Fall 2015 issue - Aurora Medical Professionals

Transcription

Volume 2 | Issue 4 | Fall 2015
Journal of
Patient-Centered
Research and Reviews
Showcasing medical advancements that
improve human health and well-being
Editorials
Integrative Medicine: In With the New
Original Research
In Vitro Growth Suppression of Renal Carcinoma Cells by
Curcumin
Reviews
Special Issue:
Integrative Medicine
Small Intestinal Bacterial Overgrowth: A Case-Based Review
Guest Editor:
Tiffany A. Mullen, DO
The Role of Traditional Chinese Medicine in the Management
of Chronic Pain: A Biopsychosocial Approach
Essentials of Herb-Drug Interactions in the Elderly With
Cardiovascular Disease
Topics
Should Primary Care Physicians Address Sleep to Improve
Weight Loss in Obese Patients? A Clin-IQ
Supplement
Proceedings of 2015 Aurora Scientific Day
ISSN 2330-068X (Print)
ISSN 2330-0698 (Online)
www.aurora.org/jpcrr
149
Journal of Patient-Centered Research and Reviews
Mission Statement
Editorial Board
To further the ongoing quest for new knowledge
by providing a medium for the communication
of clinical and laboratory research, patient
experiences and best practices in medical
education, with the purpose of improving the
quality of human health, the care of each
individual patient and the care of populations.
Dennis J. Baumgardner, MD (Editor-in-Chief)
Director of Research, Aurora UW Medical
Group; Associate Director, Center for Urban
Population Health; Clinical Adjunct Professor,
Department of Family Medicine, University of
Wisconsin School of Medicine and Public Health
© 2015 Journal of Patient-Centered
Research and Reviews is published by:
Aurora Health Care, Inc.
960 N. 12th Street, Suite 411
Milwaukee, WI 53233
Direct all correspondence
and subscription inquiries to:
Aurora Health Care
Milwaukee, WI 53233
Email: [email protected]
T: 414-219-7914
F: 414-219-3116
ISSN 2330-068X (Print)
ISSN 2330-0698 (Online)
Cover Art: A symbolic representation of
integrative medicine, which is defined by
guest editor Tiffany Mullen (p. 153) as the
combination of conventional biomedicine
with nontraditional and holistic practices
to help patients on their journey to health.
Arshad Jahangir, MD
Director, Sheikh Khalifa bin Hamad Al
Thani Center for Integrative Research on
Cardiovascular Aging; Co-Chair, Aurora
Cardiovascular Services Research Committee;
Clinical Adjunct Professor, Department of
Medicine, University of Wisconsin School of
Medicine and Public Health
Martin Oaks, PhD
Director, Histocompatibility and Transplant
Research, Aurora St. Luke’s Medical Center
Danish Siddiqui, MD
Residency Director and Chair, Department of
Obstetrics & Gynecology, Aurora UW Medical
Group; Clinical Adjunct Associate Professor,
Department of Obstetrics & Gynecology,
University of Wisconsin School of Medicine and
Public Health
Deborah Simpson, PhD
Director, Medical Education Program, Aurora
UW Medical Group; Clinical Adjunct Professor,
Department of Family Medicine, University of
Michael A. Thompson, MD, PhD
Director, Early Phase Cancer Research
Program, Aurora Research Institute;
Oncologist/Hematologist, Aurora Cancer Care
Joe Grundle
Managing Editor – Ex Officio
Julie Walters
Multimedia Designer – Ex Officio
150 JPCRR • Volume 2, Issue 4 • Fall 2015
Specialty Editors
All specialty editors have an affiliation with
Aurora Health Care unless otherwise noted.
Andy Anderson, MD, MBA
Academic and Internal Medicine
John Brill, MD, MPH
Family Medicine
R. Sean Churchill, MD
Orthopedics
Ron Cisler, PhD, MS
Center for Urban Population Health
Milwaukee, WI
Nicole A. Eull, PsyD
Psychology
Michael Farrell, MD
Internal Medicine and Pediatrics
Julian Hong, MD, MS
Radiation Oncology,
Duke University Medical Center, Durham, NC
Ariba Khan, MD, MPH
Geriatrics
Christopher Klink, PharmD, BCPS
Clinical Pharmacy
Jacob Lescher, BS
University of Wisconsin School of Medicine
and Public Health, Madison, WI
Mahek Mirza, MD
Internal Medicine Residency
Alyssa Mohorek, MD
Family Medicine
Vani Nilakantan, PhD
Aurora Research Institute
Alexandra Rezazadeh, BS
University of Wisconsin School of Medicine
and Public Health, Madison, WI
Mark Robinson, DO
Family Medicine
Steve Rommelfanger, MD, MS
Palliative Care
Ajay Sahajpal, MD
Transplant Surgery
Rebecca Schultz, MS, FNP-BC, HNB-BC
Family and Integrative Medicine
Kathleen Strube, MLS
Aurora Libraries
Lisa Sullivan Vedder, MD
Family Medicine
Jackie Tillett, CNM, ND, FACNM
Midwifery and Women’s Health
Judy A. Tjoe, MD
Surgical Breast Oncology
Leslie J. Waltke, DPT
Cancer Rehabilitation
Editorial Staff
Joe Grundle – Managing Editor
Julie Walters – Multimedia Designer
Katie Klein – Copy Editor
Karen Pankowski – Administrative Assistant
Rachel Delaney – Legal Consultant
Kathleen Strube – Library Consultant
Brenda Fay – Library Consultant
Becky Pogacar, MS, RN, NEA-BC
Nursing Operations
151
Table of Contents
Editorials
153Integrative Medicine: In With the New
Tiffany A. Mullen, DO
Original Research
156In Vitro Growth Suppression of Renal Carcinoma Cells by Curcumin
Santhi D. Konduri, PhD, Madhavi Latha Yadav Bangaru, PhD, Phu Thanh Do, PhD, Shenglin Chen, PhD,
Jeffrey Woodliff, PhD, Sanjay Kansra, PhD
Reviews
165Small Intestinal Bacterial Overgrowth: A Case-Based Review
Kristen H. Reynolds, MD
174Essentials of Herb-Drug Interactions in the Elderly With Cardiovascular Disease
Sulaiman Sultan, MD, Maria Viqar, MD, Rabaiya Ali, MD, A. Jamil Tajik, MD, Arshad Jahangir, MD
192 T
he Role of Traditional Chinese Medicine in the Management of Chronic Pain:
A Biopsychosocial Approach
John Burns, DPT, MSOM, Tiffany A. Mullen, DO
Topics
197Should Primary Care Physicians Address Sleep to Improve Weight Loss in Obese Patients?
A Clin-IQ
Kjersti E. Knox, MD
Supplement
202
Integrative Medicine: In With the New
Tiffany A. Mullen, DO │ Message from the Guest Editor
Department of Integrative Medicine, Aurora Health Care, Milwaukee, WI
In a television interview, jazz pianist Herbie Hancock
recounted a memorable experience with legendary
trumpeter Miles Davis. Early in their collaboration the
two musicians were playing together smoothly when
Herbie struck a chord that was unquestionably wrong.
Herbie was quite emphatic about this … the chord was
flat-out “wrong.”
Miles paused for an instant, then played notes around
the chord he had just heard and then continued to go
off in that direction.
Speaking about it after the show, Herbie quoted Miles
as saying that the chord he had heard was not “wrong,”
it was just “new.”
In the history of medicine, we have held a healthy
skepticism toward the “new.” However, many forwardthinking researchers and clinicians have advanced
medical care by challenging the status quo. Recall the
hard-won efforts of Dr. Barry Marshall, who proved
Helicobacter pylori as a causative infectious agent of
many gastric and duodenal ulcers by drinking his own
preparation of H. pylori-laden broth.1
While integrative medicine is not necessarily new
–– in fact, it utilizes many ancient forms of medical
practice –– the term may be new to the readers of
this journal. Thus, it is an honor to preside over this
special issue of Journal of Patient-Centered Research
and Reviews (JPCRR) dedicated to this specialty. As
guest editor, my hope is to help increase understanding
and awareness of integrative medicine by showcasing
thought-provoking research and state-of-the-art review
articles.
Correspondence: Tiffany A. Mullen, DO, Department of
Integrative Medicine, 1020 N. 12th Street, 4th Floor,
Milwaukee, WI, 53233, T: 414-219-5900, F: 414-219-5914,
Editorial
You might ask: “Why would
I want to learn more about
integrative
medicine?”
Practicing clinicians may
be interested to know that
in a recent internal study
undertaken by our health
care organization, the largest
in Wisconsin, 88% of our
own patients are using some
form of integrative medicine
[unpublished data by Martino et al. Integrative
medicine usage & attitudes study, Aurora Health Care
Consumer Insights and Innovation (December 2014)].
This is in keeping with national studies that showed
34% of people have used or regularly use integrative
medicine in their day-to-day care.2 We also know from
the literature that annual sales of supplements and
herbal medications have topped $36.7 billion.3
Integrative medicine is defined as the combination
of conventional biomedicine with nontraditional and
holistic practices to help patients on their journey to
health. Several key principles of integrative medicine4
are beautifully illustrated within the contents of this
issue:
• Effective interventions that are natural and less
invasive should be used whenever possible.
Knowing that natural isn’t always better and that
many supplements and herbal products produce welldocumented interactions not only with prescribed
pharmaceuticals but also other herbs and supplements,
Sultan et al. have presented a timely review of the
important caveats for the use of herbal supplements
in the geriatric population.5 I would comment that
integrative medicine is more than just herbals and
supplements. The goal in integrative medicine practice
is not to convert all medicines to supplements and
herbs — polypharmacy is still polypharmacy, even if
the medications are available without a prescription.
153
• All factors that influence health, wellness and
disease are taken into consideration, including
mind, spirit and community as well as the body.
Also published herein, Dr. John Burns and I review
the contemporary use of traditional Chinese medicine
as a biopsychosocial model for chronic pain
management,6 specifically highlighting the mindbody relationship aspects of traditional Chinese
medicine and how this approach differentiates it from
the traditional biomedical model.
• Whenever possible, the root cause of an illness
should be uncovered and treated.
Dr. Kristen Reynolds gives us a compelling example of
this approach in her review of small intestinal bacterial
overgrowth,7 which highlights the importance of
“digging a little deeper” so that we do not just treat
symptoms but fully address the possible underlying
causes of disease.
• Good medicine is based in good science. It is inquirydriven and open to new paradigms.
Konduri et al. report on the in vitro suppression of
clear cell renal carcinoma cells by curcumin, one of
the components of turmeric (the bright yellow/orange
root many of us associate with curry).8 Although many
more studies are needed, the thought of curcumin as a
form of “adjunct chemotherapy” highlights the use of
food as medicine, a new paradigm indeed.
• Alongside the concept of treatment, the broader
concepts of health promotion and the prevention of
illness are paramount.
It is estimated that more than 75% of chronic illness
is a result of lifestyle9 and contributes to billions in
health care spending nationally.10 Dr. Kjersti Knox, in
her Clin-IQ exploration of the relationship between
sleep and obesity, asks whether clinicians need to be
doing more to address this relationship in the primary
care setting.11
In addition to thanking the aforementioned authors
for their thought-provoking contributions to the
scientific literature, well-deserved recognition is due
Dr. Reynolds and Rebecca Schultz, NP, for their
invaluable expertise and assistance in shaping this issue.
Equally as important in understanding how to define
integrative medicine is recognizing what integrative
medicine is not. Integrative medicine is not alternative
medicine. The term “alternative medicine” implies
the substitution of conventional medicine with oftunproven treatment modalities. No respectable
integrative medicine practitioner, for example, would
advise a cancer patient against proceeding with a
standard-of-care chemotherapy or radiation therapy
protocol in favor of a “diet cure.” By contrast,
an integrative medicine provider might consider
the importance of disease-specific nutrition in the
management of a patient undergoing chemotherapy.
Integrative medicine is also not unproven or
unresearched. A MEDLINE search for “integrative
medicine” turns up 1,494 citations, and the Cochrane
database reviews 36 integrative medicine topics. (When
using the now-outdated search term “complementary
and alternative medicine,” these numbers expand
to 189,378 and 645 citations, respectively.) While
many integrative medicine topics are difficult to
fit into the randomized, double-blind, placebocontrolled paradigm, I would argue that many people
— multifaceted, multiethnic, spiritual, emotional,
physical beings — are difficult to fully understand in
the context of our current gold standard of research.
Newer, less reductionist, more personalized models
may be needed to best appreciate integrative medicine
research.
In honor of the great Miles Davis, listen for the “new
chords” contained within this special issue. May they
take you in new directions, both professionally and
personally.
References
1. Marshall BJ. The discovery that Helicobacter pylori, a
spiral bacterium, caused peptic ulcer disease. In: Marshall
BJ (ed). Helicobacter Pioneers: Firsthand Accounts From
the Scientists Who Discovered Helicobacters, 1892–1982.
Victoria, Australia: Blackwell Science Asia, 2002, pp. 165-202.
2. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL.
Trends in the use of complementary health approaches among
adults: United States, 2002-2012. Natl Health Stat Report.
2015;(79):1-16.
3. National Institutes of Health Office of Dietary Supplements.
Multivitamin/mineral supplements: fact sheet for health
Editorial
professionals.
https://ods.od.nih.gov/factsheets/MVMSHealthProfessional/#en3. Accessed September 25, 2015.
4.University of Arizona Center for Integrative Medicine.
The defining principles of integrative medicine. http://
integrativemedicine.arizona.edu/about/definition.html.
Accessed September 25, 2015.
5. Sultan S, Viqar M, Ali R, Tajik AJ, Jahangir A. Essentials
of herb-drug interactions in the elderly with cardiovascular
disease. J Patient-Centered Res Rev. 2015;2:174-91.
6. Burns J. Mullen TA. The role of traditional Chinese medicine
in the management of chronic pain: a biopsychosocial
approach. J Patient-Centered Res Rev. 2015;2:192-6.
7. Reynolds KH. Small intestinal bacterial overgrowth: a casebased review. J Patient-Centered Res Rev. 2015;2:165-73.
8. Konduri SD, Bangaru MLY, Do PT, Chen S, Woodliff J,
Kansra S. In vitro growth suppression of renal carcinoma cells
by curcumin. J Patient-Centered Res Rev. 2015;2:156-64.
9. Yoon PW, Bastian B, Anderson RN, Collins JL, Jaffe
HW; Centers for Disease Control and Prevention (CDC).
Potentially preventable deaths from the five leading causes of
death--United States, 2008-2010. MMWR Morb Mortal Wkly
Rep. 2014;63:369-74.
10.Centers for Disease Control and Prevention. The cost of
chronic diseases and health risk behaviors. http://www.cdc.
gov/chronicdisease/overview/. Accessed September 25, 2015.
11.Knox KE. Should primary care physicians address sleep to
improve weight loss in obese patients? A Clin-IQ. J PatientCentered Res Rev. 2015;2:197-200.
© 2015 Aurora Health Care, Inc.
Aurora Health Care Libraries ... making it
easy for you to find the answer.
Serving Aurora caregivers
and workgroups, patients
and community
• Over 1 million visits per year to the
Aurora Libraries website
• About 4,000 information requests
answered per year
• Over 18,000 articles provided per year
For your information inquiries, we
invite you to contact us at
[email protected]
[email protected]
X48451 (01/14) ©AHC
Editorial
155
In Vitro Growth Suppression of Renal Carcinoma Cells by
Curcumin
Santhi D. Konduri, PhD,1* Madhavi Latha Yadav Bangaru, PhD,2* Phu Thanh Do, PhD,3*
Shenglin Chen, PhD,2 Jeffrey Woodliff, PhD,3 Sanjay Kansra, PhD1,2,3,4
Aurora Research Institute, Aurora Health Care, Milwaukee, WI
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
3
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
4
Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI
1
2
PurposeMalignant clear cell renal carcinoma (ccRCC) is an aggressive tumor highly resistant to chemotherapy
and radiation. Current therapeutic approaches to management of ccRCC have not significantly improved
patient survival, therefore novel therapies are needed. Activated NFκB and STAT3 expression is
associated with ccRCC pathogenesis. The dietary polyphenol curcumin is a well-documented antitumor
agent and a known inhibitor of NFκB and STAT3 activation. Given the lack of effective therapies that
block ccRCC progression, our objective was to examine whether curcumin could suppress the growth
and migration of ccRCC cells, and whether this suppression was mediated via inhibition of NFκB and
STAT3 activity.
Methods
Human ccRCC cell lines (769-p, 786-o, Caki-1, ACHN and A-498 cells) were exposed to curcumin to
assess the impact of curcumin on ccRCC cell viability. Colony formation assay was used to assess the
effect of curcumin on ccRCC cell renewal capability. Effect of curcumin on apoptosis was determined
by annexin V binding and mitochondrial membrane depolarization assays. The anti-migratory effect of
curcumin on ccRCC cells was assessed using the wound healing assay. Effect of curcumin on NFκB
and STAT3 phosphorylation in 769-p cells was determined by western blot analysis.
ResultsIn ccRCC cells, curcumin decreased cell proliferation and cell viability, abolished clonogenic property,
induced apoptosis and blocked cellular migration. The growth suppressive and pro-apoptotic effects of
curcumin were accompanied by decreased phosphorylation of NFκB and STAT3.
Conclusions
The ability of curcumin to induce apoptosis and inhibit migration of ccRCC cells justifies additional
mechanistic and preclinical studies that examine the effect of curcumin or other NFκB and STAT3
inhibitors as potential suppressors of ccRCC tumorigenesis. (J Patient-Centered Res Rev. 2015;2:156-164.)
Keywords
curcumin, dietary polyphenol, apoptosis, renal carcinoma
The incidence of malignant clear cell renal carcinoma
(ccRCC) has risen in the last two decades, particularly
in African Americans, Hispanics and women. The
standard cytokine-based therapy with interferon-α
(IFN-α) or interleukin-2 has not been effective at
suppressing ccRCC growth (5-year survival less than
10%), and toxicity is common.1 Although the use
*Drs. Konduri, Bangaru and Do contributed equally to this
report.
Correspondence: Sanjay Kansra, PhD, Aurora Research
Institute, 960 N. 12th Street, Suite #4120, Milwaukee, WI,
53233, T: 414-219-5393, F: 414-219-5381,
of targeted therapies in the clinical management of
ccRCC has provided benefits in terms of prolonging
progression-free survival, eventually patients develop
resistance and disease recurs.2-4 Therefore, more
effective and less toxic therapeutic agents are needed.
At the molecular level, disruption of several signaling
pathways has been shown to contribute to the
development and progression of ccRCC. Mutations in
the tumor suppressor von Hippel-Lindau gene (VHL)
are common in ccRCC.5,6 The protein product of VHL,
pVHL, functions to suppress transcriptional activity
of hypoxia-inducible factor (HIF)-1α and HIF-2α.
