380–428.
Ascani S, Zinzani PL, Gherlinzoni F, Sabattini E, Briskomatis A, de Vivo
A, Piccioli M, Fraternali Orcioni G, Pieri F, Goldoni A, Piccaluga PP,
Zallocco D, Burnelli R, Leoncini L, Falini B, Tura S, Pileri SA. Peripheral T-cell lymphomas. Clinico-pathologic study of 168 cases diagnosed
according to the R.E.A.L. classification. Ann Oncol 1997;8(6):583–592.
Anderson JR, Armitage JO, Weisenburger DD; Non-Hodgkin’s
Lymphoma Classification Project. Epidemiology of the non-Hodgkin’s
lymphomas: distributions of the major subtypes differ by geographic
locations. Ann Oncol 1998;9(7):717–720.
Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, Rimsza
L, Pileri SA, Chhanabhai M, Gascoyne RD, Armitage JO, Weisenburger
DD; International Peripheral T-Cell Lymphoma Project. ALK– anaplastic
large-cell lymphoma is clinically and immunophenotypically different
from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise
specified: report from the International Peripheral T-Cell Lymphoma
Project. Blood 2008;111(12):5496–5504.
Anaplastic large-cell lymphoma in AIDS
379
5.
6.
7.
Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma
Project. International peripheral T-cell and natural killer/T-cell
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol
2008;26(25):4124–4130.
Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong
TC, Holmberg SD, Brooks JT; Adult and Adolescent Spectrum of
Disease Project and HIV Outpatient Study Investigators. Incidence
of types of cancer among HIV-infected persons compared with the
general population in the United States, 1992–2003. Ann Intern Med
2008;148(10):728–736.
Perez K, Castillo J, Dezube BJ, Pantanowitz L. Human immunodeficiency virus–associated anaplastic large cell lymphoma. Leuk Lymphoma
2010;51(3):430–438.
8.
Reimer P, Rüdiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N,
Engert A, Einsele H, Müller-Hermelink HK, Wilhelm M. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell
lymphomas: results of a prospective multicenter study. J Clin Oncol
2009;27(1):106–113.
9. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers
EL, Forero-Torres A. Brentuximab vedotin (SGN-35) for relapsed
CD30–positive lymphomas. N Engl J Med 2010;363(19):1812–1821.
10. Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett
NL, Bosly A, Pinter-Brown L, Kennedy D, Sievers EL, Gopal AK.
A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol
2009;146(2):171–179.
Avocations
Hermits in the Open
Hydraulics multiply
While muscles atrophy.
Through the evolution-scope
See the wasted limbs!
Creeping concrete around the globe
At a dizzying pace.
Creatures moving fast and furious
Up and down the terrain.
Suffocating, burning fossil,
Visible air to breath
Suspended sewers above the tarmac
Rise higher and higher.
Menacing soot defaces sun,
Vital rays are under siege.
Confused are the sunflowers
Wondering where to look.
Shadows used to embrace strangers
In the golden rays––
Masked faces, lost embraces,
Hermits in the open.
—Amanullah Khan, MD, PhD
Copyright © 2013 by Amanullah Khan. Reprinted from Sifting Shades (Dog Ear Publishing, 2013). Dr. Khan (e-mail: [email protected])
is an oncologist on the medical staff of Baylor Medical Center at McKinney.
380
Volume 28, Number 3
Primary follicular lymphoma of the duodenum
Robbie L. Graham, MD, Mabel A. Mardones, MD, and John R. Krause, MD
Follicular lymphoma, a common nodal lymphoma, is rare in the gastrointestinal tract. When seen in this location, duodenal involvement is frequent.
Most patients have localized disease, and survival appears to be excellent
even without treatment. Although the outcomes are improved, the morphologic, immunophenotypic, and genetic features remain similar to those of
nodal follicular lymphomas. We describe a woman with de novo follicular
lymphoma of the duodenum and discuss the features of this remarkably
indolent variant of follicular lymphoma.
P
rimary gastrointestinal (GI) follicular lymphoma (FL)
is a unique, uncommon variant of FL. Most cases of
primary FL of the GI tract occur in the small intestine,
with involvement of the second portion of the duodenum predominating (1). Usually an incidental finding on
endoscopy for other reasons, FL of the duodenum is a remarkably indolent form of FL that even when left untreated usually
does not develop tumorous growth, very rarely disseminates,
and does not transform into high-grade disease (2). We report
a case of de novo primary FL of the duodenum.
CASE PRESENTATION
A 52-year-old previously healthy Caucasian woman presented with 2 years of intermittent epigastric abdominal pain
associated with nausea and vomiting. These symptoms were
typically self-limiting, lasting 3 to 5 days with no clear exacerbating factors. In between her recurrent abdominal pain crises,
she remained very healthy and functional. There was no history
of foreign travel. She denied any fevers, chills, night sweats,
weight loss, diarrhea, or fatigue. She sought care for her symptoms, which initially included a computed tomography (CT)
scan of the abdomen. This revealed segmental thickening of
the proximal small bowel beginning at the ligament of Treitz
with extension over a length of 10 cm with associated mesenteric adenopathy (largest lymph node measuring 3.0 × 1.2 cm).
Her blood work, including complete blood count, complete
metabolic panel, and peripheral smear, were all unremarkable.
She was referred to an outpatient gastroenterologist who
performed a small bowel enteroscopy that revealed nodular mucosa with plaque-like lesions present in the second and third part
of the duodenum and proximal jejunum. Biopsies of the esophaProc (Bayl Univ Med Cent) 2015;28(3):381–383
gus, stomach, duodenum, and jejunum were taken. A DiffQuik stain of the stomach biopsy was negative for Helicobacter
pylori. Morphologically, the duodenal lesions showed an
infiltrate within the lamina propria that consisted of small
irregular lymphocytes forming large follicles as well as sheets
(Figure 1a). Since this finding was highly concerning for lymphoma, immunohistochemical stains were performed and
showed the infiltrates to be CD20 strongly positive, CD3/CD5
negative, CD10 weakly positive, and Bcl2 strongly positive
(Figure 1b), with a Ki-67 (proliferation index) of 25% to 30%.
The findings were consistent with grade 1 to 2 follicular
lymphoma of the duodenum, which is a variant of FL also
known as primary intestinal follicular lymphoma. Further
staging included a positron emission tomography scan, which
revealed mild to moderate hypermetabolic activity in the
distal duodenum and proximal jejunum and nearby mildly
metabolic mesenteric lymph nodes. Additionally, mild hypermetabolic activity was also detected in the gastric fundus,
the junction of the second and third portions of the duodenum, and a 3.5 cm area in the proximal transverse colon.
Her stage was determined to be stage IIA, E. It remained
unclear whether her pain was related to her newly diagnosed
lymphoma or an alternative cause, so she underwent a colonoscopy and upper endoscopic ultrasound, which were all
unremarkable. Gross abnormalities were not visualized, so
biopsies were not taken. Upon further discussion with her
oncologist, she decided to pursue active surveillance of her
disease, which includes regular radiologic imaging. Her first
6-month follow-up scans showed improving jejunal wall
thickening and adjacent mesenteric adenopathy.
DISCUSSION
The GI tract is the most common site of extranodal lymphoma, accounting for 40% of extranodal lymphomas. Of
From the Department of Pathology, Section of Hematopathology (Graham,
Krause), and the Department of Hematology/Oncology (Mardones), Baylor
University Medical Center at Dallas and Baylor Charles A. Sammons Cancer
Center, Dallas, Texas.
Corresponding author: Robbie L. Graham, MD, Department of Pathology, Section
of Hematopathology, Baylor University Medical Center at Dallas, 3500 Gaston
Avenue, Dallas, TX 75246 (e-mail: [email protected]).
381
a
b
Figure 1. Morphology of follicular lymphoma in the duodenum. (a) Follicular lymphoma stained with hematoxylin and eosin (original magnification 40×). (b) Follicular
lymphoma stained with antibody to Bcl-2 (original magnification 100×).
these, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and diffuse large
B-cell lymphoma (DLBC lymphoma) are the most common
subtypes. Conversely, FL constitutes only 1% to 3% of primary
GI lymphomas, despite it being the most common nodal lymphoma in Western populations (3). When FL involves the GI
tract, the duodenum is most often affected (89%), while other
non–small intestinal portions such as the esophagus (0%), stomach (2%), and colon (1%) are rarely involved. Most patients
are asymptomatic at presentation, although abdominal pain,
intestinal obstruction, and diarrhea can occasionally occur (4).
Endoscopically, most cases of GI FL manifest as multiple white
nodules or polyps measuring <10–20 mm, although larger or
more diffuse masses have been documented (5). Although most
GI lymphomas of types other than FL have been described in
patients with inflammatory bowel disease, celiac disease, immunodeficiencies, and after solid organ transplantation, specific
risk factors for GI FL have yet to be found (3).
The pathologic features of GI FL are similar to nodal FL
in that the diagnosis of GI FL requires the identification of
a neoplastic infiltrate forming nodular follicles. This differs
from other B-cell lymphomas such as MALT lymphoma and
DLBC lymphoma, which are typically more diffuse infiltrates
that do not routinely form nodules. Malignant follicles in FL
are usually enlarged and back to back, with vague borders
and scant or absent mantle zones. When involving the GI
tract, FL predominantly involves the lamina propria, with
occasional involvement of the submucosa. Tumor cells are
germinal center–derived B-cells and are composed of small to
medium-sized cleaved cells (centrocytes) and large noncleaved
cells (centroblasts) (6). Normal follicles have tingible body
macrophages, but neoplastic ones of grade 1 or grade 2 lack
macrophages and show a monotonous, nonpolarized appearance composed predominantly of centrocytes. If the number
of centroblasts is more than 15 per high-powered field, the
382
diagnosis is grade 3. Grade 3a has a mixture of centrocytes,
while grade 3b lacks centrocytes and shows a sheet-like proliferation of centroblasts (7). In contrast to nodal FL, FL of
the duodenum is unique in that it has always been shown to
be low grade (grade 1–2) while nodal FL is grade 3 in 10%
to 20% of cases (2).
As with low-grade nodal FL, most GI FLs express Bcl-2
and pan B-cell markers such as CD20 and CD79a. Reflecting
the germinal center derivation, tumor cells are also positive for
CD10 and Bcl-6. They do not usually express CD5, CD23,
CD43, or Bcl-1, and T-cell markers are absent (6). In the majority of duodenal tumors, CD21 and CD23 highlight a “hollow”
pattern with follicular dendritic cells arranged around the periphery of the neoplastic follicles. This is different than nodal FL,
where the follicular dendritic cells are present throughout the
follicles (8). Cytogenetic fluorescent in situ hybridization studies show the characteristic IGH/BCL2 translocation, t(14;18)
(q32;q21), in up to 90% of duodenal FL. This causes BCL2, an
anti-apoptotic protein, to be overexpressed, which is thought to
be one of the causes of lymphomagenesis (9). In addition, the
neoplastic and clonal nature of the disease can be demonstrated
by polymerase chain reaction analysis of IgH and Ig light chain
genes in the majority of cases (2).
Once a diagnosis of primary GI FL has been made, four
general treatment strategies have been used: watch and wait,
radiation therapy, rituximab monotherapy, or chemotherapy
with or without radiation (10). The largest case series of lowstage GI FL ever assembled included 56 patients who were
followed for an average of 77 months. In this study, 24 patients
chose watchful waiting. Of these, seven experienced a complete
remission and 17 had stable disease. All 19 patients treated with
local radiation attained a complete remission. Of the five patients who received rituximab monotherapy, four had complete
remission and one had stable disease. All eight patients who were
treated with chemotherapy with or without radiation attained
Volume 28, Number 3
a complete remission (2). The universal indolent behavior of
primary GI follicular lymphoma is quite different from non-GI
FL. In non-GI FL, the prognosis can be quite variable, with
5-year survival ranging from 91% to 52% depending on the
grade and stage of the tumor (11).
1.
2.
3.
4.
Harris NL, Swerdlow SH, Jaffe ES, Ott G, Nathwani BN, de Jong D,
Yoshino T, Spagnolo D. Follicular lymphoma. In Jaff ES, Harris NL,
Stein H, Vardiman JW, eds. World Health Organization Classification of
Tumours. Lyon, France: IARC Press, 2008:220–226.
Schmatz A, Streubel B, Kretschmer-Chott E, Puspok A, Jager U, Mannhalter C, Tiemann M, Ott G, Fischbach W, Herzog P, Seitz G, Stolte M,
Raderer M, Chott A. Primary follicular lymphoma of the duodenum is a
distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol 2011;29(11):1445–1451.
Misdraji J, Harris NL, Hasserjian RP, Lauwers GY, Ferry JA. Primary follicular lymphoma of the gastrointestinal tract. Am J Surg Pathol
2011;35(9):1255–1263.
Takata K, Okada H, Ohmiya N, Nakamura S, Kitadai Y, Tari A, Akamatsu
T, Kawai H, Tanaka S, Araki H, Yoshida T. Primary gastrointestinal
follicular lymphoma involving the duodenal second portion is a distinct entity: a multicenter retrospective analysis in Japan. Cancer Sci
2011;102(8):1532–1536.
5.
Shia J, Teruya-Feldstein J, Pan D, Hegde A, Klimstra D, Chaganti RSK,
Qin J, Portlock CS, Filippa DA. Primary follicular lymphoma of the
gastrointestinal tract: a clinical and pathologic study of 26 cases. Am J
Surg Pathol 2002;26(2):216–224.
6. Medeiros J. Extranodal follicular lymphoma. In Diagnostic Pathology
Lymph Nodes and Spleen with Extranodal Lymphomas. Manitoba, Canada:
Amirsys Publishing, 2011:712–723.
7. Takata K, Miyata-Takata T, Sato Y, Yoshino T. Pathology of follicular
lymphoma. J Clin Exp Hematop 2014;54(1):3–9.
8. Takata K, Sato Y, Nakamura N, Kikuti YY, Ichimura K, Tanaka T, Morito
T, Tamura M, Oka T, Kondo E, Okada H, Tari A, Yoshino T. Duodenal
and nodal follicular lymphomas are distinct: the former lacks activationinduced cytidine deaminase and follicular dendritic cells despite ongoing
somatic hypermutations. Mod Pathol 2009;29:940–949.
9. Albinger-Hegyi A, Hochreutener B, Abdou MT, Hegyi I, DoursZimmermann MT. High frequency of t(14;18) translocation breakpoints
outside of major breakpoint and minor cluster regions in follicular lymphomas: improved polymerase chain reaction protocols for their detection.
Am J Pathol 2002;3:823–832.
10. Freedman AS. Management of gastrointestinal lymphomas. In Lister A,
ed. UpToDate. Waltham, MA: UpToDate, 2013:1–19.
11. Freedman AS, Aster JC. Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma. In Lister A, ed. UpToDate.
Waltham, MA: UpToDate, 2014:1–16.
In memoriam
ALAIN J. MARENGO-ROWE, MD
Department of Pathology, Baylor University Medical Center
at Dallas
Dr. Alain Justice Marengo-Rowe, born on August 20, 1936,
died on March 4, 2015, at his home with his family by his side.
He spent his early years in Cairo, Egypt, with his French and
Italian parents and moved to Ireland at age 11. Deciding to
become a physician at a young age, he received his medical degree from the University of London and obtained qualifications
in internal medicine, pathology, hematology, and transfusion
medicine. He also held positions at The University of Cambridge and The University of Oxford. While at Cambridge, he
had great mentors, including the hemoglobin molecular biologists Herman Lehmann and Max Perutz (the latter of whom
July 2015
was awarded the Nobel Prize in 1962). Dr. Marengo-Rowe was
an officer in the Royal Air Force Medical Corps and served in
Southern Arabia for 3 years during the Yemeni revolt under the
tutelage of Dr. Perutz. There he defined blood group frequencies
in the region and discovered two new hemoglobins. Upon his
return to England, he was appointed lecturer in the Department
of Hematology at Oxford University. In 1972, Dr. MarengoRowe was recruited to Baylor University Medical Center and
began directing the newly established special hematology laboratory, blood bank, and coagulation unit. He also held senior
positions at the University of Texas Medical School in San Antonio and wrote over 100 peer-reviewed medical articles. Upon
his retirement from Baylor in 2006, he lived at his lake house
outside Dallas and made annual visits to Europe and Australia.
Primary follicular lymphoma of the duodenum
383
Tubulocystic carcinoma of the kidney
Varsha Podduturi, MD, Carol F. Adair, MD, and Haiying Zhang, MD
Tubulocystic carcinoma (TCC) of the kidney is a unique, rare, and recently
recognized neoplasm. Although originally considered a low-grade collecting duct carcinoma, TCC is now considered to be a distinct entity.
TCC should be considered in the differential diagnosis of cystic renal
neoplasms. We report a case of TCC arising in the left kidney.
K
idney cancer accounts for nearly 64,000 new cases and
14,000 deaths per year in the USA. Renal cell carcinomas include various subtypes, including clear cell,
papillary, and chromophobe. Tubulocystic carcinoma
(TCC) of the kidney is an exceedingly rare, recently recognized
subtype of renal cell carcinoma, with <100 cases reported in the
literature. Microscopically, it comprises a mixture of tubules and
variably sized cysts with low-grade nuclear features. We present
the macroscopic, histologic, and immunohistochemical findings
of a single case of TCC.
CASE REPORT
A 57-year-old man with no significant past medical history
presented with a 3-month history of abdominal and flank pain.
Computed tomography of the abdomen disclosed a mass in the
mid to lower pole of the left kidney. Biopsy was performed and
showed small fragments of fibrotic and hyalinized stroma containing dilated tubular structures. The tubular structures were lined
by highly atypical epithelial cells with nuclear enlargement and
prominent nucleoli (Fuhrman nuclear grade 3). The epithelial cells
contained abundant eosinophilic cytoplasm and had a hobnailed
appearance. The tumor cells were immunohistochemically reactive
for RCC antigen, CD10, CK903, P504-S (AMACR), and PAX8.
The patient underwent a left radical nephrectomy and periaortic lymph node dissection. Macroscopically, a 2.1 cm tan
solid mass was located in the midportion of the kidney grossly
abutting the renal sinus fat. Two cortical cysts containing clear
fluid were also identified. Microscopically, the tumor contained
cystic tubular structures with scant intervening stroma. The
tubular structures were lined by a single layer of flattened to
cuboidal to hobnail-like cells. The cells had eosinophilic cytoplasm with enlarged nuclei with prominent nucleoli (Figure 1).
Focal clear cell features were also identified. Thirty-two months
after nephrectomy, the patient was free of metastatic disease.
384
DISCUSSION
Originally, TCC was believed to be a subtype of collecting
duct carcinoma that was first described by Masson, who coined
the moniker “Bellinian epithelioma” or “carcinoma of the collecting ducts” because he thought it originated from collecting ducts
of Bellini (1). However, TCC behaved in a low-grade fashion
compared to the latter and was termed “low-grade collecting duct
carcinoma.” In 1997, MacLennan et al speculated that TCC fell
on the low-grade spectrum of collecting duct carcinomas (2). In
2004, Amin et al dubbed the tumor “tubulocystic carcinoma” (3).
TCC has a male predominance and occurs in adults with
a wide age range. Most patients present in the fifth and sixth
decades of life (4). Patients can present with abdominal pain or
distension or with hematuria or can be asymptomatic (5). Macroscopically, TCCs are usually small (≤2 cm), circumscribed,
and unencapsulated with a white or gray spongy cut surface
that is often likened to “bubble wrap” (4).
Histologically, the neoplasm comprises variably sized tubules and cysts separated by a thin fibrous septae. The cysts
and tubules are lined by a single layer of cuboidal cells with
eosinophilic cytoplasm. Hobnailing is a common pattern identified. Nucleoli are often very prominent. TCC are immunohistochemically reactive for CD10, AMACR (P504-S), CK8,
CK18, and CK19 (3, 6). These entities can also be positive for
PAX2, kidney-specific cadherin, carbonic anhydrase IX, and
parvalbumin (3). TCCs are often found coexisting with other
papillary renal neoplasms (both type 1 and type 2), including
papillary renal cell carcinomas and papillary adenomas.
The differential diagnosis for TCC includes collecting duct
carcinoma, multilocular cystic renal cell carcinoma, cystic nephroma, and mixed epithelial and stromal tumors. Collecting
duct carcinoma is more solid and has higher-grade nuclear features. Multilocular cystic renal cell carcinoma is lined by clear
cells and does not have eosinophilic cytoplasm or high-grade
nuclei. Cystic nephroma has a female predominance and can be
multiloculated; however, it is lined by a single layer of flattened
From the Department of Pathology, Baylor University Medical Center at Dallas,
Dallas, Texas.
Corresponding author: Varsha Podduturi, MD, Department of Pathology, Baylor
University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246
b
a
Figure 1. (a) Low-power view of the tumor showing multiple variably sized cystic spaces (hematoxylin and eosin, 40×). (b) Higher-power view of the hobnailed
epithelial cells with eosinophilic cytoplasm (hematoxylin and eosin, 400×).
epithelium with indistinct nucleoli and has ovarian-like stroma
within the septae. Hobnailing can be seen, but is very infrequent
(7). Mixed epithelial and stromal tumor has ovarian-type stroma
in the septae between the cystic spaces, broad septae (unlike the
thin septae in TCC), and solid areas (5).
Gene expression microarray analysis by Yang et al demonstrated a unique molecular signature of TCC when compared
with other renal tumors and normal renal tissue (4). Clustering analysis of that data revealed that TCC is closely related to
papillary renal cell carcinoma. Both type 1 and 2 dimensional
clustering placed TCC between low- and high-grade papillary
renal cell carcinoma. The most common karyotypic changes
seen in papillary renal cell carcinoma are trisomy 7 and 17
with loss of Y chromosome. Yang et al also reported that TCC
showed gain of chromosome 17, but not chromosome 7 (4).
The findings suggest a strong genetic similarity between TCC
and papillary renal cell carcinoma. TCC has been reported with
other subtypes of renal cell carcinoma (8). These tumors rarely
progress, recur, or metastasize (6). Rare cases have been reported
of metastases to lymph node, bone, pleura, and liver (8).
2.
3.
4.
5.
6.
7.
8.
1.
Rheault MJ. Pierre Masson: the father of histopathology teaching in
Canada. Ann Chir 1991;45(9):833–836.
July 2015
MacLennan GT, Farrow GM, Bostwick DG. Low-grade collecting duct
carcinoma of the kidney: report of 13 cases of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology
1997;50(5):679–684.
Amin MB, MacLennan GT, Gupta R, Grignon D, Paraf F, Vieillefond
A, Paner GP, Stovsky M, Young AN, Srigley JR, Cheville JC. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases
of a distinctive rare subtype of renal cell carcinoma. Am J Surg Pathol
2009;33(3):384–392.
Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, Shah RB, Yang Y, Chuang ST, Lin F, Tretiakova MM, Kort EJ, Teh BT. Tubulocystic carcinoma
of the kidney: clinicopathologic and molecular characterization. Am J Surg
Pathol 2008;32(2):177–187.
Alexiev BA, Drachenberg CB. Tubulocystic carcinoma of the kidney: a
histologic, immunohistochemical, and ultrastructural study. Virchows Arch
2013;462(5):575–581.
Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P,
Sibony M. Tubulocystic carcinoma of the kidney: a new entity among
renal tumors. Virchows Arch 2007;451(5):905–909.
Turbiner J, Amin MB, Humphrey PA, Srigley JR, De Leval L, Radhakrishnan A, Oliva E. Cystic nephroma and mixed epithelial and stromal tumor
of kidney: a detailed clinicopathologic analysis of 34 cases and proposal
for renal epithelial and stromal tumor (REST) as a unifying term. Am J
Surg Pathol 2007;31(4):489–500.
Bhullar JS, Varshney N, Bhullar AK, Mittal VK. A new type of renal
cancer—tubulocystic carcinoma of the kidney: a review of the literature.
Int J Surg Pathol 2013;22(4):297–302.
Tubulocystic carcinoma of the kidney
385
Unusual presentation of metastatic ovarian carcinoma as an
enlarged intramammary lymph node
Callan Mason, MD, Kendall Yokubaitis, MD, Raynal Hamilton, MD, Umesh Oza, MD, Zeeshan Shah, MD, Joseph Spigel,
MD, and Jean Wang, MD
Metastasis to the breast most commonly arises from a contralateral
primary breast malignancy; however, metastatic disease can also result
from extramammary malignancies by hematogenous or lymphatic dissemination. This case report reviews an unusual presentation of primary
ovarian carcinoma with metastasis to an intramammary lymph node.
P
rimary breast cancer is one of the most frequently occurring malignancies in women, but metastatic disease
to the breast is relatively uncommon. Although malignancies metastatic to the breast parenchyma have
no characteristic radiographic presentation, they can present
as a rounded or oval mass at the fat-parenchymal interface.
Enlarged nonfatty axillary lymph nodes with spiculated or illdefined margins have a strong association with an underlying
malignancy. This case report reviews an unusual presentation of
primary ovarian carcinoma with metastasis to an intramammary
lymph node. Breast or axillary lymph node involvement from
a primary ovarian carcinoma is rare, and ovarian carcinoma
metastatic to the breast is associated with a poor prognosis, as
it is usually related to widespread systemic disease.
CASE REPORT
An asymptomatic 58-year-old woman with no significant
past medical or family history presented for a routine screening mammogram, which revealed a 1.0 cm mass in the upper
outer quadrant of the left breast, favored to reflect an enlarging
intramammary lymph node (Figure 1a). An additional enlarged
lymph node was noted in the right axilla. Further evaluation with
bilateral breast ultrasound confirmed a mass in the upper outer
quadrant of the left breast, again favored to represent an enlarged
intramammary lymph node (Figure 1b), as well as at least two
enlarged right axillary lymph nodes. An ultrasound-guided core
biopsy of the left intramammary lymph node as well as an additional core biopsy of a right axillary lymph node were performed.
Immunohistochemical stains were positive for paired-box gene 8
(PAX8) and Wilm’s tumor gene (WT1), with a final pathologic
diagnosis of high-grade serous ovarian carcinoma.
Given the unexpected diagnosis of metastatic ovarian carcinoma, further evaluation and staging workup were initiated
with 18F-fluoro-2-deoxy-D-glucose positron emission tomog386
raphy/computed tomography (18F-FDG PET-CT). The PETCT confirmed a hypermetabolic mass in the left hemipelvis in
close association with the left ovary (Figure 2), corresponding
to the pathologic diagnosis of ovarian carcinoma. Multifocal
FDG-avid hepatic metastases were also identified, as well as
extensive serosal, peritoneal, mesenteric, and omental carcinomatosis (Figure 2b). Intra-abdominal FDG-avid lymphadenopathy, to include portocaval and bilateral common iliac chain
lymph nodes, as well as bilateral inguinal lymphadenopathy, was
demonstrated and was compatible with additional nodal metastatic disease. PET-CT evaluation of the thorax demonstrated
a hypermetabolic mass in the upper outer quadrant of the left
breast, corresponding to the biopsy-proven malignancy (Figure
2d), as well as hypermetabolic right axillary lymphadenopathy.
The patient’s laboratory values revealed an elevated CA-125 of
900 units/mL. These collective findings were compatible with
stage IV metastatic ovarian carcinoma. The patient is currently
receiving carboplatin and paclitaxel chemotherapy.