HIFs regulate the expression of genes involved in
cell survival and angiogenesis (transforming growth
Original Research
factor α, platelet-derived growth factor and vascular
endothelial growth factor).7 Thus, the consequence of
an inactive pVHL is increased growth factor expression
and growth factor receptor-mediated signaling. The
increase in receptor-mediated signaling leads to the
activation of transcription factors, including NFκB and
STAT3, which have well-defined roles in promoting
tumor growth.
Increased NFκB activity stimulates the expression of
gene proteins (bcl-2, MMP-2 and MMP-9) critical to
tumor survival and invasion. Indeed, increased NFκB
activity has been correlated with ccRCC progression, and
upregulation of the prosurvival protein bcl-2 in human
ccRCC is a common occurrence.8,9 The highly metastatic
and invasive nature of ccRCC has been attributed to
increased expression of matrix metalloproteinases (e.g.
MMP-2 and MMP-9) that promote the disruption of
extracellular matrices. Expression of bcl-2, MMP-2 and
MMP-9 is regulated by NFκB.
Constitutively activated STAT3 is associated with
tumor progression, angiogenesis and development
of chemotherapy/radiotherapy resistance.10-12 These
effects of STAT3 are believed to be mediated through
upregulation of cyclins, vascular endothelial growth
factor and bcl-2.13 Increased STAT3 expression has
been detected in human ccRCC, and STAT3 was shown
to promote interleukin-6–mediated proliferation of
ccRCC cells.14,15
NFκB and STAT3 are activated by HIF-induced growth
factors and play critical roles in promoting ccRCC
tumorigenesis. To the best of our knowledge, successful
pharmacological targeting aimed at suppressing
HIF-mediated transcription in ccRCC has not been
achieved. For this study we investigated whether the
dietary polyphenol curcumin, a known suppressor of
NFκB and STAT3 transcriptional activity,16,17 would be
effective at suppressing ccRCC tumor cell growth.
MATERIALS AND METHODS
Chemicals and Reagents
Curcumin was purchased from LTK Laboratories
(St. Paul, MN) and Sigma-Aldrich (St. Louis, MO).
786-o, Caki-1, ACHN and A-498 cells were purchased
from American Type Culture Collection (ATCC)
(Manassas, VA). 769-p cells used in this study were either
Original Research
provided by Dr. A. Sorokin (Medical College of
Wisconsin, Milwaukee, WI) or purchased from
ATCC. Phospho-p65 NFκB (S536), total-p65 NFκB,
phospho-STAT3 (S727) and total-STAT3 antibodies were
purchased from Cell Signaling Technology (Danvers, MA).
Cell Culture and Assessment of Cell Viability
769-p, 786-o, Caki-1, ACHN and A-498 cells were
maintained in complete growth medium containing
10% fetal bovine serum (FBS). Medium was replaced
every 2–3 days and subculturing done as required. To
assess cell viability, equal number of cells were seeded
in a 96-well plate in complete growth medium. After
an overnight incubation at 37° C, cells were exposed to
vehicle or curcumin in medium containing 0.5% FBS.
In experiments that evaluated the dose-dependency
of curcumin on ccRCC cell viability or on DNA
synthesis, indicated cell lines were exposed to curcumin
(0–200 µM) for 72 hours. In experiments that examined
the time-course of curcumin-induced suppression
of ccRCC cell viability, 769-p cells were exposed
to curcumin (0, 5 or 50 µM) for 1, 2 or 3 days. After
treatment, cell viability was quantitated by using either
the colorimetric MTT assay or the Cell Titer-Glo®
Luminescent Cell Viability Assay (Promega, Madison,
WI) as previously described.18,19 DNA synthesis was
measured by determining bromodeoxyuridine (BrdU)
incorporation into DNA as previously described.20
Colony Formation Assays
Colony formation ability of 769-p cells was determined
as previously described.18 To briefly summarize, 769-p
cells growing in log phase were seeded at a density of
3,000 cells/well in a 6-well plate in complete growth
medium. Cells were allowed to adhere for an overnight
period, following which the medium was replaced with
complete medium containing curcumin (0, 5, 20, 50,
100 or 200 µM). Cells were cultured for approximately
2 weeks, with a medium change (containing fresh
vehicle or curcumin) performed every 4–5 days. Crystal
violet was used to stain and visualize the colonies.
Annexin V Staining Assays
769-p cells were treated with curcumin (0, 5 or 50 µM)
for 24 hours. After treatment, cells were washed with
phosphate-buffered saline and stained with annexin
V-FITC and propidium iodide. Subsequent flow
cytometry was performed as previously described.18
157
Western Blotting
769-p cells were treated with curcumin (0, 5, 20 or
50 µM) for 30 minutes. After treatments, protein content
was determined in the cellular lysates and an equal
amount of protein subjected to electrophoresis, followed
by western blotting with the indicated antibodies as
previously described.18 The pixel intensities of the
western blot bands (p-p65 NFκB, t-p65 NFκB, p-STAT3
and t-STAT3) were quantitated using the intensity plot
and area calculation functions of the ImageJ program
available from the National Institutes of Health (http://
rsbweb.nih.gov/ij/). After normalization to the band
intensities of total proteins (t-p65 NFκB and t-STAT3),
p-p65 NFκB and p-STAT3 protein expressions were
calculated. The control (vehicle-treated sample) was
assigned an arbitrary value of 1, and fold change in the
curcumin-treated groups was calculated.
Mitochondrial Membrane Depolarization Assays
769-p cells were treated with curcumin (0, 5 or 50 µM)
for 24 hours. Cells were washed, stained with JC-1 dye,
and then analyzed by flow cytometry, according to the
manufacturer’s protocol (Cell Technology, Fremont,
CA) as previously described.18
Wound Healing Assay
Wound healing assay for migration was performed as
previously described.21 Briefly, 769-p cells were grown
to monolayer confluency in 6-well plates. A sterile p200
pipette tip was used to inflict a scratch wound. Cellular
debris was removed by washing, and subsequently phase
contrast microscopy was used to capture an image of the
wound. Impact of 24-hour curcumin treatment (0, 5 or
50 µM) on wound closure in 769-p cells was assessed.
RESULTS
Curcumin Inhibits ccRCC Cell Proliferation
and Viability
We initially investigated whether curcumin was effective
in suppressing the growth of ccRCC cell lines. To address
this, we evaluated the concentration-dependent effect of
curcumin on cell viability in a panel of human ccRCC
cell lines. 769-p, 786-o, Caki-1, ACHN and A-498 cells
were treated with curcumin and cell viability assessed.
Our data demonstrated that in all five human ccRCC
cell lines, curcumin was able to significantly (P<0.05)
suppress cell viability (Figure 1), with maximal (>90%)
growth suppression in the concentration range of
50–200 µM. In 769-p cells significant (P<0.05) growth
suppression was also detected at a lower concentration
(20 µM). Although of a small magnitude (~13%), we
did detect a significant (P<0.05) growth stimulation
in A-498 cells in response to a lower concentration
(10 µM) of curcumin.
It has been reported that genetic or epigenetic variations
in VHL can be detected in approximately 90% of human
RCC cases.22 Given that 769-p cells do not express VHL
mRNA, we used this VHL-deficient system for our
subsequent studies that examined the mechanism by
which curcumin suppressed ccRCC cell growth.23
Figure 1. Curcumin inhibits
ccRCC cell proliferation and
viability. 769-p cells (A), Caki-1
cells (B), 786-o cells (C), ACHN
cells (D) and A-498 cells (E)
were treated with the indicated
concentrations of curcumin.
After 3 days cell viability was
detected using the Cell Titer-Glo
Luminescent Cell Viability Assay.
Data were calculated as percentage
of vehicle control, and are the
mean (± standard error of the
mean, SEM) of three independent
experiments. Asterisks (*) designate
a significant difference (P<0.05) from
control values.
Original Research
We next examined the kinetics of curcumin-induced
inhibition of 769-p cell proliferation. Our data showed
that compared to vehicle treatment, 5 µM curcumin had
no significant effect on 769-p cell proliferation at either
the early time points or later time points (Figure 2A).
On the other hand 50 µM curcumin had a significant
inhibitory effect on cell proliferation as early as 1 day,
and this inhibitory effect persisted up to 3 days.
Figure 2. Curcumin inhibits ccRCC cell proliferation
in a time-dependent manner. A: 769-p cells were
treated with vehicle control, or 5 or 50 μM curcumin for
the indicated times, and cell viability was assessed. Data
are presented as optical density and are the mean
(± SEM) of at least three independent determinations.
Data are representative of two separate experiments
yielding similar results. Asterisks (*) designate a
significant difference (P<0.05) from day 1 control.
B: 769-p cells were treated with indicated concentrations
of curcumin. After 3 days, proliferation was assessed
by the BrdU incorporation assay. Data are presented
as optical density and are the mean (± SEM) of at
least three independent determinations. Data are
representative of two separate experiments yielding
similar results. Asterisks (*) designate a significant
difference (P<0.05) from control values. C: 769-p cells
were treated with indicated concentrations of ferulic
acid or vanillin, and after 2 days cell proliferation was
assessed by the MTT assay. Data are presented as
percentage of control and are the mean (± SEM) of three
independent experiments. The asterisk (*) designates a
significant difference (P<0.05) from control value.
Original Research
To confirm that the growth inhibition detected in the cell
viability assays was due to decreased DNA synthesis, we
examined the effect of curcumin on BrdU incorporation
in 769-p cells. A significant (P<0.05) inhibition of cell
proliferation was detected with 20 µM curcumin, and
maximal suppression of cell proliferation was detected
with 100–200 µM curcumin (Figure 2B).
Curcumin undergoes degradation in serum-depleted
cell culture media, resulting in the formation of
trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5hexenal, ferulic acid, feruloyl methane and vanillin.24
Both ferulic acid and vanillin have been reported to
mediate the antioxidant activity of curcumin.25-28
To address the question of whether the growth
suppressive effects of curcumin were mediated by the
degradation products of curcumin, 769-p cells were
treated with the indicated concentration of ferulic acid
and vanillin, and cell proliferation determined after
2 days. Our data showed that 50 µM ferulic acid had no
significant growth suppression of 769-p cells (Figure
2C). Although 50 µM vanillin did suppress 769-p cell
proliferation (<10%), it was approximately ninefold
less effective than curcumin (50 µM) at suppressing
growth of 769-p cells.
Curcumin Blocks Colony Formation Ability,
Induces Apoptosis and Blocks Migration of
ccRCC Cells
Next, we questioned whether curcumin had any effect
on the colony formation ability of 769-p cells. 769-p
cells were seeded in medium containing 10% FBS
and allowed to adhere for 24 hours. The medium was
then replaced with fresh medium containing 10% FBS
together with the indicated concentration of curcumin,
and colony formation was monitored over the ensuing
2 weeks. We observed that 769-p cells have a robust
ability to form colonies and that this is abolished by
curcumin in a concentration-dependent manner, with a
substantial decrease in the number of 769-p cell colonies
detected in presence of 5 µM curcumin (Figure 3A). At
higher concentrations of curcumin (20–200 µM) the
ability of 769-p cells to form colonies was completely
ablated. Therefore, we questioned whether curcumin
would induce apoptosis in ccRCC cells. To test this, 769-p
cells were treated with the indicated concentrations of
curcumin for 24 hours, washed, and incubated with JC-1
dye (a mitochondria-specific dual fluorescence probe)
per manufacturer instructions (Cell Technologies).
159
Figure 3. Curcumin blocks colony formation ability, induces apoptosis and blocks migration of ccRCC cells.
A: 769-p cells were cultured in medium containing (0–200 μM) curcumin, and colony formation was assessed after
approximately 2 weeks by crystal violet staining. Data shown are from a single experiment that was representative of
three similar experiments yielding similar results. B: 769-p cells were treated with indicated concentration of curcumin
for 24 hours, and cells were washed and labeled with JC-1 dye. Decreased red and increased green fluorescence
intensities were measured by flow cytometry. Quantitative changes in percentage of gated cells are presented as the
mean (± SEM) of three independent determinations. Data are from a single experiment that was representative of two
independent experiments. Asterisks (*) designate a significant difference (P<0.05) from control values. C: 769-p
cells were treated with indicated concentrations of curcumin for 24 hours, subjected to annexin V-FITC and propidium
iodide staining, and analyzed by flow cytometry. Live/dead cell ratios were calculated. Data are presented as
percentage of gated cells and are the mean (± SEM) of three independent determinations. Data are from a single
experiment that is representative of two independent experiments. Asterisks (*) designate a significant difference
(P<0.05) from control values. D: After forming a monolayer, 769-p cells were serum starved from 24–48 hours,
following which a scratch wound was inflicted by using a sterile p200 pipette tip. Cells were then incubated in medium
containing fetal bovine serum (FBS), either in the presence of vehicle (control) or curcumin 5 and 50 μM, for 24 hours.
Bright field microscopy was used to examine the effect of curcumin on FBS-induced cell migration. Data shown are
from a single experiment and representative of three independent experiments.
In vehicle- and 5 µM curcumin-treated cells, 93.31%
and 92.01% of the cells were detected with intact
mitochondrial membranes, respectively. However, in
50 µM curcumin-treated cells, only 29.86% of cells
presented intact mitochondrial membranes while
69.64% of the cell population presented with disruptions
in the mitochondrial membrane (Figure 3B), indicating
increased mitochondrial membrane depolarization.
cells. To test this, 769-p cells were grown to monolayer
confluence and a scratch wound was inflicted. Cells were
incubated overnight in FBS-containing medium together
with either vehicle or curcumin. Our data showed that in
both vehicle- and 5 µM curcumin-treated cells, wound
closure was complete (Figure 3D). However, 50 µM
curcumin significantly inhibited the migration of 769-p
cells, as evidenced by lack of wound closure.
To examine whether the increase in mitochondrial
membrane depolarization would lead to increased
cell death, 769-p cells were treated with the indicated
concentrations of curcumin for 24 hours, and following
trypsinization, annexin V-FITC binding and propidium
iodide staining were analyzed by flow cytometry. Our
results showed that in vehicle- and 5 µM curcumintreated cells, 1.74% and 2.29% of cells, respectively,
underwent apoptosis (Figure 3C). However, treatment
with 50 µM curcumin resulted in 75.49% of cells
undergoing cell death.
Curcumin Decreases Phosphorylation of
NFĸB and STAT3 in ccRCC Cells
Given the important role of NFκB and STAT3 in
ccRCC pathogenesis, and since curcumin has been
shown to suppress NFκB and STAT3 transcriptional
activity, we questioned whether the ability of curcumin
to induce apoptosis in ccRCC cells is accompanied
with decreased NFκB and STAT3 activation. Because
transcriptional activity of NFκB and STAT3 is positively
regulated by phosphorylation, the impact of curcumin
on the phosphorylation status of p65 NFκB and STAT3
was examined by western blotting with antibodies that
specifically detect either the phosphorylated or total
form of p65 NFκB and STAT3. Our data demonstrated
Since ccRCC tumors are highly metastatic, we questioned
whether curcumin would block migration of ccRCC
Original Research
that curcumin significantly (P<0.05) decreased
phosphorylation of p65 NFκB (S536) by 27.18% and
48.71% at concentrations of 20 and 50 µM, respectively
(Figure 4A, 4B). In addition, 20 and 50 µM curcumin
significantly (P<0.05) decreased STAT3 (S727)
phosphorylation in 769-p cells by 31.14% and 48.76%,
respectively (Figure 4C, 4D). The observed decrease
in the phosphorylated forms of p65 NFκB and STAT3
were not due to an effect of curcumin on the expression
levels of p65 NFκB and STAT3 (Figure 4A, 4C).
DISCUSSION
Both in the United States and worldwide, the incidence
of ccRCC and ccRCC-related mortality has increased
over the past decade. The National Cancer Institute
reports that approximately 54,000 new cases of renal
cancer are diagnosed and approximately 13,000 deaths
by renal cancer occur annually. Although ccRCC is
highly resistant to chemotherapy/radiotherapy, a better
understanding of the biology of ccRCC has led to the
identification of several signaling pathways currently
being examined as potential targets. It is now wellestablished that constitutively active STAT3 and NFκB
participate in ccRCC pathogenesis.9,14 Thus, suppression
of STAT3 and NFκB provides a novel therapeutic
approach to suppressing ccRCC cell proliferation. Given
the lack of effective therapies for ccRCC, and the welldocumented ability of the dietary polyphenol curcumin
to suppress STAT3- and NFκB-mediated signaling, we
examined whether ccRCC tumor suppression could be
achieved with curcumin. It is also of interest to note that
the age-adjusted incidence of kidney cancer in the United
States is the highest in the world and approximately
six times greater than rates in Asian countries where
curcumin is regularly consumed through diet. Our in
vitro study reveals that curcumin is effective at inducing
apoptosis and suppressing migration of ccRCC cells.
In vitro characterization of the growth suppressive effects
of curcumin in ccRCC cells revealed that curcumin, in a
concentration- and time-dependent manner, suppressed
769-p cell viability and colony formation ability, induced
apoptosis and blocked migration. We confirmed that the
growth suppressive effect of curcumin was not cell typespecific, as in addition to the 769-p cells, curcumininduced growth suppression was detected in a panel
of human ccRCC cell lines, including Caki-1, 786-o,
ACHN and A-498 cells. We also examined the ability
of curcumin to suppress the growth of RENCA (mouse
renal carcinoma cells) and observed a similar growth
suppressive pattern (data not shown). Of particular
significance is the ability of curcumin to suppress the
growth of IFN-α–resistant 786-o cells.29 Our future
studies will examine whether curcumin sensitizes
IFN-α–resistant ccRCC cells to IFN-α–induced growth
suppression.
We next questioned whether curcumin would decrease
viability of normal renal proximal epithelial tubule cells.
We observed that curcumin failed to induce apoptosis
in cultured normal rat renal tubular epithelial cells (data
not shown). Our observations are consistent with both
in vitro and in vivo studies demonstrating a protective
effect of curcumin on renal tubular epithelial cells.30,31
Taken together, our data clearly showed that curcumin
could be an effective growth suppressor of ccRCC cells.
Figure 4. Curcumin decreases phosphorylation
and transcriptional activity of NFκB and STAT3
in ccRCC cells. 769-p cells were treated with the
indicated concentrations of curcumin for 30 minutes,
and cell lysates were subjected to western blotting
with anti-phospho p65 NFκB antibody (A, top) and
anti-total p65 NFκB antibody (A, bottom), or antiphospho STAT3 antibody (C, top) and anti-total STAT3
antibody (C, bottom). Data presented are from a
single experiment and representative of three
independent experiments. Western blots from all
three experiments were quantified as described in
the text. Fold change in expression of p-p65 NFκB
(B) and p-STAT3 (D) from control (0 μM curcumin)
was determined. Data are the mean (± SEM) of three
independent experiments. Asterisks (*) designate a
significant difference (P<0.05) from control values.
Original Research
161
In most cases metastasis has already occurred when
ccRCC is diagnosed. Therefore, the ability of curcumin
to block cell migration of ccRCC cells was examined.
Our wound healing assay data showed that curcumin
was effective at blocking serum-induced wound closure.