DISCUSSION
While primary breast cancer is one of the most common
malignancies in women, metastatic disease to the breast is relatively rare, accounting for approximately 0.5% to 2.0% of all
breast cancer cases (1). Metastatic disease to the breast most
often arises from a contralateral primary breast malignancy;
however, hematogenous or lymphatic metastasis from extramammary malignancies may also occur. The most common
extramammary malignancies known to metastasize to the breast
include lymphoma, melanoma, lung, and gynecological primary
cancers (1). Studies reveal that axillary nodal metastases also
most commonly occur from primary breast cancer, followed
by lymphoma, and infrequently from a nonbreast primary site
or an unknown primary site (2).
Ovarian carcinoma usually presents with intraperitoneal
metastases by direct seeding into the peritoneal cavity, and distant metastasis most commonly involves the lung or pleura (3).
From the Department of Radiology, Baylor University Medical Center at Dallas.
Corresponding author: Callan Mason, MD, Department of Radiology, Baylor
University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: callan.
[email protected]).
a
b
Figure 1. (a) Annual screening mammogram of the left breast shows a
well-circumscribed dense intramammary lymph node in the upper outer
quadrant. (b) Targeted ultrasound of the upper outer quadrant of the left
breast demonstrates an enlarged intramammary lymph node with loss of
normal fatty hilum.
The most frequent sites of lymphatic involvement in ovarian
carcinoma are abdominal (47%), para-aortic (38%), mediastinal
(29%), and pelvic (17%) lymph nodes (4). Serous ovarian carcinoma is the most common ovarian malignancy to metastasize
to the breast, and metastases to the breast parenchyma or axillary lymph nodes are rare and are typically seen in patients
with advanced disease (5). Our case is particularly unusual in
that an enlarged intramammary lymph node was the patient’s
initial presentation of ovarian carcinoma, despite the disease
being widespread.
Mammographically, metastatic tumors to the breast parenchyma classically present as a rounded or oval noncalcified
mass found in the subcutaneous breast tissue at the fat-parenchymal interface. They generally lack the features of primary
breast malignancy such as microcalcifications, spiculation, or
architectural distortion. Intramammary or axillary lymph node
enlargement can also occur, and ill-defined or spiculated nodal
margins show a significant association with malignancy (2).
a
b
c
d
Figure 2. (a) PET-CT image at the level of the pelvis shows moderately intense FDG uptake within a metastatic implant involving the left adnexa (arrow). (b) Multiple
regions of hepatic metastatic disease are identified at the level of the upper abdomen, with the most intense lesion in the caudate lobe (arrow). (c) At the level of
the iliac crests, there is uptake within the omentum along the anterior abdominal wall extending into an umbilical hernia (arrow). (d) At the level of the mid thorax
there is mildly increased FDG uptake in the upper outer quadrant of the left breast (arrow), corresponding to the intramammary lymph node seen on comparison
mammogram and ultrasound.
July 2015
Unusual presentation of metastatic ovarian carcinoma as an enlarged intramammary lymph node
387
Specifically, ovarian cancer metastatic to the breast parenchyma can present as a focal mass without definite characteristic
radiographic features (6); however, a few studies reveal that
serous ovarian carcinoma metastatic to axillary lymph nodes
can occasionally demonstrate a peripheral amorphous lymph
node calcification pattern on a mammogram (7), which is
related to psammoma body formation. This calcification pattern could potentially be used to differentiate from metastatic
breast carcinoma, which typically demonstrates pleomorphic
lymph node calcifications. This case also highlights the utility of PET-CT in detecting suspected metastatic disease such
as ovarian carcinoma. PET-CT can be particularly useful for
site-specific treatment planning such as biopsy, surgery, or
radiotherapy (8).
Breast and ovarian tumors can be difficult to pathologically distinguish due to overlapping morphology (9), and immunohistochemistry may be required to distinguish the two.
Estrogen and progesterone receptor expression are inadequate
markers, as these can be seen in both breast and ovarian neoplasms. PAX8 has been shown to be an excellent distinguishing
marker between ovarian and breast carcinoma, as it is positive
in nearly all ovarian carcinoma stains and is negative in breast
cancer stains (10, 11). WT1 can also be a sensitive marker for
serous ovarian carcinoma since it is rarely positive for breast
cancer samples but is immunoreactive in up to 85% of ovarian
samples (10, 11).
Ovarian carcinoma metastatic to the breast is associated with
a poor prognosis, largely because it is associated with widespread
systemic dissemination of disease (3). On average, ovarian carcinoma metastatic to the breast is diagnosed 2 years following
the initial diagnosis of ovarian cancer (12). Several studies have
demonstrated survival rates ranging from 13 days to 3.5 years
following detection of metastatic disease in the breast (12), and
the 1-year survival rate has been reported at 40% (13). With the
unanticipated diagnosis of metastatic ovarian carcinoma, this
case not only highlights the significance of imaging workup at
388
diagnosis, but also the value of multidisciplinary communication between the radiologist, pathologist, and clinician.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Toombs BD, Klisher L. Metastatic disease to the breast: clinical, pathologic
and radiologic features. Am J Roentgenol 1977;129(4):673–676.
Walsh R, Kornguth PJ, Soo MS, Bentley R, DeLong DM. Axillary lymph
nodes: mammographic, pathologic, and clinical correlation. Am J Roentgenol 1997;168(1):33–38.
Goyal H, Mattoo V, Singla U. Isolated axillary lymph node metastasis
from serous ovarian cancer. Case Rep Oncol Med 2012:307567.
Skagias L, Ntinis A, Vasou O, Kondi-Pafiti A, and Politi E. Ovarian
carcinoma presenting with axillary lymph node metastasis: a case documented by fine-needle aspiration and brief review of the literature. Diagn
Cytopathol 2008;36(12):891–893.
Recine M, Deavers M, Middleton, L, Silva E, Malpica A. Serous carcinoma
of the ovary and peritoneum with metastases to the breast and axillary
lymph nodes: a potential pitfall. Am J Surg Pathol 2004;28(12):1646–
1651.
Moore D, Wilson D, Hurteau J, Look K, Stehman F, Sutton G. Gynecologic cancers metastatic to the breast. J Am Coll Surg 1998;187:178–181.
Singer C, Blankstein E, Koenigsberg T, Mercado C, Pile-Spellman E,
Smith S. Mammographic appearance of axillary lymph node calcification in patients with metastatic ovarian carcinoma. Am J Roentgenol
2001;176(6):1437–1440.
Viswanathan C, Bhosale PR, Shah SN, Vikram R. Positron emission
tomography-computed tomography imaging for malignancies in women.
Radiol Clin N Am 2013;51(6):1111–1125.
Yamasaki H, Saw D, Zdanowitz J, Faltz L. Ovarian carcinoma metastasis
to the breast: a case report and review of the literature. Am J Surg Pathol
1993;17(2):193–197.
Xiang L, Kong B. PAX8 is a novel marker for differentiating between
various types of tumor, particularly ovarian epithelial carcinomas. Oncol
Lett 2013;5(3):735–738.
DeLair DF, Corben AD, Catalano JP, Vallejo CE, Brogi E, Tan LK. Nonmammary metastases to the breast and axilla: a study of 85 cases. Mod
Pathol 2013;26(3):343–349.
Ozguroglu M, Ersavasti G, Ilvan S, Hatemi G, Demir G, Demirelli F.
Bilateral inflammatory breast metastases of epithelial ovarian cancer. Am
J Clin Oncol 1999;22(4):408–410.
Loredo D, Powell J, Reed W, Rosenbaum J. Ovarian carcinoma metastatic to breast: a case report and review of the literature. Gynecol Oncol
1990;37(3):432–436.
Volume 28, Number 3
Leukoencephalopathic changes on magnetic resonance
imaging associated with a thermogenic dietary supplement
(Thermatrim)
Cristina I. Olivas-Chacon, MD, Manuel Treviño-Garcia, MD, John James Chua-Tuan, MD, Jose M. Rodriguez-Cordero, MD,
Alfonso H. Gil-Valadez, MD, Nassim Akle, MD, Jesus E. Calleros, MD, and Luis R. Ramos-Duran, MD
Acute toxic leukoencephalopathy can be caused by exposure to many
compounds. Reversibility has been described in some cases with prompt
recognition and withdrawal of the offending agent. Its association with
a thermogenic supplement has never been reported. We describe two
such cases in young women taking a commercially available thermogenic
dietary supplement who presented with acute neurologic deficits and a
common magnetic resonance imaging pattern.
D
ue to the increasing prevalence of obesity in Western
countries, the use of thermogenic dietary supplements
is becoming more frequent. Toxic leukoencephalopathy
may be caused by exposure to a wide variety of agents,
including cranial irradiation, therapeutic agents, illicit drugs,
and environmental toxins (1). Its association with a thermogenic supplement has not been reported. Such is the purpose
of this report.
CASES
Pertinent findings for the two patients are summarized in
Table 1. Magnetic resonance imaging (MRI) during the acute
episode in both patients revealed extensive symmetric restricted
diffusion involving the entire corpus callosum, the pons, and
subcortical white matter with reduced apparent diffusion coefficient values. No abnormal enhancement was seen (Figures 1
to 3).
Both women were using the dietary thermogenic supplement Thermatrim for weight loss. The first patient had taken
the supplement within the previous 2 months, and the second
patient within the previous 3 weeks. They received supportive
therapy and recovered within 2 to 5 days. Both patients had a
benign clinical course with progressive clinical improvement and
were discharged within the first week of admission. Two-month
follow-up MRI of the first patient showed almost complete
resolution of the findings.
DISCUSSION
Leukoencephalopathy describes the structural changes of
cerebral white matter in which myelin suffers the most extensive
damage (1). The neurological findings in acute toxic leukoencephalopathy can reverse with prompt recognition and withProc (Bayl Univ Med Cent) 2015;28(3):389–391
Table 1. Patient findings
Variable
Case 1
Case 2
19
17
Headache
+
+
Photophobia
+
0
Phonophobia
+
0
Blurred vision
0
+
Abnormal brain magnetic resonance imaging
+
+
Physical examination
+
+
Neurological examination
+
+
Blood
+
+
Toxicology screening
+
+
Cerebrospinal fluid
+
+
+
+
Age (years)
Presenting symptoms
Normal findings
Clinical recovery in 2 to 5 days
drawal of the offending agent (2). Definite findings on MRI to
predict reversible versus irreversible and severe outcomes have
not been determined.
Similar though less extensive findings have been described
in the clinicoradiological syndrome of mild encephalitis/encephalopathy with reversible splenial and white matter lesions
(MERS Type II). This entity presents in patients with clinically
mild encephalopathy and reversible lesions involving the entire
corpus callosum with bilateral extension into the subcortical
white matter (3, 4). First reports described this rare entity in
patients who had seizures with secondary generalization (5)
and in patients with toxicity or drug sensitivity to antiepileptic
From the Department of Radiology, Texas Tech University Health Science Center,
El Paso, Texas (Olivas-Chacon, Chua-Tuan, Akle, Calleros, Ramos-Duran); the
Department of Radiology, Instituto Tecnológico y de Estudios Superiores de
Monterrey and TecSalud, Mexico (Treviño-Garcia, Rodriguez-Cordero); Department
of Neuroanatomy, Universidad Autónoma de Nuevo León, Mexico (Gil-Valadez).
Corresponding author: Cristina Ivette Olivas Chacon, MD, 4800 Alberta Avenue,
El Paso, TX 79905 (e-mail: [email protected]).
389
a
b
c
Figure 1. MRI in Case 1. (a) Sagittal fast spin echo T2-weighted image demonstrates diffuse swelling and abnormal hyperintense signal of the entire corpus callosum (arrowheads). There is also abnormal hyperintensity of the pontine tegmentum (arrow). (b) Sagittal T1 contrast-enhanced image shows absence of abnormal
enhancement. (c) Follow-up MRI fast spin echo T2-weighted image after 2 months shows resolution of the white matter changes.
drugs (6). Subsequently, this entity has widened its spectrum
and has been associated with different clinical neurologic and
nonneurologic conditions, including postinfectious disorder
(7), rapid withdrawal of antiepileptic drugs (8), high-altitude
a
cerebral edema (9), and various metabolic disorders (hypoglycemia and hypernatremia) (10).
Due to the heterogeneous entities linked to mild encephalitis/encephalopathy with reversible splenial and white matter
b
Figure 2. Axial MRI in Case 1. (a) Fast spin echo T2-weighted imaging, diffusion-weighted imaging (b1000), and apparent diffusion coefficient (ADC) maps demonstrate abnormal T2 hyperintense signal intensity and matching restricted diffusion of the subcortical white matter (top row), corpus callosum (middle row), and the
pontine tegmentum (bottom row), as indicated by the arrows. (b) Two-month follow-up imaging utilizing the same sequences shows near complete interval resolution
of the white matter changes.
390
Volume 28, Number 3
Thermogenic supplements have been associated with significant side effects, including anxiety, insomnia, cardiovascular
disorders, and central nervous system stimulation, among others (15). However, these reports originate from isolated case
reports due to the lack of forthcoming users experiencing said
adverse effects.
This is the first time that reversible white matter lesions
have been reported to be associated with a thermogenic dietary
supplement. A larger series of patients needs to be studied to
assess the specificity and correlation of these findings as a direct
cause of acute leukoencephalopathy. Further product-specific
research on thermogenic aids is needed to determine levels of
effectiveness and safety for consumers.
a
b
1.
2.
3.
c
4.
5.
Figure 3. MRI in Case 2. Axial T2-weighted imaging shows abnormal T2 hyperintense signal (arrows) of the (a) subcortical white matter, (b) corpus callosum,
and (c) pontine tegmentum. Diffusion-weighted (b1000) imaging and apparent
diffusion coefficient (ADC) maps demonstrate restricted diffusion in the same
distribution.
lesions, there is controversy regarding their pathogenesis. No
unequivocal hypothesis has been formulated regarding the nature of the lesions. Several theories have been postulated, including intramyelinic edema due to transient disruption of energy
metabolism, which may cause reversible myelin vacuolization
(11), antiepileptic drug toxicity-induced reversible demyelination (12), alteration of the arginine-vasopressin system which
may affect brain hydric content (13), and development of an
inflammatory infiltrate with influx of inflammatory cells and
molecules possibly combined with related cytotoxic edema (14).
The usage of thermogenic dietary supplements is widespread
for augmentation in overall metabolism and “fat burning” in
expectation to support weight loss by the consumer. Thermatrim
is a thermogenic dietary supplement marketed via the Internet
and available to the general public. Its contents profile states
it contains garcinia cambogia, chromium picolinate, chitosan,
equisetum arvense, momordica charantia, herbal sources of caffeine such as guarana, and other purported metabolic-supporting ingredients such as carnitine and Ilex paraguariensis, though
there is a lack of information on the quantities of ingredients
and other specific product information.
July 2015
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N
Engl J Med 2001;345(6):425–432.
McKinney AM, Kieffer SA, Paylor RT, SantaCruz KS, Kendi A, Lucato
L. Acute toxic leukoencephalopathy: potential for reversibility clinically
and on MRI with diffusion-weighted and FLAIR imaging. AJR Am J
Roentgenol 2009;193(1):192–206.
Takanashi J, Imamura A, Hayakawa F, Terada H. Differences in the time
course of splenial and white matter lesions in clinically mild encephalitis/
encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci
2010;292(1–2):24–27.
Takanashi J, Barkovich AJ, Shiihara T, Tada H, Kawatani M, Tsukahara H, Kikuchi M, Maeda M. Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. AJNR Am J Neuroradiol
2006;27(4):836–838.
Chason DP, Fleckenstein JL, Ginsburg MI. Transient splenial edema in
epilepsy: MR imaging evaluation. In Proceedings of the 34th Annual Meeting of the American Society of Neuroradiology, June 21–27, 1996, Seattle,
WA. Chicago: Old Smith Printers.
Kim SS, Chang KH, Kim ST, Suh DC, Cheon JE, Jeong SW, Han
MH, Lee SK. Focal lesion in the splenium of the corpus callosum in
epileptic patients: antiepileptic drug toxicity? AJNR Am J Neuroradiol
1999;20(1):125–129.
Notebaert A, Willems J, Coucke L, Van Coster R, Verhelst H. Expanding
the spectrum of MERS type 2 lesions, a particular form of encephalitis.
Pediatr Neurol 2013;48(2):135–138.
Mirsattari SM, Lee DH, Jones MW, Blume WT. Transient lesion in
the splenium of the corpus callosum in an epileptic patient. Neurology
2003;60(11):1838–1841.
Hackett PH, Yarnell PR, Hill R, Reynard K, Heit J, McCormick J. Highaltitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology. JAMA 1998;280(22):1920–1925.
Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ.
Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev 2009;31(3):217–220.
Oster J, Doherty C, Grant PE, Simon M, Cole AJ. Diffusion-weighted imaging abnormalities in the splenium after seizures. Epilepsia
2003;44(6):852–854.
Ramirez JA, Mendell JR, Warmolts JR, Griggs RC. Phenytoin neuropathy:
structural changes in the sural nerve. Ann Neurol 1986;19(2):162–167.
Dóczi T, Szerdahelyi P, Gulya K, Kiss J. Brain water accumulation after the
central administration of vasopressin. Neurosurgery 1982;11(3):402–407.
Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H,
Suzuki M, Yamamoto T, Shimono T, Ichiyama T, Taoka T, Sohma O,
Yoshikawa H, Kohno Y. Clinically mild encephalitis/encephalopathy with
a reversible splenial lesion. Neurology 2004;63(10):1854–1858.
da Silva WV, de Andrade Gomes Silva MI, Tavares Toscano L, Dantas de Oliveira KH, de Lacerda LM, Sérgio Silva A. Supplementation
prevalence and adverse effects in physical exercise practitioners. Nutr Hosp
2014;29(1):158–165.
Leukoencephalopathic changes on magnetic resonance imaging associated with a thermogenic dietary supplement (Thermatrim)
391
Baylor news
■ Baylor Scott & White Health and
Tenet to partner on five North Texas
hospitals
Baylor Scott & White Health and Tenet
Healthcare Corporation announced a definitive
agreement to partner on providing care through
five North Texas hospitals. The partnership will
focus on delivering integrated, value-based care
to communities in Rockwall, Collin, and Dallas
counties.
Through this new partnership, the two organizations will jointly own Centennial Medical
Center, Doctors Hospital at White Rock Lake,
Lake Pointe Medical Center, and Texas Regional
Medical Center at Sunnyvale—currently owned
and operated by a subsidiary of Tenet—and
Baylor Medical Center at Garland—currently
owned and operated by Baylor Scott & White
Health. Baylor Scott & White Health will hold a
majority ownership interest in the five hospitals,
and all five will operate under the Baylor Scott
& White Health brand. The transaction is subject to regulatory review and customary closing
conditions.
“This is an exciting step as we partner with a
like-minded organization to create a strong network that will improve the health of individuals,
families, and communities across eastern and
northeastern Dallas,” says Gary Brock, president and chief operating officer of Baylor Scott
& White Health, North Texas. “This partnership
demonstrates our commitment to advancing
population health in North Texas.”
The partnership will be governed by a
jointly appointed board of managers. In addition, each hospital will have a governing board
and independent medical staffs and medical
staff leadership responsible for certain medical
staff and clinical matters. Tenet will continue to
manage the operations of Centennial Medical
Center, Doctors Hospital at White Rock Lake,
Lake Pointe Medical Center, and Texas Regional
Medical Center at Sunnyvale on behalf of the
partnership. Baylor Scott & White Health will
continue to manage Baylor Medical Center at
Garland. The leadership teams for each hospital
will remain in place, and there should be little
to no change for employees at the five hospitals. In addition, each hospital will maintain an
independent medical staff, and physicians will
retain their current hospital privileges.
Separately, Tenet’s North Texas accountable care organization recently entered into
392
an affiliation agreement with the Baylor Scott
& White Quality Alliance (BSWQA). For members of the BSWQA, a leading accountable
care organization in Texas, this agreement increases convenient access to coordinated and
integrated care by adding four hospitals, six
outpatient centers, and more than 170 physicians to the network.
Collaborating with health plan partners such
as UnitedHealthcare enables BSWQA physicians
to support a value-based health care model
in which they receive payment incentives for
achieving total cost savings by meeting certain
evidence-based measures, such as disease
management, primary care screenings, and
patient safety.
■ Baylor Scott & White Quality Alliance
■ Baylor Health Care System telestroke
and UnitedHealthcare collaborate to
improve patient care in North Texas
BSWQA and UnitedHealthcare are collaborating to improve care coordination
and enhance health services for more than
52,000 North Texas residents enrolled in
UnitedHealthcare’s employer-sponsored
health plans. BSWQA is an accountable care
organization established in 2011 as part of
Baylor Scott & White Health’s strategy to improve health care delivery. BSWQA’s network
of more than 3800 primary and specialty care
physicians and 46 hospitals and post-acute
care facilities will be available to people enrolled in UnitedHealthcare employer-sponsored
health plans. BSWQA will leverage population
health management, including care coordination, disease management, preventive health
services, a health information exchange, and
data analytics, to deliver a higher standard of
quality care at lower costs.
The two organizations will help shift Texas’
health care system to one that rewards quality
and value instead of the volume of procedures
performed. BSWQA is one of 250 new accountable care programs UnitedHealthcare has committed to in 2015 as it engages in deeper, more
collaborative relationships with physicians and
hospitals across the country.
UnitedHealthcare will complement BSWQA’s
established population health infrastructure with
technology and actionable patient data, enabling
physicians to take specific measures to improve quality and lower costs. Actionable data
can include patient profiles, specific Healthcare
Effectiveness Data and Information Set (HEDIS)
gaps, and real-time information about emergency room and inpatient admissions. A team of
care coordinators will support community-based
care coordination, such as helping with transition
plans after an individual is discharged from the
hospital, scheduling follow-up appointments, and
closing care gaps.
program increases use of clotbusting drug
Before Baylor Health Care System (BHCS)
began its hub-and-spoke model of stroke care
with telemedicine in 2013, Baylor Medical
Center at Irving had treated only one stroke
victim with tissue plasminogen activator (rtPA).
In the program’s first 26 months, 56 of 58
eligible patients received the clot-busting drug
that minimizes the damage caused by a stroke
if it is administered within 3 to 4.5 hours after
symptoms begin.
(BUMC) is the system’s hub, and Baylor
Irving is one of the seven community hospital spokes, with more hospitals planning to
come aboard in the near future. The system,
often called telestroke, allows neurohospitalists on the medical staff at BUMC to evaluate
patients remotely and make recommendations
to emergency medicine doctors at community
hospitals. The doctors use iPads and laptop
computers to communicate. The physicians
located at BUMC use a portable robot to view
and evaluate stroke patients at the community
hospitals.
Typically, if an emergency medicine doctor suspects a patient has had a stroke, the
BUMC telestroke team is notified. The team,
which is always available, includes a program
manager, clinical coordinator, vascular neurologists, neurosurgeons, and radiologists. The
team recommends the most appropriate care
after the evaluation.
The telemedicine program has allowed
Baylor Irving to be certified as a primary
stroke center by The Joint Commission, a
certification that acknowledges facilities “that
make exceptional efforts to foster better outcomes for stroke care.” Four participating
hospitals—Baylor Medical Center at Garland,
Baylor Regional Medical Center at Plano,
Baylor Regional Medical Center at Grapevine,
RECENT GRANTS
• Development of microRNA biomarkers
for noninvasive detection of colorectal
cancer
Principal investigator: Ajay Goel, PhD
Sponsor: National Cancer Institute
Funding: $360,402
Award period: 7/1/2015–6/30/2016
• Familial and early onset colorectal
cancer
Principal investigator: Ajay Goel, PhD, and
C. Richard Boland, MD
Sponsor: National Cancer Institute
Funding: $372,400
Award period: 8/1/2015–7/31/2016
• Models for optimal liver transplant
outcomes
Principal investigator: Sumeet Asrani, MD
Sponsor: Board of Trustees of Leland
Stanford Jr. University/National Institute
of Diabetes and Digestive and Kidney
Diseases
Funding: $67,141
Award period: 7/1/2014–6/30/2015
• Use of integrated personal omics
profiling to identify biomarkers for
autoimmune disease
and Baylor All Saints Medical Center at Fort
Worth—also have this certification. Other
spoke hospitals include The Heart Hospital
Baylor Denton and Baylor Medical Centers in
Waxahachie and Carrollton.
Nationally, about 15% to 40% of patients
with symptoms of an acute stroke arrive at
hospitals in time to receive rtPA; however,
the treatment rate is low. Only about 6.7% of
ischemic stroke patients receive the therapy at
certified US primary stroke centers, and about
2% are treated at noncertified US hospitals.
The treatment rate for hospitals participating
in the BHCS hub-and-spoke system is more
than 12%.
Dion Graybeal, MD, architect of and medical director for BHCS’s hub-and-spoke stroke
program, estimated that BUMC stroke teams
will consult on about 800 cases in community
hospitals this year. “We’ve seen an increase in
consultations from all of our regional medical
centers. Also, we don’t just log on and log off
only where there are cases to be evaluated.
We’re constantly monitoring quality processes
and working toward performance improvement,”
he said.
July 2015
Principal investigator: Brandi Cantarel,
PhD
Sponsor: The Discovery Foundation
Funding: $60,000
Award period: 11/24/2014–11/23/2015
• Spatial organization of the transcriptome
in pustular psoriasis
Principal investigator: Gerlinde
Obermoser, MD
Sponsor: National Psoriasis Foundation
Funding: $75,000
Award period: 6/1/2015–5/31/2016
• Next-generation sequencing-based
approaches for the development of
epigenetic biomarkers for predicting
therapeutic outcome in patients with
colorectal cancer
Principal investigator: Ajay Goel, PhD
Sponsor: Cancer Prevention and Research
Institute of Texas
Funding: $886,982
Award period: 8/1/2014–8/30/2017
• Short-course therapy for multidrugresistant tuberculosis based on
pharmacokinetic/pharmacodynamic
answers for biological variability
■ Baylor University Medical Center
performs first POEM procedures in
Texas
A surgeon on the medical staff at BUMC
recently performed two peroral endoscopic
myotomies (POEM) as part of a clinical trial,
marking the first time that this minimally invasive technique has been done in Texas. The
two procedures involved patients with achalasia,
a rare disorder that prevents proper digestion.
One of the patients underwent the procedure as
an alternative to the Heller myotomy; the other
patient had completed the Heller myotomy by a
Principal investigator: Tawanda
Gumbo, MD
Sponsor: National Institute of Allergy and
Infectious Diseases
Funding: $736,025
Award period: 11/15/2014–7/31/2015
• DC-ASGPR as a novel target for
controlling graft-versus-host disease
and allograft rejection
Principal investigator: Sangkon Oh, PhD
Sponsor: National Institute of Allergy and
Infectious Diseases
Funding: $392,000
Award period: 1/1/2015–3/31/2016
• Glycemia reduction approaches in
diabetes: a comparative effectiveness
study
Principal investigator: Priscilla Hollander,
MD, PhD
Sponsor: George Washington University/
National Institute of Diabetes and Digestive
and Kidney Diseases
Funding: $216,609
Award period: 8/1/2014–7/31/2015
chest approach in 2010 but later reexperienced
swallowing difficulties.
The POEM procedure has grown quickly
in popularity worldwide over the past 6 years.
As an incision-free alternative to surgery, the
POEM technique represents a larger trend in
endoscopic surgery. As Steven Leeds, MD,
an esophageal surgeon on the medical staff
of BUMC’s Department of Minimally Invasive
Surgery, stated, “Surgical endoscopy is paving the way for many new procedures, and
the POEM procedure is only the tip of the
iceberg.”
UPCOMING CME PROGRAMS
The A. Webb Roberts Center for Continuing Education of Baylor Scott & White Health is
offering the following programs:
Chest Cancer Conference, July 18, 2015, at Baylor Sammons Cancer Center
Hematologic Malignancies 2015, October 3, 2015, at Baylor Sammons Cancer Center
42nd Annual Williamsburg Conference on Heart Disease, December 6–8, 2015, at
Williamsburg Conference Center, Williamsburg, Virginia
For more information, call 214.820.2317 or visit www.cmebaylor.org.
Baylor news
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PHILANTHROPY NOTES
■ $2 million Rees-Jones Foundation
grant to support Canine Companions
for Independence
The Rees-Jones Foundation has made
a generous $2 million grant in support of
the Canine Companions for Independence®
at Baylor Scott & White Health–Kinkeade
Campus. In honor of this gift, the building
that houses functions in support of the dogs
will be named the Jan Rees-Jones Canine
Center. The center will house a veterinary
clinic and radiology lab equipped for minor
procedures and observation of each dog in
residence. The center will also be equipped
with a food prep kitchen, grooming spa, and
laundry facility in addition to office space for
the kennel staff.
In 2014, Baylor Scott & White Health
announced its partnership with Canine
Companions for Independence, the nation’s
premiere assistance dog training program,
to provide a Canine Companions training site
in the heart of North Texas. Slated to open
in August 2015, it will be the first Canine
Companions training center in Texas and the
first to be connected with a major health care
system.
At the Kinkeade Campus, three types of
assistance dogs will be trained to master
more than 40 specialized commands.
Service dogs assist adults with physical
disabilities by performing everyday functions
like turning on lights, picking up dropped
keys, or opening a door; skilled companions
enhance independence for children and adults
with cognitive and developmental disabilities;
and facility dogs work with a professional in a
visitation, education, criminal justice, or health
care setting. The average cost to breed and
train each assistance dog is $50,000, and
assistance dogs are provided free of charge
to individuals.
The POEM procedure takes a cameraequipped tube, called an endoscope,
through the mouth into the esophagus. From
there, a small hole is made in the lining of
the esophagus and the endoscope travels
along the muscle layer passing the lower
sphincter. There, the layer of muscle causing the obstruction is cut to allow passage
of food. The small hole in the esophageal
394
To provide this service to the community,
the Foundation is seeking community support
to cover capital and operating costs for the
construction and maintenance of the Kinkeade
Campus. To date, more than $3.5 million has
been raised in support of this program.
■ Joan Lunden to speak at 16th
annual Celebrating Women
luncheon
Joan Lunden, breast cancer survivor
and former host of Good Morning America,
will be the featured speaker at the 16th
annual BHCS Foundation Celebrating
Women luncheon on Thursday, October
15, at the Hilton Anatole Hotel in Dallas.
Joan Lunden is an award-winning journalist,
bestselling author, health and wellness
advocate, motivational speaker, successful
entrepreneur, and a mom of seven children.
As the longest-running host ever on early
morning TV, Joan greeted viewers every
morning on Good Morning America for
nearly 20 years. In June 2014, Joan was
diagnosed with triple-negative breast
cancer, which required chemotherapy,
surgery, and radiation. Since then, she
has shared her journey with the world,
becoming a prominent voice in the breast
cancer community. An eternal optimist, Joan
decided to take her diagnosis and turn it
into an opportunity to help demystify cancer
treatment.
Since the first Celebrating Women luncheon
in 2000, more than $24 million has been raised
to support BHCS’s fight against breast cancer.
Every 4 hours, someone in Dallas–Fort Worth
is diagnosed with breast cancer. Donations to
Celebrating Women have supported advanced
diagnostic equipment, innovative clinical
research, and most importantly, safe, quality,
compassionate care for Baylor’s patients and
lining is then repaired and the endoscope
is removed.
“The procedure is shorter in duration and
requires minimal instrumentation,” Dr. Leeds
said. “And since the POEM procedure does not
require access through the abdomen or chest,
there is no risk for injuring intra-abdominal
organs, especially in patients with previous
surgeries.” The minimally invasive technique
families. Approximately 1200 passionate men
and women attend the Celebrating Women
luncheon each year in a show of support for
Baylor’s efforts to fight the disease.
■ $100,000 grant to allow physicians
to perform innovative surgeries in
utero
The leaders at the Fetal Care Center at
BUMC have a clear vision: to become the
first center in North Texas to provide perinatal
correction of spina bifida and to develop new
treatments for other complicated birth defects.
Thanks to a recent $100,000 grant from the
RGK Foundation, the Fetal Care Center is well
on its way to realizing this vision.
Currently, North Texas families must travel
far from home to places such as Houston, San
Francisco, or Philadelphia to receive this type
of care for their unborn child. The first step to
offer this care at BUMC is getting an advanced
ultrasound system. The RGK Foundation grant
will do just that, by funding the purchase of
a Toshiba APLIO 300 V3 Ultrasound Imaging
System. This will be located in the hospital’s
Maternal Fetal Care Unit.
The increase in capabilities will allow the
Fetal Care Center to diagnose and treat a
wider range of high-risk obstetric patients. In
the near future, the center will be able to care
for mothers whose unborn babies have spina
bifida and other medically complicated birth
defects. Generous donor support will allow the
Fetal Care Center to provide more innovative
diagnostic testing, new fetal interventional
procedures, more fetal surgeries, and
expanded pre- and postcare for moms and
their babies in Dallas.
For information on how you can support
these or other initiatives at Baylor, please
contact the Foundation at 214.820.3136.
generally affords patients reduced pain, faster
recovery, and equivalent ability to swallow compared with the traditional Heller myotomy.
■ Baylor Research Institute study
reveals that uterine cooling can
reduce C-section blood loss
A never-before-seen childbirth technique
could help a woman’s body heal itself through
Volume 28, Number 3
ACCOLADES
David J. Ballard, MD, PhD, chief quality officer at Baylor Scott & White and president of the STEEEP Global Institute, was
named one of the 2015 “Experts Leading
the Field of Patient Safety” by Becker’s
Hospital Review.
The American College of Physicians selected W. Mark Armstrong, MD, MACP,
for the Ralph O. Claypoole Sr. Memorial
Award for Devotion of a Career in Internal
Medicine to the Care of Patients. This award
is given to proven role models who have
demonstrated excellence in and devotion to
the clinical care of patients. Dr. Armstrong is
chief of the general internal medicine division at BUMC.
The American Society of Transplantation
has awarded Jacqueline O’Leary, MD,
its Clinical Science Investigator Award. Dr.
O’Leary is medical director of the Liver and
Transplant Unit at the Baylor Annette C. and
Harold C. Simmons Transplant Institute. The
annual award is given to only one US clinical
investigator who has made a substantial
contribution to the field of transplantation
medicine.
C. Richard Boland, MD, chief of
gastroenterology at BUMC, received two
awards for his achievements in gastroenterology research. In May 2015, the
American Gastroenterology Association
presented Dr. Boland the William Beaumont
Prize in Gastroenterology. This award, given
out every 3 years, recognizes those with
an “outstanding contribution of major importance for the field of gastroenterology.”
In October 2015, the Collaborative Group
of the Americas on Inherited Colorectal
Cancer will present Dr. Boland a Lifetime
Achievement Award.
Marvin J. Stone, MD, past chief of
oncology at BUMC, received the Lifetime
Achievement Award from the American
Osler Society during its annual meeting in
April 2015.
temperature changes, according to a pilot study
from Baylor Research Institute (BRI). Led by a
team of physicians and nurses from BUMC, the
study explored “uterine cooling,” an experimental method that showed significant results in
early testing. The theory is based on biological
fact: Cold temperatures make some smooth
July 2015
muscles contract. The research suggests that
the uterus is among that group.
The study, cocreated by Jack Stecher, MD,
an anesthesiologist on the medical staff at
BUMC, and Jamie Crowson, CRNA, investigated the use of cold temperatures to fight
uterine atony, a condition that prevents the
uterus from self-contracting. It can often
lead to postpartum hemorrhage, which is the
leading cause of maternal death in the world,
accounting for 38 instances every 100,000
births. The two researchers engaged Janice
Mitchell, MD, a physician on the medical staff
at BUMC, to serve as the study’s principal investigator.
Organizers divided the study’s participants
into two groups of 100 women, all of them receiving cesarean sections. While uterine hemorrhage is common in both natural and surgical
childbirth, the researchers studied cesarean
section patients because the uterus is exposed
during the procedure, which allowed the team
to test its cooling method more easily. Women in
the control group had standard surgeries, which
protect the exposed uterus with sponges soaked
in a saline solution at 99°F. Women in the test
group had their uteruses covered with sponges
soaked in the same solution, but they were
cooled to 30°F. The women who underwent the
cooling technique bled an average of 32% less
than women in the control group. Given those
dramatic differences, the results could imply big
changes in obstetric practice.
“It’s unique because it’s a nonthreatening,
nonpharmaceutical method that’s simple and
that people can conceptualize,” Dr. Mitchell
said. “We hope to apply it on a much larger
scale to see whether it decreases the need for
emergency hysterectomies, blood transfusions,
and even more.”
While this study was isolated to cesarean
section patients, the findings suggest uses
for uterine cooling beyond surgery, including
during intrauterine balloon procedures after
vaginal delivery. “Vaginal births comprise
nearly two-thirds of all deliveries, and those
patients are still at risk for uterine atony and
bleeding,” said Crowson, a nurse anesthetist
at BUMC. “In these cases, intrauterine balloon
devices inflated with saline are sometimes
placed to slow and stop bleeding.” Chilling
those balloons could represent an opportunity
to apply these findings to vaginal hemorrhage
circumstances, he added.
A future BRI study, now in enrollment, could
determine if below-freezing temperatures also
Baylor news
work on women who require a cesarean section
after spending hours in labor without success.
This is the so-called “tired uterus” effect. “We
want to analyze those patients who have had
a dysfunctional labor experience to see if the
cold is as effective on a uterus that has been
working all day as opposed to one that hasn’t
gone through an all-day labor,” Dr. Stecher said.
If future investigations corroborate this pilot
study’s findings, it could shift the way babies
are delivered, potentially helping the 3% to
6% of women who suffer from postpartum
hemorrhage.
■ Using big data to help the tiniest
patients
An increasing number of babies across
the country are born addicted to opioids and
require intensive care, according to a study
analyzing MEDNAX Clinical Data Warehouse
statistics from 299 neonatal intensive care
units (NICUs) around the United States. The
study results are reported in a paper authored
by a Baylor researcher and published by the
New England Journal of Medicine. The illness,
called neonatal abstinence syndrome (NAS), is
a drug withdrawal syndrome that most commonly occurs after in utero exposure to opioids. It can lead to seizures, difficulty feeding,
respiratory complications, and low birthweight
in affected infants.
The study, titled “Increasing Incidence of the
Neonatal Abstinence Syndrome in U.S. Neonatal
ICUs,” directly addressed the NICU care of these
infants and found that NAS is responsible for a
substantial and growing portion of resources
dedicated to critically ill neonates in NICUs
nationwide.
Dr. Veeral N. Tolia, a neonatologist on staff at
BUMC, led a team of researchers from US hospitals that determined that between 2004 and
2013 the rate of NICU admissions nationwide
for NAS increased almost fourfold, from 7 to 27
cases per 1000 infants. The research also found
that the length of hospitalization increased by
more than 40%, from 13 to 19 days. The total
percentage of NICU days attributed to NAS increased by more than 500%, with eight centers
reporting one in five of all NICU days devoted to
care of these infants in 2013.
The team also found that a substantial number of these infants presented after maternal
exposure to prescription opioid pain relievers,
a class of medication that the Food and Drug
Administration (FDA) recently has chosen to regulate more tightly. The study found that among
395
these NICU patients, treatment with medication
was common, occurring in 87% of the infants
from 2012 to 2013. This is also problematic
because of the scarce research about the best
way to care for these infants. None of the commonly used medications are FDA approved for
treating NAS, and there is substantial variability
in how these infants are treated.
■ 30 years of innovation: organ
transplant program celebrates three
decades, thousands of lives saved
What started as a heroic effort to save a
5-year-old girl has turned into one of the largest
and most renowned transplant centers in the
country. The Baylor Annette C. and Harold C.
Simmons Transplant Institute, a leader in solid
organ transplantation in the US, has successfully
transplanted more than 7300 organs over
the last 30 years and continues to push the
boundaries of innovation.
“We plan to maintain our status as a
recognized world leader in both transplant science
and patient care,” said Göran Klintmalm, MD,
PhD, chairman of the transplant institute since
its inception. “We will do this not only by focusing
on innovations in transplantation surgery, but also
by researching alternative treatments.”
Dr. Klintmalm has literally coauthored the
textbook on liver transplantation, the surgery
that began the transplant institute 30 years ago.
Through the urging of then-First Lady Nancy
Reagan, the medical community took notice of
a little girl from Indiana named Amie Garrison,
who was in desperate need of a liver transplant.
The only resource at that time for the surgery,
in Pittsburgh, Pennsylvania, could not take
the case. The surgeon known as the father of
solid organ transplantation, Thomas Starzl, MD,
PhD, asked a pioneering team of physicians at
BUMC to take the case. Within hours of BUMC
president and CEO Boone Powell Jr. agreeing to
the operation, teams from Pennsylvania, Indiana,
and Canada—where a pediatric donor liver was
located—mobilized to perform the time-sensitive
surgery.
Baylor Annette C. and Harold C. Simmons
Transplant Institute, which includes both
BUMC and Baylor All Saints Medical Center at
Fort Worth, is one of the largest multispecialty
transplant centers in the country. Through the
dedication of the transplant medical staff, Baylor
has been “first” in a number of areas and is
credited with milestones:
• First and only adult living liver donor program
in North Texas
396
• First islet cell transplant in North Texas
• First certified ventricular assist device
program in the US
• First matched unrelated donor bone marrow
transplant in Texas
• First adult liver transplant in the Southwest
• World’s first extracorporeal perfusion
(bridge to transplant) using a genetically
engineered pig liver, allowing the patient
to survive and successfully undergo liver
transplantation
• First heart/lung/heart “domino” procedure in
North Texas, in which a patient with terminal
emphysema receives a single heart and two
lungs, while another patient with cardiomyopathy receives the good heart from the
patient with emphysema
• First paired kidney donor transplant in North
Texas
■ Baylor Scott & White Health–affiliated
Hope Clinic moves into new facility,
receives top national recognition
Hope Clinic in Garland has a lot to
celebrate these days. The 501(c)(3) nonprofit,
faith-based organization has been providing
medical care and resources for Garland’s
medically indigent since 2002, operating
out of small, overcrowded quarters. In 2011,
Hope Clinic entered into an agreement
to collaborate with HealthTexas Provider
Network, a Baylor Scott & White Health
affiliate, in connection with the operation
of the clinic where services are provided to
patients. The clinic was recently moved into
a newly renovated location that more than
doubles patient-care space. Adding to the
excitement, the clinic received the National
Committee for Quality Assurance Level 3
recognition as a patient-centered medical
home—the organization’s top certification.
From primary care to chronic disease
management and prescription assistance
programs, from behavioral health care to spiritual
care, the clinic assists those most in need. Last
year, prescription assistance totaled $500,000.
Under a new arrangement with North Texas Food
Bank, clinic patients with dietary restrictions are
able to obtain food boxes designed for those
with diabetes and heart disease.
“Hope Clinic is all about giving back,” said
Jenny Williams, executive director of Hope Clinic.
“The patients served deserve this commitment
to quality. Providing charitable medical care
is not about enabling people. Poverty opens
up a multitude of needs. We give patients the
necessary tools and resources, equipping them
to move forward in life.”
■ Two Baylor Scott & White Health
hospitals among top 100 for quality
BUMC and Baylor All Saints Medical Center
at Fort Worth were among the top 100 large
US hospitals based on 40 measures of quality
sought by the Affordable Care Act (ACA),
according to a Kentucky-based organization
that focuses on patient safety, quality, and
efficiency of care. The SafeCare Group, a
software company, conducted the analysis that
used ACA’s metrics aimed at reducing hospital
readmissions, curtailing hospital-acquired
conditions, and achieving value-based care.
The Baylor Scott & White Hospitals received the
100 SafeCare Hospitals distinction in the over400 beds category. The organization said that
400,000 deaths and 5.1 million preventable
complications would be reduced annually if all
US hospitals matched the performance of the
top 100.
■ Baylor researcher’s hollow fiber
system tuberculosis model approved
by European FDA equivalent
The European Medicines Agency (EMA), the
equivalent of the FDA, has approved the use
of the hollow fiber system for the development
of drugs to treat and prevent tuberculosis. The
hollow fiber system model of TB was developed about 12 years ago by Tawanda Gumbo,
MD, investigator at BRI and the director of the
Center for Infectious Diseases Research and
Experimental Therapeutics at Baylor Institute for
Immunology Research. This model, sometimes
called the “glass mouse,” is used to select and
evaluate possible drugs and treatment regimens
before they are tested in clinical trials. The system aids researchers in determining which
drugs to combine and at what doses to effectively fight multidrug-resistant Mycobacterium
tuberculosis, the causative agent of TB.
“This is a significant advance over many
drug development models. The ‘glass mouse’
hollow fiber model has now been found to have
a forecasting accuracy of within 94% of the
clinical values that have been observed later
in tuberculosis clinical trials,” Dr. Gumbo said.
The approval allows for the hollow fiber
system to be used in the development of TB
drugs. Dr. Gumbo’s group is working to expand
its uses to other clinical conditions. They are
also collaborating with other BRI investigators in
projects that will utilize the hollow fiber system.
Volume 28, Number 3
Precision medicine: hype or hope?
Robert G. Mennel, MD
I
recently attended the 10th Annual Harvard Personalized
Medicine Conference. One presentation at this meeting was
preceded by a video outlining the course of a patient who
was diagnosed 4 years earlier with a stage IV non–small
cell lung cancer—a diagnosis that normally would portend a
6-month survival. However, this woman who never smoked
had an EGFR mutation, which predicted a longer response
based on treatment with erlotinib, a drug that inhibits the
pathway activated by the EGFR mutation and was not approved by the Food and Drug Administration until May 2013
(1, 2). She was treated on a clinical trial with erlotinib and
had a remarkable response. However, a year later, her tumor
developed resistance to this drug because of a second mutation. This is a common scenario that oncologists frequently
experience. A few years ago this woman would have never
made it to this point, since we had no drugs to effectively
treat her at the outset.
This case was especially poignant for me since my wife and
I experienced the exact same scenario in 2008 and 2009. My
wife had a cough, which was initially thought to be pneumonia. However, a computed tomography (CT) scan (Figure 1a)
showed a mass, mediastinal adenopathy, and a pleural effusion.
A bronchoscopic biopsy diagnosed an adenocarcinoma. My
extreme depression was somewhat alleviated when I found out
that she expressed a mutation in exon 19 (L747-A750 deletion)
of the EGFR gene. I knew that we had a chance for a prolonged response, and I hoped that if our remission lasted long
enough, the explosion of scientific discovery that was occurring
in this field might actually produce a cure (a hope that most
patients have). The first part of my dream came true. The first
CT 7 weeks after starting erlotinib (Figure 1b) showed a near
complete response, and her brain metastases had disappeared
with just one erlotinib tablet per day. However, a year later she
developed a T790 mutation, which caused the erlotinib to be
ineffective (3). No new drug had been developed, and she died.
It was bittersweet for me to watch the video shown at Harvard’s
personalized medicine meeting. Thankfully, the woman in the
video had her carcinoma a couple years later than my wife. In
that interval, new drugs had been developed, which this woman
was able to get through a clinical trial.
A panoply of clinical trials exists with these new therapies
that are being developed at an amazing pace. Unfortunately,
even though these trials offer the possibility of life-prolonging
results, as was evidenced in this woman in the video, most
physicians do not offer these trials to their patients. This
woman in the video obtained another complete response,
which she is still enjoying 4 years later. I doubt that she
is cured, but she is getting closer, and another drug may
come along before she has her next recurrence. Since this
woman’s last drug was made available to her, the science has
mushroomed at an even faster pace with the development of
next-generation sequencing, RNA sequencing, metabolomics,
and other building blocks of systems biology that identify for
physician-scientists the mutations that are really important
for the patient they are treating. If my wife’s illness had started
5 years later, my grandchildren would still be enjoying their
loving and fun grandmother.
What has allowed these amazing therapies to develop?
The answer is discovery of disease mechanisms through an
investment in research. Th e groundwork was laid in the
1980s with the development of the polymerase chain reaction, which allowed expanded research on DNA and brought
genetics into the modern era (4). This led to a much better
understanding of what drives the growth of tumors and gave
oncologists targets to develop much more effective and directed therapies against. The science and therapies have not
been limited to oncology. Examples include ivacaftor (5) to
treat type 3 cystic fibrosis, L-dopa to treat Segawa’s dystonia
(6), and the 12/14 translocation to define people at risk for
sudden death because of the long QT interval (7), to name
just three. Medicine, and especially oncology, has entered
a new era. But what is the real promise of this new era in
medicine? The stories enumerated above are amazing and
could not have been told 10 years ago.
However, we do not know the targets for most of the diseases that we see, and in oncology we have an especially difficult problem. After we discover an effective drug against a
driver mutation, the tumor will usually discover a way around
From the Charles A. Sammons Cancer Center and Baylor University Medical
Center at Dallas, Dallas, Texas.
Corresponding author: Robert G. Mennel, MD, Charles A. Sammons Cancer
Center, 3410 Worth Street, Suite 580, Dallas, TX 75420 (e-mail: RobertMe@
baylorhealth.edu).
397
b
a
Figure 1. (a) The initial CT scan showing the left lung mass (1a), a pleural effusion (1b), and mediastinal adenopathy (1c). (b) The CT scan after 47 days of erlotinib
showing near complete resolution of the pathologic findings.
our therapy, as was demonstrated in my wife’s case. This leaves
oncologists and their patients at the point that they started a
number of months earlier. This scenario should not be a surprise, since there are many different metabolic pathways in the
cell. Let me ask a simple question: If you had a specific route
to work and one day the route that you normally took was
blocked, would you be able to find your way to work? I think
you would, since it is a rarity to have only one way to get to any
destination. Figure 2 shows some of the pathways in a cell used
by tumors for growth. Think of this as a roadmap. If our drug
blocked one growth pathway, don’t you think that the tumor
would find another pathway for growth, like you would find
another route to work?
Have we made progress? Yes, without a doubt we have
made remarkable progress! Where do we need to go from
here? Straight ahead! We need to stay the course or, better
yet, chart a new course. As director of the Baylor Precision
Medicine Institute, I have a very vested interest in precision
or personalized medicine. I honestly think that the principles
of precision medicine will change the practice of medicine to
a much greater degree than it has already. However, there are
a number of obstacles to the promise of precision medicine.
These obstacles are the expectations of patients and physicians,
the culture of physicians, and the ability to do the needed
research.
Precision medicine needs to simultaneously increase and
decrease the expectations of patients and physicians. The examples that I have given above will excite patients and physicians
alike. However, this excitement will lead to unrealistic expectations of what precision medicine can accomplish right now,
at this point in history. If precision medicine cannot produce
now what people are expecting it to produce, precision medicine’s development will be delayed. We cannot promise what
we cannot deliver now. Therefore, we need to simultaneously
curb the enthusiasm about what precision medicine can produce at this time, while increasing the enthusiasm over what
precision medicine will eventually deliver in the future. The
398
potential accomplishments of precision medicine are without
bounds. Five years ago, there was virtually no effective therapy
for metastatic melanoma. Now we have ipilimumab, BRAF
inhibitors, MEK inhibitors, and PD-1 and PD-L1 inhibitors.
The four images in Figure 3 show remarkable responses that
occurred during the vemurafenib trial. These results, which
would have never been witnessed 2 years before, are so exciting that patients and physicians may interpret them as cures.
They are not usually cures. However, they are probably the
first steps on the journey to cure most disease. They are the
first steps on the research journey.
Research is the paramount event that will allow precision medicine to reach its full expectations. Research may
also delay the development of precision medicine. These two
statements frame a paradox. If we sequence a person’s genome,
we will find thousands of mutations. However, we will know
what to do with <1% of them. The remaining 99% comprise
the basis for the basic and clinical research that is needed to
advance precision medicine. This delineates the enormity
of precision medicine’s task. This research is expensive, and
research dollars are being cut back. How are we going to pay
for this research? There are more questions than investigators and patients to answer these questions. Where are the
investigators and patients going to come from? How are we
going to frame the most important questions to be answered
and convince investigators to cooperate in answering these
questions? The gold standard for clinical research is the randomized controlled trial. If you have a drug against the driver
mutation or its products causing the disease, is it ethical to do
a randomized controlled trial in a group of patients with this
driver mutation? The precision medicine community needs a
coordinated plan to approach all of these questions. This organized approach is needed in a medical research community
that prefers to work independently, is very protective of its
data, is not likely to freely share data, generally lacks banked
biologic data to answer questions, and for the most part does
not have adequate informatics to solve their problems. This is
Volume 28, Number 3
Figure 2. A simplified representation of a cell’s proliferation pathway. Image courtesy of Abcam.
an enormous but surmountable problem for precision medicine that needs to be solved.
The culture that physicians practice in is another obstacle
to the implementation of precision medicine. Most physicians
are not fluent in the principles of precision medicine. Research
in precision medicine will take more time than the standard
care of patients. This will require a culture change for all of
us. Medicine has made amazing progress in the 45 years that I
have been a physician. But if we are honest with ourselves, we
do not have the answer to most of the diseases that we treat.
Therefore, research is necessary.
We need to stay our course in very unfriendly waters, continuing the basic research and translating these findings into
new diagnostics and new therapies. We need to do this in an era
July 2015
where research funding is decreasing and where most patients
are not enrolled in clinical trials but are treated with standard,
often ineffective therapies. As physicians, we need to be honest with ourselves and recognize areas where our therapies are
inadequate; if our patients still want therapy, we need to find
trials that make sense and not continue to treat them with
therapies that usually do not work. This is easy to say but difficult to do. Precision medicine can deliver amazing results now,
but the promise for even greater results in the future is huge.
In order to reach this prediction for precision medicine, we as
physicians need to use the science that is available, encourage
and participate in basic and clinical research, and ask ourselves
whether the therapies that we are using are effective or ineffective and in need of a new treatment paradigm.
Precision medicine: hype or hoax?
399
Figure 3. Positron emission tomography scans before and after vemurafenib therapy showing the dramatic response with the early use of this drug.
1.
Nguyen KS, Neal JW. First-line treatment of EGFR-mutant non-smallcell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors.
Biologics 2012;6:337–345.
2. Yap TA, Popat S. Toward precision medicine with next-generation
EGFR inhibitors in non-small-cell lung cancer. Pharmgenomics Pers Med
2014;7:285–295.
3. Ding D, Yu Y, Li Z, Niu X, Lu S. The predictive role of pretreatment
epidermal growth factor receptor T790M mutation on the progressionfree survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer
patients: a meta-analysis. Onco Targets Ther 2014;7:387–393.
4. Nguyen KS, Neal JW, Wakelee H. Review of the current targeted
therapies for non-small-cell lung cancer. World J Clin Oncol
2014;5(4):576–587.
5. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P,
Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen
400
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F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator
in patients with cystic fibrosis and the G551D mutation. N Engl J Med
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Yosunkaya E, Karaca E, Basaran S, Seven M, Yüksel A. Marked improvement in Segawa syndrome after L-dopa and selegiline treatment. Pediatr
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Mahida S, Hogarth AJ, Cowan C, Tayebjee MH, Graham LN, Pepper
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Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann
TT, Sotoodehnia N, Rossin EJ, Morley M, Wang X, et al. Genetic association study of QT interval highlights role for calcium signaling pathways
in myocardial repolarization. Nat Genet 2014;46(8):826–836.