Since degraded curcumin is known to yield dietary
ferulates, especially in buffered medium and serumfree medium, we questioned whether the growth
suppressive effects of curcumin we observed were due
to the generation of ferulic acid and vanillin. However,
because 50 µM ferulic acid had no significant growth
suppressive effect on 769-p cell viability and vanillin’s
modest growth suppressive effect on 769-p cell viability
was approximately nine times less than curcumin at an
equimolar concentration, we concluded that the growth
suppressive effect of curcumin on ccRCC cell viability
is not mediated by its degradation products, suggesting
a direct effect of free curcumin. Our conclusion would
be consistent with a response to a query raised from
a recent article that described the antitumor effects of
curcumin in pancreatic cancer patients.32 In their rebuttal
the authors demonstrated that the suppressive effect of
curcumin on tumor necrosis factor-α–activated NFκB
in human myeloid cells is not mediated by dietary
ferulates, as both ferulic acid and vanillin failed to block
NFκB activation by this protein.
Phosphorylation of the p65 subunit of NFκB regulates
the DNA binding and transcriptional activity of
NFκB.33 Likewise, in melanocytic cells, constitutively
phosphorylated STAT3 has been shown to accumulate
in the nucleus and promote cell survival.34 In examining
the impact of curcumin on NFκB- and STAT3-mediated
transcription in ccRCC cells, we found there is a
robust expression of constitutively phosphorylated p65
NFκB and STAT3 in 769-p cells. Further, when 769-p
cells are exposed to curcumin, a rapid decrease in the
phosphorylation of transcription factors p65 NFκB
and STAT3 was observed. Although our data clearly
showed that curcumin decreases STAT3 and NFκB
phosphorylation, the mechanism of this suppression in
ccRCC cells remains to be determined. One of the key
kinases that phosphorylate p65 NFκB is IKKα, which
phosphorylates p65 NFκB on serine 536.35 In multiple
myeloma cells, curcumin inhibited constitutively
activated IKK.36 It is possible the observed decrease
in p65 NFκB phosphorylation in ccRCC cells could
be due to curcumin-induced suppression of IKKα
activity. Likewise, the inhibitory effect of curcumin
on STAT3 phosphorylation could involve suppressing
receptor-associated Janus kinase(s) or the nonreceptor
tyrosine kinase Src. Interestingly, Yonezawa et al.
demonstrated the suppression of RCC cell growth by
Src kinase inhibitor PP1 and that this was accompanied
with decreased STAT3 activation.37 Our future studies
will examine the role of IKKα and Src in mediating the
growth suppressive effects of curcumin in ccRCC cells.
Recent studies suggested the potential of targeting
NFκB and STAT3 signaling axes in ccRCC as
novel therapeutic approaches.38,39 To this end, the
proteasome inhibitor bortezomib induced apoptosis in
ccRCC cells in a NFκB-dependent manner; however,
just the suppression of NFκB was not sufficient to
induce apoptosis in ccRCC cells, demonstrating the
requirement of engaging additional signaling targets
in inducing apoptosis in ccRCC cells.40 It is reasonable
to conclude that the ability of curcumin to target two
essential signaling arms in ccRCC, STAT3 and NFκB,
might be the underlying basis of its pro-apoptotic effect.
Although curcumin is an effective and selective
(i.e. targets tumor cells but not normal cells41,42)
antitumor agent, its use in a clinical setting has been
limited, primarily due to its well-documented poor
pharmacokinetic profile. To overcome this limitation,
novel approaches to enhancing the bioavailability of
curcumin are now the focus of several studies. These
include coadministration of curcumin and piperine (an
inhibitor of glucuronidation), which resulted in a 2,000%
increase in bioavailability of curcumin.43 Another
approach has led to the generation of nanoparticles
of curcumin. Nanoparticle curcumin was effective at
suppressing the growth of MCF-7 breast cancer cells,44
and at inhibiting NFκB activity and inducing apoptosis in
human pancreatic tumor cell lines.45 Liposomal curcumin
also was shown to be an effective anticancer agent in
a pancreatic cancer xenograft model.46,47 Additionally,
complexing curcumin with micelles or phospholipids
has proved to improve its bioavailability.48,49 Finally,
synthetic curcumin analogs (e.g. EF-24, HO-3867)
were reported to have increased bioavailability when
compared to curcumin and are more effective than
curcumin at suppressing tumor growth.50,51 Interestingly,
following an intraperitoneal administration of HO-3867
in rats, the synthetic curcumin analog was detected in
the blood, liver, stomach and kidney.51
Original Research
Given the excellent safety profile of curcumin, and the
recent efforts aimed at enhancing its bioavailability, we
anticipate that clinical trials examining the efficacy of
curcumin or its synthetic analogs in suppressing ccRCC
tumorigenesis will be conducted.
CONCLUSIONS
We report a robust growth suppressive and proapoptotic in vitro effect of curcumin on ccRCC cells.
Although in vitro findings do not necessarily translate
into clinical care, if the growth suppressive effects of
curcumin on ccRCC are validated in clinical trials,
this therapeutic approach could complement existing
therapies.
Patient-Friendly Recap
• Curcumin, a commonly used food additive in
Southeast Asia, is known to inhibit the growth
of several types of cancer cells in experimental
settings.
• The authors studied whether curcumin could
block growth and migration of malignant kidney
cancer cells.
• The authors found that curcumin decreased the
viability of kidney cancer cells as well as their
ability to migrate.
• Given its few side effects, curcumin (or its
synthetic analogs) could be considered for
clinical trials aimed at deveoping novel therapies
for kidney cancer.
Conflicts of Interest
None.
References
1. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma.
N Engl J Med. 1996;335:865-75. CrossRef
2. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of
sunitinib for metastatic renal-cell carcinoma: an expandedaccess trial. Lancet Oncol. 2009;10:757-63. CrossRef
3. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced
clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:
125-34. CrossRef
4. Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task
Force report: optimizing treatment of advanced renal cell
carcinoma with molecular targeted therapy. J Natl Compr
Canc Netw. 2011;9 Suppl 1:S1-29.
5. Kim WY, Kaelin WG. Role of VHL gene mutation in human
cancer. J Clin Oncol. 2004;22:4991-5004. CrossRef
Original Research
6. Ashida S, Furihata M, Tanimura M, et al. Molecular detection
of von Hippel-Lindau gene mutations in urine and lymph
node samples in patients with renal cell carcinoma: potential
biomarkers for early diagnosis and postoperative metastatic
status. J Urol. 2003;169:2089-93. CrossRef
7. Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible
factor-1 modulates gene expression in solid tumors and
influences both angiogenesis and tumor growth. Proc Natl
Acad Sci U S A. 1997;94:8104-9. CrossRef
8. Tomita Y, Bilim V, Kawasaki T, et al. Frequent expression of
Bcl-2 in renal-cell carcinomas carrying wild-type p53. Int J
Cancer. 1996;66:322-5.
9. Oya M, Takayanagi A, Horiguchi A, et al. Increased nuclear
factor-kappa B activation is related to the tumor development
of renal cell carcinoma. Carcinogenesis. 2003;24:377-84.
CrossRef
10. Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al. Signal
transducer and activator of transcription-3, inflammation, and
cancer: how intimate is the relationship? Ann N Y Acad Sci.
2009;1171:59-76. CrossRef
11. Al Zaid Siddiqui K, Turkson J. STAT3 as a target for inducing
apoptosis in solid and hematological tumors. Cell Res.
2008;18:254-67. CrossRef
12.Huang S. Regulation of metastases by signal transducer
and activator of transcription 3 signaling pathway: clinical
implications. Clin Cancer Res. 2007;13:1362-6. CrossRef
13.Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity
up-regulates VEGF expression and tumor angiogenesis.
Oncogene. 2002;21:2000-8. CrossRef
14.Horiguchi A, Oya M, Shimada T, Uchida A, Marumo K,
Murai M. Activation of signal transducer and activator of
transcription 3 in renal cell carcinoma: a study of incidence
and its association with pathological features and clinical
outcome. J Urol. 2002;168:762-5. CrossRef
15.Guo C, Yang G, Khun K, et al. Activation of Stat3 in renal
tumors. Am J Transl Res. 2009;1:283-90.
16.Singh S, Aggarwal BB. Activation of transcription factor
NF-kappa B is suppressed by curcumin (diferuloylmethane)
[corrected]. J Biol Chem. 1995;270:24995-5000. CrossRef
17.
Bharti AC, Donato N, Aggarwal BB. Curcumin
(diferuloylmethane) inhibits constitutive and IL-6-inducible
STAT3 phosphorylation in human multiple myeloma cells.
J Immunol. 2003;171:3863-71. CrossRef
18.Bangaru ML, Chen S, Woodliff J, Kansra S. Curcumin
(diferuloylmethane) induces apoptosis and blocks migration
of human medulloblastoma cells. Anticancer Res. 2010;30:
499-504.
19. Bobustuc GC, Smith JS, Maddipatla S, et al. MGMT inhibition
restores ERalpha functional sensitivity to antiestrogen therapy.
Mol Med. 2012;18:913-29. CrossRef
20.Kansra S, Yamagata S, Sneade L, Foster L, Ben Jonathan
N. Differential effects of estrogen receptor antagonists on
pituitary lactotroph proliferation and prolactin release. Mol
Cell Endocrinol. 2005;239:27-36. CrossRef
21.Kansra S, Stoll SW, Johnson JL, Elder JT. Src family kinase
inhibitors block amphiregulin-mediated autocrine ErbB
signaling in normal human keratinocytes. Mol Pharmacol.
2005;67:1145-57. CrossRef
22.Nickerson ML, Jaeger E, Shi Y, et al. Improved identification
of von Hippel-Lindau gene alterations in clear cell renal
tumors. Clin Cancer Res. 2008;14:4726-34. CrossRef
23.Shinojima T, Oya M, Takayanagi A, Mizuno R, Shimizu N,
163
Murai M. Renal cancer cells lacking hypoxia inducible factor
(HIF)-1alpha expression maintain vascular endothelial growth
factor expression through HIF-2alpha. Carcinogenesis.
2007;28:529-36. CrossRef
24.Wang YJ, Pan MH, Cheng AL, et al. Stability of curcumin
in buffer solutions and characterization of its degradation
products. J Pharm Biomed Anal. 1997;15:1867-76. CrossRef
25.Srinivasan M, Sudheer AR, Menon VP. Ferulic acid:
therapeutic potential through its antioxidant property. J Clin
Biochem Nutr. 2007;40:92-100. CrossRef
26.Sudheer AR, Muthukumaran S, Kalpana C, Srinivasan M,
Menon VP. Protective effect of ferulic acid on nicotine-induced
DNA damage and cellular changes in cultured rat peripheral
blood lymphocytes: a comparison with N-acetylcysteine.
Toxicol In Vitro. 2007;21:576-85. CrossRef
27.Makni M, Chtourou Y, Fetoui H, Garoui EM, Boudawara T,
Zeghal N. Evaluation of the antioxidant, anti-inflammatory and
hepatoprotective properties of vanillin in carbon tetrachloridetreated rats. Eur J Pharmacol. 2011;668:133-9. CrossRef
28.Kanski J, Aksenova M, Stoyanova A, Butterfield DA. Ferulic
acid antioxidant protection against hydroxyl and peroxyl
radical oxidation in synaptosomal and neuronal cell culture
systems in vitro: structure-activity studies. J Nutr Biochem.
2002;13:273-81. CrossRef
29.Tomita S, Ishibashi K, Hashimoto K, et al. Suppression of
SOCS3 increases susceptibility of renal cell carcinoma to
interferon-alpha. Cancer Sci. 2011;102:57-63. CrossRef
30.Tong QS, Zheng LD, Lu P, et al. Apoptosis-inducing effects
of curcumin derivatives in human bladder cancer cells.
Anticancer Drugs. 2006;17:279-87. CrossRef
31.Chiu J, Khan ZA, Farhangkhoee H, Chakrabarti S. Curcumin
prevents diabetes-associated abnormalities in the kidneys
by inhibiting p300 and nuclear factor-kappaB. Nutrition.
2009;25:964-72. CrossRef
32.Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial
of curcumin in patients with advanced pancreatic cancer. Clin
Cancer Res. 2008;14:4491-9. CrossRef
33. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination:
the control of NF-[kappa]B activity. Annu Rev Immunol.
2000;18:621-63. CrossRef
34.Sakaguchi M, Oka M, Iwasaki T, Fukami Y, Nishigori C.
Role and regulation of STAT3 phosphorylation at Ser727
in melanocytes and melanoma cells. J Invest Dermatol.
2012;132:1877-85. CrossRef
35. Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W. IkappaB
kinases phosphorylate NF-kappaB p65 subunit on serine
536 in the transactivation domain. J Biol Chem. 1999;274:
30353-6. CrossRef
36.Bharti AC, Donato N, Singh S, Aggarwal BB. Curcumin
(diferuloylmethane) down-regulates the constitutive activation
of nuclear factor-kappa B and IkappaBalpha kinase in human
multiple myeloma cells, leading to suppression of proliferation
and induction of apoptosis. Blood. 2003;101:1053-62.
CrossRef
37.Yonezawa Y, Nagashima Y, Sato H, et al. Contribution of
the Src family of kinases to the appearance of malignant
phenotypes in renal cancer cells. Mol Carcinog. 2005;43:
188-97. CrossRef
38.Sourbier C, Danilin S, Lindner V, et al. Targeting the nuclear
factor-kappaB rescue pathway has promising future in human
renal cell carcinoma therapy. Cancer Res. 2007;67:11668-76.
CrossRef
39.Horiguchi A, Asano T, Kuroda K, et al. STAT3 inhibitor
WP1066 as a novel therapeutic agent for renal cell carcinoma.
Br J Cancer. 2010;102:1592-9. CrossRef
40.An J, Sun Y, Fisher M, Rettig MB. Maximal apoptosis of
renal cell carcinoma by the proteasome inhibitor bortezomib
is nuclear factor-kappaB dependent. Mol Cancer Ther.
2004;3:727-36.
41.Ohori H, Yamakoshi H, Tomizawa M, et al. Synthesis and
biological analysis of new curcumin analogues bearing an
enhanced potential for the medicinal treatment of cancer. Mol
Cancer Ther. 2006;5:2563-71. CrossRef
42. Syng-Ai C, Kumari AL, Khar A. Effect of curcumin on normal
and tumor cells: role of glutathione and bcl-2. Mol Cancer
Ther. 2004;3:1101-8.
43.Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas
PS. Influence of piperine on the pharmacokinetics of curcumin
in animals and human volunteers. Planta Med. 1998;64:353-6.
CrossRef
44.Kumar SS, Mahesh A, Mahadevan S, Mandal AB. Synthesis
and characterization of curcumin loaded polymer/lipid based
nanoparticles and evaluation of their antitumor effects on
MCF-7 cells. Biochim Biophys Acta. 2014;1840:1913-22.
CrossRef
45.Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticleencapsulated curcumin (“nanocurcumin”): a novel strategy
for human cancer therapy. J Nanobiotechnology. 2007;5:3.
CrossRef
46.Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated
curcumin: in vitro and in vivo effects on proliferation, apoptosis,
signaling, and angiogenesis. Cancer. 2005;104:1322-31.
CrossRef
47.Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin
with and without oxaliplatin: effects on cell growth, apoptosis,
and angiogenesis in colorectal cancer. Mol Cancer Ther.
2007;6:1276-82. CrossRef
48.Ma Z, Shayeganpour A, Brocks DR, Lavasanifar A, Samuel
J. High-performance liquid chromatography analysis of
curcumin in rat plasma: application to pharmacokinetics
of polymeric micellar formulation of curcumin. Biomed
Chromatogr. 2007;21:546-52. CrossRef
49.Liu A, Lou H, Zhao L, Fan P. Validated LC/MS/MS assay
for curcumin and tetrahydrocurcumin in rat plasma and
application to pharmacokinetic study of phospholipid complex
of curcumin. J Pharm Biomed Anal. 2006;40:720-7. CrossRef
50.Adams BK, Cai J, Armstrong J, et al. EF24, a novel synthetic
curcumin analog, induces apoptosis in cancer cells via a redoxdependent mechanism. Anticancer Drugs. 2005;16:263-75.
CrossRef
51.Dayton A, Selvendiran K, Kuppusamy ML, et al. Cellular
uptake, retention and bioabsorption of HO-3867, a fluorinated
curcumin analog with potential antitumor properties. Cancer
Biol Ther. 2010;10:1027-32. CrossRef
Original Research
Small Intestinal Bacterial Overgrowth: A Case-Based Review
Kristen H. Reynolds, MD
Aurora Wiselives Center and Aurora UW Medical Group, Aurora Health Care, Milwaukee, WI
AbstractSmall intestinal bacterial overgrowth (SIBO) is a condition of increased microbial load in the small
intestine. The microbes feed on dietary carbohydrates and starches via fermentation, leading to gas
production, inflammation and damage to the lining of the small intestine. Clinical presentation is varied,
including abdominal pain, bloating, malabsorption and systemic symptoms. SIBO is associated with
many challenging and chronic conditions such as fibromyalgia, chronic fatigue and chronic pain
syndromes, and has been shown to be a causative factor in two out of three cases of irritable bowel
syndrome. Symptoms improve with antimicrobial treatment, but recurrence is common. Many providers
may not be aware of SIBO. This narrative review highlights a clinical case and the most recent literature
regarding SIBO, including history, clinical presentation, prevalence, pathophysiology, diagnostic workup,
treatment and prevention. Integrative medicine approaches, including diet, supplements and manual
therapies, are also reviewed. SIBO can be a challenging condition and requires an integrative, patientcentered approach. Further studies are needed to guide clinicians in the workup and treatment of SIBO.
(J Patient-Centered Res Rev. 2015;2:165-173.)
Keywords
small intestinal bacterial overgrowth, SIBO, irritable bowel syndrome, IBS
Our understanding of the important role of gut bacteria
(the microbiome) in health and disease is rapidly
evolving. This narrative review highlights small intestinal
bacterial overgrowth (SIBO, pronounced “see-boe”),
a condition of increased microbial load in the small
intestine. The microbes feed on dietary carbohydrates
and starches via fermentation, leading to gas production,
inflammation and subsequent damage to the lining of
the small intestine. Clinical presentation is varied and
can include abdominal pain, bloating, malabsorption
and systemic symptoms.1 This article will review
the history, epidemiology, pathophysiology, clinical
presentation, diagnosis, treatment and controversies of
this underrecognized and often-challenging condition.
Illustrative Case
A previously thriving 8-year-old girl presented
with onset of sore throat, fever and abdominal pain.
Streptococcal pharyngitis was ruled out and the
Correspondence: Kristen H. Reynolds, MD,
Aurora Wiselives Center, 8320 W. Bluemound Road,
Suite 125, Wauwatosa, WI, 53213, T: 414-302-3800,
F: 414-302-3813, Email: [email protected]
Review
diagnosis of viral pharyngitis made. Within a few days
the fever and sore throat resolved, but the abdominal
pain remained and severe insomnia ensued. Additional
workup during the following two months included a
normal abdominal ultrasound and extensive blood
work, with the only abnormal results being elevated
bilirubin, thought secondary to Gilbert’s syndrome and
confirmed by a gastroenterologist. The mother (and
author) pursued lactulose breath testing (LBT). Results
showed a rise in hydrogen consistent with SIBO. The
child was treated with a 2-week course of rifaximin
200 mg by mouth 3 times a day, with resolution
of abdominal pain and insomnia within 2 days of
treatment. Repeat breath testing was not performed, as
clinical symptoms had improved.