Volume 28, Number 3
Update on the Baylor Scott & White Quality Alliance
Carl E. Couch, MD, MMM
T
he US health care system has been widely characterized
as having unsustainably rising cost, continuing quality
issues, and uncoordinated or disintegrated delivery of
care. Accountable care organizations (ACOs) focus on
clinical integration in care delivery while improving quality and
reducing costs. Clinical integration is considered essential to
true systemic change and meaningful reform that expands coverage, improves quality and care coordination, rewards effective
and efficient care, promotes innovation, and helps control cost
(1). After 2 full years in operation, the Baylor Scott & White
Quality Alliance (BSWQA) has made significant progress in
achieving these elements of meaningful reform. BSWQA is a
physician-led, patient-centered comprehensive network, with
more than 3900 primary and specialty care physicians, 46 hospitals, a number of post–acute care facilities, and other members
of the care continuum assuming joint responsibility for accessible and efficient care delivery. In the past year, BSWQA has
collaboratively managed the health of patient populations, including more than 40,000 lives attributed to BSWQA through
the Baylor Scott & White North Division employee health
plan, Humana Medicare Advantage product, Aetna Medicare
Advantage product, Scott & White’s Vital Traditions Medicare
Product, and most recently the Aetna Whole Health–BSWQA
ACO health plan. Preliminary data captured from these agreements point to BSWQA’s notable improvements in important
quality, efficiency, cost, and outcome measures that have led to
achieving the Triple Aim™—“Better Care, Better Health, and
Better Value.”
POSITIVE OUTCOMES IN POPULATION HEALTH MANAGEMENT
Data over a 2-year period show that BSWQA population
health strategies are working. Within the Baylor Scott & White
North Division employee health plan population, readmission
rates dropped 15% (Figure 1a), admissions per thousand were
reduced by 9% (Figure 1b), and an internal projected analysis
showed a $10 million savings in medical plan costs (actual vs.
target) (Figure 1c). In addition, there was an increase in “innetwork” usage of BSWQA physicians, along with a growing
number of high-acuity patients being assigned to nurse care
managers. Throughout its 2 years in operation, BSWQA has met
or exceeded all quality metrics set forth in all of its managed care
contracts. Many of these accomplishments were driven by the
deployment of three key population health strategies centered
on improving quality and coordinating care:
• Patient-centered medical homes (PCMHs). BSWQA’s
patient-centered medical home model is the primary driver
for many BSWQA quality initiatives developed to improve
care. As the first step in maintaining wellness and managing
chronic disease for its patients, the patient-centered medical
home serves as the stimulus for BSWQA quality improvements and efficiencies, such as developing physician-directed
care teams, increasing the rate at which generic medications
known to reduce costs are prescribed, and creating protocols
to achieve standardized, quality care. Characterized by teambased physician-led primary care physicians, these PCMHs
have been shown widely to improve outcomes and lower
costs for patients served by them.
• Care coordination. Appropriate care resources are assigned
to patients in accordance with their health risk status. Registered nurse care managers are assigned to the 5% of patients
who are sickest, who drive half the cost of health care and
need special care coordination resources. These care managers augment physician services by facilitating posthospital
transitions, coordinating specialty visits, helping to navigate
the health system, and coaching patients in self-management
and wellness. The next 15% of rising-risk patients are assigned to medical assistant health coordinators, who perform transitional care management and close gaps in care.
The 80% of generally well patients are contacted through
automated modes of communication, such as patient portals
and Televox, reminding them of screenings and wellness
visits that may be due.
• Data analytics. Through risk stratification and predictive
modeling, BSWQA is segmenting patients into specific
health risk pools and tailoring their care appropriately. To
prepare for future cost savings and align financial incentives
with the work being done to improve efficiencies and quality, BSWQA has developed a shared savings distribution
model. Supporting BSWQA’s belief in the equitable distriFrom Baylor Scott & White Quality Alliance, Dallas, Texas.
Corresponding author: Carl E. Couch, MD, MMM, President, Baylor Scott &
White Quality Alliance, 8080 N. Central Expressway, Suite 900, Dallas, TX 75246
401
b
a
95
100
20%
86
20%
18%
80
9% drop
15% drop
60
10%
40
20
0%
2012
0
2014
2012
c
530
$521.47
520
2014
$516.22
510
500
$494.00
490
$480.63
480
470
460
2013
2014
Target
Actual
Figure 1. Outcomes of the Quality Alliance population health strategies for the Baylor Scott & White North Texas Division employee health plan population, including
(a) all-cause readmission rates, (b) admissions per thousand, and (c) medical plan costs (actual vs. target).
bution of shared savings, this model allows all physicians to
earn a percentage of savings based on attribution as well as
on a pro rata basis within the respective primary care and
specialty care pools of the distribution method. The only
caveat to participating in shared savings is the requirement
for physicians to achieve clinical integration measures such
as local pod meeting attendance and website usage and to
remain a member in good standing for 1 full year.
over time. In addition, the BSWQA ACO is now an important
differentiator among competing health plan options.
BSWQA activity centered on contract agreements with payers and employers is quickly ramping up our covered lives, which
are expected to grow to just over 400,000 by January 2017. This
is astronomical growth considering our humble beginnings of
managing the health of the 34,000 lives through the Baylor Scott
& White North Texas Division employee health plan.
SIGNIFICANT GROWTH IN COVERED LIVES
The word is out: BSWQA is doing great work as demonstrated by the improved outcomes mentioned above, which
were realized in just 2 short years in operation. These improvements and savings have prompted the development of BSWQA’s
compelling story for accountable care driving positive outcomes
and true health care transformation through population health
management. As its story continues to unfold, payers and employers are taking notice of BSWQA achievements and seeking
collaborative agreements to use the organization and its providers as a preferred network for their patients. These agreements
are becoming a vital element for creating the value-driven care
delivery model of the future.
New collaborations between payers have been emerging, and
the Aetna Whole Health–BSWQA ACO health plan continues
to be actively marketed throughout the Dallas–Fort Worth area.
These types of value-based network contracts are viewed by payers and employers as a way to control costs and ensure quality
BUILDING THE POPULATION INFRASTRUCTURE
BSWQA can credit achievements in improving care not
only to the incredible collaborative and accountable efforts of
its physicians, administrators, and staff, but also to invaluable
resources provided by a solid population health infrastructure.
BSWQA’s population health infrastructure was built following the playbook for population health set forth by industry
experts and reported by the Advisory Board Company (2)
(Table 1).
In an industry inundated with overwhelming change and
what seems like endless reform requirements, it is often difficult to see the light at the end of the tunnel. There have
been ACO skeptics everywhere. However, the impressive early
results emerging from BSWQA’s population health efforts
are inspiring. To see BSWQA’s hard work associated with
true care transformations among our patient populations
is testament to the organization’s competence in forming a
network of willing physicians and hospitals. It also confirms
402
Volume 28, Number 3
Table 1. The population health strategies of Baylor Scott & White Health Quality Alliance
Playbook for population health*
Prioritize a list of key initiatives with
stakeholder buy-in
BSWQA’s response
BSWQA focuses on delivering value by eliminating unnecessary services, better managing chronic disease, and
improving coordination of care.
Invest in information exchange, analytics, Substantial investments have been made in Humedica, Crimson Real-Time, Explorys, and Crimson Care Manager.
and patient-facing technology
All systems are up and running and offering a longitudinal patient view, as well as automated patient identification,
risk stratification, predictive modeling, and workflow analysis functionality.
A patient portal called FollowMy Health (an AllScripts solution) has been made available by Baylor Health Care
System.
The BSWQA information technology committee is hopeful to announce that the patient’s medical data can be
viewed at the point of care utilizing the system’s health information exchange browser. Stay tuned.
Develop a preferred partner network with BSWQA is a broad network of primary and specialty care physicians, hospitals, post–acute care facilities, and
shared culture and accountability
other members of the care continuum willing to assume joint responsibility for patient access and care delivery. It
participates in managed care contracts with the North Texas Division employee health plan and Medicare Advantage programs through Humana, Aetna, and Scott & White Vital Traditions. As a result of its success in managing
more than 40,000 lives, prominent payers and employers in the market are seeking direct contracting opportunities with BSWQA.
Train and redeploy existing staff to match BSWQA’s broad network of primary and specialty care physicians—with their proficiency in disease management
new demand for patient services
and adult preventive health services, their solid reputation for high-quality care and patient satisfaction, along with
their existing capacity for superior practice management—is central to BSWQA development.
*The playbook is from the Advisory Board Company (2).
BSWQA indicates Baylor Scott & White Health Quality Alliance.
BSWQA’s capacity to generate positive outcomes as it begins
the transition from volume-based to value-based care delivery. Even more inspiring is the health transformation being
achieved throughout the nation that is already causing a shift
in the health care cost curve. A new report from the Council
of Economic Advisors stated that according to recent data,
health care spending and prices are growing at their slowest
rates in decades (3). Specifically, the Centers for Medicare
and Medicaid Services had a 6% annual increase in spending
from 2002 through 2011, but for the past 2 years only a 1%
increase. While this marked slowdown likely has many causes
that are not fully understood, the available evidence suggests
that, as a nation, contributions to meaningful reform such
as ACOs are already having an impact and improving the
quality of care for patients.
Adding to BSWQA accomplishments is the honor of being
named by Becker’s Hospital Review as one of the “100 Accountable Care Organizations to Know,” being recognized among
the Top 30 ACOs in the country by SK&A Consulting, and
earning ACO accreditation from the National Committee
for Quality Assurance. As we round out 2015, BSWQA care
July 2015
strategies will continue to focus on value and accountability.
BSWQA will concentrate on becoming more proficient in
managing patient populations and will continue to explore opportunities to participate in direct contracting with employers
and payers. BSWQA’s performance initiatives will be selected
to target best cost-reduction opportunities for each contracted
population. In addition, BSWQA is beginning to serve as the
population health integrator for Baylor Scott & White Health,
now the largest not-for profit health system in Texas.
1. American Hospital Association. Clinical integration: the key to real
reform. TrendWatch 2010(February), 1-12. Available at http://www.
aha.org/research/reports/tw/10feb-clinicinteg.pdf; accessed May 12,
2015.
2. The Advisory Board Company. Playbook for Accountable Care: Lessons
for the Transition to Total Cost Accountability. Washington, DC: Advisory
Board.
3. Council of Economic Advisors. Trends in Health Care Cost Growth and
the Role of the Affordable Care Act. Washington, DC: Executive Office of
the President of the United States, November 2013. Available at https://
www.whitehouse.gov/sites/default/files/docs/healthcostreport_final_noembargo_v2.pdf; accessed May 12, 2015.
Update on the Baylor Scott & White Quality Alliance
403
Nobel laureates and their medical schools:
who selected whom?
Allen B. Weisse, MD
B
y the beginning of 2015, the United States had largely
recovered from the economic crisis of 2008. The Dow
had topped 18,000; unemployment was down; productivity was up. Despite this, much of the American
public is uneasy about the future. Dating even before the Great
Recession, poll after poll registered the belief that the outlook
was bleak. When asked, “Do you think your children will grow
up to be as well off or better off than you are?” the reply was
usually in the negative. This was not only the case for those in
the shrinking middle class and those lower on the economic
ladder. The affluent, those in the top 1% or 5% of the income
spectrum, were equally unenthusiastic about the future.
This angst about the prospects awaiting their children has
spurred efforts to obtain the best education possible to evade
the glum fate threatening them. In cities such as New York,
young parents, when they can afford it, seek out preschool
or kindergarten programs that will give their kids a better
edge in the future. Private grammar and high schools are
often engaged. And then, before one knows it, high school
graduation is upon them and the frantic search for the “right”
college begins. For those contemplating a career in medicine,
where the openings for medical school are limited, the emphasis is on obtaining a place in one of the elite colleges in
the hope that this will ease the pathway into medical school.
And with this, a future success in life will be achieved. Is such
a belief justified?
No emblem of success in medicine is greater than that of
a Nobel Prize in Medicine or Physiology. For those reaching
this pinnacle, is it in any way related to the colleges or graduate
schools attended along the way? Between 1901 and 2014, 207
individuals received the Nobel Prize in Physiology or Medicine.
Of these individuals, 95 were Americans. Among these, 17
received their formal educations abroad before settling in the
United States, where the bulk of their research was performed.
This leaves 78 who, in the course of their education, were confronted by college selection and later medical school selection
in the United States. Details of their education and biographical facts are available online from the Nobel Foundation (1).
Identification of the 10 most selective colleges was obtained
from a common source, U.S. News and World Report (2). The
10 most selective of our 141 medical schools was also obtained
from this source (3).
404
Table 1. Ranked undergraduate colleges attended by 78 Nobel
laureates
Rank
Institution
Number
1
Princeton University
0
2
Harvard University
2
3
Yale University
5
4
Columbia University
6
4
Stanford University
0
4
University of Chicago
1
7
Massachusetts Institute of Technology
1
8
Duke University
0
8
University of Pennsylvania
2
California Institute of Technology
1
10
Other undergraduate schools
60
Table 1 indicates the undergraduate colleges attended by
the 78 Nobel laureates included in our sample. Since the total
number of undergraduate institutions in the United States is
over 3000, the 10 schools constitute only a fraction. Nevertheless, 18 of the 78, or 23%, attended one of these highly rated
schools, attesting to their drawing power for the intellectually
gifted. Still, three quarters of the group attended one of the
lower-ranked colleges.
Table 2 lists the top 10 medical schools and the numbers
of Nobel laureates who attended them in the course of their
education. The total tallied is 77, since one of the Nobel laureates, Gertrude B. Elion, a biochemist and pharmacologist, never
obtained a doctorate degree. Here, the denominator of our
calculation (“Others”), the number of medical schools in the
United States, is much lower than the number of undergraduate
schools applying to Table 1. However, this number has grown
over the years. In 1930, there were 76 US medical schools; in
1950, 79; in 1984, 127. Currently there are 141 US medical
From the Department of Medicine (retired), Rutgers–New Jersey Medical School,
Newark, New Jersey.
Corresponding author: Allen B. Weisse, MD, 164 Hillside Avenue, Springfield,
NJ 07081 (e-mail: [email protected]).
Table 2. Top-rated research schools of medicine attended by
77 Nobel laureates
Rank
Institution
MD
PhD MD/PhD Total
1
Harvard University*
12
6
–
18
2
Stanford University*
–
–
–
–
3
Johns Hopkins University*
8
2
–
10
4
University of California, San Francisco*
–
–
–
–
5
University of Pennsylvania
1
–
–
1
6
Washington University in St. Louis
3
–
–
3
7
Yale University*
–
2
–
2
8
Columbia University*
3
2
–
5
9
Duke University
–
–
–
–
10
University of Washington
–
1
–
1
Other medical schools
17
18
2
37
77
*Also among the top 10 rated for graduate schools in science.
schools in existence. Using these figures one can estimate that
over the last 50 years or so, the highly ranked schools have constituted roughly between 8% (10/127) and 13% (10/76) of the
total. Among the 77 individuals counted, 40 (52%) obtained
their MD or PhD degrees from one of the top 10 schools. As
in Table 1, this disproportionate figure reflects the desirability
of these highly rated institutions.
What is not shown in the table is that, among these 40,
only 11 (28%) had attended a top 10 college prior to entering medical school. In other words, the bulk of these did not
require a degree from an elite top 10 college before being accepted into that institution’s graduate program. During the
period studied, none of the laureates attending a top 10 school
obtained both MD and PhD certification, although two attending lower-ranked schools did. This will probably change in the
future, given the highly specialized work currently in progress.
In the gathering of these data some interesting demographic
findings regarding the Nobel laureates’ birthplaces emerged.
Many of them were born in the Northeast, the most densely
populated section of the country. New England produced 11
laureates, but only one was from Boston. New York City claimed
17 as their birthplace.
Women were underrepresented. Rosalyn Yalow, a developer
of radioimmunoassays (Nobel in 1977), was the first native-born
American woman to be so honored. However, over the next 27
years, only 4 more American women joined her in receiving
this award. Such a disappointing finding is tempered by the fact
that today the number of women in American medical schools
is often equal to and, at times, greater than the number of men.
Although no attempt has been made to quantify this, a reading of the 78 biographies revealed that a number of future Nobel
Prize winners were often disengaged during their early school
years and had only lackluster records during that time. Others
began their intellectual pursuits in the humanities or other nonscientific pursuits before being directed into the field of bioscience.
July 2015
An associated concern about selective colleges has been
addressed at some length by the provocative author Malcolm
Gladwell (4). He notes that more than half of all American
students who start out in science, technology, or mathematics programs drop out after the first or second year. It appears
that many very bright students, when accepted into one of
the top-ranked schools, become intimidated by the prodigies
around them. This results in a diminishing of self-esteem and
abandonment of this course of study. Gladwell argues that, had
they matriculated in a second- or third-tier college, they would
have succeeded in their initial goals and emerged with the credentials enabling them to function in these fields to the benefit
of society, which needs more of such professionals. Although
this phenomenon does not appear to apply to medical schools,
given their high graduation rates, it poses an intriguing pedagogical question: When is the “best” school not the best choice?
Finally, how valid is this “retrospectroscopic” approach to
addressing the questions posed? Are the findings concerning this
small and highly selective group applicable to the hundreds of
thousands of students applying to college or medical school?
Are our numbers just too small? How reliable is U.S. News and
World Report? Is the awarding of a Nobel Prize the best gauge for
universal success when errors of omission have been so common
in the past history of the Nobel Foundation (5)? Such doubts
may be justified, but the results reflected from even this small
facet of investigation are compelling.
We Americans like to think of ourselves as egalitarian in contrast to our British cousins. Although their educational system
is organized differently from ours, it was enticing to determine
the relationship of their two major universities to the awarding
of the Nobel Prize. During the time period covered, 25 Nobel
Prizes in Medicine or Physiology were awarded to citizens of
the United Kingdom. Of those so honored, 15, or 60%, had
attended either Oxford or Cambridge. This does not seem terribly different from the 52% of American Nobel laureates who
attended top-tier medical schools in the United States. Perhaps
we are more class conscious than we would like to think.
On the other hand, tucked into Harlem, of all places, is a
small cluster of incongruously designed Gothic buildings that
represent the City College of New York. This once tuition-free
public institution, catering mainly to the children and grandchildren of impoverished immigrants, served as an intellectual
incubator for 13 Nobel Prize winners, 6 of them in Medicine or
Physiology. Not a bad record for a college with no great financial
endowment, no hoary traditions, and no long historical record
of scholarly achievements.
1.
2.
3.
4.
5.
Nobel Foundation and Nobel Media. All Nobel laureates in physiology
or medicine. Available at http://nobelprize.org/nobel_prizes/medicine/
laureates; accessed April 7, 2015.
U.S. News and World Report. Best Colleges, 2015 Edition. Washington,
DC: U.S. News and World Report, 2014:72.
U.S. News and World Report. Best Graduate Schools, 2015 Edition.
Washington, DC: U.S. News and World Report, 2014:64.
Gladwell M. David and Goliath. New York: Little, Brown & Co.,
2013:63–95.
Weisse AB. Notes of a Medical Maverick. New York: iUniverse, 2010:101–
128.
Nobel laureates and their medical schools: who selected whom?
405
On Camel Rides and Moses Maimonides
John Davis Cantwell, MD
W
hile in Morocco, mainly to celebrate a 75th birthday
by riding camels in the Sahara desert with my wife
and several good friends, I also had another objective. I wanted to visit the old city (medina) of Fes
and to find the home of the legendary Middle Ages physician,
Jewish theologian, and philosopher, Moses Maimonides, said
to be a direct descendent of King David.
The sand dunes in the Sahara were formidable, as I’d heard
(Figure 1). The 1-hour camel ride was enjoyable (sort of ), although the downhills were a bit hard on my postoperative low
back. I could only imagine what it must have been like to make
the 52-day journey to Timbuktu in years past.
The medina of Fes is a maze of narrow, twisting alleyways,
lined with souks (shops) selling a wide variety of goods, mainly
food, clothing, and various crafts. Unlike the medina of Marrakech, this one is free of motorized vehicles, although traversed
by heavily laden donkeys and horses (Figure 2), their owners
shouting a harsh balak, which roughly translates into “get out
of my way.”
Our guide, Jalil, had grown up in the medina and took us to
the house where Maimonides lived during his 5 years in the city.
Now a restaurant (Figure 3), the interior revealed the mosaics
and various beautiful mismatched Berber carpets, so typical of
the country. Nearby was a sign (Figure 4) noting the former site
of a hospital dating back to the time of Maimonides, where he
most likely trained in medicine.
MOSES MAIMONIDES
Maimonides (Figure 5) was born in Cordoba, southern
Spain, in 1135. The Almohad Berber dynasty conquered Cordoba when he was a teenager, forcing his family to try different
areas in Spain more tolerant of Jews before coming to Fes. He
trained in medicine both in Cordoba and in Fes. The fanatic
Islamic sect of Almohad eventually took over Fes in 1145, after a
9-month siege. Maimonides had departed for Egypt years before
and eventually settled in Old Cairo, where he died at age 69.
A prolific writer and thinker, Maimonides produced a
14-volume work on codification of Jewish law among his many
works. He became the chief rabbi of all the lands controlled
by Saladin, the sultan of Egypt and Syria, and was also the
personal physician to Saladin (who had defeated the crusaders
in Jerusalem) and to Saladin’s son, Al-Afdal. The latter was said
406
a
b
Figure 1. The author and his wife, Marilyn, riding in the Sahara desert.
to have had “unhealthful habits” and was “burdened by black
thoughts and physical symptoms,” which no doubt kept his
physician busy.
THE APHORISMS
I was mainly interested in perusing some of the 10 medical books of aphorisms Maimonides wrote. As Nuland noted,
he was “a commentator on the art of medicine as it had been
From Piedmont Heart Institute, Atlanta, Georgia.
Corresponding author: John Davis Cantwell, MD, Piedmont Heart
Institute, 275 Collier Road, NW, Suite 500, Atlanta, GA 30309 (e-mail:
[email protected]).
Figure 4. A sign indicating the hospital location where Maimonides probably
worked.
Figure 2. The medina of Fes.
handed down to him by Hippocrates and especially Galen,
basing the commentary on his world view and the experiences he had had when caring for his many thousands of
patients” (1).
He described a number of common conditions, from
pneumonia and asthma to diabetes and hepatitis. He had the
chutzpah to criticize Galen for contradictions “in that which
he previously stated,” saying that “this requires explanation.”
He also challenged Galen’s belief that the testicles were more
a
b
Figure 3. The former home of Maimonides, now a restaurant.
July 2015
important than the heart, pointing out that one could live without testicles (i.e., eunuchs) but not without the heart. It would
take another 500 years before William Harvey disproved Galen’s
theory of the circulation.
Some of Maimonides’ aphorisms (1, 2) are still pertinent
today, such as the following:
• “The more perfect a person becomes in one of the sciences, the more cautious he grows, developing doubts,
questions, and problems
that are only partially
solved” (whereas one
defi cient in science will
fi nd it “easier to understand every difficulty”).
• “Immobility is as great a
deterrent to the maintenance of health as activity
is of benefit.”
• “One should not neglect
physical exercise for the
body as do people of learning who diligently study
the entire day and night
without any gymnastics.”
• “Moderate physical exercise . . . is good both for
the body and soul.”
• “It is not good for a person
to drink more than a reasonable amount of wine.”
• “Thus, rejoicing and happiness alone will make many
people’s illness milder. For
On Camel Rides and Moses Maimonides
407
• “Excessive ingestion of walnuts causes hindrance of speech.”
• “Excrement of goats, mixed with barley flour and kneaded
with vinegar, dissolves hand inflammation.”
• “The consumption of rabbit heads, as much as one is able
to eat, helps against tremors.” (Sorry, I can’t eat many rabbit heads.)
• “The wearing of rabbit skins strengthens the bodies of the
elderly and the young.”
• “Mustard oil trickled into the ear of a deaf person restores
hearing.” (Maybe I’ll try that on a friend who is going deaf.)
• “Ivory, if pulverized and the teeth brushed therewith, whitens them.”
• “If his right testicle is larger he will give rise to male offsprings; if it is the left, he will give rise to females.” (I’ll test
this in a patient whose wife is pregnant.)
• “A cattle hoof, if burned and drunk with oxamel, shrinks an
enlarged spleen and stimulates the desire for coitus.” (Worth
a try, even if one’s spleen isn’t enlarged.)
Figure 5. 18th-century portrait of Maimonides.
others, both the illness on the one hand as well as the emotional upset that led to it disappear.”
• “Colchicine . . . dissolves inflammation of gout.”
SUMMARY
A birthday celebration trip to Morocco featured a camel
riding adventure in the Sahara desert and a visit to the home
of the noted physician, Jewish theologian, and philosopher
Maimonides. After a prolific life, Maimonides died in Egypt
and was buried in Tiberias in the Holy Land, a site that some
still debate. His medical aphorisms were referred to for centuries after his death. Many hospitals and schools throughout
the world today bear his name, such was his influence. His
gravestone says simply, “From Moses to Moses, none arose
as Moses.”
Of less value are off-the-wall statements:
• “Radishes and beets and the like are quite often altered and
converted to blood, but only a small amount.”
408
1.
2.
Nuland SB. Maimonides. New York: Schokem Books, 2005.
Rosner F, Muntner S, eds. The Medical Aphorisms of Moses Maimonides.
New York: Yeshiva University Press, 1971.
Volume 28, Number 3
DAVID BRUCE HELLMANN, MD: a conversation with the editor
David Bruce Hellmann, MD, and William Clifford Roberts, MD
D
r. David Hellmann (Figure 1) gave medical grand
rounds at Baylor University Medical Center at Dallas
on November 18, 2014, and between his wonderful
grand rounds and his noon presentation to the medical
houseofficers, the following interview was done. Dr. Hellmann
is one of the modern greats in internal medicine. Since 1996,
he has been professor of medicine at The Johns Hopkins School
of Medicine and, since 2000, chairman of the Department of
Medicine at Johns Hopkins Bayview Medical Center, where
40% of the Hopkins Department of Medicine faculty works.
He also is vice dean and vice president for research at Bayview
Medical Center and the Aliki Perroti Endowed Professor at
Johns Hopkins University School of Medicine.
Dr. Hellmann was born on March 2, 1951, in Louisville,
Kentucky, and that is where he grew up. He graduated magna
cum laude from Yale College, New Haven, in 1973, and from
the Johns Hopkins University School of Medicine (faculty
selection to Alpha Omega Alpha) in Baltimore in 1977. His
3-year training in internal medicine was on the Osler Medical Service at The Johns Hopkins Hospital. In July 1980, he
moved to San Francisco, California, to do a 2-year fellowship
in rheumatology/clinical immunology and upon completion
was appointed assistant clinical professor of medicine at the
University of California, San Francisco (UCSF). By 1985, he
was acting chief of the Division of Rheumatology/Clinical Immunology at their Moffitt Hospital. In 1986, he returned to
Johns Hopkins as assistant professor, deputy director of the
Department of Medicine, and associate physician-in-chief of
The Johns Hopkins Hospital. By 1987, he was clinical director
of the Division of Molecular and Clinical Rheumatology and
by 1989, associate professor in the Department of Medicine
and the Mary Betty Stevens Endowed Chair in Rheumatology.