Six months later the child again developed abdominal
pain and insomnia with a similar viral pharyngitis
trigger, and repeat LBT confirmed recurrent SIBO.
Clinical symptoms did not improve with a repeat course
of rifaximin. After four months of ongoing symptoms,
multiple weeks of missed school, weight loss and
guaiac-positive stool, esophagogastroduodenoscopy
and colonoscopy were performed, remarkable for only
“mild inflammation” on gastric biopsy. Disaccharidase
testing was normal. Further review of the breath test
165
revealed elevations in both methane and hydrogen
(elevated methane requires combination antimicrobial
therapy). Given the child’s young age, parents chose
to avoid neomycin and pursue herbal treatment. The
child’s insomnia and abdominal pain resolved within
1 week of a 4-week course of neem (an Indian herb)
and allicin (the active component in garlic), an herbal
treatment for SIBO.
History
SIBO was first described in the literature in 1939 by
Barber and Hummel, who observed the development of
macrocytic anemia in patients with intestinal strictures.2
In the mid-20th century, Sidney Hass developed the
Specific Carbohydrate Diet and had much success treating
children with celiac disease and other gastrointestinal
disorders with this diet. Shortly after he published his
book, The Management of Celiac Disease, in 1951, the
diet fell out of favor as gluten was recognized as the
culprit in celiac disease (the Specific Carbohydrate Diet
eliminates all grains). Dr. Hass’ work was furthered by
Elaine Gottschall, author of Breaking the Vicious Cycle,
and Natasha Campbell-McBride, author of the book
and diet Gut and Psychology Syndrome. These diets are
currently used in the treatment and prevention of SIBO
as they are low in fermentable starches.3
In 2000, Pimentel and his team at Cedars-Sinai
Medical Center published a report showing that SIBO
was present in 78% of patients with irritable bowel
syndrome (IBS), and that treatment with antibiotics
improved symptoms.4 Since then numerous studies have
supported bacterial overgrowth as a cause for IBS,5 and
in 2014 Pyleris et al. showed that 67% of patients with
IBS have SIBO as evidenced by duodenal aspiration and
culture.6 Once a bacterial basis for IBS was established,
the nonabsorbable antibiotic rifaximin was shown to
improve IBS with just one course.7 In May 2015 the
U.S. Food and Drug Administration (FDA) approved
rifaximin for the treatment of diarrhea-predominant
IBS. Many experts consider IBS and SIBO to be one in
the same.
IBS affects up to 11.2% of the population8 and is a
challenging condition to manage and treat. Bacterial
overgrowth is a piece of the IBS puzzle that until now
has been underrecognized. Just as ulcers were thought to
be due to stress and it took over a decade for clinicians
to accept Helicobacter pylori as the primary etiology,
SIBO also has been dismissed by much of the medical
community. New research is bringing this condition to
light.
Epidemiology
The prevalence of SIBO in the general population
is unknown but estimated to be 0–35% in healthy
individuals.9 Anywhere from 30% to 85% of adult
patients with IBS are estimated to have SIBO,9-11 with
the most current data reporting 67% as determined by
duodenal aspiration and culture.6 Two meta-analyses
have shown 3.5–9.6-fold increased odds of SIBO in
patients with IBS.12 In the United States and Europe,
one in five school-aged children have been diagnosed
with abdominal pain-related functional gastrointestinal
disorders, including IBS and functional abdominal pain;
SIBO has been shown to occur in 34% of pediatric
IBS patients.10 A 2015 study demonstrated that 63%
of children aged 4–17 years who were hospitalized for
abdominal pain had SIBO.13
Elderly patients may be particularly susceptible to SIBO
due to a lack of gastric acid and the use of medications
that slow gastrointestinal transit.9 SIBO prevalence may
be as high as 15% in the elderly and is an important
cause of unexplained diarrhea in this population.12,14
SIBO also is common in patients with liver cirrhosis
(50%), celiac disease (50%)9 and gastroparesis (39%).15
Pathophysiology
There are several physiologic mechanisms in place
to prevent bacterial overgrowth in the small intestine.
These include gastric acid, the migrating motor complex
(MMC, a brush-like wave that washes the small bowel
during fasting), the intestinal mucosa, the gut-immune
system, enzymes, commensal bacteria and the physical
barrier of the ileocecal valve.2 Anything disrupting these
mechanisms can increase the risk of SIBO.14
The MMC is a cyclic, recurring motility pattern that
occurs in the stomach and small bowel between meals.
Regulation of the MMC is complex and involves
various hormones and activation of the enteric and
parasympathetic nervous systems. Phase III of the
MMC, the most active of its four phases, has been
shown to be absent or decreased in SIBO, IBS and
functional dyspepsia, and can be induced by motilin,
erythromycin and serotonin. Vagotomy abolishes part
of the MMC. Nerve damage to the MMC plays a part
Review
in diabetic gastroparesis, and erythromycin is a wellknown treatment that works by restoring the gastric
MMC and enhancing gastric motility.16
Diabetic enteropathy, gastric bypass, pseudo-obstruction,
adhesions, narcotics and Ehlers-Danlos syndrome are
known risk factors that slow gastrointestinal transit, and
thus predispose individuals to SIBO. The association of
proton pump inhibitors with SIBO had been conflicting
until a 2013 meta-analysis showed an odds ratio for SIBO
of 2.282 (95% confidence interval [CI]: 1.238–4.205)
in those who used proton pump inhibitors compared to
those who did not.1 Table 1 lists various conditions that
can predispose one to developing SIBO. See Table 2 for
factors that protect against the development of SIBO
and Table 3 for factors that affect the microbiome and
may influence SIBO development.
Infectious gastroenteritis can lead to SIBO and IBS
through damage to the enteric nerves of the MMC;
Table 1. Conditions that predispose toward development
of small intestinal bacterial overgrowth
Achlorhydria (surgical, iatrogenic, autoimmune)
Motor abnormalities
Scleroderma
Intestinal pseudo-obstruction
Diabetic enteropathy
Vagotomy
25% of patients with acute gastroenteritis will
develop postinfectious IBS.17 Studies have shown
that the bacteria involved in infectious gastroenteritis,
specifically Campylobacter jejuni, Salmonella,
Escherichia coli and Shigella, produce cytolethal
distending toxin (Cdt). Cdt antibodies cross-react with
vinculin, a key protein in the tight junctions lining
the gut and a player in nerve cell motility, through
molecular mimicry. This alters the enteric nervous
system, thus affecting motility and predisposing to
IBS and SIBO. Blood biomarkers to anti-Cdt and
anti-vinculin are elevated in diarrhea-predominant
IBS, and may be helpful in distinguishing this from
inflammatory bowel disease in the workup of chronic
diarrhea.18
The organisms accounting for overgrowth in SIBO
are mainly gram-negative aerobes and anaerobic
species, including Escherichia coli, Enterococcus
spp., Klebsiella pneumonia and Proteus mirabilis.9
Another class of microbes involved with SIBO includes
methanogens, primitive anaerobes that belong to the
kingdom Archaea. Methanogens feed off of hydrogen
and produce methane. Methanobrevibacter smithii is the
dominant methanogen in the intestine. These organisms
are difficult to cultivate and are resistant to many
common antibiotics.19
Methane was previously thought to be an inert gas, but
current evidence suggests it acts like a neuromuscular
transmitter to slow intestinal transit.19 The presence
Abnormal communication between colon and small bowel
Fistulas between colon and small bowel
Resection of ileocecal valve
Structural abnormalities
Systemic and intestinal immune deficiency states
Surgical loops (billroth ii, entero-entero anastomosis,
Rou-en-Y)
Duodenal or jejunal diverticula
Partial obstruction of small bowel (stricture, adhesions,
tumors)
Table 2. Factors that protect against development of small
intestinal bacterial overgrowth
Gastric acid
Pancreatic enzymes
Bile acids
Cholecystectomy
Large small-intestinal diverticulosis
Motility
Systemic diseases (celiac, cirrhosis, pancreatic exocrine
insufficiency, nonalcoholic fatty liver)
Migrating motor complex
Biofilm
Alcoholism
Secretory immunoglobulin A
Reprinted from Chedid et al. Herbal therapy is equivalent
to rifaximin for the treatment of small intestinal bacterial
overgrowth. Glob Adv Health Med. 2014;3(3):16-24, with
permission from Global Advances in Health and Medicine LLC.
Review
167
Table 3. Extrinsic factors that alter the gut microbiome
and may influence development of small intestinal bacterial
overgrowth
FODMAPs* (fructose, lactose, galactans, fructans,
sugar alcohols)
Proton pump inhibitors
Antimotility agents
Fiber
Prebiotics
Probiotics
Antibiotics
*FODMAP is an acronym for a group of highly fermentable
foods (fermentable oligo-, di-, and monosaccharides and
polyols).
of methane on breath testing is almost universally
associated with constipation-predominant IBS.19-22
Imbalances in the gut microbiome known as dysbiosis
are a key feature in SIBO. Such imbalances can disrupt
epithelial tight junctions, increasing small intestinal
permeability, translocation of endotoxins and induction
of proinflammatory cytokines. The gut microbiota
has a bidirectional interaction with immune function,
digestion, metabolism and gut-brain communication.
Dysbiosis has been linked to disorders of mood and
behavior as well as numerous gastrointestinal and
systemic disorders.11
Clinical Presentation
The manifestations of SIBO have been described as
“protean,” and can range from mild IBS-type symptoms
to severe enteropathy, malabsorption, weight loss and
malnutrition.11 Typical presentation includes abdominal
pain, bloating, flatulence, nausea and altered bowel
patterns, including diarrhea and/or constipation.2
Systemic symptoms are thought to be secondary to
cellular injury from enterotoxin production and bacterial
adhesion.1 Inflammation can be profound.23 This can
lead to a damaged intestinal lining and malabsorption,
resulting in systemic manifestations of anemia,
weight loss, neuropathy, osteoporosis and nutritional
deficiencies.2 In addition to IBS, SIBO is associated
with fibromyalgia, chronic fatigue syndrome, restless
leg syndrome, rosacea, arthralgias, chronic prostatitis
and pelvic pain syndromes, Parkinson’s, interstitial
cystitis and more.11,24,25 Fatigue is the most prevalent
symptom in children diagnosed with SIBO (75%),10 and
was a prominent feature in the case described.
Diagnosis
SIBO has conventionally been defined as an excessive
concentration of bacteria in the small intestine based on
culture of a jejunal aspirate. This approach is limited
in clinical practice by high cost, invasive nature, lack
of standardization, sampling error and an inability to
reach the distal small bowel.2 More recently, SIBO
diagnosis has been defined as “measurable changes
in exhaled gases produced by the metabolism of orally
ingested carbohydrates,” otherwise known as breath
testing.2 Breath testing is more readily available,
safe, inexpensive and noninvasive, and may be more
inclusive when lactulose is used as the substrate as it
is more likely to include cases of distal SIBO. There
was staunch criticism of the breath test after it started
being used for IBS, though it was used without question
for SIBO prior to that.25 With recent studies confirming
bacterial overgrowth as an underlying etiology for IBS,
along with the challenges of small bowel aspiration,
breath testing is regaining momentum as a useful
diagnostic tool.
Breath testing relies on the principle that bacterial
metabolism
(fermentation)
of
nonabsorbed
carbohydrates is the sole source of hydrogen and
methane gas in exhaled breath. After ingestion of a
substrate, hydrogen and methane can be measured by
gas chromatography in exhaled breath and reported
in parts per million (ppm). Lactulose and glucose are
the most frequently used substrates for breath testing.
Glucose is a monosaccharide that is completely
absorbed in the proximal small intestine. In the presence
of SIBO, it is fermented into gases that are absorbed
and can be measured via exhaled breath. Since it does
not reach the distal small intestine, it may miss cases of
distal SIBO. Lactulose is a nonabsorbable disaccharide
and has been clinically used as an osmotic laxative.2 It
passes intact through the normal small intestine to the
colon where it is metabolized to short-chain fatty acids
and gases that are also absorbed and can be measured
Review
via exhaled breath; in the presence of SIBO, lactulose
is fermented in the small intestine, causing an earlier
rise in breath gas.2 It is important to measure both
hydrogen and methane, as treatments vary based on
the gas present.
Lactulose breath testing is the most commonly used
procedure for diagnosing SIBO,11,22 and QuinTron
Instrument Company (Milwaukee, WI) is the analyzer
most frequently cited in the literature.21 Test preparation
requires a 36-hour limitation of slowly-absorbed
carbohydrates (such as bread and potatoes) and fiber,
as well as a restriction on certain medications. The
protocol includes a baseline breath sample followed by
oral ingestion of 10 g of lactulose in 200 ml of water.
Subsequent breath samples are collected every 15–20
minutes over a 120–240-minute period.2
Evaluating breath test results is difficult due to lack
of a reliable and reproducible gold standard test for
SIBO and variable accuracy for both glucose breath
testing (GBT) and LBT. A 2014 review calculated the
sensitivity, specificity and diagnostic accuracy to be
63%, 82% and 72% for GBT and 53%, 86% and 55% for
LBT, respectively. They concluded GBT to be the most
accurate test for diagnosing SIBO, with a caveat that it
may miss distal SIBO, as glucose is quickly absorbed in
the proximal small intestine.2 A more recent study using
GBT as the gold standard showed a higher sensitivity
(64%) for LBT.2 Testing for methane in addition to
hydrogen improves diagnostic accuracy.2 There remains
a need for a gold standard test for SIBO.2
It is important to view results with the clinical context
in mind. If a patient reports symptoms of increased gut
motility (loose stools) after ingestion of lactulose, then
the substrate may have reached the colon early. This
may result in a late spike in methane and/or hydrogen,
with otherwise low levels throughout the rest of the test.
Interpretation of hydrogen breath test results is also
challenging, as there is no universally recognized or
validated standard for a positive study. A baseline (fasting)
breath hydrogen level of ≥ 20 ppm or a rise in hydrogen of
≥ 12 ppm from baseline is considered positive.2,10 Many
microbes (including methanogens and sulfate-reducing
bacteria) utilize hydrogen gas as their energy source,
which can impair the accurate detection of hydrogen.5
Review
Methane breath testing positivity is variably defined in
the literature, ranging from > 1 ppm to ≥ 3–12 ppm at
any time during the test. Methane breath testing may
show two patterns: a high baseline level and early rise
in breath methane associated with SIBO, or a late rise
corresponding to the arrival of lactulose at the colon.19
Experts in the field typically consider a breath methane
≥ 3 ppm to be positive if constipation is present, and
≥ 12 ppm to be positive if constipation is absent.26
Treatment
The treatment and subsequent prevention of SIBO
are directed at eliminating the microbial overgrowth,
modifying the diet and addressing motility issues.
Antimicrobials for SIBO include both prescription and
herbal options.
Prescription Antimicrobials: There are many different
antibiotics that have been used for the treatment of
SIBO. A 2013 review of SIBO treatment with any
antibiotic versus placebo demonstrated an odds
ratio of 2.55 (95% CI: 1.29–5.04) for breath test
normalization.12 One of the most studied antibiotics
for SIBO is rifaximin, with an overall breath test
normalization rate of 49.5% (95% CI: 44.0–55.1) in
eight clinical trials.12 Rifaximin is a nonabsorbable
antibiotic with minimal side effects. It is the antibiotic
of choice for SIBO22 and works best in hydrogenpredominant cases. Rifaximin must be dosed at
550 mg orally 3 times a day for 2 weeks, as lower
doses and twice-daily dosing are not as efficacious.27
Rifaximin has been shown to be safe and effective in
the pediatric setting at a dose of 600 mg daily28 (the
author prefers to divide this into twice daily dosing),
and was used with initial success in the illustrative
case presented. Insurances should now be covering
rifaximin given the recent FDA approval; prior
authorization may be needed.
For methane-predominant SIBO, the combination of
rifaximin with neomycin (500 mg orally twice daily)
is the most effective therapy for clinical improvement
of SIBO and elimination of breath methane in the
adult population.19,29 Methane on breath testing is
almost universally associated with constipation, and
the combination of rifaximin and neomycin improves
constipation in a manner dependent on eradication of
breath methane to < 3 ppm.20,30
169
Breath test normalization is highly associated with
clinical improvement. Further randomized, double-blind
controlled trials are needed to clarify best treatment
options for SIBO.12
Prebiotics and Probiotics: Treatment with antibiotics
alone does not fully address the microbial dysbiosis
associated with SIBO, as antibiotics do not restore
normal flora. Probiotics are thought to enhance gut
barrier function, decrease inflammation, stabilize gut
flora and potentially modulate visceral hypersensitivity.
The addition of pre- or probiotics is an understudied
but possible option for the treatment of SIBO.12 Some
experts currently avoid pre- and probiotics during the
initial stages of treatment, as these could theoretically
feed the underlying bacterial overgrowth.
Guar gum is a prebiotic agent that favors the growth of
Bifidobacteria and Lactobacillus species, among others.
Rifaximin combined with partially hydrolyzed guar gum
was used in one study with a breath test normalization
rate of 85% (95% CI: 70.2–94.3).31
Herbal Antimicrobials: Antibiotic treatment of SIBO
comes with variable success, potential for adverse
side effects and unknown long-term consequences on
the gut microbiota. Relapse of SIBO, which occurred
in the aforementioned illustrative case, is common,
with recurrence rates up to 44% within 9 months
after successful eradication.32 For these reasons, many
patients and clinicians have looked to herbals (plantbased compounds) for the treatment of SIBO. There are
many herbals with documented antimicrobial activity.
Though commonly used by herbalists, naturopaths and
holistic clinicians for years, the use of antimicrobial
herbs for SIBO had not been reported in the literature
until recently.
A ground-breaking study from Johns Hopkins in
2014 showed that herbal therapies are at least as
effective as rifaximin (46% vs. 34%, respectively;
P=0.24) for resolution of SIBO by LBT, and appear
to be as effective as triple antibiotic rescue therapy for
rifaximin nonresponders (57.1% vs. 60%, P=0.89), with
fewer adverse effects.11 Experts in the field have used
peppermint oil, neem, allicin, berberine (goldenseal or
Oregon grape), wormwood (Artemisia) and oregano
(Origanum). The Johns Hopkins study used a proprietary
blend, which is described in the paper and included
several of these botanicals.11
A number of double-blind, placebo-controlled studies
have shown enteric-coated peppermint oil (standard dose
0.2 ml, 3 times a day) useful in improving the symptoms
of IBS, and a 2002 case report of enteric-coated
peppermint oil for SIBO described both laboratory and
clinical improvement.33 The active component in garlic,
allicin, has been shown to have activity against enteric
pathogens34 and is essential in the herbal treatment of
methane-positive SIBO.25,26 For additional information
on dosing botanicals, see Allison Siebecker’s website
www.siboinfo.com.