For 1 year spanning 1994 to 1995, he was acting director of the
Department of Medicine and the acting physician-in-chief of
The Johns Hopkins Hospital. In 2000, Dr. Hellmann became
chairman of the Department of Medicine at the Johns Hopkins
Bayview Medical Center and director and cofounder of The
Johns Hopkins Center for Innovative Medicine.
His contributions to the Johns Hopkins institutions have
been enormous. He has served on numerous important committees and has received teaching awards from the Johns
Hopkins Osler medical housestaff. Despite these numerous
time-consuming activities, Dr. Hellmann has
continued his investigative activities and has
published nearly 100
articles in peer-reviewed
medical journals, edited 13 books, including
three editions of Current
Rheumatology: Diagnosis
& Treatment, and written
nearly 100 chapters in
various textbooks. Along
the way he has been associate editor and editor
in chief of Medicine, a
journal that has published
Figure 1. David Hellmann, MD.
numerous classic articles
through the years. He and
his wife, Linda, are the proud parents of two successful offspring. Dr. Hellmann is one of the kindest and most informed
physicians I have been privileged to meet, and it was an honor
to have him at Baylor University Medical Center.
William Clifford Roberts, MD (hereafter, Roberts):
Dr. Hellmann, it’s really a pleasure to speak with you. To start,
could you talk about your early years, your parents, and your
siblings?
David Bruce Hellmann, MD (hereafter, Hellmann): I
grew up in Louisville, Kentucky, and had the most wonderful of
childhoods. My father was a solo family practitioner (Figure 2).
No one in his family had been a physician or had gone to
college. The searing experiences in his life were the Great Depression, in which his family lost their house and his father, an
From the Department of Medicine, Johns Hopkins University School of Medicine
and Johns Hopkins Bayview Medical Center, Baltimore, Maryland (Hellmann)
and the Baylor Heart and Vascular Institute, Baylor University Medical Center
at Dallas (Roberts).
Corresponding author: David B. Hellmann, MD, MACP, Chairman, Department
of Medicine, Johns Hopkins Bayview Medical Center, 5200 Eastern Avenue,
Mason F. Lord Building, Center Tower, Room 322, Baltimore, MD 21224
409
Figure 2. At age 7, with his father, Jack K. Hellmann, MD, 1958.
engineer, lost his job, and war. Before finishing high school, he
joined the Army Air Force and was a navigator during World
War II. During the war he dropped napalm in parts of Asia.
Although he didn’t speak much of his experiences, like many of
that generation, he told me one time that the planes did not fly
very high or very fast so he saw the devastation that was brought.
Given these experiences, he decided that he would be guided
by 1) spending his whole life promoting health and 2) working
only for himself. Those two principles at that time (late 1940s
to 1950s) meant he would become a physician. Through the
G.I. Bill, he attended an abbreviated college and full medical
school. Four of his five children attended his graduation. My
mother was a chemistry major and later in life became a talented
math teacher.
Another experience influenced my career choice. When I
was 5, I developed Legg-Calve-Perthes disease, the softening
of the hipbone. (It’s an idiopathic avascular necrosis of the hip
that occurs chiefly in young boys [90%] between the ages of
5 and 6.) Initially, I was thought to have tuberculosis of the
hip because my parents during my first year lived in public
housing where tuberculosis was common. Additionally, I had
a positive PPD at age 5. Quickly, however, it became clear that
it wasn’t tuberculosis. For about a year I did not walk normally. For about 4 to 6 months I was in a full-body cast that
kept my right leg from moving. The cast was from my belly
button to my knees. Later I was in a brace and then crutches.
I remember well the kindness of the nurses and physicians
while I was in a cast.
We moved to St. Matthews, Kentucky, when I was 3 or 4
and lived there when I developed Legg-Calve-Perthes disease.
On one side of our house was a huge cornfield and on the other,
a neighbor with nine children. That family ran the local bakery
and the father (Mr. Bernie Bowling), who also was the mayor,
noticed I couldn’t walk. He invented an “Irish mailer,” a tricyclelike device with two wheels in the back and one in the front. It
410
was guided by the feet and propelled by hand bars connected
to a drive chain. He altered the “mailer” by removing the bars
and replacing the guide wheel with a wheel with pedals so that
I could lie on the plywood and propel myself using handles
on the wheels. As a result, I had no impediment or drawback
to going wherever I wanted. Now that I have two children, I
marvel at my parents and my neighbor for not making me feel
limited in any way. My illness introduced me to medicine and
also perhaps instilled in me the sense that you cannot count
on everything working out well and that you need to put your
own effort into an endeavor to get where you want to go. I have
experienced people’s generosity throughout my life. I’m not a
particularly religious person but I was raised with the concept
that grace is a gift from God and that these gifts are received not
because you deserve them but because someone has to receive
them and you are the lucky recipient. As I look back on my
life, I have been showered with gifts of grace, including from
Mr. Bowling, our neighbor.
Roberts: How long were you in the cast?
Hellmann: In total, 1 year. I was in the cast for 4 to 6
months, then in a big heavy metal brace. A few classmates
in kindergarten called me Chester, a character in Gunsmoke
who walked with a limp. That’s about as harsh as it got. From
the brace I went to crutches, and by the year’s end the hip
hardened with a good ball and socket. There were no residual
consequences. People who don’t get the care that I received
often need an early hip replacement. The only consequence I
remember was having a bigger foot than before so I had to get
two pairs of shoes for about a year after.
I am the second oldest of five children, the oldest male. By
the time I was ready to try and walk again, I could have won
the Olympics in hopping. I was a phenomenal hopper on my
left leg and a very rapid crawler, the two ways I was allowed to
get around. I asked my younger brother, Don, how to walk.
He took about a nanosecond and said, “Well, put one foot in
front of the other.” I tried that and immediately fell. I started
to crawl. My sister, a born leader, grabbed me by my shirt and
said, “You’re a Hellmann and no Hellmann is going to crawl.
Walk!” So with my sister’s words of “encouragement,” I kept at
it and soon walked again.
Roberts: Does anyone know what causes that disease?
Hellmann: No.
Roberts: What is your father’s name?
Hellmann: Jack King Hellmann. He was not named John
because his father was Frederick Heinrich Hellmann, the first
of 12 children to be born in the USA. My great-grandfather
was a pacifist and didn’t want to be in Bismarck’s army in
the 1870s. He came to this country as a dairy farmer in St.
Louis and then was transferred with his company to Louisville, Kentucky, where my dad was born. My grandfather
didn’t believe in formality because everyone referred to him
as Henry or Heine, so he wanted his son (my dad) to be Jack.
My uncle’s name was Bruce, which is my middle name. He
did not give my uncle a middle name because he said people
don’t use middle names.
Roberts: When did your father live?
Volume 28, Number 3
Hellmann: March 21, 1925, until May 14, 1999. He developed multiple sclerosis when I was in college/medical school
and spent the last 16 years of his life in a nursing home. There
he dressed every day in a coat and tie and even after 16 years
had patients streaming in to visit him. He probably made many
diagnoses sitting there unable to move his arms or legs but just
by listening and knowing the patients very well. He may have
received some graces but he was also cursed with health challenges. His experience was a great educator for me. In medical
school I wrestled with the question of what my father’s illness
meant, and I always exhorted to give people hope. Did it mean
sugarcoating when people had metastatic cancer or did it mean
misrepresenting the seriousness of an illness like systemic lupus
erythematosus? It struck me that in almost everyone I’d met
from any culture, part of hope means having a sense of control
over your life. I saw in my father’s case that multiple sclerosis
robbed him of the sense of control that he had had. For many
years my father functioned fine, but I saw that he woke up each
day with doubt, something absent unless one has an illness or
has suffered some unexpected tragedy.
Most of us who are able to take our health for granted believe we have control over our lives. I came to understand that
the art of medicine was to help each person restore a sense of
control, and since each person does this differently—through
religion, love, exercise, diet, literature, and combinations—one
of the really attractive aspects of being a physician is that you are
asked to have a Shakespearean range. You are given the chance
to try to understand people and help them restore a sense of
control in a way that works for them. Sometimes this means
that the physician just stays out of the way.
I remember once treating a woman who had terrible rheumatoid arthritis and she rapidly and dramatically improved.
One slow day in clinic, I asked her what she thought made her
better. I expected her to laud my talents and stroke my ego and
instead she looked at me quizzically, doubtfully, and said, “Okay,
I’ll tell you.” She then explained to me that she had been going
to a Polish healer who had been chanting up and down over
9 inches of her body with his hands (the 9 inches apparently was
an important part of this), and she believed that his chanting
made her better and that her improvement had nothing to do
with the treatment I had prescribed. As a man of science and
a man whose ego had been wounded, I was about to try and
debunk her notion but caught myself and said, “Who am I to
understand fully what is the faith that heals?” Had she lauded
my white coat, I would have smiled and been happy with her
answer. Instead, I realized she had figured out a way that was
harmless that had helped her reestablish control. So, I swallowed hard and thanked her for the bravery she was showing in
explaining to me what she had discovered. I told her I would try
to figure out how to apply her method to other people. What
she was reteaching me was the principle that illness robs one of
the sense of control and that becoming healthy again requires
reestablishing control.
Roberts: What was your mother’s name?
Hellmann: Mary Jane Hellmann.
Roberts: When did she live?
July 2015
Hellmann: August 26, 1925, to May 31, 2008.
Roberts: What was your home life like with your mother and
father gone so much?
Hellmann: I had an ideal childhood. Our first house was
next to a cornfield. The school was only one-third of a mile from
home. I walked every day to school with neighbor kids and
often with our dog that had learned the route. In kindergarten,
I was taught a few things, but mostly played in a sandbox with
others. There were hordes of children, and we all played on the
weekends and after school. My mother would ring a cowbell
when dinner was ready. My brother made the mistake of telling
her when he was late that he hadn’t heard the bell the first time.
We were called to lunch on the weekends by the volunteer fire
department, which had a siren that rang out to tell the kids it
was noontime. Mr. Bowling and his family raised chickens.
I have vivid memories of their preparing some chickens for
cooking by wringing their necks. We were free to explore. There
was no sense of threat to us from outside. I have nothing but
wonderful memories.
My father, who was very interested in education, always said
that he wasn’t leaving us an inheritance but would do everything
possible to support us and get us into the best schools possible.
Being in the Armed Service and meeting people from around
the country opened his eyes to the rest of the world. He had a
rule that none of his children would go to college in Kentucky.
He believed that it was good to explore the world. Of course,
these are rules that ambitious parents make and that children
don’t necessarily follow.
Roberts: What was the size of St. Matthews when you were
there?
Hellmann: St. Matthews was located just outside of Louisville. Its population was about 10,000. Louisville was about
300,000.
Roberts: Your father’s practice was in St. Matthews?
Hellmann: No. His was in Louisville, maybe 5 or 6 miles
from our house. My dad was always partial to cars, and as soon
as he could afford it he had an Oldsmobile, a fancy car in those
days. The five of us often would go on rounds with him, both
at the hospital and on home visits. Sometimes we were left to
fight in the car, and other times we went inside with him. Even
as a 5-year-old, I could see that our father was playing a special
role in the lives of the people we were visiting. I was struck that
he had the privilege of seeing and witnessing how health or ill
health was influencing the lives of the ones he was caring for. I
came to appreciate that he was doing something special.
Roberts: Where did your father go to college?
Hellmann: He went to the University of Louisville for college and medical school. They had an accelerated program where
after 2 years in college one could be selected to go to medical
school. Lots of veterans from World War II were in a hurry to
complete their schooling. When he received his MD degree, he
also received his undergraduate degree. He did a 1-year rotating
internship at St. Joseph’s Hospital (no longer there) and then
went into family practice. He was an internist at heart. When he
graduated from medical school his goal was to go into internal
medicine and be a consultant. Because neither his parents nor
David Bruce Hellmann, MD: a conversation with the editor
411
my mother’s parents were wealthy and he had four offspring
already, further training was not possible.
Roberts: Your father was the first in his family to go to college?
Hellmann: Yes. And my mother, one of fi ve, won a
scholarship to college and also was the first and only one
in her family to attend college. She graduated with a BS in
chemistry.
Roberts: What did her parents do?
Hellmann: Her father finished only sixth grade, but being
quite good at arithmetic he became treasurer of a wholesale
grocery store. I went with him to the grocery warehouse on
occasion, took the elevator to the second or third floors, and
was mesmerized by all the food and by the gigantic safe in
his office.
Roberts: Did most of your mother’s and father’s siblings live
in the Louisville area?
Hellmann: Yes. We moved to a new house when I was 6,
and my maternal grandfather’s house was between our house
and our parish school. He worked until he was 82, when he
fell, broke his hip, and soon died. Like a lot of families at the
time, he had a key under his front doormat, and we were welcome to stop by his house on the way home from school. My
favorite dessert in life is oatmeal cookies from Plehn’s Bakery
in Louisville, Kentucky, which is the German bakery that Mr.
Bowling, our next-door neighbor, ran. To this day, my kids,
when they want to please me, will FedEx to me some of these
oatmeal cookies that my grandfather introduced to me. I went
to a parochial school named Holy Spirit that focused more on
building character than it did on teaching academics.
Roberts: Was this junior high or high school?
Hellmann: This was grade school. I never was in a class
smaller than 45 students. In the third grade I was in a split class:
half was third grade and the other half was fourth grade. The
desks were made for two students, and I sat next to a fourth
grader. When the nun was trying to teach the third graders, the
fourth grader was always sticking a pencil in my leg and when
she taught the fourth grade I was sticking him in his leg. I don’t
think anyone would have suggested that this was going to be
the route to an academic career, but they did try to teach me
when to speak and when not to.
Roberts: Were you able to skip a grade with that setup?
Hellmann: No. I attended St. Xavier High School. My
mother was very interested in a religious education; father not
so much, but he was very interested in their good reputation for
academic preparation. I grew up hearing only about Harvard,
Yale, and Princeton. My father repeated those school names at
least 5000 times. I applied to all three, and got into only one,
namely Yale. The first time I saw Yale was when I showed up
for the first day of classes. At that time it was unusual not to
visit each campus before enrolling.
Roberts: You entered Yale in what year?
Hellmann: I entered in 1969 and graduated in 1973.
Roberts: What was your home life like growing up? You indicated that to see your father you almost had to go on rounds with
him. Obviously he was quite busy. Did you eat dinner together as
a family? I gather that home life was pleasant, not a lot of arguing?
412
Hellmann: My father, I believed, was seared by his early
experiences: his father losing their house and moving a number
of times during the Depression; having lived through World
War II, he understood that one couldn’t necessarily count on
anything and that chaos could occur at any time. These experiences plus his love for the profession of medicine meant that he
worked many hours daily. Vacations were rare. I remember my
family going on only two vacations in the first 12 or 13 years
of my life, both times to Daytona Beach, Florida—once by car
and once by airplane. These experiences combined to create an
incredible work ethic for our family.
My mother, after she raised five children, spent 20 to 25
years as a math teacher. At her funeral one of her former students
came up and explained that my mother had great enthusiasm
for chess and had the school adopt an annual chess tournament
where the children were the chess pieces. This person also told
me that during a math test my mother discovered that one of
the children was trying to open a book when he wasn’t supposed
to. My mother suggested that the students get their books out
and sit on them and that would inspire them. As a physician I
was familiar with various medicines being administered rectally
but that was the first time I had heard of mathematics being
administered rectally!
Roberts: Did school always come easy for you?
Hellmann: Yes, but I did not take it seriously until around
seventh or eighth grade. Before that I was more interested in
playing football. Then I started trying in school and appreciated
that I was doing well. From that time on and particularly in
high school, I really exerted myself. My high school prided itself
on the fact that most students went to college. I was shielded
from the pressures many kids are under today. The high bar at
my high school was simply going to college. About 85% of the
graduating students went to college.
Roberts: Were you an athlete in high school? Did you play
sports?
Hellmann: I was small in high school, going from
128 pounds my junior year to 168 pounds my senior year. In
18 months I gained about 40 pounds and multiple inches. If
that growth spurt had occurred earlier, I probably would have
played football. I was on the track team my third and fourth
years.
Roberts: What’s your height?
Hellmann: 5′10″.
Roberts: What have your siblings done?
Hellmann: My older sister, Jean, became a high school
English teacher and then a guidance counselor. She retired in
2012. My younger brother, Don, became a banker, and my next
brother, John, initially worked with the Baptist Health System
in Tennessee and then joined a group that staffs emergency
medicine physicians. My other sister, Sue, has focused entirely
on being a mother for her two children and does a great job.
She was also the main caregiver to my mother in the last few
years of her life because my mother had developed Lewy body
dementia, a variant of Parkinson’s disease. It’s Parkinson’s with
hallucinations and sometimes psychosis. My mother had been
a talented athlete and had won the tennis championships in
Volume 28, Number 3
Louisville as a teenager. This mathematician and tennis player
played into her late 70s.
Roberts: Did your father participate in that at all?
Hellmann: He did a little bit. He realized that he had
multiple sclerosis when playing tennis because he stopped being
able to hit the ball well due to the double vision.
Roberts: Did you get a full scholarship to Yale?
Hellmann: At that time and even now, Yale provides money
to any student who needs it. Since my father didn’t need it I
wasn’t provided a scholarship. Scholarship was directly related
to financial need. The tuition at Yale at that time was $3,003,
and that was a lot of money. The cost of education already had
exceeded the rate of inflation.
Roberts: How did Yale and New Haven hit you? It sounds
like you hardly ever went out of the city of Louisville. Now you are
in New England surrounded by very smart people.
Hellmann: I loved it. I feel that each school I have attended
starting with high school has been an enormous gift to me.
The major value of Yale for me was that it opened my eyes to
so many intellectual subjects and most importantly gave me
a group of friends who are still among the closest friends I
have. Every year I get together with about five or six buddies
from Yale. We’ve watched each other’s children grow up and
get married. That closeness is still a great support for me.
In Louisville, I knew students who were interested only in
football and beer, and I knew students who were interested
only in poetry and mathematics. At Yale, I met students who
were interested in both. In a sense I felt alone as a high school
student in Louisville, but at Yale I found others like me. That
was incredibly validating to me.
I found a family and a community and my eyes were
opened to a whole new world. I took history courses from John
Morton Blum, a great Theodore Roosevelt scholar, and heard
Shakespearean lectures from Alvin Kernan. Kernan’s lectures
on Shakespeare were so enchanting that the lecture hall was
filled—some students were “hanging from the rafters” to hear
him speak. My favorite course was the 19th and 20th century
French novel taught by Victor Brombert. Although my high
school French was pretty good, at Yale we were reading 400- to
600-page French novels every week and I struggled. In those
days, the Yale French group was generally generous in their
grading, but after I bombed the midterm exam, the teaching
assistant suggested that I drop the course before my poor performance was indelibly recorded in my final grade. I told them
that I harbored no illusions about my skills but that I really
liked the course and wanted to hang in there. After the final the
professor said to me, “Magnifique!” He explained that while I
hadn’t done all that well, I had greatly exceeded the expectations
suggested by my midterm exam. Providing the broader exposure
to so many different subjects was one of the greatest gifts from
Yale. I felt like I went to an intellectual Disneyland where my
admission ticket never expired.
Roberts: What did you major in?
Hellmann: Chemistry.
Roberts: When you entered Yale, did you know you wanted
to be a physician?
July 2015
Hellmann: I think I did, but like many teenagers I did not
want to please my parents. My father always said, “Do whatever
you want but do it well.” His subliminal message, however, was
that he couldn’t imagine how anyone could have as much fun
or have a better professional life than being a physician. I knew
that my becoming a physician would please him, but being a
little rebellious I wasn’t eager to fit into the mold he thought
I should be in.
Roberts: Were there many books in your home?
Hellmann: My parents collected a lot of books, especially
my dad: the classics and also the Time-Life series. I was introduced to Vladimir Nabokov, a Russian-American writer who
famously or infamously wrote Lolita, Bend Sinister, and Speak,
Memory, as well as Graham Greene novels and various books on
Rousseau. We had a 2-volume version of the Oxford English
Dictionary, and that played a minor role in my life because
during high school I won a motorcycle. There was a singing
group “The Monkeys” that followed the Beatles, and they made
a movie Monkeys Go Home. To try to drum up publicity for
this movie, the radio station announced a contest. The object
of the contest was to come up with as many words as possible
from the letters in the title of the movie. I heard about this
contest the same night that a rare snowstorm hit Louisville. (It
doesn’t take much snow to cancel school so I knew that there
wouldn’t be school the next day.) I was particularly interested
in arithmetic and took the letters from the title and made every
combination of the letters, as a code, and checked out every one
of the combinations to find out which was an actual word using
the Oxford Dictionary. I finished this project at 4:00 am and
knew that I had won. There simply could not be anybody who
had a more exhaustive list. Then I was somewhat discouraged
as a month or two passed and I hadn’t heard anything. I was
out playing basketball and listening to the radio station, and
as I was going up for a shot I heard my name called out as the
winner of the “Monkeys Go Home” contest! I was 15 years old
and I owned a motorcycle. I thought that that was perhaps one
of the first lessons where academics could actually pay dividends.
Roberts: What happened to the motorcycle? Did your father
let you keep it?
Hellmann: He did. I was able to ride it when I had a driver’s
license. I kept it for maybe 2 years. I just drove it around the
neighborhood.
Roberts: No accidents?
Hellmann: I survived.
Roberts: Were there any teachers in grade school, junior high,
or high school who had a particular influence on you?
Hellmann: Yes, my high school biology teacher my freshman year taught the subject in such an engaging way that it
really fueled my interest in science. My fabulous senior year
English teacher opened my eyes to literature. I also remember
my fourth-grade den mother in Cub Scouts. I ended up writing a play for our troop and we presented it at some activity.
I’m sure it was terrible, but I remember her because she gave
me safe harbor for thinking differently about projects and for
communicating that it was okay to think differently. There were
a few teachers that encouraged me to be “different.”
413
Roberts: Do you read fast now?
Hellmann: I don’t think I read particularly fast now. I
am tenacious. I remember around the age of 7 or 8 playing
football with the older kids in the neighborhood. I wasn’t
particularly large, but it was known that when I tackled I did
not let go. The older kids would drag me but I would not let
go. There was talk that “Elmer’s Glue” should be replaced with
“Hellmann’s glue.”
Roberts: What happened when you brought your report cards
home?
Hellmann: My father was very encouraging. He kept describing a broader world that was out there and to keep up my
efforts because he believed that if I sustained these efforts I
could go other places and do other things. He was very laudatory and encouraging. I had an eighth-grade teacher who had
48 hormonally surging guys in her class and she was giving up
hope of teaching us. She took me aside and told me I was good
at math and gave me the teacher’s version of the math books
and told me to teach myself.
Roberts: Your mother must have very proud of that effort?
Hellmann: Yes. It was my mother who taught me multiplication because she was good at it. I have fond memories
of being in the kitchen with her learning multiplication. I
won the school competition in multiplication in the fourth
grade. One of my father’s former teachers had found out about
this competition and gave me a beautiful German clock as a
reward.
Roberts: Did the family eat together at night?
Hellmann: We did. My father came home around 6:30 pm.
We would all eat together, and at 7:30 pm he was gone, back
to the hospital, and then he would be home by 10:00 pm. He
worked all day on Saturdays at the hospital and half a day on
Sundays.
Roberts: How did you go back and forth to New Haven from
Louisville?
Hellmann: I would usually fly to LaGuardia and then take
a car service to New Haven. In my junior year I had my own
car and would drive the trip. It was 850 miles and I would drive
straight through.
Roberts: When it came time to pick medical school, how did
you do it?
Hellmann: My father, who had never laid eyes on Johns
Hopkins, played a large role. While growing up, I frequently
heard my dad talk about Johns Hopkins. I knew as a high school
student, for instance, that A. McGehee Harvey was the chairman of the Department of Medicine at Hopkins. In addition,
my next-door neighbor in Louisville, David Waller, was 10
years older and had gone to Harvard College and then to Johns
Hopkins Medical School. David Waller became a psychiatrist
on the faculty at the University of Texas Southwestern. His wife,
Barbara Waller, also a physician, was a noted dean of students
for many years there.
I applied to Johns Hopkins early and was accepted. I withdrew from most other schools where I had been accepted.
Although I was offered a very generous scholarship at the University of Kentucky Medical School—with all tuition and books
414
paid and even being paid to attend—my father, well along with
multiple sclerosis, never blinked about my choosing Hopkins,
even though a scholarship was unavailable. (That institution
offered scholarships only on the basis of need.) Now that I’m
a father with grown children, I perceive how great an act of
generosity that was back then. He firmly believed that if I went
to Johns Hopkins, my life would be different. It’s a life that he
wanted me to have. He would have loved having the opportunities that I got.
Roberts: What struck you about Hopkins? There are a lot of
bright people at Yale but yet you raised yourself a notch because it’s
quite a select group that goes to Johns Hopkins for medical school.
Hellmann: Hopkins is a wonderful institution. At every
institution I have been very privileged. (I have this disease called
metaphorosis in which I can’t talk for very long without appealing to a metaphor.) The best medical schools allow one the
opportunity to climb the Mt. Everest of the profession. There
are some medical schools that are not very big hills, not even
mountains. But there are some that really give you the opportunity to go to the peak of the profession. Johns Hopkins is one
of those places. Hopkins has become a better place over time because while it has always provided a lot of inspiration, it did not
always cherish its students. It said, “Here’s Mt. Everest, and the
view from the top is unparalleled, but we are not going to give
you Sherpas or provide you with any oxygen tanks, so you are
pretty much on your own. It’s a very high and dangerous climb.
Don’t expect that everyone is going to make it, and there might
be some bodies along the way.” Today, it still offers inspiration
but it also cherishes its students and provides essential supplies.
The school does not tell anyone that they will be carried; you
have to march and climb. But it gives you clothing and hooks
you with us; there are times when you are going to be pulled
and times when you will be pulling other people, but we are
all going to make it together. It is possible to both inspire and
take good care of people. I’m very grateful that Johns Hopkins
introduced me to extraordinary people and values and a love
of the profession of medicine.
Roberts: Were there any surprises after you had been at
Hopkins for a while?
Hellmann: I was surprised how hard we worked. I thought
I had worked hard in college, but in medical school classes were
9:00 am to 5:00 pm every day, and during the first 6 months
we had Saturday classes in histology. I tell people this now and
they shudder and think it would have been easier to be waterboarded than have these experiences. I also had extraordinary
roommates. We worked all the time. We loved it. I came to
understand that no matter how hard I had worked in college,
it was nothing compared to medical school. I remember when
a roommate had opted to take clinical rotations earlier than
I did, and the other roommates sat around listening to him
telling us what it was like. The only other time I remember
being astounded was when I was first learning the facts of life
from some of my friends in grade school and could not quite
fathom what they were telling me. To hear my roommate talk
about staying up all night and then working the entire next
day seemed unfathomable. I had thought if you stayed up all
Volume 28, Number 3
night you got a week off. And yet at the same time while I was
shaking in my boots at the horror of this description, I couldn’t
help but perceive that my roommate felt this was a fascinating
and wonderful experience.
Roberts: Were there any professors and/or teachers who had a
particular influence on you in medical school?
Hellmann: There were many. Dr. Mary Betty Stevens was
one of the few female faculty members. She was head of rheumatology, and she ran a 40-bed rheumatology unit. It was an
extraordinary clinical experience, and many opted for it. The
faculty at that time had lunch together, so as students we got to
have lunch with Dr. Stevens. We were struck that few patients
remembered the name of their doctors. The exception was Mary
Betty Stevens; they all remembered her name. She made a dramatic impression on everyone. I remember having lunch with
her one day and she leaned over, put her arm around me, and
said, “Dave, I know what you are going to be. And when you
figure it out, come see me.” She was right. I ultimately decided
to be a rheumatologist.