Prokinetics and Diet: Addressing gut motility and
modifying the diet are two important aspects of SIBO
treatment that are aimed at preventing recurrence. As
previously mentioned, the migrating motor complex is
thought to be disrupted in the case of SIBO, and agents
that activate the MMC are essential for preventing
recurrence. The most commonly used agents are
low-dose erythromycin, prucalopride and low-dose
naltrexone. Other agents such as ginger show promise.
Erythromycin has long been used to stimulate
gastrointestinal motility, especially for diabetic
gastroparesis.16 Historically, tegaserod (a serotonin
agonist) was given in an attempt to improve phase III
of the MMC. Both medications have been shown to
prevent recurrence of SIBO;24,35 however, tegaserod has
been withdrawn from the U.S. market for safety reasons.
Prucalopride (available in Canada and Europe) is a safer
alternative to tegaserod but has not been directly studied
for SIBO.
Low-dose naltrexone is an opioid antagonist that can
stimulate intestinal motility, may have anti-inflammatory
properties, and has been used successfully for the
prevention of SIBO. It is contraindicated in those taking
chronic opioids.24 Ginger promotes gastric emptying and
motility and modulates serotonin receptors in the enteric
nervous system. Ginger has documented efficacy as an
antiemetic,36 though it has not been well-studied for
prevention of SIBO recurrence.
5-hydroxytryptophan (5-HTP) is a precursor to
5-hydroxytryptamine (5-HT, or serotonin). Intravenous
Review
5-HT has been shown to activate the MMC, though
intraluminal administration did not affect motility.16
A combination of 5-HTP and ginger is available on
the market and has been used successfully in the
prevention of SIBO recurrence.26 The nine-herb
combination product STW 5 (Iberogast®, Steigerwald
Arzneimittelwerk GmbH, Darmstadt, Germany) has
5-HT agonist properties, has been extensively studied
for IBS and was shown to be a safe and effective option
for improving motility.37 Though Iberogast is a European
product, it is available online.
Additional interventions aimed at preventing recurrence
include addressing gastric acid levels (removing
acid-blocking medications and supplementing with
hydrochloric acid if needed), correcting ileocecal
valve dysfunction (through acupuncture, osteopathic
manipulation or visceral manipulation), addressing any
neurological deficits and treating concomitant diseases
that contribute to SIBO.38 Seeking and addressing the
root cause(s) of SIBO are paramount to successful
treatment and prevention of recurrence.
Dietary modification is essential for prevention
of recurrence and has a powerful influence on the
gut microbiome. Dietary change helps to heal the
mucosal lining and also can be used during treatment
to alleviate symptoms. Various recommended diets
include the Specific Carbohydrate Diet, the Gut
and Psychology Syndrome (GAPS) Diet, the Low
FODMAP Diet, the Cedars-Sinai Diet, the Paleo
Diet or a combination of these. Dr. Siebecker of
the SIBO Center for Digestive Health (Portland,
OR) has created the SIBO Specific Diet, which is a
combination of the Specific Carbohydrate Diet and
Low FODMAP Diet. It is even more restrictive, but
may offer relief in challenging cases.3
A 2-week elemental meal replacement consisting of
predigested nutrients in powdered form can be used
for treatment, but it is difficult, expensive and may
not work as well for methane-producing bacteria.39
The idea behind any treatment diet is to starve the
bacteria while feeding the patient. Vivonex Plus®
(Nestlé HealthCare Nutrition Inc., Florham Park, NJ)
is an elemental meal replacement that has been shown
to be highly effective in normalizing breath tests and
improving clinical symptoms.40
Review
FODMAPs
(fermentable
oligo-,
diand
monosaccharides and polyols) — short-chain
carbohydrates that are poorly absorbed in the small
intestine — are highly fermentable and increase
the osmotic load in the intestine, thus increasing
luminal distention and symptoms such as visceral
hypersensitivity. A 2013 observational study of
IBS patients (13% of whom had documented
SIBO) showed symptomatic improvement on a
Low FODMAP Diet.41 A subsequent randomized
crossover trial provided additional confirmation of
the effectiveness of a Low FODMAP Diet in the
setting of IBS.42
Dietary adherence can be challenging. Consultation
with a dietitian, written information and positive breath
test results can help patients maintain the diet.41
Conclusions
There is increased recognition of small intestinal
bacterial overgrowth as a contributing factor in IBS,
functional abdominal pain and a host of other chronic
conditions. Though SIBO can be challenging to treat
and tends to be recurrent, there are many conventional
and integrative treatments that can provide significant
relief for patients. Treatment for each individual is
unique and must be tailored to the specific clinical
condition. Further studies are desperately needed to
help clinicians better understand the workup, treatment
and prevention of this challenging condition.
• Small intestinal bacterial overgrowth, or SIBO,
is a chronic infection that damages the intestinal
lining over time.
• SIBO is thought to be a causative factor in a
majority of cases of irritable bowel syndrome.
• While SIBO symptoms like pain and fatigue can
improve with antimicrobial treatment, recurrence
is common.
• I ntegrative medicine approaches, particularly
herbal supplements and dietary changes,
may provide significant relief for patients
with SIBO.
171
Acknowledgments
The author would like to thank Dennis Baumgardner,
MD, for his years of ongoing support and guidance,
and Brenda Fay, MLIS, and Elisa Sibinski, BS, for
their kind and generous assistance with references.
None.
References
1. Lo WK, Chan WW. Proton pump inhibitor use and the risk
of small intestinal bacterial overgrowth: a meta-analysis. Clin
Gastroenterol Hepatol. 2013;11:483-90. CrossRef
2. Saad RJ, Chey WD. Breath testing for small intestinal bacterial
overgrowth: maximizing test accuracy. Clin Gastroenterol
Hepatol. 2014;12:1964-72. CrossRef
3. Siebecker A. Small intestine bacterial overgrowth: dietary
treatments. http://www.siboinfo.com/diet.html. Accessed
September 22, 2015.
4. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal
bacterial overgrowth reduces symptoms of irritable bowel
syndrome. Am J Gastroenterol. 2000;95:3503-6. CrossRef
5. Shah ED, Basseri RJ, Chong K, Pimentel M. Abnormal breath
testing in IBS: a meta-analysis. Dig Dis Sci. 2010;55:2441-9.
CrossRef
6. Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas
V, Barbatzas C, Pimentel M. The prevalence of overgrowth by
aerobic bacteria in the small intestine by small bowel culture:
relationship with irritable bowel syndrome. Dig Dis Sci.
2012;57:1321-9. CrossRef
7. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect
of a nonabsorbed oral antibiotic (rifaximin) on the symptoms
of the irritable bowel syndrome: a randomized trial. Ann
Intern Med. 2006;145:557-63. CrossRef
8. Lovell RM, Ford AC. Global prevalence of and risk factors for
irritable bowel syndrome: a meta-analysis. Clin Gastroenterol
Hepatol. 2012;10:712-21. CrossRef
9.Sachdev AH, Pimental M. Gastrointestinal bacterial
overgrowth: pathogenesis and clinical significance. Ther Adv
Chronic Dis. 2013;4:223-31. CrossRef
10.Korterink JJ, Benninga MA, van Wering HM, DeckersKocken JM. Glucose hydrogen breath test for small intestinal
bacterial overgrowth in children with abdominal pain-related
functional gastrointestinal disorders. J Pediatr Gastroenterol
Nutr. 2015;60: 498-502. CrossRef
11.Chedid V, Dhalla S, Clarke JO, et al. Herbal therapy is
equivalent to rifaximin for the treatment of small intestinal
bacterial overgrowth. Glob Adv Health Med. 2014;3:16-24.
CrossRef
12.Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis:
antibiotic therapy for small intestinal bacterial overgrowth.
Aliment Pharmacol Ther. 2013;38:925-34. CrossRef
13.Siniewicz-Luzeńczyk K, Bik-Gawin A, Zeman K,
Bąk-Romaniszyn L. Small intestinal bacterial overgrowth
syndrome in children. Prz Gastroenterol. 2015;10:28-32.
CrossRef
14.Quigley EM. Small intestinal bacterial overgrowth: what it is
and what it is not. Curr Opin Gastroenterol. 2014;30:141-6.
CrossRef
15.George NS, Sankineni A, Parkman HP. Small intestinal
bacterial overgrowth in gastroparesis. Dig Dis Sci.
2014;59:645-52. CrossRef
16.Deloose E, Janssen P, Depoortere I, Tack J. The migrating
motor complex: control mechanisms and its role in health
and disease. Nat Rev Gastroenterol Hepatol. 2012;9:271-85.
CrossRef
17.Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal
symptoms six months after bacterial gastroenteritis and risk
factors for development of the irritable bowel syndrome:
postal survey of patients. BMJ. 1997;314:779-82. CrossRef
18.Pimentel M, Morales W, Rezaie A, et al. Development
and validation of a biomarker for diarrhea-predominant
irritable bowel syndrome in human subjects. PloS One.
2015;10:e0126438. CrossRef
19.Triantafyllou K, Chang C, Pimentel M. Methanogens,
methane and gastrointestinal motility. J Neurogastroenterol
Motil. 2014;20:31-40. CrossRef
20.Pimentel M, Chatterjee S, Chow EJ, Park S, Kong Y.
Neomycin improves constipation-predominant irritable
bowel syndrome in a fashion that is dependent on the
presence of methane gas: subanalysis of a double-blind
randomized controlled study. Dig Dis Sci. 2006;51:1297301. CrossRef
21.Chatterjee S, Park S, Low K, Kong Y, Pimental M. The
degree of breath methane production in IBS correlates with
the severity of constipation. Am J Gastroenterol. 2007;102:
837-41. CrossRef
22.Pimentel M, Chow EJ, Lin HC. Normalization of lactulose
breath testing correlates with symptom improvement in
irritable bowel syndrome: a double-blind, randomized,
placebo-controlled study. Am J Gastroenterol. 2003;98:412-9.
CrossRef
23.Lin HC. Small intestinal bacterial overgrowth: a framework
for understanding irritable bowel syndrome. JAMA.
2004;292:852-8. CrossRef
24.Turnbull LK, Mullin GE, Weinstock, LB. Principles of
integrative gastroenterology: systemic signs of underlying
digestive dysfunction and disease. In: Mullin GE (ed).
Integrative Gastroenterology. New York, NY: Oxford
University Press, 2011, pp. 89-98.
25.National College of Natural Medicine Continuing Education
Online. 2014 SIBO Symposium. http://cemoodle.ncnm.edu/
course/category.php?id=130. Accessed September 22, 2015.
26.National College of Natural Medicine Continuing Education
Online. 2015 SIBO Symposium. https://cemoodle.ncnm.edu/
course/search.php?search=SIBOSymposium+2015. Accessed
September 22, 2015.
27.Scarpellini E, Gabrielli M, Lauritano CE, et al. High dosage
rifaximin for the treatment of small intestinal bacterial
overgrowth. Aliment Pharmacol Ther. 2007;25:781-6.
CrossRef
28.Scarpellini E, Giorgio V, Gabrielli M, et al. Rifaximin
treatment for small intestinal bacterial overgrowth in children
with irritable bowel syndrome. Eur Rev Med Pharmacol Sci.
2013;17:1314-20.
29.Low K, Hwang L, Hua J, Zhu A, Morales W, Pimentel M.
A combination of rifaximin and neomycin is most effective
in treating irritable bowel syndrome patients with methane on
lactulose breath test. J Clin Gastroenterol. 2010;44:547-50.
CrossRef
Review
30.Pimentel M. Rifaximin and neomycin improves constipation.
[Comprehensive reports on the latest advances in
gastroenterology and hepatology from American College
of Gastroenterology 2013 Annual Scientific Meeting].
Gastroenterol Hepatol. 2014;10(Abstract P1689):1-22.
31.Furnari M, Parodi A, Gemignani L, et al. Clinical trial: the
combination of rifaximin with partially hydrolyzed guar gum
is more effective than rifaximin alone in eradicating small
intestinal bacterial overgrowth. Aliment Pharmacol Ther.
2010;32:1000-6. CrossRef
32. Lauritano EC, Gabrielli M, Scarpellini E, et al. Small intestinal
bacterial overgrowth recurrence after antibiotic therapy. Am J
Gastroenterol. 2008;103:2031-5. CrossRef
33.Logan AC, Beaulne TM. The treatment of small intestinal
bacterial overgrowth with enteric-coated peppermint oil: a
case report. Altern Med Rev. 2002;7:410-7.
34.Ross ZM, O’Gara EA, Hill DJ, Sleightholme HV, Maslin DJ.
Antimicrobial properties of garlic oil against human enteric
bacteria: evaluation of methodologies and comparisons with
garlic oil sulfides and garlic powder. Appl Environ Microbiol.
2001;67:475-80. CrossRef
35.Pimentel M, Morales W, Lezcano S, Sun-Chuan D, Low
K, Yang J. Low-dose nocturnal tegaserod or erythromycin
delays symptom recurrence after treatment of irritable
bowel syndrome based on presumed bacterial overgrowth.
Gastroenterol Hepatol (N.Y.). 2009;5:435-42.
36.Ernst E, Pittler MH. Efficacy of ginger for nausea and
vomiting: a systematic review of randomized clinical trials.
Br J Anaesth. 2000;84:367-71. CrossRef
37.Ottillinger B, Storr M, Malfertheiner P, Allescher HD. STW 5
(Iberogast®)–a safe and effective standard in the treatment of
functional gastrointestinal disorders. Wien Med Wochenschr.
2013;163:65-72. CrossRef
38.Siebecker A. Small intestine bacterial overgrowth: prevention.
http://www.siboinfo.com/prevention.html. Accessed September
22, 2015.
39.Siebecker A. Small intestine bacterial overgrowth: elemental
diet, drawbacks. http://www.siboinfo.com/elemental-formula.
html. Accessed September 22, 2015.
40.Pimentel M, Constantino T, Kong Y, Bajwa M, Rezaei A, Park
S. A 14-day elemental diet is highly effective in normalizing
the lactulose breath test. Dig Dis Sci. 2004;49:73-7. CrossRef
41.de Roest RH, Dobbs BR, Chapman BA, et al. The low
FODMAP diet improves gastrointestinal symptoms in patients
with irritable bowel syndrome: a prospective study. Int J Clin
Pract. 2013;67:895-903. CrossRef
42.Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A
diet low in FODMAPs reduces symptoms of irritable bowel
syndrome. Gastroenterology. 2014;146:67-75.e5. CrossRef
JPCRR online
Did you know that all articles published in
Journal of Patient-Centered Research and
Reviews (JPCRR) are freely available online?
Our open access, interactive website not only provides archived
journal content but also supplemental materials for articles, author
instructions, editorial policies and the journal’s Twitter feed. It also
is the place to submit a manuscript for consideration by JPCRR.
Snapshot of the JPCRR
readership map over a
30-day period.
Visit www.aurora.org/jpcrr today!
Review
173
Essentials of Herb-Drug Interactions in the Elderly With
Cardiovascular Disease
Sulaiman Sultan, MD,1,2 Maria Viqar, MD,3 Rabaiya Ali, MD,1 A. Jamil Tajik, MD,4 Arshad Jahangir, MD1,4
Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging (CIRCA),
Aurora Research Institute, Aurora Health Care, Milwaukee, WI
2
Internal Medicine, Aurora Health Care, Milwaukee, WI
3
Cardiac Electrophysiology, Dallas Medical Physician Group, Dallas, TX
4
Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke’s Medical Centers, Aurora University of Wisconsin
Medical Group, Milwaukee, WI
1
AbstractAs the number of individuals, particularly the elderly, using herbal products with prescription drugs
continues to grow, the risk for adverse interactions increases but remains poorly recognized. The true
incidence and nature of adverse herb reactions or herb-drug interactions remains unknown since
no postmarketing surveillance mechanism exists. Adverse events are greatly underreported, and
information regarding safety mainly comes from case reports and suboptimally conducted studies in a
limited number of healthy young volunteers or patients with limited comorbidities. Therefore, convincing
evidence for the safety of herbal products in the elderly is lacking, and the true magnitude of problems
that herb-drug interactions pose to public health, particularly in elderly patients with cardiovascular
diseases, is not known. Since cardiovascular diseases themselves are life-threatening, necessitate use
of multiple medications and occur in a population with extensive comorbidities, the risk of herb-drug and
herb-disease interactions is not minor and cannot be ignored. This review addresses these concerns in
an effort to raise awareness about the use of herbal medicine by the elderly and its potential adverse
impact on the efficacy of prescription medications that can increase predisposition to catastrophic
events such as major bleeding, inadequate anticoagulation leading to undesired clotting, transplant
organ rejection and life-threatening cardiac arrhythmias. (J Patient-Centered Res Rev. 2015;2:174-191.)
Keywords
complementary therapy, herb, integrative medicine, cardiovascular agents, elderly, herb-drug
interaction
The use of herbal and dietary supplements continues to
increase, rising from 2.5% in 1990 to 12.1% in 1997,1-3
with a 2007 National Health Interview Survey showing
that U.S. adults annually spend more than $33.9 billion
out of pocket on complementary health approaches.4
Nonvitamin, nonmineral dietary supplement use
(17.9%) was greater than any other complementary
health approach per another national survey from
2012 (Figure 1).5 Total sales of herbal and dietary
supplements in 2013 was reported to be 7.9% higher
than 2012, making the 10th year in a row in which herb
sales increased over the previous year.6 Sales of the
Correspondence: Arshad Jahangir, MD,
2801 W. Kinnickinnic River Parkway, Milwaukee, WI,
53215, T: 414-649-3909; F: 414-649-3551,
top 10 herbal supplements in 2012 are summarized in
Table 1,7 and the global herbal market for 2015 is
projected to be greater than $93 billion.8
Natural products –– including vitamins, herbs, amino
acids, minerals and probiotics –– are often sold as
dietary supplements and regulated as food products by
the U.S. Food and Drug Administration (FDA). Unlike
allopathic medicines, these supplements do not need
FDA approval of their safety and efficacy. Since the
use of herbal products is increasing, particularly by
elderly patients who also use medicinal products, the
likelihood of adverse interactions is rising.9 Nahin and
colleagues,10 investigating the relationship between
prescription medications and supplements in patients
age 75 years or older, showed that 82.5% of patients
used at least one supplement and 54.5% used three or
more; the average number of prescription medications
Review
• Use of nonvitamin,
nonmineral dietary supplements
was highest in the Mountain,
Figure 1.Pacific,
Percentage
of North
U.S. adults
and West
Centralwho
used complementary
health approaches, by
regions.
type, in the past 12 months (2012).5 Note:
• Use of yogahealth
with deep
Not all complementary
approaches
breathing
orfigure.
meditation
was
are presented
in this
Source:
approximately
40%
higher
www.cdc.gov/nchs/data/databriefs/db146.pdf.
in the Pacific and Mountain
regions than in the United
States overall.
in 2012.
Figure 1. Percentage of adults who used complementary health approaches in the past 12
months, by type of approach: United States, 2012
20
17.9
15
Percent
Central region as in the United
States overall.
10
8.5
8.4
6.8
5
0
4.1
Nonvitamin, Chiropractic
or
nonmineral
osteopathic
dietary
supplement manipulation
Yoga
Massage
Meditation
3.0
Special
diets
NOTE: Not all complementary health approaches are presented in this figure.
SOURCE: CDC/NCHS, National Health Interview Survey, 2012.
used per patient was 3.5, whichu.s.
wasdepartment
similar to the
complementary
and services
alternative medicine, cardiovascular
of health
and human
average number of dietary supplements used
byforthe
diseases,
elderly
and each of the individual herbs
centers
disease
control and
prevention
national center
for health statistics
same population.
discussed
in this review. We also manually searched
references and articles written with a focus on the risk
Although drug-drug interactions are typically taken
of herb-drug interactions, particularly those used in the
into account, the importance of herb-drug interactions
care of patients with cardiovascular diseases.
is slowly being recognized as a potential factor
affecting outcomes in the elderly, especially those with
Factors Affecting Herb-Drug Interactions in the
multiple comorbidities,11-13 polypharmaceutical use14
Elderly
and aging-associated physiological changes that alter
Factors contributing to drug-herb interactions include
pharmacokinetics and pharmacodynamics.15 Drugs
patient-related factors (age, body size/composition,
with a narrow therapeutic index, such as anticoagulants,
metabolism and kidney function, genetics, lifestyle and
chemotherapeutics, organ antirejection agents and
comorbidities) as well as drug- and herb-related factors
antiarrhythmic compounds, are particularly vulnerable
(amount, route and time of administration). This is
to interaction.
particularly relevant to the elderly in whom the chances
for adverse interactions are higher due to presence of
The majority of patients taking herbal supplements do
aging-associated comorbidities,11 use of polypharmacy14
not disclose such to health care professionals.16 Thus, the
and reduced functional reserves.20 Poor nutritional status,
risk for potential interactions between supplements and
impaired organ function and genetic variants in drug
medications can go undetected; therefore, it is important
metabolism are other factors that increase predisposition
for providers and patients to educate themselves.17,18
to adverse interactions.21-28 With aging, drug metabolism
In this review we describe common herbal remedies
and elimination pathways also are affected by changes
used by the elderly and their potential interactions with
in the liver or intestinal membranes harbouring the
cardiovascular drugs. We also highlight regulatory issues
cytochrome P450 enzyme superfamily or other enzymes
regarding herbal supplements and discuss possible ways
that metabolize drug to a form that can then be eliminated
to improve safety and minimize adverse effects.
through the kidney or the gut. This is especially true for
interactions between herbs, such as St. John’s wort or
Search Strategy and Selection Criteria
grapefruit juice, that have inhibitory effects on CYP3A4
We searched Medline, the National Center for
enzymes or P-glycoprotein transporter protein.12,13,29,30
Complementary and Integrative Health (NCCIH)
website, the Natural Standard Research Collaboration at
Aging is associated with a reduction in kidney mass, renal
19
Medline Plus and the Cochrane database from 1966
blood flow and the number of functioning glomeruli that
to February 2015 for information on herbal products
reduces kidneys’ ability to eliminate drugs, resulting in
using the key words herbs, herb-drug interactions,
prolongation of their elimination half-life and potential
Review
175
Table 1. The 10 top-selling herbal dietary supplements
in the food, drug and mass market channel in the United
States for 20127 (per SymphonyIRI Group*)
Herb (Latin Name)
Sales
(in U.S. dollars)
1. Cranberry (Vaccinium macrocarpom)
$65,483,940
2. Garlic (Allium sativum)
$34,950,540
3. Saw palmetto (Serenoa repens)
$31,775,810
4. Soy (Glycine max)
$28,017,310
5. Ginkgo (Ginkgo biloba)
$25,853,420
6. Milk thistle (Silybum marianum)
$21,143,560
7. Black cohosh root (Actae racemosa )
$16,925,990
8. Echinacea (Echinacea spp.)
$15,898,880
9. St. John’s wort (Hypericum
perforatum)
$12,193,790
10. Ginseng§ (Panax ginseng)
$11,136,960
†
‡
*Source of data: SymphonyIRI Group Inc., a Chicago-based
market research firm. “FDM market sales data for herbal
supplements, 52 weeks ending December 23, 2012.”
Synonym: Cimicifuga racemosa.
†
Echinacea collectively refers to supplements made from
roots and/or aerial parts of plants from three species in the
genus Echinacea, including E. angustifolia, E. pallida and E.
purpurea.
‡
It is not clear from the SymphonyIRI data whether this figure
also includes the sales of American ginseng root products
(made from Panax quinquefolius), the sales of which are not
as high as sales of supplements made from Asian ginseng
(P. ginseng).
§
for adverse effects. There is limited data on drug-herb
interactions in the elderly, particularly those 80 years
and older, who are at higher risk of adverse interactions
with drugs that have a narrow therapeutic index, such as
anticoagulants and sedatives.31,32
Common herbal remedies and their potential
interactions with drugs that produce adverse effects on
the cardiovascular system are summarized in Online
Supplemental Appendix 1. We have narrowed this
review to the purported use, potential side effects and
interactions of the top 10 selling plant products (per a
SymphonyIRI Group report7) and grapefruit juice with
drugs used in cardiovascular medicine in the elderly.
Cranberry
Cranberry (Vaccinium macrocarpton) fruits and extracts
have been used in traditional medicine to treat urinary
tract infections (UTI), diabetes, H. pylori-induced
gastric ulcers, and blood and digestive disorders.
The exact mechanism of action is not known, but the
inhibitory effect of cranberry proanthocyanidins on
growth, adhesion and virulence of E. coli bacteria has
been suggested to prevent infections.18 Although a few
small studies demonstrated benefit from cranberry
use in women with recurrent UTIs, a 2012 Cochrane
review showed no statistically significant differences
when the results of a much larger study were included
and recommended against the use of cranberry for UTI
prevention.33 This inconsistency in study results could be
due to the variability in study designs, cranberry products
used, study compliance or differences in pathogenesis
of UTI in different groups such as young children,
sexually active young adults or the elderly. Some case
reports in the elderly34,35 reported raised international
normalized ratio (INR) and life-threatening bleeding
with coadministration of warfarin and cranberry. In
12 young healthy volunteers, a single dose of warfarin
after 2 weeks of cranberry juice consumption caused
a 30% elevation in INR,36 suggesting the potential for
adverse event may be higher in elderly patients who
have multiple comorbidities. Therefore, cranberry juice
should be avoided in patients on chronic anticoagulant
therapy. Some studies have reported that cranberry juice
inhibits CYP2C9 and CYP3A4,37 however, others have
not confirmed these findings.38 Due to these inconsistent
findings, additional research is warranted to clarify
cranberry’s efficacy and safety in the elderly with
multiple comorbidities.33
Garlic
Garlic (Allium sativum), a medicinal herb, has many
potential benefits with its antimicrobial, immuneenhancing and anticholesterolemic effects, and is
widely used for heart disease, high blood pressure,
high cholesterol and prevention of stomach and colon
cancers. Some clinical studies have shown aged garlic
extract to be a safe adjunct treatment to conventional
antihypertensives39 and to improve glycemic control
and lipid profile when used in combination with
antidiabetics.40 An enhanced antihyperglycemic response
was described in a woman on chlorpropamide after eating
a curry containing garlic and Momordica charantia
Review
(bitter melon), another plant product used for medicinal
purposes.41 Garlic is used as a dietary supplement by
patients infected with human immunodeficiency virus
(HIV) and can cause detrimental effects, including
severe gastrointestinal toxicity, when coadministered
with protease inhibitors like ritonavir.42 In a controlled
trial of patients with coronary artery disease randomized
to receive either garlic oil (4 g/day) or placebo taken
with prescribed nitrates, garlic significantly decreased
total serum cholesterol and increased serum highdensity-lipoprotein cholesterol.43 However, other trials
have shown no significant effects on total cholesterol,
low-density-lipoprotein cholesterol, blood pressure,
platelet count or triglycerides in patients taking garlic
supplements.36,44
Garlic is believed to have antithrombotic activity45 and
decrease platelet aggregation,46 which can increase
clotting time and risk of bleeding when taken with
anticoagulants such as warfarin.47 However, in healthy
volunteers, garlic in combination with warfarin was
shown to have no effect on INR or bleeding risk over
short-term follow-up.36,44 Garlic should be used with
caution in those on oral anticoagulants, as garlicassociated postoperative bleeding48 and spontaneous
spinal epidural hematoma49 have been reported. It is
recommended that garlic supplements be discontinued
about 10 days before elective surgical procedures,
especially in patients on antiplatelet agents or
anticoagulants.48
Saw Palmetto
Saw palmetto (Serenoa repens), an extract of the ripe
berries of the American dwarf palm, is the most widely
used phytotherapeutic agent for benign prostatic
hyperplasia. Other purported uses include treatment of
genitourinary conditions, for augmentation of breast
size, to increase libido and sperm production, and as a
mild diuretic. While there is some ambiguity around its
mechanism of action, saw palmetto has demonstrated
inhibitory effect on prostatic estrogen receptors50 and
antiandrogen activity51 including inhibition of 5-alpha
reductase,51,52 the enzyme responsible for conversion of
testosterone to its active metabolite dihydrotestosterone.
Earlier studies reported short-term efficacy of saw
palmetto in ameliorating benign prostatic hyperplasia
symptoms;53 however, this claim has been refuted in
subsequent studies. In a randomized, double-blind study
Review
of saw palmetto using standard dose (320 mg/day) for
a year, Bent and colleagues54 failed to demonstrate
benefits in improving symptoms or objective measures
of benign prostatic hyperplasia over placebo. Tacklind
et al.’s Cochrane review demonstrated similar negative
results of saw palmetto, even at higher doses,55 which
was confirmed in a more recent trial (CAMUS) funded
by the NCCIH that used up to 960 mg/day of saw
palmetto extracts in men with moderate lower urinary
tract symptoms.56
Reported adverse reactions from saw palmetto include
sexual dysfunction, fatigue, tachycardia, angina
pectoris, extrasystole,57 hypertension,58 intraoperative
hemorrhage,59 bleeding susceptibility,60 pancreatitis61 and
cholestatic hepatitis.62 In vitro studies suggest that saw
palmetto inhibits some cytochrome P450 isoenzymes,
including CYP2D6, CYP2C9 and CYP3A4.63 However,
human studies indicated no clinically relevant effect
on the majority of cytochrome P450 isoenzymes.64
Published reports of elevated INR in a patient on
warfarin after taking a saw palmetto-containing product
(curbicin) that normalized after discontinuation of
curbicin65 and excessive bleeding in a middle-aged man
undergoing a surgical procedure to remove a brain tumor
raise concerns regarding the risk of bleeding.59
Soy
Soy, obtained from Glycine max (fam. Fabaceae),
a plant in the pea family, has been used in Japanese
cuisine for thousands of years, with a recent boost
in sales of soy phytoestrogens in American markets
after publication of a study by the Women’s Health
Initiative showing harmful effect of estrogen-progestin
combination and the belief that natural phytoestrogens
may safely prevent bone loss and the consequences of
estrogen deficiency without harmful effects.66 It is sold
as food (tofu, soy milk) or dietary supplements (tablets,
capsules). Purported benefits of soy protein include
alleviation of menopausal symptoms, osteoporosis
and hyperlipidemia. Soy protein products contain
bioactive phytoestrogens or isoflavones, which have
partial estrogen agonist and antagonist properties.67
Earlier studies demonstrating soy protein’s beneficial
effects on low-density-lipoprotein cholesterol and other
cardiovascular risk factors or in reducing hot flashes in
women68,69 were not confirmed by more recent studies.70
Mixed estrogenic and antiestrogenic properties of
177
isoflavones make their effects on cancers complex, and
it remains to be determined if isoflavone supplements
increase the risk of endometrial hyperplasia.71
The long-term safety of soy isoflavones has not been
established. Controversy exists regarding the beneficial
effect of soy food versus isoflovane aglycones in
promoting mammary and endometrial carcinogenesis
in animal models,72,73 and its use should be avoided in
women with breast cancers or other hormone-sensitive
tumors. Soy isoflavones decrease the absorption of
levothyroxine and should not be used in conjunction.74
Soy can inhibit CYP3A4 and CYP2C in vitro.75
Fermented soybean contains high level of vitamin
K and may decrease the activity of warfarin or other
anticoagulants.76 Cases of botulism from homefermented tofu have been reported.77 Natto, a Japanese
food made from fermented soybean containing high
levels of vitamin K, strongly antagonized the effects of
warfarin in experimental models,78 markedly reduced
the effects of acenocoumarol, a warfarin-derivative
anticoagulant,79 and decreased INR to subtherapeutic
levels when coadministered with warfarin76 (Table 2).
Table 2. Common herbs interacting with warfarin
Herbs that increase
anticoagulant effect
(potentiate risk of
bleeding)
Herbs that decrease
anticoagulant effect
(potentiate risk of
thromboembolism)
Alfalfa
Angelica
Bilberry
Cannabis
Capsicum
Cat’s claw
Chamomile
Clove
Cranberry
Danshen
Devil’s claw
Fenugreek
Fever few
Garlic
Ginger
Ginkgo biloba
Grapefruit juice
Kava
Kelp
Lycium
Motherwort
Red clover
Saw palmetto
Yohimbine
Camellia sinensis
Coenzyme Q
Ginseng
Licorice
Soya
St. John’s wort
Ginkgo
Ginkgo derived from the Ginkgo biloba leaf is popular
and one of the most widely used herbal medicines
in the world. Its active constituents are terpenoids,
flavonoids and ginkgolides A, B and C, which have
purported beneficial effects for Alzheimer’s dementia,80
senile macular degeneration, tinnitus81 and peripheral
arterial disease.82 Overall the evidence for ginkgo’s
beneficial effect in patients with dementia or cognitive
impairment is inconsistent in the literature, and the
majority of trials report no significant difference
between ginkgo and placebo in improving dementia
or cognitive impairment.83 Ginkgo biloba extracts
can inhibit thromboxane A2 synthesis84 and have
inhibitory effects on platelet aggregation through
increase in cyclic adenosine monophosphate, cyclic
guanine monophosphate production and matrix
metalloproteinase-9 activation, or inhibition of plateletactivating factor.85,86 Therefore, there is concern
regarding increased risk of bleeding with ginkgo
when coadministered with anticoagulants (Table 2)
or antiplatelet drugs such as ticlopidine.87 Bleeding
events attributed to ginkgo use in warfarin-associated
intracerebral hemorrhage,88 ibuprofen-associated
intracerebral mass bleeding,89 aspirin-associated
spontaneous hyphema,90 postoperative bleeding91
and subphrenic hematoma requiring laparoscopic
evacuation92 have been reported.
Clinical studies in healthy volunteers over short-term
follow-up are presented as evidence for ginkgo’s safety
and lack of significant effect on blood coagulation or
platelet function.93,94 Ang-Lee et al. identified increased
potential for bleeding with ginkgo extracts and
recommended discontinuation 36 hours before surgery.95
The American Society of Anesthesiologists recommends
patients discontinue herbal medicines (including
ginkgo) 2 weeks before elective surgery.96 Ginkgo is
also a potent peripheral vasodilator,97 and long-term
ingestion can potentiate the effect of antihypertensives
with excessive reduction of blood pressure. Gingko is
a weak inhibitor of CYP3A4 (Table 3) and should be
used cautiously with drugs metabolized by this enzyme
system. Other adverse ginkgo-drug interactions include
risk of priapism when combined with antipsychotic drug
risperidone,98 seizure with anticonvulsants (valproic acid
or phenytoin),99 coma with antidepressant trazodone100
and virological failure with efavirenz, a non-nucleoside
reverse transcriptase inhibitor.101
Review
Table 3. Drugs affecting CYP3A4 enzymes*
Strong inhibitors
(≥ 5-fold ↑ in AUC or > 80% ↓ in CL)
Strong inducers
(≥ 80% ↓ in AUC)
Boceprevir, clarithromycin, conivaptan, grapefruit juice,† indinavir, itraconazole,
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telaprevir, telithromycin, voriconazole
Moderate inhibitors
(≥ 2-fold but < 5-fold ↑ in AUC or 50–80% ↓ in CL)
Carbamazepine, phenytoin,
rifampin, St. John’s wort‡§
Moderate inducers
(50–80% ↓ in AUC)
Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem,
erythromycin, fluconazole, fosamprenavir, grapefruit juice,† imatinib, verapamil
Weak inhibitors
(≥ 1.25-fold but < 2-fold ↑ in AUC or 20–50% ↓ in CL)
Bosentan, efavirenz, etravirine,
modafinil, nafcillin
Weak inducers
(20–50% ↓ in AUC)
Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol,
cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo,§ isoniazid, nilotinib,
oral contraceptives, ranitidine, ranolazine, tipranavir/ritonavir, zileuton
Amprenavir, aprepitant, armodafinil,
echinacea,§ pioglitazone,
prednisone, rufinamide
*Note that this is not an exhaustive list. Source: U.S. Food and Drug Administration (http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#cypEnzyme).
he effect of grapefruit juice varies widely among brands and is concentration-, dose- and preparation-dependent. Studies
T
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g. high dose, double
strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g. low dose, single strength).
†
The effect of St. John’s wort varies widely and is preparation-dependent.
‡
Herbal product.
§
AUC, area under curve; CL, clearance.
Milk Thistle
Milk thistle (Silybum marianum) extract is a popular
herbal product used for mushroom poisoning (Amanita
phalloides), chemoprevention and hepatoprotection
in the setting of hepatitis or cirrhosis. Silymarin is a
flavonoid complex, extracted from the seeds of milk
thistle, with active constituents silibinin, isosilybinin,
silydianin, silychristin and other phenol compounds.
Silymarin has strong antioxidant activity102 and
exhibits antiviral, cytoprotective,103 anti-inflammatory,
immunomodulatory,
anticarcinogenic104
and
antiapoptotic effects. Silymarin inhibits both phase I
and phase II liver enzymes, but has limited effect on
in vivo pharmacokinetics of several drugs105 despite
inhibiting the activity of CYP and uridine 5’-diphosphoglucoronyltransferase
enzymes
and
reducing
P-glycoprotein transport. Metabolic interactions of
milk thistle with substrates metabolized by CYP3A4 or
CYP2C9 or transported by P-glycoprotein, especially
drugs with a narrow therapeutic index such as
anticoagulants or digoxin, cannot be excluded106,107 and
should be monitored closely.
Review
Black Cohosh
Black cohosh (Cimicifuga racemosa) is used as an herbal
remedy for relief of symptoms of premenstrual tension,
menopause and other gynecological disorders. The
exact mechanism of action of black cohosh is unclear.