Roberts: What were some of her characteristics that made
Dr. Stevens such an impressive personality?
Hellmann: She was a meticulous physical examiner. She
was able to find clues in fingernails, in the skin; she could look
at the back of patients’ eyes and come up with clinical clues as
to what the patient had, and she was often right. She was also
a gifted interviewer. She could make patients come alive. She
could make both their illness and their lives and personalities
come forward: the drama of the science of clinical medicine
and the natural drama of people’s lives.
Dr. Philip Tumulty was the Osler incarnate at Johns Hopkins
at that time, and he deeply impressed patients. He was an extraordinary physician because of his knowledge, his history,
and his interpersonal interactions. I particularly remember the
clinicopathologic conferences that Dr. Tumulty conducted.
Up until that time I had seen maybe three or four. They were
titanic intellectual battles of the internists and pathologists. It
was physiology or anatomy or pathophysiology. Then I saw Dr.
Tumulty do a clinicopathologic conference, and I remember his
beginning. Instead of summarizing the clinical information, it
turned out that he had known the patient and he talked about
the patient as a person. He did something that had not been
done since Christ: he made this dead person come alive. We all
understood that this exercise was not a pathophysiologic experiment; it was the intricate story and puzzle of a person who had
walked this Earth, who had loved and been loved, and who had
cared about their work. I was mesmerized that he could bring a
person back to life. And then he solved their puzzle. Like many
others who witnessed Dr. Tumulty, I wanted to be like him.
Dr. Victor McKusick (Figure 3), chair of medicine at that
time, instilled a love of medical history and an interest in human
genetics. Dr. McKusick would make rounds with the students 3
days a week, and every student would present to him and everyone was terrified to do so because he was totally unpredictable.
We later realized that he was an extraordinarily kind human
being but his curiosity was so broad and his interest so wide
that one couldn’t anticipate any question. You could anticipate
July 2015
Figure 3. McGehee Harvey, Victor A. McKusick, John D. Stobo, David Hellmann,
and Edward Benz in Dr. McKusick’s home, about 1995.
that he would always ask the history of something. If you were,
for example, treating a patient with Wilson’s disease, he would
ask, “Who was Wilson?” But he was just as likely to ask, if the
patient was wearing glasses, how you could tell if the patient
was nearsighted or farsighted by looking at their glasses. Or
he might ask you about your tie and whether the stitching revealed that it was American-made or British-made. His interests
were broad and we later realized that his questions were never
meant to shame anyone but to exhibit that you should always
approach every person you meet with wonder that could take
you anywhere. I was deeply impressed by him.
Roberts: Do you think he enjoyed being chairman?
Hellmann: I think he loved being chairman. I don’t think
he loved some of the aspects of being chair, but his sense of
medical history was such that he felt that by being the “Osler
professor” he had connected himself in almost familial fashion
with William Osler. Being the descendent of William Osler was
the apogee of his aspiration.
Roberts: You started to speak of A. McGehee Harvey.
Hellmann: Dr. Harvey was the chair when I first began
medical school. In my third year (1975), Dr. McKusick became
chairman. As senior students we asked Dr. Harvey (who had
retired) if we could join him in a seminar series. He agreed.
Hopkins was the kind of place where you could approach the
most towering figures and they would embrace you. Later, when
I joined the faculty, I came to know him more intimately and
had the privilege of being his physician the last 5 or 6 years of
his life. Getting to know him better was one of the extraordinary
gifts that I received from a patient.
Roberts: What was his age when he died?
Hellmann: I think he died in his mid-80s. He lived a long
time after being chairman. He threw himself into the history of
medicine and wrote a number of books about medical history,
particularly the history of Johns Hopkins.
Roberts: What did you do during the summer months while
in medical school?
Hellmann: I became enamored of cardiac physiology in my
first year because of Bill Milnor, who taught it. I went to Richard
Ross, then chief of cardiology (later dean), and told him that I
415
wanted to do research in cardiology. He gave me three names,
including Bertram Pitt, who was glad to have me. I spent that
summer and another year during medical school working in a
dog lab in cardiology. Dr. Pitt was working on a drug, made by
Abbott, at that time trying to dilate coronary arteries. It was a
magical time at Hopkins. Bernadine Healy was a fellow while I
was there as a medical student. To imagine that I worked with
someone who ultimately became head of the National Institutes
of Health was inspiring. Dr. Pitt later headed cardiology at the
University of Michigan Medical School, where he has been
responsible for major trials in cardiology. I also met a number
of the technicians in cardiology that were African American,
so I learned the two sides of Johns Hopkins. Vivien Thomas
was the famous surgical technician who had helped Dr. Alfred
Blalock and Dr. Helen Taussig come up with the “blue baby”
operation. Thomas had been head of the dog lab when I was a
surgical student and attempted to teach me dog surgery. I think
he recognized that I had the hands of a rheumatologist. I had
a wonderful time doing cardiologic research and spent many
summers there. I wrote two papers that were published and
had the opportunity to make several presentations at Hopkins.
Thanks to Dr. Pitts’ generosity, I ended up winning an award
in research given at medical school graduation.
Roberts: When it came time to pick your specialty, was it difficult or easy to focus solely on medicine?
Hellmann: It was a little difficult because to my surprise I
loved everything. The only specialty I excluded pretty quickly
was pediatrics. I met my wife when I was taking pediatrics. She
was a pediatric social worker. At that time Hopkins thought
that in pediatrics it was important to know your patient as a
person—a theme of my grand rounds—so each medical student
was assigned a patient to visit in the community. They realized
that students were probably incompetent to go on these home
visits alone, and therefore each was assigned a social worker.
I was randomly assigned to my future wife. My patient was a
15-year-old girl who was pregnant. She lived a half-block from
the hospital. At that time Baltimore was the capital of lead
poisoning in the United States. I, as a self-proclaimed hotshot
medical student, went on the home visit with a mission to save
this girl’s child from lead poisoning. I asked her family all sorts
of invasive questions and rightly angered them. A Baltimore
jury would have acquitted them of understandable or justifiable homicide. Fortunately, my future wife had much greater
diplomacy and she came to my rescue, soothing the feelings that
I had riled. I thought since she had saved my life it was only
appropriate that I invite her to lunch, and she’s been saving my
life for the last 38 years. As a result I tell students that if you
can find your true love while doing a basic clerkship, go for it,
but don’t expect to remember much of that specialty. I don’t
remember pediatrics very much and was totally incompetent in
taking care of our children. I enjoy conversation, and pediatrics
didn’t allow me to talk to the patients. I found surgery and the
immediacy of the results very attractive, but ultimately I realized
that for me the two things that gave me meaning were getting to
know people over time and solving complicated medical puzzles.
Those two requirements came together in internal medicine.
416
Figure 4. With Linda Hellmann.
By the end of my third year, it was clear to me that I wanted to
go into internal medicine.
Roberts: What is your wife’s name?
Hellmann: Linda Smith Hellmann (Figure 4).
Roberts: What is her birthday?
Hellmann: June 27, 1949.
Roberts: What were the features of Linda that attracted you
to her?
Hellmann: Well, she’s beautiful. She is an extraordinarily
generous person who is also extremely strong. She, perhaps by
professional training or perhaps by instinct, never allows a gap in
understanding between two people to stand. She always insists
on exploring the gap and understanding it. I had the sense that
I had a quiet but strong personality. Although I had thought
that most good ideas were ones I had thought of, I’ve learned
that other people can have very good ideas, too! I realized that
I was going to need a partner who was not shy about being able
to challenge my views and could challenge them, as she showed
that first day, diplomatically.
Roberts: When did you get married?
Hellmann: May 28, 1977, 24 hours after I graduated from
medical school. She is from outside of Philadelphia and I was
from Kentucky, and we thought we would have a wedding
coincide with medical school graduation because all the family
was already in town.
Roberts: Was your father able to come?
Hellmann: Yes. He was still walking at that time. He and
my mother adored my wife. The first time my mother met
Linda, she put her arm around her and turned to me and said,
“David, I want you to know that I’m on Linda’s side.”
Volume 28, Number 3
Roberts: Was picking Hopkins to do your internship difficult,
or did you look around at a number of places first?
Hellmann: I did look around. Other than Hopkins, the
place that really attracted me was the University of Rochester
(New York). I was very impressed that their medical residents
were very happy. I didn’t know much about Dr. George Engel,
but apparently even then he had a profound effect on that
place raising awareness of the importance of knowing patients
as people. As chairman of medicine, he was one of the first in
the country to emphasize the importance of the personal and
social aspects of providing medical care. Although potentially
attracted to Rochester, my future wife and I drove there together
in January and my car heater did not work. When we got to the
hotel we spent the first 45 minutes sitting on the radiator trying
to thaw our rear ends. My wife turned to me and said, “If you
come here, you are coming by yourself!” That experience plus
the fact that I really enjoyed Hopkins, she had a good job there,
and I was accepted, made the decision to intern at Hopkins easy.
Roberts: Did you live in the compound?
Hellmann: Yes. It had been built very quickly right after
World War II, and it now was 40 years later and still there.
Sometimes it was nicknamed “the hatchery” because so many
houseofficers had so many children while there. East Baltimore
then was a pretty gritty place, but this was an oasis with a swimming pool, and everyone was working the same long hours. A
substantial percentage of residents lived there. We only needed
one car since work was not much more than 100 yards away
and it was also easier to have meals together.
Roberts: Your residency at Hopkins was 3 years? Were there
any major events during that time that stayed with you?
Hellmann: Yes. As an intern, I was assigned to care for
an 11-year-old boy who had failed chemotherapy for acute
leukemia. Johns Hopkins was one of the few places at that
time doing bone marrow transplants. Unfortunately, the transplant didn’t work and he died. As the intern, I was also the
phlebotomist and felt completely out of my depth. I didn’t
really know how to take care of a child. I went in to explain
to him the reasons for switching physicians on him and how
he had been dealt bad cards in life that he never asked for and
shouldn’t have to endure all the pain and suffering that he had
been through. He listened without saying a word. He had
built cars and painted them. He reached over for his favorite
one—a Mustang—and without a word handed it to me. In
that instant I was converted from a cynic to an optimist. I
didn’t realize it at the time, but ultimately I came to conclude
that human beings are not always attractive, that they are
capable of great cruelty, but I realized if humans were capable
of creating a child who while dying could take in the worth
of an awkward intern and reach out at a time of suffering to
give a gift of something that mattered most to him, that we
had to be made out of good stuff. That experience has stayed
with me more than the shortcomings of people. I became an
optimist having lived 27 years as a pessimist and cynic. Life
as an optimist has been a whole lot more fun than I remember as a pessimist. I also thought that it embodied aspects of
medicine that I love. Living a long life is possible because of
July 2015
modern medicine and great teamwork providing care, but as
wonderful as medicine is it could still be more wonderful.
The other aspect is I have been astounded in my career by
the generosity of patients, in what they have taught me about
medicine and the opportunities they have given me. I feel I’ve
been given unspeakable gifts throughout my life. I realize medicine is a partnership and the physician is the junior partner.
Roberts: How did you pick rheumatology?
Hellmann: During my surgical clerkship I was assigned
to urology. Late one night the chief resident tried to extol the
virtues of urology to me, hoping to attract me to urology. The
ultimate sales pitch from his side was that in urology there are
only three problems and urologists could fix each of them. I
thought that could be attractive to someone but it wasn’t to
me. I liked ambiguity and challenging puzzles, so the breadth
of rheumatology was very attractive. I wouldn’t say I was a fast
learner but I ultimately enjoyed learning. I love looking in the
back of eyes and looking for the early signs of central nervous
system lupus. I was looking for a field that would frequently
call on me to integrate all of these skills and experiences. And
rheumatology did that. Immunology was a negative for some
but it was a great challenge for me. I was impressed that many
of the clues in rheumatology were attainable at the bedside.
The laboratory was an important tool for confirming suspicions
rather than in shaping impressions on what was going on. At
Johns Hopkins at the time, the best doctors I knew were rheumatologists: Mary Betty Stevens and Lawrence Shulman. Some
people thought that Osler himself had been a rheumatologist
and was greatly interested in lupus. There is a picture of Dr.
Tumulty at the chalk board, and he wrote the initials of four
diseases and three of them were rheumatic diseases. I was surrounded by physicians who were interested in rheumatology
even before the field had been defined.
Roberts: How did you decide to go to San Francisco for your
rheumatology fellowship?
Hellmann: My wife wanted to go to California because her
sister lived there. Since I generally don’t want to do things that
most people want to do, I did not want to go there. Somewhat
reluctantly I did interview at UC-SF at the urging of several
professors at Hopkins who said that I needed to meet Jack
Stobo. He had been an Osler houseofficer and chief resident,
and everyone talked about him with awe. He was head of the
rheumatology program at UC-SF. I went and was smitten by
the program from the beginning. People were on fire and excited about what they were doing. They had both a broad and
a basic science experience. I felt this was the place for me and
fortunately I was accepted.
Roberts: That was a 2-year program?
Hellmann: Yes. I had anticipated that it would be a longer
program because at that time I thought I was going to be a
basic scientist and spend an extra 3 years in laboratory training.
The training at John Hopkins I loved, but I also felt that it
could be made better. I was physically and spiritually exhausted when leaving Hopkins—so much so that I thought that I
never wanted to see another patient. It was in the more relaxed
circumstances of UC-SF that I realized the most enjoyable
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Figure 5. At home with children, Jessica and Matt, and the family dog, about
1990.
part was seeing patients and feeling confident about it. They
lost their program director at that time and asked me, only
a fellow, if I would do morning report and other jobs. Jack
Stobo was very definitive —he kiddingly used to advise me,
“You can be wrong, but be definite,” especially in treatment
recommendations. I tried to incorporate my wife’s diplomacy
and would diplomatically but firmly challenge him. We had
some heated arguments (always civil) during conferences, and
I told my wife that we needed to start looking for a place to
go because I sure wasn’t going to last in San Francisco. I was
stunned when at the later part of my first year, Dr. Stobo
asked me to join the faculty and become the clinical director
for rheumatology in his division. Linda was pregnant at the
time with our first child, Matt (Figure 5). His birth and that
offer came about the same time. Things were coming together
in my own view of what I wanted to do with my career so I
accepted. Working with Jack Stobo was such a fabulous experience that when he was recruited back to Hopkins in 1985
as the Osler Professor and Chairman of the Department of
Medicine, I eagerly accepted his offer to join him in 1986 as
executive vice chairman and then later as director of the Osler
housestaff training program.
My time at Hopkins has had symmetry: I spent the first 14
years on the Broadway (Johns Hopkins Hospital) campus and
the last 14 years on the Johns Hopkins Bayview Campus (what
used to be The Baltimore City Hospitals) (Figure 6). During that
time I have served three exceptional Osler Professors of Medicine: first Jack Stobo (1986–1994), then Ed Benz (1995–2000)
(Ed is now the president and CEO of the Dana Farber Cancer
Institute), and now Mike Weisfeldt (2001–2014). Although
418
Figure 6. At Johns Hopkins.
they have different personalities, each was a magnificent leader
and mentor.
Roberts: Could you summarize your grand rounds presentation earlier today?
Hellmann: My grand rounds was a description of our creation of an educational initiative entitled the Aliki initiative,
named for a Greek philanthropist, Mrs. Aliki Perroti. It attempts
to make sure that the training of every medical student and
resident incorporates the Oslerian notion that the foundation
to being a great physician is knowing your patient well and
knowing him or her as a person. Osler said, “It is much more
important to know what sort of a patient has a disease than
what sort of a disease a patient has.” For the last 7 years we have
tried to create an experience that imbues that principle in every
medical student and resident. We’ve found to do so requires
two things: first, people have to be given the gift of time. It’s
not possible to get to know patients well, either medically or
personally, without adequate time. And second, you have to
have a curriculum and faculty that teach you what to do with
that time. Just sitting in the conference room is not adequate.
One must get a very good history and physical exam, talk to
the primary care physician, the patient, and family, and visit
with the patients after they leave the hospital to understand
what challenges they have. It is only by having both the gift of
time and a curriculum of what to do with that time that you
can get to know patients as people and derive the satisfaction
that comes from doing so.
Roberts: You started this program in 2007?
Hellmann: Correct.
Volume 28, Number 3
Roberts: Have you made many changes in the program during
the subsequent 7 years?
Hellmann: We’ve made a number of changes. In the beginning we realized that the gift of time wasn’t enough, that
we needed faculty who knew what to do with that time. We
had to create a faculty development program. Over time we
have extended the Aliki initiative not only to one floor but to
all the general medical floors and more recently extended it
to the intensive care units and to the outpatient areas. During
this time we have also been able to do a number of research
projects to assess the impact of the Aliki initiative on our patients, their families, and our students, residents, and faculty.
One outcome we’ve found, somewhat to our surprise, is that
patients who are on the Aliki initiative are much less likely to
require readmission within 30 days if they have heart failure.
On the non-Aliki service, the latest rehospitalization within 30
days for heart failure was 14%, whereas on the Aliki initiative
for heart failure the readmission was only 4% within 30 days.
We also found that patient satisfaction with the physician is
much higher on the Aliki service than on the general medicine services. The Aliki initiative now involves 20 staff faculty
and they meet every week to discuss how they can make the
experience better. A byproduct of these discussions was the
creation of a laboratory for education, something that does
not exist in many places. From this laboratory, we’ve learned
a few things about teaching, something that has led to many
of the faculty receiving academic awards for their teaching.
Dr. Roy Ziegelstein, the co-director of the Aliki initiative, was
selected 2 years ago to become the vice dean of education of
the entire school of medicine.
Roberts: Do you have any hobbies?
July 2015
Hellmann: My two individual passions are history and literature. My favorite authors are Tolstoy and Shakespeare. I don’t
know much about music, but I am absolutely enraptured with
Beethoven’s 9th symphony. With my penchant for metaphors,
I fancy that when Beethoven composed this symphony in 1824
he did so while trying to envision the potential good that “the
promise of medicine” could deliver to our patients and to society.
I firmly believe that medicine is a public trust and that it is our
joyful opportunity and obligation to get up each day and ask how
we in health care can pay back society a higher dividend for the
extraordinary investment society has made in us. In the fourth
movement of the symphony, Beethoven suggests the heights to
which medicine could ascend. He begins by playing a beautiful
melody six times with just cello (which in my mind symbolizes
research), then six times with just viola (symbolizing education),
and then six times with just violin (representing patient care).
Then Beethoven does what no medical center, in my opinion,
has accomplished: he puts it all together by having the entire
orchestra play the melody. Since you have heard the melody 18
times, it of course sounds familiar. Yet the ineffable beauty of the
sound created by the whole orchestra is also shockingly new. Not
only does Beethoven cherish the music created by each musician,
his orchestration ensures that musicians achieve a greatness in
playing together that cannot be attained by playing separately. I
suspect that medical centers could learn something from listening
to Beethoven. I believe we will deliver the promise of medicine
only when we learn how to orchestrate so that clinicians, educators, and scientists play together in the same harmonious way
that the musicians do in Beethoven’s 9th.
Roberts: Dr. Hellmann, thank you. I wish that we had more
time.
419
Reader comments
LOW-VOLTAGE ELECTROCARDIOGRAM IN A PATIENT WITH
TAKOTSUBO SYNDROME ASSOCIATED WITH HYPERTHYROIDISM
The article by Omar et al (1), published in the April 2015
issue of Proceedings, about a 61-year-old woman with hyperthyroidism admitted with takotsubo syndrome includes an
electrocardiogram (ECG) revealing atrial fibrillation with rapid ventricular response and nonspecific ST-T wave changes,
while echocardiography and contrast ventriculography showed
marked extensive left ventricular hypocontractility with a left
ventricular ejection fraction of 35% to 39%. Figure 1 depicts
the ECG in an elongated horizontal layout, and even if one
assumes standard calibration (1.0 mV = 10 mm), some of the
ECG leads reveal low QRS voltage. Recently, low QRS voltage has been reported in association with TTS (2). Would the
authors oblige by providing information as to the changes in
voltage, from a possibly available ECG of their patient prior
to the index admission and subsequent ECGs recorded during
hospitalization and at follow-up?
—John E. Madias, MD
Icahn School of Medicine at Mount Sinai, New York, NY
Elmhurst Hospital Center, Elmhurst, NY
E-mail: [email protected]
1.
2.
Omar S, Ali E, Mazek H, Mahmood T, Soontrapa S, Suarez J. Takotsubo
cardiomyopathy associated with hyperthyroidism treated with thyroidectomy. Proc (Bayl Univ Med Cent) 2015;28(2):194–195.
Madias JE. Transient attenuation of the amplitude of the QRS complexes
in the diagnosis of takotsubo syndrome. Eur Heart J Acute Cardiovasc Care
2014;3(1):28–36.
The Authors Reply:
I would like to thank Dr. Madias for his interesting letter. As
he mentioned, it has been reported that low QRS voltage and
attenuation of the amplitude of the QRS complexes are a highly prevalent sign in patients with takotsubo syndrome. Serial
electrocardiograms in our patient prior to the index admission
and during hospitalization showed both low QRS voltage and
attenuation of the amplitude of the QRS complexes (Figure).
—Sabry Omar, MD
Texas Tech University Health Science Center,
Lubbock, Texas
420
Figure. Serial electrocardiograms in the patient with takotsubo syndrome prior
to the index admission and during hospitalization showed both low QRS voltage
and attenuation of the amplitude of the QRS complexes.
Proc (Bayl Univ Med Cent) 2015;28(3):420
From the Editor
Facts and ideas from anywhere
“THE PILL” AND ITS FOUR MAJOR
DEVELOPERS
In 2012, Jonathan Eig published The Birth of The Pill: How
Four Crusaders Reinvented Sex and
Launched a Revolution (1). In 36
chapters the fascinating story is
told.
She was already 71 years of
age, had loved sex, and had spent
William C. Roberts, MD.
40 years seeking a way to make
it better. She wanted a scientific
method of birth control that would allow women to have sex
as often as they liked without becoming pregnant. She was
Margaret Sanger (1879–1966) (Figure 1), one of the legendary
crusaders of the 20th century. She was meeting with Gregory
Goodwin Pincus (1903–1967), a scientist with a genius IQ
but a dubious reputation. He was 47 and had been rejected
as a radical by Harvard, humiliated in the press, and left with
no choice but to conduct his oftentimes controversial experiments in a converted garage. He was a biologist and perhaps
the world’s leading expert in mammalian reproduction in the
1930s.
Pincus knew about Margaret Sanger; almost everyone in
the US did. It was Sanger who had popularized the term “birth
control” and almost singlehandedly launched the movement for
contraceptive rights in the US. Women would never gain equality, she reasoned, until they were freed from sexual servitude.
Sanger had opened the nation’s first birth control clinic in 1916
and helped launch dozens more around the world. But all she
had to work with were condoms and cervical caps, usually ineffective, impractical, and difficult to obtain. Sanger explained to
Pincus that she was looking for an inexpensive, easy-to-use, and
completely foolproof method of contraception, preferably a pill.
It should be something biological, she said, something a woman
would swallow every morning, with or without the consent of
the man with whom she was sleeping; something that would
make sexual intercourse spontaneous, with no forethought or
fumbling, no sacrifice of pleasure; something that would not
affect a women’s fertility if she wished to have children later in
life; something that would work everywhere from the slums of
New York to the jungles of Southeast Asia; something 100%
Figure 1. Margaret Sanger. Photo: Public domain.
effective. She asked Pincus, “Could it be done?” She had approached other scientists earlier and they said it could not be
done. They had argued that it was dirty, disreputable work. And,
even if somehow it could be done, they argued there would be
no point. Thirty states and the federal government still had laws
prohibiting birth control. Why go to the trouble of making a
pill no drug company would dare to manufacture and no doctor
would dare prescribe? But Sanger held out hope that Gregory
Pincus was different, that he might be bold enough or desperate enough to try.
Also, times were changing. In 1948, only 2 years earlier,
a college professor in Indiana named Alfred Charles Kinsey
published a study called “Sexual Behavior in the Human Male”
to be followed 5 years later by “Sexual Behavior in the Human Female,” studies which disclosed that people were much
freer with sex than previously admitted. Sex for the pleasure of
women was an idea that was unthinkable in 1950. Worse, it
was dangerous. What would happen to the institutions of marriage and family? What would happen to love? If women had
the power to control their own bodies, if they had the ability
to choose when and whether they got pregnant, what would
they want next? Science, argued Sanger, would give women the
chance to become equal partners with men.
Once Sanger asked Pincus to start working on a pill, he
drove directly to his office at the Worcester Foundation for
421
Experimental Biology, an institution he had founded with one
of his colleagues, Hudson Hoagland, to speak with one of his
researchers, M. C. Chang. While the foundation started out
in a renovated barn in Worcester, by 1950, it had moved to
an ivy-covered brick home in a residential section of nearby
Shrewsbury. Pincus had known of Chang and enticed him to
join the foundation for a salary of $2000 a year ($26,000 by
today’s standards). Chang, who knew Pincus by reputation,
thought he would be working in one of America’s prestigious
institutions and that his fellowship would include free lodging.
He did get free lodging, but his room was at the YMCA. He
and Pincus would travel to and from work by bus. Later, Chang
would move to the foundation, sleeping on a small bed in a
corner of a converted laboratory using Bunsen burners to heat
his meager meals. As a strict Confucian, Chang apparently did
not mind. Pincus told Chang that he had spoken to Margaret
Sanger about her desire for a pill to prevent pregnancy. It had
to be a pill, not an injection, jelly, liquid, or foam, and not a
mechanical device used in the vagina. When Pincus talked in
this way with a sense of purpose, his colleagues paid attention.
Pincus knew from the beginning that it would be one thing to
build a birth control pill and another to persuade the world to
accept it.
Pincus and Chang already knew that injections of the
hormone progesterone prevented ovulation in rabbits. Nevertheless, for many reasons, scientists had not tried to explore
the implications for humans. There were too many risks. Also
at the time, progesterone was very expensive. Pincus and
Chang knew how progesterone functioned. When an egg is
fertilized, progesterone prepares the uterus for implantation
and shuts down the ovaries so no more eggs are released.
In effect, Pincus recognized, nature already had an effective
contraceptive. Now the task was to see if they could produce
it, modify it, and put it to use. Fortunately, new technology
was making progesterone less expensive to obtain. If Sanger
would pay for it, Pincus thought he had a good idea of how
to proceed.
He and Chang began by repeating their experiments done in
Pennsylvania 13 years earlier, adjusting the dosages and means
of delivery to get a feel for progesterone and how it worked.
They started with rabbits. Pincus sent a request for funding to
the Planned Parenthood Federation of America, the women’s
health and advocacy group that Sanger had helped form. He
asked for $3100: a $1000 stipend for Chang, $1200 for the
purchase of rabbits, $600 for animal food, and $300 for miscellaneous supplies. Sanger wrote to Pincus that they had $2000
but Pincus and Chang got to work.
The first results were what they had expected: the animals
receiving progesterone did not appear to ovulate! They next
moved to rats, and once again the experiment worked: there
were no pregnant rats and once again larger doses had a longerlasting effect. Within a relatively brief period, the Worcester
Foundation had about 20 scientists and operated on an annual
budget of $300,000, about $63,000 of which was contributed
by local residents.
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Fortunately, it was a time of enormous growth in the pharmaceutical industry. By the late 1940s and early 1950s, drug
makers like G.D. Searle & Company were competing fiercely
to discover and market new ones. In the 1940s, Searle, a small
pharmaceutical company based in Skokie, Illinois, and other
drug companies were looking for ways to synthesize cortisone,
which had recently been demonstrated to relieve arthritic pain.
Pincus persuaded the drug company that he could synthesize
cortisone by pumping serum through the adrenal gland of sows
and spent $500,000 of Searle’s money trying to prove it. But
before Searle could make use of Pincus’ new technology, researchers at the Upjohn Company found a simpler and less
expensive way to do the job.
In the fall of 1951, hoping to repair the relation with Searle
and secure their help on Margaret Sanger’s progesterone project,
Pincus went to Skokie to meet with Albert L. Raymond, the
drug company’s director of research. Pincus failed in his initial
attempt to acquire money from Searle.
Sanger. Who was Margaret Sanger? She was from a family
of 11 children. She was number 6, born in 1879, in Corning,
New York. Her mother was frail and submissive and died of
tuberculosis at age 50. Her father was a charming stonecutter. Maggie, as she was known, left home at an early age and
enrolled at Claverack College, a boarding school in New York’s
Hudson Valley. She earned her way through and began speaking out on suffrage and women’s emancipation. She enrolled
in nursing school at White Plains Hospital in Westchester
County, New York. Though she considered marriage “akin to
suicide,” at the age of 22 she met a handsome young painter
and architect named William Sanger. They fell in love, married, and built a home in Hastings-on-Hudson, Westchester
County, New York. Soon came three children, two boys and
a girl.
Not happy with either suburbia or marriage, in 1912,
Margaret and her family moved to New York City and she
began spending time in Greenwich Village. There she discussed sexual freedom, voluntary motherhood, and the need
for women to have more autonomy in the bedroom and in
society. During this time, Sanger worked for William Wald’s
visiting nurse service, a group of nurses sent out by the Henry
Street Settlement House to care for poverty-stricken women,
and often helped the women through childbirth. Sanger was
astonished by the poverty and misery: children sick, dirty,
and underfed; tuberculosis rampant; and women seemingly
unaware of how their bodies worked and the risk of repeated pregnancies and venereal disease. In the 1920s, the state
health department distributed circulars warning women that
pregnancies occurring too close together were dangerous,
predisposing mothers to tuberculosis. But the same department barred women from receiving information about how
to prevent pregnancy.
Doctors estimated that one-third of all pregnancies in
the US at the time ended in abortion. Sanger became convinced that women should have the right to contraception.
In 1913, she wrote a 12-part series of articles about sex and
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reproduction for The Call, a radical newspaper. Sanger rejected the idea of full-time motherhood. She became involved
in the right to vote for women and the drive to prohibit the
sale of alcohol, with the idea that if men stopped drinking,
they would be less abusive and less likely to force their wives
to have sex.
In 1914, soon after the publication of Sanger’s newspaper,
The Woman Rebel, the US Post Office Inspector issued a warrant
for her arrest, charging her with four counts of violating US
obscenity laws. Sanger, now 34 years old, chose not to appear
in court. Instead, she jumped bail, left her family, and moved to
Europe, where she fell in love with 55-year-old Henry Havelock
Ellis, one of the world’s preeminent sexual psychologists. Ellis
had made it his mission to solve the mysteries of sex, collecting
histories from men and women in an effort to prove that physical intimacy was natural and varied. Ellis introduced Sanger to
more intellectuals, including the science fiction writer H. G.
Wells, George Bernard Shaw, Bertrand Russell, and Lorenzo
Portet.
Ellis mentored Sanger. Now for the first time she had a plan.
At first she had seen contraception primarily as a way to help
women control the size of families. Now she was beginning to
believe that if sex were disconnected from childbirth, women
might be liberated in ways they had never imagined: there would
be changes in marriage, in the meaning of family, and in career
and educational opportunities for women.
While Sanger was in Europe, her husband was arrested by
Anthony Comstock, a special agent for the Postal Service, for
distributing pamphlets about birth control. Comstock made
it his mission to fight smut in America, almost singlehandedly creating a strict set of antiobscenity laws. Comstock was
appointed special agent for the YMCA Committee for the
Suppression of Vice. While leading raids and smashing up sex
devices, pornographic pictures, and contraceptives, Comstock
became famous for guarding America from pornography and
disease. In 1873, he had persuaded Congress to pass a bill banning the use of the mail for transporting “any obscene, lewd,
lascivious, or filthy book, pamphlet, picture, paper, letter,
writing, print or other publication of an indecent character.”
After that, every state had its own antiobscenity laws, many
of which made it illegal to sell or disseminate information on
contraceptives. To enforce the federal law, Comstock was appointed a special obscenity agent of the US Post Office. Soon
after, he was authorized to carry a gun. The Comstock Law
defined immorality so broadly that it could have included
nearly anything. Thus, it was not surprising that it was deemed
to ban not only the sale of contraceptive devices but also the
transmission of information regarding contraception. The law
influenced policy and kept women from getting birth control
for decades!
Soon after her arrival in England, Sanger wrote to her
husband that she considered their 12-year marriage over. She
asked for a divorce, but he did not feel the same way. In 1915,
however, Sanger’s husband was convicted on obscenity charges
with a judge saying he had violated not only the laws of man,
July 2015
but the law of God in his scheme to prevent motherhood. He
served 30 days in prison. Only then did Margaret agree to
return home. Soon afterwards, her 5-year-old daughter Peggy
developed pneumonia and died. For the rest of her life she
was tormented by dreams of babies. This tragedy, however,
did not compel her to pay more attention to the care of her
two surviving children. Instead, Sanger went back to work.
She began by posing for publicity photos, wearing a wide
Quaker collar with her young son by her side, looking like
a respectable young mother. It was about this time that she
began using the phrase “birth control” instead of contraception. The key word in the phrase was “control.” If women
truly got to control when and how often they gave birth, they
would hold a kind of power never before imagined. Without
control, women were destined to be wives and mothers and
nothing more.
In 1916, Sanger opened her first birth control clinic in
Brooklyn, where a team of nurses distributed condoms and
pessaries (flexible rubber caps that were commonly sold in drug
stores as a “womb support” but in reality functioned similarly to
a diaphragm or cervical cap). The clinic, of course, operated in
direct violation of New York state law, so no one was surprised
when police raided the place 10 days after it opened, confiscating contraceptive devices and arresting Sanger. She served
30 days in the penitentiary charged with illegal distribution of
birth control products.
Sanger gradually became more sophisticated in her radicalism. Instead of challenging society’s conservative views on sex
and challenging obscenity laws, she tried to recruit physicians,
scientists, and corporate leaders to join her crusade, emphasizing the benefits to public health. She encouraged women to see
their doctors to get fitted for diaphragms, hoping that doctors
would be valuable allies in her fight. One of her allies at the
time was a wealthy widower named James Noah Slee, who met
Sanger and quickly fell in love with her. Slee was 20 years older
than Sanger and had been president of the 3-in-1 Oil Company,
makers of the product that almost every American at the time
kept on hand to grease typewriters, bicycle chains, and sewing
machines. Sanger had been separated from her first husband 7
years when she met Slee. In 1922, she finally divorced William
Sanger and married the crusty aristocratic Slee. Slee gave Sanger
all the money she wanted for her cause. She and her husband
now owned their own company to design and market birth
control devices.
By 1925, more than 1000 doctors from around the world
sought admission to Sanger’s annual birth control conference held in New York City. British economist John Maynard
Keynes, as well as Norman Thomas, W. E. B. Du Bois, Upton Sinclair, and Bertrand Russell attended. The birth control
movement was clearly gaining visibility in the US and spreading
quickly around the world. Overall, the birth rate in the US
fell 30% between 1895 and 1925, even though women had
begun to marry at younger ages. By 1930, the Birth Control
League, the organization Sanger founded, was overseeing 55
clinics in 23 cities.
423
In 1932, US Custom officials, citing obscenity laws, seized
a box of experimental diaphragms sent to Sanger by a Japanese
physician and father of 12 who believed his new design would
make contraceptives more effective. Sanger and her allies challenged the seizure, arguing that the law was blocking scientific
progress and hindering the advancement of medicine. In a landmark decision, a New York State Board of Appeals judge agreed.
After that, as long as physicians were involved, it would be legal
to use the mail to spread information about contraception or
to ship contraceptive devices. The decision opened the door for
the American Medical Association to recognize contraception
as preventive medicine.
Pincus. In January 1952, Pincus filed a report to Planned
Parenthood stating that 10 mg doses of progesterone
administered orally had suppressed ovulation in 90% of the
rabbits tested. The results were good enough to justify tests on
women, and he was ready to begin. When her second husband
died in 1942 at the age of 83, Sanger inherited $5 million. She
gave some of the money to the birth control movement, some
to friends, and spent much of it on lavish vacations. Planned
Parenthood had grown rapidly in the 1940s, adding branches
across the country. It was led mostly by businessmen and male
physicians. Prescott S. Bush, a Connecticut businessman whose
son and grandson would both become US presidents, served
as treasurer for Planned Parenthood’s first national fundraising
campaign in 1947. The organization unfortunately was frightened by the idea of doing something that had never been tried
before: giving medicine to healthy women simply to improve
their lifestyles. A scandal or a lawsuit could sink the entire
organization. Planned Parenthood was not ready to go out on
a limb and certainly not for Pincus.
Gregory Goodwin Pincus (Figure 2) fancied himself a poet,
philosopher, tiller of the soil, and lover of women. His passion
Figure 2. Dr. Gregory Pincus. Photo from Images from the History of Medicine,
Library of Congress, ID 186672.
424
for life and ideas was great. As a teenager he wrote in his diary, “Our one duty is self-development; man’s job is to get the
most out of his talents and to help others do the same.” It was
not sex, money, or fame that guided Pincus. It was his quest
for greatness, a desire that never ebbed as long as he lived. The
Pincus family arrived in New York City in 1891 from Odessa,
a cosmopolitan Russian city. The anti-Jewish pogroms were
sweeping Russia at the time and the Pincuses fled. They moved
to a New York City slum and from there to Colchester, Connecticut, and then to a kibbutz.
In 1902, Lizzie Lipman and Joseph Pincus married, and
six offspring followed. Gregory (“Goody”) was the first, arriving in 1903. He worked his way through Cornell University
washing dishes and waiting tables. One day during his senior
year, Pincus returned home to find a visitor with his family. Her
name was Elizabeth Notkin, 4 years older than he. The five Pincus boys had never seen anyone like Lizzie. She cursed, drank,
and chain-smoked cigarettes. In 1923, she and Goody married
before a judge while she visited him at Harvard where he was
doing a PhD in biology. It wasn’t long before she was pregnant
with her first child. At age 27, Goody Pincus was appointed an
instructor in the department of general physiology at Harvard.
A year later he was promoted to assistant professor of biology.
At Harvard he experimented mostly with rats, studying how
they responded to heat and light. When he graduated, he had
a postdoctoral fellowship, studying for 2 years at Harvard and
1 year in Europe.
In Europe for the first time, Pincus began researching the
eggs of mammals, the subject that would become his life’s
work. He returned to Harvard as a professor in 1930. Pincus’
interest was how animals passed along genetic traits, and that
led him to the study of mammalian eggs, specifically how
they were fertilized and how they developed in vitro. He tried
hormone injections to see how they affected rabbits and at one
point noted that estrogen injections prevented pregnancy. In
1934, Pincus announced to the National Academy of Sciences
that he had fertilized rabbit eggs in a test tube, transplanted
them into the body of a host mother, and brought the baby
rabbits to term. This was radical research at the time. He also
wrote in a grant application that his goal was to apply his
in vitro technique to humans. His work began to attract an
unusual amount of attention beyond the academic community. The New York Times cited his work for the first time in a
1934 article. The newspaper unfortunately went on to portray
Pincus as a sinister scientist trying to grow babies in bottles.
After fertilizing rabbit eggs and restoring them to their mother,
Pincus took another step: letting the eggs become embryos
while remaining in the glass. In 1936, Pincus achieved parthenogenetic development of a rabbit ovum; they had begun
the reproductive process without any fertilization, simply by
manipulating the environment surrounding the egg. Not long
after that, Pincus transplanted the egg successfully into surrogate female rabbits. The press called this “immaculate conception.” In the same year Harvard marked its 300th anniversary
with a pamphlet listing the greatest scientific discoveries made
Volume 28, Number 3
by its faculty in three centuries of study. Pincus’ work made
the list. The same year he published his groundbreaking book,
The Eggs of Mammals.
With each new discovery, each audacious claim, and each
speech before a scientific body, Pincus attracted more attention in the mainstream press. Newspapers all over the country
carried reports of his research. In 1937, Collier’s Magazine published a feature story on Pincus’ work. A critic was quoted as
saying, “If babies were made in test tubes, it would be the ruin
of women.” Pregnancy not only improved a woman’s looks, the
critic noted, but also improved her nervous system. Suddenly,
Pincus was being portrayed as a revolutionary or, worse, a deviant. Soon after the Collier’s article, Harvard gave Pincus the
news: He would receive a grant to study for one more year at
the University of Cambridge in England and then he would
be finished. Thus, at age 34, Pincus had already published a
groundbreaking book and a number of attention-grabbing
scientific studies and was on the cusp of what appeared to be
a brilliant career, teaching and conducting research at one of
the wealthiest and most prestigious universities in the world.
But, suddenly, he was gone.
Pincus probably was the victim of small-mindedness and
anti-Semitism, but he was also undone by his own outsized
ego. He couldn’t find another college willing to hire him. His
classmate, Hudson Hoagland, who had left Harvard and gone
to work in Clarke University in Worcester, rescued him. The
Pincuses arrived in Worcester in the fall of 1938, and Pincus
went back to work on hormones. In 1944, he and several other
scientists organized a major conference on hormones. They
called it the Laurentian Hormone Conference. Pincus became
the chairman of the conference, a position he maintained for
the rest of his life.
In 1944, he and Hoagland made a move almost entirely
unheard of in the American scientific community. They founded their own laboratory, calling it the Worcester Foundation
for Experimental Biology. Hoagland and Pincus proved to
be excellent salesmen, and the people of Worcester responded generously. Hoagland in particular had a gift for raising
money. He had come from an affluent family and projected
an image of sophistication. He was no slouch as a scientist,
but it was clear from the start that Pincus was the real genius
and Hoagland the organization man. At first the two scientists
operated out of a room at the Worcester State Hospital, but
they soon had enough money to hire a dozen workers and
purchase a 12-acre estate in nearby Shrewsbury. By 1951, the
foundation employed 57 men and women, making it by some
accounts the largest privately owned independent scientific
research institution in the country.
The family had little money and lived in several crowded
apartments and finally found a place at the Worcester Lunatic
Asylum, a frightening and dangerous place, but it saved money
on rent and enabled Pincus to concentrate more completely on
his work. He did not own a car or drive one until in his 40s.
He would take a bus or hitch a ride with another scientist to
get to work each day. Pincus was an accomplished Scrabble
July 2015
and chess player and devoured mystery novels. At the beach he
would swim more than a mile out to sea. In the early 1950s,
with the Worcester Foundation being more stable, the Pincus
family bought a house. It looked more like an old hotel than a
house, and Pincus paid $30,000 for it (about $260,000 today).
The red brick structure had a dozen bedrooms, 10 fireplaces,
and a furnished basement where Pincus sometimes offered free
lodging to visiting scholars. They had parties lasting late into the
night and leaving nearly everyone drunk. Inebriated or sober,
Lizzie was razor sharp, every bit her husband’s intellectual equal
when conversations were not so scientific. She spoke French
and Russian fluently.
Despite his exile from Harvard, Pincus was beginning to
establish a reputation for leadership among his peers. He was
not only a brilliant scientist but he had a gift for organizational
work. The Laurentin Hormone Conference became the biggest
and most important hormone conference in the world and, as a
result, Pincus, with no university or corporate affiliation and no
landmark discovery to call his own, became an influential player
in the scientific community. He helped decide which scientists
would be invited to the conference each year, who would be
permitted to present papers, and whose papers would be cited
in the yearly conference report.
McCormick. In the fall of 1950, shortly before Gregory
Pincus first met Margaret Sanger, Sanger received a letter from
a 75-year-old woman named Katharine Dexter McCormick
(1875–1967) (Figure 3). It read, “I want to know a) where you
Figure 3. Suffragists Katharine McCormick and Mrs. Charles Parker, April 22,
1913. Photo: Library of Congress (LC-USZ62-93552).
425
think the greatest need of financial support is today for the
National Birth Control Movement; and b) what the present
prospects are for further birth control research, and by research, I mean contraceptive research.” For Pincus and Sanger,
the timing of the letter could not have been more fortuitous.
McCormick was one of the world’s wealthiest women, and
after years of personal struggle and tragedy (her husband
was schizophrenic) she was at last free to spend that wealth.
McCormick was the recently widowed wife of Stanley McCormick, the youngest son of Cyrus McCormick, inventor
and manufacturer of the mechanized reaper and one of the
wealthiest men in the world. Katharine was 29 years old at
the time of her wedding, fierce and lovely, a leader in the
women’s movement and one of the first women to graduate
with a degree in science from the Massachusetts Institute of
Technology. She had intended to go to medical school, but
marriage changed that.
With her husband ill, she sensed that hormones, a word
coined in 1905, may have been responsible for her husband’s
condition and she became a student of these chemical messengers. In 1909, she began volunteering with the Women’s
Suffrage Movement and by 1921 began collaborating with
Sanger, who was busy planning the first American birth control
conference in New York. When her husband died in 1947, Mrs.
McCormick inherited more than $35 million, including almost
32,000 shares in the McCormick-owned company International
Harvester. Sanger too was now a widow, her husband having
died in 1943. McCormick knew exactly what she wanted to
do with her money.
In January 1952, Sanger stopped to visit Katharine McCormick in her mansion in Santa Barbara, California. Just before
the visit, Sanger had received a report from Pincus indicating
the results of the experiments he and Chang had performed
on rabbits and rats, explaining the effects of hormone injections versus administration by mouth. He confirmed that the
oral doses were 90% effective and said he hoped to experiment
with different progesterone compounds that might work better. Pincus concluded that the experiments “demonstrate unequivocally that it is possible to inhibit ovulation in the rabbit
and successful breeding in the rabbit with progesterone. . . . It
has been demonstrated furthermore that following the sterile
period, normal reproduction may ensue.” In June 1952, McCormick made plans to visit the Worcester Foundation to see
firsthand what was happening there. She met with Hoagland
and Chang and learned about the progesterone work underway,
but she did not see Pincus who was out of town. After that visit,
McCormick became Sanger’s leading expert on the Pincus plan
for contraceptive research.
Rock. Pincus recognized that what the pill project needed
now was not necessarily a biologist but a product champion—
someone who could build a team to do the scientific work,
forge alliances with manufacturers needed to supply chemicals,
and if all went well, spread the news of the coming invention
so it might have a chance of acceptance. He knew what to do
next: test progesterone in women. To do that he would have to
426
Figure 4. Dr. John Rock. Photo: Library of Congress (LC-USZ62-128825).
add a player to his team—a physician, preferably a gynecologist, someone who could reassure the patients involved in the
experiments that they were safe and would convey to the drug
companies supplying the progesterone that no one would be
harmed by the experiments. He considered several but came
down to a physician named John Rock (1890–1984) (Figure 4),
who like Pincus was a Harvard man. Rock was respected by
his peers and adored by his patients. He was tall, slender, and
silver-haired with a gentle smile and a calm, deliberate manner.
Even the name connoted strength, solidity, and reliability, and
he was a Catholic.
Born in 1890 in Marlborough, Massachusetts, Rock was a
son of an Irish saloonkeeper, and although he was big, strong,
and athletic, he preferred playing with his sisters, and his
brothers sometimes called him “sissy.” He gained admission to
Harvard and attended not only college there but also medical
school. In 1926, he became director of the sterility clinic at
the Free Hospital for Women in Boston. While the Catholic
Church opposed abortion, Rock believed a woman’s health was
more important than the health of her fetus and that pregnancies should be terminated when they imperiled patients’
lives. “Religion,” he used to tell his daughter, “is a very poor
scientist.” Over time Rock underwent a fundamental change
as compassion for his patients overwhelmed his compulsion to
tow the church’s line. He sympathized with women who came
to his office who said they were afraid of becoming pregnant
again, whether it was because their bodies were worn out or
because they couldn’t imagine caring for more children. Rock
began seeing that many couples wanted contraception because
they wanted to delay, not avoid, becoming parents. In 1931,
he was one of 15 Boston doctors (and the only Catholic)
to sign a petition calling for the repeal of the state’s ban on
contraception.
In 1925, Rock married Anna Thorndyke, a Boston woman
who shared his sense of adventure, having served as an ambulance driver in France during World War I. He was 35 and she
29 at marriage. They had five children together. He adored his
Volume 28, Number 3
wife and had no fear of showing his affection publicly. In his
practice, he counseled pregnant women and delivered babies
but he also worked with women who could not conceive and
came to believe that sexual intercourse offered an important
bond for husbands and wives as they struggled unsuccessfully
to have children.
Although Sanger did not want Pincus to include Rock on
his team investigating progesterone because of her mistrust
of the Catholic Church, Pincus saw in Rock not only a talented scientist but also an important promoter of his new,
as yet unrealized, birth control pill. Rock had already gained
a small measure of fame as the Catholic doctor who dared
defy his own church. In 1944, he made headlines when he
achieved the first successful in vitro fertilization of human
ova. In 1948, Rock had published a book called Voluntary
Parenthood stating: “Nothing in a life of a man and woman
is going to be as important to themselves or society as their
parenthood.”
Gregory Pincus and John Rock had met in the 1930s when
Pincus was still at Harvard. In the 1940s when Rock began
experimenting with in vitro fertilization of human ova, one
of his first steps was to send his research assistant to Pincus
for guidance. Rock was unusual among fertility specialists at
the time because he also asked husbands to have their semen
tested. He suspected (and his suspicions were confirmed in
later years) that men were responsible for a large percentage of
infertility problems. He was also unusual in that he operated
a rhythm clinic down the hall from the fertility clinic. Rock’s
rhythm clinic was the first free clinic in Massachusetts to offer birth control advice. The women visiting his rhythm clinic
were asked to chart their menstrual cycles and sex lives for 3
months. After that, Rock tried to instruct the women who had
regular cycles when they could safely have sex with little risk
of fertilization. He knew that many of the women were using
diaphragms, douches, and condoms, but the law would not
allow him to prescribe or even discuss those items unless the
woman’s health was in serious jeopardy! Rock had long believed
that the church and the state of Massachusetts were wrong for
rejecting birth control.
In 1952, Pincus and Rock attended the same scientific
conference and chatted between sessions about their work.
When Rock described his work with the pregnant women,
Pincus suggested to him that he try progesterone without
estrogen. Rock experimented with different combinations
of hormones in different methods of delivery, trying to find
the medicine that worked best and caused the fewest side
effects. He did not ask his patients to sign consent forms but
he did explain to the women that the medicine they were
about to take would not directly help their infertility. This
was how experiments were done at the time. He started the
women on 50 mg of progesterone and 5 mg of estrogen and
escalated gradually to 300 mg of progesterone and to 30 mg
of estrogen. When the first round of treatments ended, no
one had died and no one had become seriously ill. Thirteen of
the 80 women in Rock’s care became pregnant. Rock told col-
July 2015
leagues about this promising result which came to be known
as “The Rock Rebound.” The women taking the hormones
were often convinced they were pregnant because the hormones produced many of the same symptoms as pregnancy.
The women were desperate to have children since most had
been trying for years.
When he learned of Rock’s work, Pincus was pleased but
not surprised that the progesterone was having a contraceptive
effect. The important thing to Pincus was the fact that Rock’s
patients were not dying. Here was proof, it seemed to him, that
it was safe to give progesterone to women. Rock told Pincus
that he was encouraged by his work with progesterone, but that
he had a big problem: patients receiving the hormone believed
that they were pregnant, no matter how much he assured them
they were not. And they were crushed when the truth finally
became clear to them.
Pincus proposed an elegant solution and one that would
have enormous consequences for his own work and for the
future of women around the world. To keep the women from
ovulating while permitting monthly menstruation, the simplest
solution was to have the women stop taking the progesterone
pills for 5 days each month. It made sense to both men.
Early clinical trials. One company supplying hormones
for his progesterone experiments was G.D. Searle. Although
the drug maker had had no success with Pincus a year earlier,
company officials had never given up on the brilliant but
unpredictable scientist. Searle officials continued to believe
that Pincus might come up with something useful, and it was
a lot less expensive for the drug company to write grants for
the Worcester Foundation than it would have been to hire its
own researchers. For these reasons, despite Pincus’ failures,
Searle agreed to pay the foundation $62,400 for a 12-month
period beginning in June 1953. In addition, Pincus would
receive shares of Searle’s stock starting with 19 shares valued
at $921.50. Officials at Searle had not committed to a new
contraceptive, and they asked Pincus not to publicize their
involvement in his project. They told Pincus that they would
not have anything to do with a birth control pill that interfered
with the menstrual cycle.
Because Massachusetts law banned all forms of contraception, Pincus devised a method to test a birth control formula by
calling it a “fertility treatment.” If he had still been on the faculty
of Harvard or even if he had still been operating in affiliation
with Clarke University, he never would have gotten away with
it. Pincus saw himself as more than a research scientist now.
He was an activist, a crusader, and a businessman. He was also
a builder of coalitions.
In the 1950s, there was still no law requiring physicians
to inform patients that they were being included in an experiment. Rock told his patients that the progesterone they
were receiving would shut down their ovaries and make it
impossible to get pregnant, that the treatment would simulate
pregnancy and might cause nausea, and that they would have
a better chance of becoming pregnant when the experiment
was complete.
427
Beginning in 1953, Pincus and Rock enlisted 27 of Rock’s
patients at the Free Hospital for a 3-month trial. Because Pincus
wanted to be certain that the hormone was effective in halting
ovulation, women who failed to ovulate regularly were not
included. The women enlisted were still infertile, but Rock
did not know what was causing their infertility. Instead of the
progesterone-estrogen mix that Rock had used in the past,
the women in this experiment received only progesterone and
they received the tablets daily for 3 weeks of each month,
stopping for a week to allow them to menstruate. The tests
were demanding and the testing was referred to as “the Pincus
progesterone project” or PPP because so many urine specimens
were tested. Pincus tested the urine specimens in Shrewsbury.
Pincus also included a gynecologist in Worcester, Dr. Henry
Kirkendall, and asked him to recruit 30 women for a study
similar to Rock’s. The women would need to take their own
temperature every day and record their findings. They also
were expected to take daily vagina smears and collect their own
urine for hormone analyses. The progesterone dosage would
be high, between 250 and 300 mg a day. The women were
not paid for their participation, nor were they informed that
the results might lead to the invention of a new form of birth
control. Most of them were doing it simply because a trusted
doctor had asked them to.
In the first year of the trials, Pincus, Rock, and Kirkendall
enrolled 60 women. Unfortunately, half of the women enrolled
dropped out either because the test procedure was too demanding or because the side effects were too disturbing. Unfortunately, in that experiment 15% of the women showed signs of
ovulation while taking progesterone, significantly worse results
than Pincus had seen with rabbits and rats.
In the meantime, Russell Marker, George Rosenkranz,
and Frank Colton had developed synthetic progesterone
(progestin), which was 4 to 8 times more potent than the
natural progesterone, and the new compound was able to
survive absorption in the digestive tract, which meant it
could be taken orally. This was the compound that Pincus
was searching for.