Recent findings suggest some of the physiological
effects of black cohosh may be due to compounds that
bind and activate serotonin receptors.108 It also contains
complex biological molecules, such as triterpene
glycosides, which block osteoclastogenesis in vivo and
in vitro, thereby reducing cytokine-induced bone loss
(osteoporosis).109 A National Center of Complementary
and Integrative Health (NCCIH)-funded study found
black cohosh, whether used alone or with other
botanicals, failed to relieve hot flashes and night sweats
in postmenopausal women.110 In a Cochrane systematic
review of 16 randomized controlled trials, recruiting
a total of 2,027 perimenopausal or postmenopausal
women, no significant difference between black cohosh
and placebo in the frequency of hot flashes or in
menopausal symptoms was found.111
179
The current evidence on the safety of black cohosh is
inconclusive due to poor reporting. Davis et al. showed
no increase in the incidence of primary breast cancer
in black cohosh-treated transgenic mice, but increased
lung metastasis of preexisting breast cancer.112 While
uncommon, a few cases of black cohosh-related
hepatotoxicity were reported.113 Although a 2011 metaanalysis refuted this concern,114 regulatory agencies in
Australia, Canada and the European Union released
statements regarding the “potential association”
between black cohosh and hepatotoxicity. The United
States Pharmacopeia advises that black cohosh products
be labeled with a cautionary statement of hepatotoxicity.
This is a change from its expert committee’s 2002
decision, which required no such statement.115
Echinacea
Echinacea (Echinacea purpurea, Echinacea pallida
and Echinacea angustifolia) is known mainly for its
immunostimulant properties used for the prevention and
treatment of common cold and influenza, but efficacy
studies have yielded inconsistent results.116 Randomized,
double-blind, placebo-controlled trials showed no
beneficial effects of unrefined echinacea or echinacea
capsules on symptoms of common cold or rhinovirus
infection compared to placebo.117,118 Echinacea use has
been reported to cause side effects such as nausea,
dizziness and gastrointestinal upset. Echinacea inhibits
hepatic enzymes CYP1A2 and CYP2C9. Echinacea
has a complex effect on CYP3A4 activity, inhibiting
intestinal CYP3A4 but increasing hepatic CYP3A4
activity (Table 3),119 therefore the effect on oral versus
parenteral medications could be different. Thus, the
effect of echinacea in the elderly using medications
metabolized by CYP3A4 should be closely monitored
or used with caution.120
Echinacea does not change the pharmacokinetics of
digoxin, a P-glycoprotein substrate,121 nor does it alter the
pharmacokinetics of chlorzoxazone (CYP2E1 probe),122
debrisoquine (CYP2D6 probe)122 or tolbutamide
(CYP2C9 probe).119 In 12 healthy subjects, after a single
dose of warfarin before and after taking echinacea for
14 days, the pharmacokinetics and pharmacodynamics
of warfarin were not significantly altered.123 Liver
toxicity with elevation of transaminases was reported
in patients using echinacea,124 and caution should be
used when combining it with other medications that
can harm the liver.52,125 Echinacea may decrease the
effects of cyclosporine and steroids because of the
immunostimulant effect and complex effect on CYP3A4
activity,120,125 therefore transplant patients should be
advised against using this herb.
St. John’s Wort
St. John’s wort or St. Joan’s wort (Hypericum
perforatum), a perennial herb first used as a supplement
by the ancient Greeks, is popular in Europe and the
United States. It is used as a folk remedy for depression,
anxiety, mental health conditions and sleep disturbances.
Studies measuring the effectiveness of St. John’s wort
in treating depression have yielded conflicting results.
A large 2002 study showed the herb to be no more
effective than placebo in treating moderately severe
major depression.126 Linde et al.’s Cochrane analysis127
of St. John’s wort for major depression reviewed 29
randomized, double-blind studies comprising 5,489
people and concluded that hypericum extracts were
more effective than placebo and as effective as standard
antidepressants with a lesser toxicity profile for major
depressive episodes. However, the authors noted studies
conducted in German-speaking countries were more
favorable to hypericum than others including the United
States. They recommended further investigating the
reasons for these differences.
Due to its potential for drug interactions St. John’s
wort is not a benign supplement, and its current use
as an over-the-counter medicine for depression is not
endorsed by the FDA. Its active constituent hyperforin
is a well-known activator of the pregnane X receptor,128
which results in enhanced expression of the drug efflux
transporter ABCB1 (P-glycoprotein)129 and induction of
CYP3A4 (Table 3), an enzyme involved in metabolism
of the majority of prescription medications used in
cardiovascular practice.130 Thus, potentially serious
adverse reactions can occur from coadministration with
drugs metabolized through CYP3A4 or transported by
P-glycoprotein. Hypotension and delayed emergence
from anesthesia were associated with prior use of St.
John’s wort.131 In HIV patients, it can decrease plasma
levels of indinavir, resulting in failure of antiretroviral
therapy.129 It can reduce drug levels of ethinylestradiol,132
and women taking St. John’s wort with oral contraceptives
could experience an unplanned pregnancy or increased
breakthrough bleeding due to decreased efficacy.133 It
can increase docetaxel’s plasma clearance, reducing its
efficacy and peak plasma concentration, thus causing
Review
undertreatment of cancer patients.134 It causes a nearly
50% decrease in cyclosporine levels in organ transplant
recipients,135 and cases of acute transplant rejection
have been reported.135-137 The consequent potential
for transplant rejection is a life-threatening effect and
justifies abolishing use of St. John’s wort in this patient
population.138 Reduced levels of digoxin also have been
reported.139 St. John’s wort can alter anticoagulation
properties of warfarin resulting in unstable INR values,140
and bleeding complications were reported in elderly
taking warfarin141 (Table 2 and Online Supplemental
Appendix 1). It can cause hypertensive crisis with foods
rich in tyramine.142 Additionally, use of St. John’s wort
is associated with the induction of mania or hypomania
in patients suffering with bipolar disorder,143 and it has
been implicated with causing reversible photosensitivity
and erythematous skin lesions after sun exposure.144
Ginseng
American ginseng (Panax quinquefolius) and Asian
ginseng (Panax ginseng) belong to the genus Panax
in which the main active constituents are steroidal
saponins called ginsenosides,145 whereas Siberian
ginseng (Eleutherococcus senticosus) is in the same
family but not genus, with eleutherosides as the active
component. These are commonly used herbs worldwide,
consumed in various forms including as tea and other
beverages. They are used mainly for beneficial effect in
stress reduction, memory enhancement, attention deficit
hyperactivity disorder, sexual dysfunction and alleviation
of menopausal symptoms. They also have shown
immunomodulatory, antidiabetic, anti-aging, antifatigue
and anticancer properties. The content of ginsenosides
in the Asian ginseng depends on the raw (white) root
versus steamed (red) ginseng root. Most ginsenosides
and eleutherosides were reported to have an inhibitory
effect on enzymes CYP1A2, CYP2C9, CYP2C19,
CYP2D6 and CYP3A4.146 One case of imatinib-induced
hepatotoxicity after concurrent ginseng ingestion in a
patient with chronic myelogenous leukemia was reported,
which resolved after short course of corticosteroids and
ginseng withdrawal.147 Another case reported similar
findings with concomitant use of antiretroviral drug
raltegravir and ginseng in an HIV-positive patient with
long-term hepatitis C.148 Thus, ginseng should be used
with caution with other CYP3A4-metabolized drugs and
in patients with preexisting liver conditions. Surprisingly,
Gurley et al. noted ginseng did not affect other CYP
enzymes except for slight inhibition of CYP2D6.149
Review
Ginsenosides can inhibit platelet aggregation and
thromboxane formation in vitro,150 prolong activated
partial thromboplastin time and thrombin time in
rats,151 and cause irreversible human platelet inhibition
by panaxynol, a constituent of ginseng.152 Decreased
anticoagulant effects of warfarin in a patient whose
therapy had been stable previously153 and thrombosis
with a subtherapeutic INR were reported.154 American
ginseng also was shown to reduce warfarin effect in
healthy volunteers.155 In contrast, other ginseng species,
including Asian ginseng156 and Korean red ginseng,157
did not affect warfarin’s anticoagulant effect. In 12
healthy subjects, ginseng treatment for 2 weeks did not
affect either the pharmacokinetics or pharmacodynamics
of a single 25-mg dose of warfarin.140 Long-term effects
of ginseng in elderly with comorbidities have not been
systematically assessed. Because of the potential for
platelet inhibition in humans, ginseng use should be
discontinued in patients at least 1 week before surgery.95
There is also conflicting evidence of estrogenic properties
of ginsenosides. Human studies in pregnancy and lactation
are lacking, but there is in vitro evidence of teratogenicity
in animal embryos with ginsenoside use. Thus, caution
should be exercised with ginseng’s use during pregnancy
and lactation and should be avoided if possible. Ginseng
may lower blood sugar levels, and this effect may be greater
in patients with diabetes than in nondiabetic individuals.
Hypoglycemia has been described with concomitant
use of ginseng with oral hypoglycemic agents,158 and its
use has been reported to reduce postprandial increment
of glucose in nondiabetics.159 Caution is advised when
using it with antidiabetic medicines or supplements
that might lower blood sugar (devil’s claw, ginger,
fenugreek, gum and guar), and blood glucose levels
may require closer monitoring and dose adjustments.
Ginseng may increase cardiac repolarization and QTc
interval160 as well as proarrhythmic risk by additional
increase in the bioavailability of antiarrhythmic agents
due to reduced metabolism.161 Siberian ginseng was
reported to reproducibly elevate digoxin concentrations,
which normalized after discontinuation and increased
after resumption of ginseng.162 Ginsenosides, which
include more than 20 saponin glycosides with a nucleus
similar in structure to steroid hormones,163 can cause
mastalgia,164 functionally abnormal vaginal bleeding165
and gynecomastia in males. Coingestion of American
ginseng with antidepressants like phenelzine can cause
side effects like nervousness, anxiousness, headache
181
and insomnia.166 Hypertension has been reported with
chronic ginseng ingestion, with normalization of blood
pressure after ginseng discontinuation.167
Grapefruit Juice
Grapefruit (Citrus paradisi) juice is commonly used
for its medicinal effect in regulating glucose levels
in diabetics, to prevent cancer and in lowering serum
cholesterol levels in cardiovascular diseases. Active
ingredients within grapefruit juice (furanocoumarins
and the flavonoids naringenin and bergamottin) have
an inhibitory effect on P-glycoprotein, organic anionic
transporting polypeptide and CYP3A4 enzymatic
activity in intestinal enterocytes, mostly affecting
orally administered drugs. This can lead to elevations
of the serum concentrations of drugs transported by
P-glycoprotein or metabolized by CYP3A4 substrates
(Table 3) and cause adverse effects. Even a single
exposure to one glass of the grapefruit juice can produce
clinically significant interaction, and with the half-life
of CYP3A4 being > 8 hours, its reversal inhibition by
grapefruit increases the bioavailability and blood levels
of drugs metabolized by this enzyme (Table 3) up to 72
hours.168,169 Therefore, repeated juice intake can result
in adverse effects even if not taken concomitantly with
drugs. This effect is present whether grapefruit is taken
as a whole fruit or in juice form, causing clinically
relevant increase in blood concentration of affected
drugs that can result in adverse effects.170 Some examples
include exaggerated antihypertensive response with
calcium channel blockers (felodipine),171 increased risk
of rhabdomyolysis and hepatotoxicity with statins,168
hypoglycemia with antidiabetics (repaglinide), increased
steady-state concentration of cyclosporine, potentiation
of toxicity with antiarrhythmics with QT prolongation
and torsades de pointes,172 and augmentation of
antiplatelet activity of cilostazol leading to pupura.173
There also are case reports of elevated INR and hematoma
with grapefruit juice ingestion in patients previously
stabilized on warfarin.174 Therefore, drug interactions
with grapefruit juice are a concern, especially in
situations when the magnitude of interaction is large, in
drugs with a narrow therapeutic index and in the elderly
with multiple comorbidities and polypharmaceutical
regimens. Its use in such populations should be
limited and the potential for adverse grapefruit and
drug interaction should be discussed with the elderly
taking drugs metabolized through CYP3A (Table 3)
or transported through P-glycoprotein to avoid any
potential adverse effect.
Federal Regulation of Herbal Supplements
Herbal supplements are “medicinal” products of
plant origin that are not officially recognized as drugs
nor intended for use as conventional foods, but are
considered part of treatment modalities in integrative
medicine. Unlike drug products that must be proved
safe and effective before marketing, herbal or dietary
supplements do not need prior FDA authorization before
being marketed except for “new dietary ingredients”
marketed after October 15, 1994, which only require
demonstration of safety and not efficacy by submitting
a premarket notification 75 days prior to the launch
of the new product. However, the FDA does require
manufacturers to register with its agency.
The U.S. Dietary Supplement Health and Education Act
of 1994 defines and regulates dietary supplements.175
Under the act, supplements are effectively regulated
by the FDA for Good Manufacturing Practices under
21 CFR Part 111.176 The current Good Manufacturing
Practices (cGMP) final rule177 ensures consistency
by requiring information about manufacturing,
packing, labeling, identity, quality, strength, purity and
composition in the manufacture of dietary supplements.
However, without validated analytical standards and
methods to detect the active ingredients of the vast
majority of herbal supplements, it is difficult for the
FDA to detect potency or dosing requirements for
these herbal products. The cGMP final rule requires
that manufacturers, not the FDA, determine the quality
specifications for their products, and companies that
want to use less stringent specifications can do so
without penalty.178
Manufacturers may make three types of claims for
their dietary supplement products: health claims,
structure/function claims and nutrient content claims.
These claims are not endorsed by the FDA, and the
manufacturer is solely responsible for ensuring the
accuracy and truthfulness of these claims. Thus, by
law, if a dietary supplement makes a claim, it must
state a “disclaimer” that the FDA has not evaluated the
claim. The disclaimer also must state that this product
is not intended to “diagnose, treat, cure or prevent any
disease,” because only a drug can legally make such
a claim. Manufacturers, packagers and distributors of
Review
dietary supplements are required to report any serious
adverse events to the FDA within 15 business days after
being notified (i.e. consumer complaints), but they are
not required to do any active surveillance and reporting
on their own. They also need to provide any additional
medical information they obtain within a year of the
adverse event report.
Consumers and other health care providers are
encouraged to report similar adverse events to the
FDA. The FDA has intervened by identifying harmful
dietary supplements or potential contamination, but
while FDA’s curbing measures have had some impact, it
has not been enough to restrict the access of hazardous
botanicals to general consumers when manufacturers
can simply introduce new similar formulations.179 With
the limited resources available to the FDA, and presence
of 1,800 manufacturers and more than 75,000 products
in the supplement market,178 enforcement of existing
laws is difficult.180 The FDA cannot fully accomplish
its mission of consumer protection without increased
resources and regulations on the industry.
Limitations of Scientific Evidence on Efficacy
and Safety
Most of the scientific knowledge on herbal remedies
and herb-drug interactions comes from in vitro studies,
animal studies and case reports; there is a lack of
validated controlled clinical trials. Information about
pharmacokinetics, pharmacodynamics, efficacy and
safety of herbal products in the elderly population with
cardiovascular diseases,181 who also have multiple
comorbidities and take different medicines, is particularly
limited.182 Lack of safety data for cardiovascular disease
patients is a recurring phenomenon in herbal medicine,
with no rigorous attention given to adverse events or
interactions with prescription drugs.13 Even when data
are available for other populations, typically healthy
volunteers or low-risk patients without comorbid
conditions, findings are often questionable because
of a lack of consistency in research methods, small
number of subjects, absence of placebo groups, lack of
standardization of supplements and absence of data on
herb-drug interactions. Thus, findings for specific herbal
products are of limited usefulness for making decisions
about efficacy or safety. The dramatic increase of dietary
supplement sales in the last two decades has unmasked
several herbal adverse effects and life-threatening
herb-drug interactions as discussed in this review,
Review
particularly with the use of St. John’s wort. The elderly
are particularly susceptible to herb-mediated changes to
CYP activity and should be properly instructed to avoid
supplements that can increase adverse efects.149,183 For
example one study reported ginseng inhibited CYP2D6
in elderly but not younger subjects.184
Most of the information about drug-herb interactions
comes from clinical practice, but a systematic assessment
of such interactions by collecting data from clinical
studies may provide additional insights. In addition,
the system for reporting adverse effects needs to be
closely followed by consumers, health care providers
and manufacturers to report adverse interactions as
emphasized by the Institute of Medicine.185
Inadequate Quality Control Measures
Herbal and dietary supplement manufacturers in the
United States include a blanket warning on labels
rather than specifying adverse effects and potential
interactions.133,186,187 Additionally, herbal products
may be contaminated with other substances, contain
attenuated quantity or quality of active ingredients188 or
many not contain the intended ingredient at all, causing
variations in their side effect profiles.189 A 2013 study of
44 popular supplements sold by 12 companies showed
most of the herbal products tested were of poor quality,
often diluted or replaced by cheap fillers like soybean,
wheat and rice.190 A recent investigation by the New York
Attorney General’s office into store-brand supplements
at four national retailers showed all but five of the 24
products tested to be either contaminated or replaced by
another plant product.191
Despite FDA guidelines mandating manufacturers to
avoid contamination, supplements repeatedly have been
reported to contain adulterant compounds, including other
herbs, heavy metals,28,192 anabolic steroids22 or prescription
drugs193 as well as contaminant microbials,27 pesticides
and other compounds26 that put unsuspecting consumers
at risk of adverse side effects and herb-drug interactions.
Several cases of potentially life-threatening hepatotoxicity
(leading to liver transplantation in some) attributed
to Herbalife® products (Los Angeles, CA) marketed
for promoting energy, ﬁtness and weight control were
recently documented.194 In an analysis of 20 herbal/dietary
supplements marketed as natural slimming products, eight
formulations contained sibutramine, five had sibutramine
with phenolphthalein and one was adulterated with
183
synephrine.21 Sibutramine has a potential for abuse or
addiction and elevates blood pressure and heart rate,
posing significant risk to patients with heart disease, heart
failure, arrhythmias or stroke,195 while phenolphthalein is
known to have carcinogenic properties. In June 2011, two
New Jersey dietary supplement companies were forced to
shut down all manufacturing and distribution following
FDA investigation into violations of misbranding food
labels, selling products containing a major food allergen
and having unhygienic conditions; a dead rodent cut in
half along with rodent excreta and pellets were found on a
blender motor platform, and bags of raw ingredients were
gnawed through by rodents and covered with rodent urine
and feces.196
No package inserts for herbal supplements describing
potential adverse events or drug interactions are required,
and patients have no way of distinguishing safe from
potentially harmful supplements. Direct-to-consumer
advertisement featuring extravagant, unsubstantiated
and dubious health claims by the supplement industry197
continues despite regulatory guidelines. The Federal
Trade Commission provides oversight and guidance but
relies on advertisement surveillance for enforcement
of its guidelines rather than approval before use. Thus,
despite levying millions of dollars of fines yearly,
misleading marketing campaigns continue to thrive.198
Underreporting of Adverse Herb Reactions and
Herb-Drug Interactions
An FDA-commissioned study estimated receiving less
than 1% of all adverse events associated with dietary
supplements.199 Many herb-related adverse events are
underreported by patients or clinical practioners,200
probably for a multitude of reasons. Consumers perceive
herbal products as “natural remedies” carrying minimal
to no risk,201 and are thus unable to correlate any adverse
effects and more likely to blame prescription medicines
when encountering a side effect. Most complementary
medicine users fail to disclose herbal product use to their
physicians.202 Consumers may lack direction on how to
file a complaint or may assume it is the role of the health
care provider once informing them of an adverse event.