In May 1953, as Pincus and Rock were launching their
first round of tests on humans, Sanger and McCormick met
with Pincus and see if he was someone McCormick might
wish to support. The women were not put off by the cheaply
furnished offices, the poor ventilation in the animal rooms,
or the jerry-rigged appearance of the laboratories. If anything,
they seemed captivated by the place’s strappy charm and were
especially enthusiastic about Pincus’ plan for testing John
Rock’s patients. As the tour concluded, McCormick asked
Pincus how much money he needed. Pincus had already negotiated a grant of $17,500 from Planned Parenthood to
cover the first year of clinical trials. McCormick had agreed
to pay half that amount. McCormick now asked how much
it would take to fund the entire research project. How much
to get the pill? Pincus answered $125,000. The next day McCormick phoned Pincus to say she would write a check for
$10,000 with more to come. By this time, Searle was funding
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the Worcester Foundation at a rate of about $5600 a month,
making it the foundation’s biggest private backer by far and
accounting for about 8% of the foundation’s total income.
Also Searle at this time was paying about one-third of Pincus’
$15,000 annual salary, when the median family income in
the US was $5,000.
By the fall of 1953, the Worcester Foundation had 46 grants
providing a total of $622,000 in income. All but 11% was
spent on research. Fortunately, Pincus received $50,000 from
McCormick to build an animal testing center which was needed
desperately. Meanwhile, he continued to try different progesterone compounds to see which one worked best and continued
to look for ways to test on women.
More than ever, McCormick was taking charge. Sanger
was in poor health, low on energy and increasingly cantankerous. While Sanger at times was distracted or incapacitated by
illness, it was McCormick who urged the work forward. She
was beholden to no one and was free to speak her mind. McCormick alone among the team of developers had the courage
and independence to declare that all women, married or not,
should have access to the pill.
About half of the women in Rock’s and Kirkendall’s study
dropped out. Testing a birth control pill was more difficult
than testing other drugs. It was one thing to try a new medication in sick people who wanted to get better, but these were
healthy young women volunteering for experiments. Pincus
told McCormick that he would need to test hundreds if not
thousands more women and have more staff—doctors, nurses,
and clerks—as well as more examining rooms. After a year of
work and a dropout rate of about 50% in their first round of
testing, Pincus and Rock had completed research on only about
30 women.
In March 1954, Pincus and his wife went on a trip to Puerto
Rico where he lectured at medical schools and before groups
of doctors. He was impressed by the quality of work done on
the island and encouraged to learn that dozens of birth control clinics were in operation. He concluded that experiments
could be done in Puerto Rico on a relatively large scale. Best of
all, birth control had been legal in Puerto Rico since 1937! In
Puerto Rico, overpopulation and poverty had long been serious issues. The island was poor and crowded and family sizes
were large. By age 55, the average mother in Puerto Rico had
given birth to 6.8 children. Just over 8% of married Puerto
Rican women under the age of 50 had volunteered for sterilization. Although abortion was illegal in Puerto Rico, it became
so commonplace in the 1950s that Puerto Rico developed an
international reputation as a place where the procedure could
be obtained, no questions asked. Finally, McCormick and Rock
agreed with Pincus that Puerto Rico was the place to go to study
the women they needed.
As Pincus began planning Puerto Rican trials for the birth
control pill in 1954, another scientist, Jonas Salk, was launching the first trials of his polio vaccine. Salk would spend tens
of millions of dollars on his vaccine trial, while Pincus would
operate on a first-year budget of less than $20,000. Salk would
Volume 28, Number 3
go on to test his drug on 600,000 children during field trials
while Pincus was hopeful that he could round up 300 subjects.
Neither Salk nor Pincus were concerned with profiteering from
their inventions. In 1954, as Pincus negotiated with Planned
Parenthood for support and funding and arranged with Searle
and Syntex for supplies of the necessary progesterone compounds, he, like Salk, focused on the scientific work, not on
the money. While the public clamor for birth control hardly
equaled the clamor for a polio vaccine, the growing concern
was about population growth.
When Pincus first visited the island in February 1954,
he met Dr. Edris Rice-Wray, medical director of Puerto Rico’s Family Planning Association. She was not from Puerto
Rica but from Detroit. She had earned a bachelor’s degree
at Vassar College and her medical degree at Northwestern
University. In 1949, she had moved to San Juan with her
two children after divorcing her husband in Chicago. Dr.
Rice-Wray became the point person for Pincus’ study in
Puerto Rico.
In the meantime, Pincus had found another site to acquire
women for his study, namely, Worcester State Hospital, an
asylum more than a century old. It was not difficult for Pincus
to obtain permission to experiment on patients at the asylum.
No permission slips needed to be signed. The directing physician, Dr. Bardwell Flower, a Harvard graduate, was pleased to
have a few more physicians on hand in his enormous hospital.
It helped too that McCormick offered money to paint and refurbish some of the asylum’s wards in exchange for cooperation
in the progesterone study. They administered progesterone
and estrogen in varying doses to women diagnosed with paranoia, schizophrenia, melancholia, manic depression, chronic
alcoholism, Alzheimer’s disease, Pick’s disease, and others.
Pincus managed to enroll 16 women—all of them classified
as psychotics—for the first round of progesterone testing. He
also gave the hormone to 16 men to see how it would affect
their sterility. (Sanger and McCormick, however, had made
it clear that they did not trust men to take responsibility for
contraception, and they wanted women to possess control
of their own bodies and their own fertility.) The pill in the
men had varying results, and that side of the study was soon
discontinued.
In February 1955, Pincus visited McCormick in Boston
to bring her up to date. In late 1954, Pincus began experimenting on animals with a new group of progestins that were
many times more powerful than natural progesterone. Two
of the compounds seemed especially promising. One, called
norethindrone, had been developed by Syntex, and the other,
named norethynodrel, had been developed by Searle. Pincus
and Chang preferred the Searle product because the female animals with it did not develop slightly masculine characteristics.
Pincus informed Searle that he wanted to use the compound
norethynodrel and intended to try it as an oral contraceptive
for women. Searle agreed to send the experimental drug under
the condition that the bottles were unlabeled and Searle was
not mentioned as the supplier.
July 2015
Pincus brought McCormick up to date on the advantages
of doing clinical trials in Puerto Rico. This time he would begin
a new experiment with nurses and medical students on that
island. He would drop the endometrial biopsies, which were
extremely uncomfortable and scared off participants. In addition, the students would be required by the faculty to participate as part of their studies. If the young women were worried
about the stigma of being birth control subjects, Pincus had a
solution: he would label the project a “study of the physiology
of progesterone in women.” And once the nurses and students
enrolled, word would spread that the substances were safe and
effective. From there it would get easier. Pincus told McCormick
the new drugs would cost about 50¢ a gram, which would mean
expenses of about $5000 for the treatment of 100 women during the first year of testing. In addition, he would need money
for physicians, nurses, secretaries, travel, and printed materials.
For the first year the total operating expenses would probably
be about $10,000. McCormick assured him that money would
not be a problem.
In late 1955, John Rock reported to Searle preliminary results of his tests with the new progestin compound norethynodrel. Rock’s test showed that progestins stopped the pituitary
gland from producing the hormones that signaled the ovaries
to release eggs. But the pill had other effects that were not yet
clearly understood. It appeared to change the consistency of
the cervical mucus, making it more hostile to sperm. Rock
indicated that he was relatively confident that the Searle progestin was safe and that it would not affect the woman’s ability
to get pregnant. He was optimistic enough to encourage Searle
to promote the drug more widely, but he was nowhere near as
optimistic as Pincus. Additional results by Rock showed that
both norethynodrel and norethindrone appeared effective. Best
of all, they worked at doses of only 10 mg per day, which was
one-thirtieth of the progesterone dose Pincus and Rock had
been giving earlier.
In October 1955, Pincus and Sanger went to Japan to attend a meeting where he initially had planned to announce
that an oral contraceptive for humans was nearly ready when,
in fact, he had not yet decided which form of the contraceptive worked best and at which dose. Sanger was greeted as a
hero in Tokyo. The number of reported abortions in Japan had
increased from 246,000 in 1949 to just over 800,000 in 1952,
and the number of sterilization operations jumped from 6000
in 1949 to more than 44,000 in 1956. Sanger opposed abortion
as a method of birth control and believed that Japan needed an
oral contraceptive more desperately than most nations. She also
believed that the country was well positioned to take advantage
of innovations in contraception. Literacy rates, for example,
were high. Midwives were active even in remote villages. If it
worked in Japan, Sanger strongly hoped it would work all over
Asia and the world.
In February 1956, Pincus flew to Puerto Rico to see if he
could salvage the trials. The university students and nurses
had all quit. He needed a new approach. He met with Dr.
Rice-Wray who was both the medical director of the Family
429
Planning Association and director of the training center for
nurses at the Department of Health’s Public Health Unit, in
a poverty-stricken district of San Juan. These dual roles made
her an ideal guide to Puerto Rico for Pincus and Rock. She
knew her way around the communities where the field trials
would be taking place, and she was a rebel who had given
up a comfortable medical practice in Chicago because she
believed that women should have access to contraception.
Rice-Wray began by visiting the superintendent of the housing development, a man who saw first hand the effects of
overpopulation and the burdens it placed on young mothers.
He turned over a detailed list of all the community’s residents
and promised that his staff would help Rice-Wray recruit
subjects. She enlisted a strong, smart, ebullient nurse whom
everyone in the area knew. Puerto Rican government officials
approved the study.
By the end of March 1956, Rice-Wray and her nurse associate had selected a group of 100 women as well as a control group of another 125. Though almost all were Catholic,
Rice-Wray encountered only one woman who said her religion
prohibited her from enrolling in the study. The subjects receiving the birth control pill were told that they were taking an
experimental new contraceptive. The women in the control
group were told they were part of a survey on family size. They
used Searle’s compound, norethynodrel. The subjects were
supposed to take one pill a day for 20 days before stopping.
Dr. Rice-Wray began distributing birth control pills in April
1956. She gave each woman a full bottle, enough to last 20
days. She told her patients to wait 5 days after completing one
bottle before starting another. Even though she tried to keep
the instructions simple, mistakes occurred. One patient went
home and took all the pills at once. Others shared them with
friends. Doctors, nurses, and social workers tried handing out
calendars. They tried giving women beads on a string to help
them count. Nothing worked.
A newspaper got wind of the study and reported it. Afterwards, 30 women dropped out of the trial, some because their
husbands objected, others because they were worried about
what their priest would say, and still others because they were
experiencing unpleasant side effects. After 6 months, an additional 48 patients had quit, leaving only about 20 of the
original 100. After a slow start, the study was never again at a
loss for volunteers. By the end of 1956, 221 women had participated. Seventeen of those women had gotten pregnant—a
fact that might have been troubling to some scientists but not
to Pincus. The pregnancies had nothing to do with the pill, he
told Katherine McCormick. Women were getting pregnant
because they weren’t following instructions. They either forgot
to take the pill every day or chose not to take it because the
side effects were becoming too much to bear. Among the first
221 women in the study, 38 (17%) reported negative reactions
to the drug and at least 25 women withdrew from the study
specifically because of the side effects. In December 1956, Dr.
Rice-Wray and Pincus traveled to Skokie, Illinois, to present
their findings to the officials at G.D. Searle, which had already
430
patented norethynodrel and had recently trademarked a new
name for the drug, calling it Enovid.
By 1957, Pincus and Rock both felt confident that the pill
worked and that it worked safely. Their biggest challenge was
to get more women to try it and at the same time see if they
could do something about the side effects. Pincus believed that
most of the side effects were psychosomatic. To test that theory,
he designed a simple experiment. One group of women was
given Enovid with the usual warnings about possible reactions.
Another group was told they were getting Enovid but was given
a placebo instead along with the same warnings on side effects
given to the first group. The third group received the real Enovid
and no warnings about the side effects. The side effects were
23% in the first group, 17% in the second group, and 6% in
the third group. Pincus’ experiment violated two basic rules of
modern medical research: his patients were not informed of the
purpose of the study, nor were they warned of the risks. The
results nevertheless convinced him that he was right. Many of
the side effects were imaginary.
Pincus sought more patients. He contacted Clarence Gamble of Proctor & Gamble fame who had been sponsoring research in Puerto Rico for years, and Gamble offered to fund a
second trial. He connected the Pincus team with the medical
director at Ryder Memorial Hospital in a city 35 miles from
San Juan. The women came to the hospital for two reasons: to
have babies and, immediately afterward, to get sterilized. If it
were not for the latter procedure, they would have delivered
at home by midwives. The area chosen by Gamble was a slum
region with no toilets or sewers and housing so crowded there
was scarcely room for a squeezed pedestrian. Gamble hired a
woman to take a census of La Vega, going door to door asking mothers how many children they had, whether they were
sterilized, and what type of birth control they were using, if
any. Enovid was offered to the women who had been denied
sterilization at the hospital. There was no trouble finding willing patients, but once again side effects complicated the work.
Women complained of breakthrough bleeding, nausea, and
headaches. Nevertheless, women desperate to avoid pregnancy
continued to enroll in the studies.
With trials now underway in two Puerto Rican communities, Pincus and his team began to work on a third location
in Port au Prince, Haiti. Increasing numbers of patients gave
Pincus and Searle hope that they might have enough information to prove Enovid’s safety.
At one point, Pincus and Chang discovered that Searle’s
compound had accidentally been contaminated with a tiny
amount of synthetic estrogen, also known as mestranol. Pincus had always tried to avoid the estrogen, and when he
learned of this accidental contamination he ordered the drug
company to get rid of estrogen—not only because he felt it
might be unsafe but also because he thought the estrogen
might have been responsible for some of the side effects. To
his surprise, however, not only did the nausea persist, but
women began experiencing even more breakthrough bleeding.
As a consequence, it dawned on Pincus that the accidental
Volume 28, Number 3
contamination might have been a good thing. With more
experimentation, he found that breakthrough bleeding increased when the estrogen dose fell, and nausea and breast
pain increased when it rose. He also discovered that when
the estrogen levels were too low, the pill was less effective in
preventing pregnancy. Now, instead of purifying the pill, he
suggested that Searle intentionally make it 10 mg tablets with
1.5% mestranol. The side effects did not disappear completely
but the bleeding almost stopped.
Still in the first months of 1957, the dropout rates remained high and the number of women enrolled in this study
was low—too low, Pincus believed, to win approval from
the Food and Drug Administration (FDA). In an effort to
remove emphasis on the number of patients enrolled in the
trial, Pincus stopped talking about women altogether. Instead
he talked about the number of menstrual cycles observed: in
the 1279 cycles when the regime of treatment was meticulously followed, there was not a single pregnancy. Simply
put, 1279 menstrual cycles sounded a lot more impressive
than 130 women.
Searle faced difficult questions: What were the rules for
testing the pill in healthy people? How far did a company have
to go to prove such a product? Was 1 year of testing enough
to measure long-term effects? Pincus urged Jack Searle not to
get bogged down. In the end, there was no way to answer such
questions because no one had ever done anything like this.
There were risks with any drug, but the rewards for this drug
in particular were like no other. This was a drug that had a
chance to make money, change lives, change the culture, and
combat massive world problems, such as hunger, poverty, and
overcrowding. Childbirth also was dangerous, especially for
women who were sick or weak or starving. There was no way
to measure how many lives might be saved by a reliable contraceptive. In the end, Jack Searle concluded that the potential
rewards outweighed the risks.
FDA submission. Searle did hedge its bet in one important
way: Instead of seeking approval from the FDA for a birth
control pill, the company applied for the approval of Enovid
as a treatment for menstrual disorders. Searle’s application to
the FDA in 1957 made no mention of contraception. Amenorrhea, dysmenorrhea, and menorrhagia were the menstrual
problems Enovid was said to combat. The company also claimed
that the new drug would be used to treat infertility, because
even though the number of cases was small, tests showed that
women resting the ovaries for several months were more likely
to become pregnant when they stopped taking the drug. The
FDA inspectors could not reject the drug as a contraceptive
because Searle was not asking for approval as a contraceptive.
The only question was whether it worked safely and effectively
in treating menstrual disorders.
On June 10, 1957, after taking 2 months to review the application filed by G.D. Searle and company, the FDA approved
the sale of Enovid for infertility and menstrual irregularities.
About the same time, the drug was approved for the same uses
in England under the brand name Enavid. It turned out that
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Searle did not have to market the pill as birth control because
men and women were learning for themselves what it could do.
It did not hurt that the FDA had required the drug company
to include a warning on each bottle that said that “Enovid
prevented ovulation”; in other words, the real purpose of the
drug was listed as if it were a side effect. That statement was
like a free ad.
In 1958, 17 states still had laws banning the sale, distribution, or advertisement of contraception. Gradually, one state
at a time, the laws were being overturned. Those in place were
largely unenforced. It was clearer than ever that most Americans
favored some type of birth control.
In 1959, drugs came with labels and nothing more. There
were no informational inserts to tell patients how the drug
should be used or to warn them of possible side effects. If patients needed instructions beyond those printed on the bottle,
they asked their physicians. For good reason, Searle was more
worried than usual about how this drug would be received if
they had received permission to sell it as birth control. For
one thing, women would be taking it by choice rather than
by necessity. They would be trying it for replacement of other
forms of birth control, not to ease pain or cure an illness. Searle
wanted to set the right tone, striking a balance between the
pill’s medical uses and its social benefits. Searle invited John
Rock who believed strongly in Enovid to help them with their
pitch. He suggested the company use phrases such as “child
spacing,” “postponement of pregnancy,” and “suppression of
ovulation” in its writings rather than contraception or birth
control. Searle would settle eventually on “family planning”
as its euphemism of choice. In a brochure prepared for physicians, Rock spent 1.5 pages describing the menstrual cycle for
general practitioners who were perhaps not as familiar with it
as gynecologists. Enovid, he wrote, “completely mimics” the
natural action of progesterone in suppressing ovulation. In a
separate brochure for patients, he wrote: “Enovid is an artificially made hormone that is chemically quite similar to the
two hormones, estrogen and progesterone, naturally produced
in the human ovary.”
On July 23, 1959, G.D. Searle asked the FDA to approve
Enovid for birth control. (Though it was not yet officially recognized as birth control, more than 500,000 women were taking
the pill.) Though the number of women enrolled in clinical
trials for the pill remained small, Searle submitted the biggest
new drug application in American history at that time, with 20
volumes of data. In 1959, the FDA had only four full-time and
four part-time physicians assigned to investigate the 369 new
drug applications submitted that year. Those seven investigators
were under extreme pressure to keep up with applications, but
they had little time to conduct their own research or maintain
their professional education. The Enovid application wound
up on the desk of one of the part-timers, Pasquale DeFelice, a
34-year-old obstetrician-gynecologist, who was still completing
his residency at Georgetown Medical Center in Washington,
DC. He was Catholic, and he was on his way to becoming the
father of 10 children.
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DeFelice seriously questioned the validity of the use of a
progesterone and the small number (n ≈ 130) of patients studied
and asked Searle for more data. Searle went back to work to collect more data. In the meantime, DeFelice sent a questionnaire
to 61 US physicians who had considerable experience with the
drug. The response barely favored release of Enovid as a birth
control agent. Despite considerable FDA hesitancy, DeFelice
phoned Searle on April 7, 1959, indicating the agency’s approval. The official announcement was May 9, 1960. The world
has not quite been the same since.
Soon after the pill was accepted, Pincus began working on a
pill with lower hormone levels, and by 1964 Searle began selling Enovid-E, with a hormone dose of only 2.5 mg, reducing
the cost for consumers to only $2.25 a month and reducing or
eliminating the side effects for many.
Looking back more than a half century, it seems unbelievable that a group of brave, rebellious misfits—Sanger, Pincus,
McCormick, and Rock—made such a radical breakthrough
and did it with no government funds and comparatively little corporate money. Pincus made relatively little money on
his invention—only his wages from Searle and the company
stock he purchased. He never patented the drug, but he had no
regrets. He was a pure scientist.
If there was one problem with Pincus’ invention, it was
that even educated women sometimes had difficulty using it.
Healthy young women were not accustomed to taking medicine every day. Sometimes they forgot or they lost track of how
many tablets they had taken since the start of the menstrual
cycle. Nervous men found themselves reminding their wives
and girlfriends, which led to friction. The men wondered if
the women might secretly be trying to get pregnant, and the
women suspected that the men cared more about the women’s
sexual availability than their health. After one such marital
spout, David T. Wagner of Geneva, Illinois, decided not to
leave the matter entirely in his wife’s hands. Wagner took a
piece of paper and put it on the dresser in their bedroom. On
the paper he wrote the days of the week; he then placed one
pill atop each day. When Doris swallowed a pill, the day of the
week would be revealed and husband and wife both would have
confirmation that she had taken it. Wagner said that this did
wonders for their relationship. Wagner, a product engineer for
432
Illinois’ Toolworks, began sketching a pill box that would also
function as a calendar. In 1962, he applied for a patent on a
circular pill dispenser. Searle declined interest in his invention,
but Ortho’s contraceptive pill hit the market in February 1963,
and it arrived not in a bottle but in a beautiful “Dialpack.”
Eventually, all the pill producers used the distinctive package
that Wagner had devised.
In 1967, Time magazine put the pill on its cover, reporting
that “in a mere 6 years it has changed and liberated the sex
and family life of a large and still growing segment of the US
population: eventually, it promises to do the same for much
of the world.”
In 2010, British scientists released the results of a 40-year
study, “Mortality among contraceptive pill users,” that showed
that women taking the birth control pill were less likely than other
women to die of heart disease, cancer, and other ailments (2).
The study, which tracked 46,000 women, helped ease concerns
about elevated risks of cancer or stroke. The women who took
the pill were 12% less likely to die of any cause during the study.
In 2011, Laura Pincus Bernard, Goody’s daughter, walked
through the empty halls of the ivy-covered building where her
father once worked, where Chang once slept, and where animals
once mated or attempted to mate before giving their lives to
science. The place was deserted except for a lone woman tapping a computer keyboard at her desk. That something so big
and world-changing had come from so humble a place seemed
a little short of a miracle.
William Clifford Roberts, MD
May 20, 2015
1.
2.
Eig J. The Birth of the Pill: How Four Crusaders Reinvented Sex and Launched
a Revolution. New York: W. W. Norton & Company, 2014 (388 pp.).
Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee
AJ. Mortality among contraceptive pill users: cohort evidence from
Royal College of General Practitioners’ Oral Contraception Study. BMJ
2010;340:c927.
Volume 28, Number 3
Volume 28
Number 3
July 2015
Scott & White Hospital -Brenham
McLane Children’s Scott & White Hospital - Temple
Baylor Medical Center at McKinney
Metroplex Health System - Killeen
Baylor All Saints Medical Center at Fort Worth
Baylor Scott & White Hospital - Hillcrest
Baylor Regional Medical Center at Grapevine
Pages 289–432
www.BaylorScottandWhite.com
The largest not-for-profit health care system in Texas,
and one of the largest in the United States, Baylor Scott
& White Health was born from the 2013 combination of
Baylor Health Care System and Scott & White Healthcare.
For more information on our 43 hospitals and more than
500 patient care sites, please visit www.BaylorHealth.com
and www.sw.org.
Original Research
291 West Nile virus and the 2012 outbreak: the Baylor University Medical
Center experience by A. Mora Jr. et al
296 Comparison of long-term follow up of laparoscopic versus open
colectomy for transverse colon cancer by S. Agarwal et al
300 Mortality by treatment in patients ≥80 years of age with
gastroesophageal cancer seen in a 20-year period at a single
medical center by T. Barnett et al
304 Trends in the neonatal mortality rate in the last decade with respect
to demographic factors and health care resources by V. Govande et al
307 Effect of adding tetracaine to bupivacaine on duration of
ambulatory shoulder surgery by L. T. Pearson et al
312 Comparison of documentation and evidence-based medicine
use for non–ST-segment elevation myocardial infarction among
cardiology, teaching, and nonteaching teams by A. Metting et al
317 Assessment of leadership training needs of internal medicine
residents at the Massachusetts General Hospital by T. N. Fraser et al
321 Abstracts from the First Annual Scholarly Day
Review Article
325 Uses, limitations, and complications of endobronchial ultrasound
by B. A Jalil et al
Case Studies
331 Recurrent hospitalization for self-injuries and suicide attempts:
case study of a super-utilizer by J. W. Roden-Foreman et al
334 Radiographic findings in the nail-patella syndrome by J. A. West and
T. H. Louis
337 Solitary supratentorial Listeria monocytogenes brain abscess in an
immunocompromised patient by J. A. West et al
340 Asplenia and fever by M. L. Huebner and K. A. Milota
342 Myroides odoratimimus bacteremia in a diabetic patient
by T. R. Endicott-Yazdani et al
344 Right-sided hydropneumothorax as a presenting symptom of
Boerhaave’s syndrome (spontaneous esophageal rupture)
by S. Rassameehiran et al
347 Pneumomediastinum in inflammatory bowel disease
by N. Mihatov and A. Z. Fenves
350 Pulmonary veno-occlusive disease as a cause of pulmonary
arterial hypertension by M. Porres-Aguilar et al
353 Pulmonary artery catheter–induced perforation treated with coil
embolization by D. S. Kumar et al
355 A hybrid repair of a superior mesenteric artery pseudoaneurysm
using open mesenteric bypass and endovascular exclusion
by T. A. Cumbie et al
358 Allergic acute coronary syndrome (Kounis syndrome)
by S. Memon et al
363 Blood cyst of the anterior mitral leaflet causing severe mitral
regurgitation by S. Madhavan et al
365 Right-sided superior vena cava draining into the left atrium in a
patient with persistent left-sided superior vena cava emptying into
the right atrium diagnosed by echocardiography by C. Clark and L.
MacDonald
367 Spontaneous coronary artery dissection in a 22-year-old man on
lisdexamfetamine by A. M. Afzal et al
369 Worsening dyspnea in a 38-year-old woman by D. L. Glancy et al
371 Chronic pulmonary embolism in a young athletic woman
by T. R. Larsen and T. C. Ball
375 Nonhepatic hyperammonemic encephalopathy due to undiagnosed
urea cycle disorder by T. Mahmood and K. Nugent
378 Anaplastic large-cell lymphoma in AIDS by M. Krol et al
381 Primary follicular lymphoma of the duodenum by R. Graham et al
384 Tubulocystic carcinoma of the kidney by V. Podduturi et al
386 Unusual presentation of metastatic ovarian carcinoma as an
enlarged intramammary lymph node by C. Mason et al
389 Leukoencephalopathic changes on magnetic resonance imaging
associated with a thermogenic dietary supplement (Thermatrim)
by C. I. Olivas-Chacon et al
Editorials and Interview
397 Precision medicine: hype or hoax? by R. G. Mennel
401 Update on the Baylor Scott & White Quality Alliance by C. E. Couch
404 Nobel laureates and their medical schools: who selected whom?
by A. B. Weisse
406 On camel rides and Moses Maimonides by J. D. Cantwell
409 David Bruce Hellmann, MD: a conversation with the editor
by D. B. Hellmann and W. C. Roberts
From the Editor
421 Facts and ideas from anywhere by W. C. Roberts
Miscellany
290
295
303
320
370
380
383
392
420
Clinical research studies enrolling patients
Avocations: Photograph by Dr. Solis
Avocations: Photograph by Dr. Rosenthal
Avocations: Poem by Dr. Khan
In memoriam
Baylor news
Reader comments: Low-voltage electrocardiogram in a patient
with takotsubo syndrome associated with hyperthyroidism
(J. E. Madias, with response by S. Omar)
www.BaylorHealth.edu/Proceedings
Indexed in PubMed, with full text available through PubMed Central

full PDF - Baylorhealth.edu

Transcription

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