Health providers have limited training on herbal adverse
effects, toxicities and herb-drug interactions,203 and may
underrecognize their occurrence. A prospective study
looking into web-based questionnaires administered
to health care providers noted that approximately 73%
of physician respondents did not know how or where to
report adverse events related to dietary supplements.204
The Dietary Supplements Information Expert Committee
has recommended enhancing data collection approaches,
improving coordination of adverse event-related
surveillance programs, strengthening education programs
for public and health care sectors and conducting further
research into safety of dietary supplements.205 Reports
of suspected or documented adverse events may be
submitted voluntarily to the FDA’s MedWatch program206
or other organizations such as a poison control center.
Public Misperception of Benefits of Herbal
Supplementation
The public seems to believe that dietary supplements,
like pharmaceuticals, undergo scrutiny and rigorous
research before marketing. According to a nationwide
interactive poll of 1,010 respondents, 59% of the
respondents believed the supplements were approved by a
government agency before being sold, 68% believed that
listing potential side effects on labels was a requirement
and 55% believed that supplement manufacturers were
required to make scientific evidence-backed safety
claims.207 Similarly, the PEW Internet and American
Life Project reported 52% of users to have visited health
sites believed “almost all” or “most” health information
on the Internet is credible.208 While some media sources
provide a wealth of accurate information, others contain
false, unsubstantiated information or even conflicting
statements. For example, in a study of Internet marketing
of herbal products197 at least 81% of websites were found
to make one or more health claims, with more than 50%
claiming to treat, prevent, diagnose or cure specific
diseases despite regulations barring such statements.
Another study investigating 12 weight-loss supplements
sold online identified eight ingredients with reported lifethreatening cardiac adverse effects or death.209 Warning
about potential adverse effects did not appear on the web
pages. One product’s list of ingredients included ma huang
(Chinese ephedra), even though marketing of ephedracontaining products is banned in the United States. The
popular belief that natural supplements confer health
benefits210 without potential for harm211 makes consumers
vulnerable to making choices that could be deleterious.
Knowledge Barriers Between Patients and
Providers Regarding Herb-Drug Interactions
Many herbal supplements contain active ingredients
that have strong biological effects and can make them
unsafe in certain situations, especially when consumed
Review
in large amounts or taken with drugs that can alter their
pharmacokinetic and pharmacodynamics parameters.
Despite increased educational initiatives and the large
body of literature on herbal remedies, there remains
a considerable knowledge gap on herb-related safety
issues among both health care providers212 and health
store employees213 who are usually the first point of
contact for consumers interested in buying herbal
remedies. This lack of knowledge exchange can
result in distribution of inconsistent information that
can heighten confusion and spread false messages,
thus further complicating issues. Physicians are
advised to be aware of potential therapeutic benefits
of complementary and alternative medicinal agents
while at the same time wary of their unwanted risks,
toxicities and potential interactions. Better recognition
of herb profiles will allow physicians to identify herbdrug interferences, antagonisms and synergies and
assist in formulating better goal-driven individualized
health care plans.
Initiatives like the Dietary Supplement Verification
Program from U.S. Pharmacopeia can ensure that
products are labeled correctly and devoid of contaminants.
It is also important for health care providers to develop
good communication with their patients and create a
comfortable environment for discussing herbs and other
supplements. Consumers are encouraged to consult
with their medical providers when concomitantly using
nutraceuticals with prescription drugs. It is prudent to
work with preparations manufactured by companies that
adhere to Good Manufacturing Practices pharmaceutical
standards. However, many of these products are not
readily available to the public over the counter. Without
the same oversight for herbal products that is required
for allopathic medicine, the public risks self-medicating
with substances that are potentially ineffective,
deleterious or both, leading to harmful consequences.
Conclusions
Most medications, herbal preparations and
nutraceuticals have notable effects on biochemical
pathways and can influence wound healing, metabolic
processes, coagulation and cardiovascular function.
They also can interact with other prescribed drugs. A
large portion of the data available regarding the effects
of herbal medicines is anecdotal and lacks proper
evidence regarding safety in the elderly with multiple
comorbidities. Quality control standards are highly
Review
variable and marketing of many products misleading
or potentially harmful when used by the vulnerable
population taking multiple medicines.
Public and health practitioners need to be reminded
that herbal supplements are bioactive compounds
and could have adverse effects when combined with
medications whose effectiveness and safety can be
altered by natural products such as St. John’s wort
or grapefruit juice. General guidelines or expert
opinion-based recommendations have been provided
in peer-reviewed journals, but national guidelines
are needed. The National Center for Complementary
and Integrative Health provides information about
commonly used herbs and their potential for
drug interactions. Major academic centers (e.g.
Mayo Clinic, Memorial Sloan-Kettering Hospital
and University of Maryland) also provide this
information, and links to these sites are provided in
Online Supplemental Appendix 2.
• Herbal products are sold as dietary supplements
and not subject to the same regulatory standards
as pharmacological drugs.
• The FDA previews “dietary ingredients” for
safety, but not for effectiveness.
• Elderly patients with comorbidities using
multiple medications and dietary supplements are
at increased risk of adverse interactions.
• Unlike drugs, supplements are not intended to
treat, diagnose, prevent or cure diseases, and such
claims need to be proven scientifically before
accepted by the public or health care providers.
• Products sold as “natural” are not always safe.
Always remember –– safety first.
Funding Sources
Dr. Jahangir is supported by a grant from the National
Heart, Lung, and Blood Institute (R01 HL101240) and
intramural research funding from Aurora Health Care,
Milwaukee, WI.
None.
185
References
1. Miller KL, Liebowitz RS, Newby LK. Complementary and
alternative medicine in cardiovascular disease: a review of
biologically based approaches. Am Heart J. 2004;147:401-11.
CrossRef
2. Yeh GY, Davis RB, Phillips RS. Use of complementary
therapies in patients with cardiovascular disease. Am J
Cardiol. 2006;98:673-80. CrossRef
3. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in
alternative medicine use in the United States, 1990-1997:
results of a follow-up national survey. JAMA. 1998;280:
1569-75. CrossRef
4. Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs
of complementary and alternative medicine (CAM) and
frequency of visits to CAM practitioners: United States, 2007.
Natl Health Stat Report. 2009;(18):1-14.
5. Peregoy JA, Clarke TC, Jones LI, Stussman BJ, Nahin RL.
Regional variation in use of complementary health approaches
by U.S. adults. NCHS Data Brief. 2014;(146):1-8.
6. American Botanical Council. Herbal dietary supplement
retail sales up 7.9% in 2013 (Sept. 3, 2014). http://cms.
herbalgram.org/press/2014/2013_Herb_Market_Report.html
?ts=1436473622&signature=9feba666bd696318fedbcbc
61c8180f1. Accessed July 23, 2015.
7. Lindstrom A, Ooyen C, Lynch ME, Blumenthal M. Herb
supplement sales increase 5.5% in 2012: herbal supplement
sales rise for 9th consecutive year; turmeric sales jump 40%
in natural channel (available online at http://cms.herbalgram.
org/herbalgram/issue99/hg99-mktrpt.html).
HerbalGram.
2013;(99):60-5.
8. Daniells S. Herbal supplement sales to hit $93.15 billion by
2015: report (Jan. 13, 2011). http://www.nutraingredients-usa.
com/Markets/Herbal-supplement-sales-to-hit-93.15-billionby-2015-Report. Accessed July 23, 2015.
9. Baum C, Kennedy DL, Forbes MB, Jones JK. Drug use in the
United States in 1981. JAMA. 1984;251:1293-7. CrossRef
10. Nahin RL, Pecha M, Welmerink DB, et al. Concomitant use
of prescription drugs and dietary supplements in ambulatory
elderly people. J Am Geriatr Soc. 2009;57:1197-205.
CrossRef
11. Samaras D, Samaras N, Lang PO, Genton L, Frangos E,
Pichard C. Effects of widely used drugs on micronutrients: a
story rarely told. Nutrition. 2013;29:605-10. CrossRef
12. Tachjian A, Maria V, Jahangir A. Use of herbal products and
potential interactions in patients with cardiovascular diseases.
J Am Coll Cardiol. 2010;55:515-25. CrossRef
13. Jahangir A, Viqar M, Tachjian A. Reply to: Use of herbal
products and potential interactions in patients with
cardiovascular diseases. J Am Coll Cardiol. 2010;56:905-9.
CrossRef
14. Carlson JE. Perils of polypharmacy: 10 steps to prudent
prescribing. Geriatrics. 1996;51:26-30, 35.
15. Mirza M, Strunets A, Shen WK, Jahangir A. Mechanisms of
arrhythmias and conduction disorders in older adults. Clin
Geriatr Med. 2012;28:555-73. CrossRef
16. Thomson P, Jones J, Evans JM, Leslie SL. Factors influencing
the use of complementary and alternative medicine and
whether patients inform their primary care physician.
Complement Ther Med. 2012;20:45-53. CrossRef
17.AARP and National Center for Complementary and
Alternative Medicine Survery Report. Complementary and
alternative medicine: what people aged 50 and older discuss
with their health care providers. https://nccih.nih.gov/sites/
nccam.nih.gov/files/news/camstats/2010/NCCAM_aarp_
survey.pdf. Accessed September 20, 2015.
18.National Center for Complementary and Alternative
Medicine. Time to talk about CAM: health care providers and
patients need to ask and tell (NIH News, June 6, 2008). http://
www.nih.gov/news/health/jun2008/nccam-06.htm. Accessed
September 20, 2015.
19.MedLine Plus. Ginseng, Panax. http://www.nlm.nih.gov/
medlineplus/druginfo/natural/patient-ginseng.html. Accessed
July 23, 2015.
20. Johnson JC. General concepts of geriatric medicine. Clin
Podiatr Med Surg. 1993;10:23-33.
21. Vaysse J, Balayssac S, Gilard V, Desoubdzanne D, MaletMartino M, Martino R. Analysis of adulterated herbal
medicines and dietary supplements marketed for weight loss
by DOSY 1H-NMR. Food Addit Contam Part A Chem Anal
Control Expo Risk Assess. 2010;27:903-16. CrossRef
22. Geyer H, Parr MK, Koehler K, Mareck U, Schänzer W, Thevis
M. Nutritional supplements cross-contaminated and faked
with doping substances. J Mass Spectrom. 2008;43:892-902.
CrossRef
23.U.S. Food and Drug Administration. Steam dietary
supplement (safety alert; Aug. 24, 2009). http://
www.fda.gov/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/ucm174339.htm.
24. U.S. Food and Drug Administration. FDA warns consumers
to avoid red yeast rice products promoted on internet as
treatments for high cholesterol products found to contain
unauthorized drug (news release; Aug. 9, 2007). http://www.
fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/
ucm108962.htm. Accessed May 15, 2010.
25. Navarro VJ. Herbal and dietary supplement hepatotoxicity.
Semin Liver Dis. 2009;29:373-82. CrossRef
26. Dara L, Hewett J, Lim JK. Hydroxycut hepatotoxicity: a case
series and review of liver toxicity from herbal weight loss
supplements. World J Gastroenterol. 2008;14:6999-7004.
CrossRef
27. Stickel F, Droz S, Patsenker E, Bögli-Stuber K, Aebi B, Leib
SL. Severe hepatotoxicity following ingestion of Herbalife
nutritional supplements contaminated with Bacillus subtilis.
J Hepatol. 2009;50:111-7. CrossRef
28. Saper RB, Phillips RS, Sehgal A, et al. Lead, mercury, and
arsenic in US- and Indian-manufactured Ayurvedic medicines
sold via the Internet. JAMA. 2008;300:915-23. CrossRef
29. Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The
effect of grapefruit juice on drug disposition. Expert Opin
Drug Metab Toxicol. 2011;7:267-86. CrossRef
30. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition,
absorption/elimination/transporter interplay and the role of
food on drug absorption. Adv Drug Deliv Rev. 2008;60:717-33.
CrossRef
31.Fernández-San-Martin MI, Masa-Font R, Palacios-Soler
L, Sancho-Gömez P, Calbö-Caldentey C, Flores-Mateo
G. Effectiveness of Valerian on insomnia: a meta-analysis
of randomized placebo-controlled trials. Sleep Med.
2010;11:505-11. CrossRef
32. Shi Y, Dong JW, Zhao JH, Tang LN, Zhang JJ. Herbal insomnia
medications that target GABAergic systems: a review of the
psychopharmacological evidence. Curr Neuropharmacol.
2014;12:289-302. CrossRef
Review
33. Jepson RG, Williams G, Craig JC. Cranberries for preventing
urinary tract infections. Cochrane Database Syst Rev.
2012;10:CD001321. CrossRef
34. Griffiths AP, Beddall A, Pegler S. Fatal haemopericardium
and gastrointestinal haemorrhage due to possible interaction
of cranberry juice with warfarin. J R Soc Promot Health.
2008;128:324-6. CrossRef
35. Rindone JP, Murphy TW. Warfarin-cranberry juice interaction
resulting in profound hypoprothrombinemia and bleeding. Am
J Ther. 2006;13:283-4. CrossRef
36.Mohammed Abdul MI, Jiang X, Williams KM, et al.
Pharmacodynamic interaction of warfarin with cranberry
but not with garlic in healthy subjects. Br J Pharmacol.
2008;154:1691-700. CrossRef
37. Greenblatt DJ, von Moltke LL, Perloff ES, Luo Y, Harmatz
JS, Zinny MA. Interaction of flurbiprofen with cranberry
juice, grape juice, tea, and fluconazole: in vitro and clinical
studies. Clin Pharmacol Ther. 2006;79:125-33. CrossRef
38. Lilja JJ, Backman JT, Neuvonen PJ. Effects of daily ingestion
of cranberry juice on the pharmacokinetics of warfarin,
tizanidine, and midazolam--probes of CYP2C9, CYP1A2, and
CYP3A4. Clin Pharmacol Ther. 2007;81:833-9. CrossRef
39. Ried K, Frank OR, Stocks NP. Aged garlic extract reduces
blood pressure in hypertensives: a dose-response trial. Eur J
Clin Nutr. 2013;67:64-70. CrossRef
40. Ashraf R, Khan RA, Ashraf I. Garlic (Allium sativum)
supplementation with standard antidiabetic agent provides
better diabetic control in type 2 diabetes patients. Pak J Pharm
Sci. 2011;24:565-70.
41. Aslam M, Stockley IH. Interaction between curry ingredient
(karela) and drug (chlorpropamide). Lancet. 1979;1:607.
42.Laroche M, Choudhri S, Gallicano K, et al. Severe
gastrointestinal toxicity with concomitant ingestion of
ritonavir and garlic. (abstr.) Can J Infect Dis. 1998;9 Suppl
A:471P.
43. Bordia A, Verma SK, Srivastava KC. Effect of garlic (Allium
sativum) on blood lipids, blood sugar, fibrinogen and
fibrinolytic activity in patients with coronary artery disease.
Prostaglandins Leukot Essent Fatty Acids. 1998;58:257-63.
CrossRef
44. Macan H, Uykimpang R, Alconcel M, et al. Aged garlic
extract may be safe for patients on warfarin therapy. J Nutr.
2006;136:793S-795S.
45. Banerjee SK, Maulik SK. Effect of garlic on cardiovascular
disorders: a review. Nutr J. 2002;1:4. CrossRef
46. Rahman K, Billington D. Dietary supplementation with aged
garlic extract inhibits ADP-induced platelet aggregation in
humans. J Nutr. 2000;130:2662-5.
47. Evans V. Herbs and the brain: friend or foe? The effects
of ginkgo and garlic on warfarin use. J Neurosci Nurs.
2000;32:229-32. CrossRef
48. German K, Kumar U, Blackford HN. Garlic and the risk of
TURP bleeding. Br J Urol. 1995;76:518. CrossRef
49. Fedder SL. Spinal epidural hematoma and garlic ingestion.
Neurosurgery. 1990;27:659. CrossRef
50. Di Silverio F, D’Eramo G, Lubrano C, et al. Evidence that
Serenoa repens extract displays an antiestrogenic activity in
prostatic tissue of benign prostatic hypertrophy patients. Eur
Urol. 1992;21:309-14.
51. Ernst E. The risk-benefit profile of commonly used herbal
therapies: ginkgo, St. John’s wort, ginseng, echinacea,
Review
saw palmetto, and kava. Ann Intern Med. 2002;136:42-53.
CrossRef
52. Miller LG. Herbal medicinals: selected clinical considerations
focusing on known or potential drug-herb interactions. Arch
Int Med. 1998;158:2200-11. CrossRef
53. Wilt T, Ishani A, Stark G, MacDonald R, Mulrow C, Lau J.
Serenoa repens for benign prostatic hyperplasia. Cochrane
Database Syst Rev. 2000;(2):CD001423. CrossRef
54. Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign
prostatic hyperplasia. N Engl J Med. 2006;354:557-66.
CrossRef
55. Tacklind J, Macdonald R, Rutks I, Stanke JU, Wilt TJ. Serenoa
repens for benign prostatic hyperplasia. Cochrane Database
Syst Rev. 2012;12:CD001423. CrossRef
56. Barry MJ, Meleth S, Lee JY, et al. Effect of increasing doses
of saw palmetto extract on lower urinary tract symptoms: a
randomized trial. JAMA. 2011;306:1344-51. CrossRef
57. Braeckman J. The extract of Serenoa repens in the treatment
of benign prostatic hyperplasia: a multicenter open study.
Curr Therap Res. 1994;55:776-85. CrossRef
58. Plosker GL, Brogden RN. Serenoa repens (Permixon). A
review of its pharmacology and therapeutic efficacy in benign
prostatic hyperplasia. Drugs Aging. 1996;9:379-95. CrossRef
59. Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage
associated with the use of extract of Saw Palmetto herb: a case
report and review of literature. J Intern Med. 2001;250:167-9.
CrossRef
60.Bressler R. Herb-drug interactions. Interactions between
saw palmetto and prescription medications. Geriatrics.
2005;60:32, 34.
61. Jibrin I, Erinle A, Saidi A, Aliyu ZY. Saw palmetto-induced
pancreatitis. South Med J. 2006;99:611-2. CrossRef
62. Hamid S, Rojter S, Vierling J. Protracted cholestatic hepatitis
after the use of prostata. Ann Intern Med. 1997;127:169-70.
CrossRef
63. Yale SH, Glurich I. Analysis of the inhibitory potential of
Ginkgo biloba, Echinacea purpurea, and Serenoa repens on
the metabolic activity of cytochrome P450 3A4, 2D6, and
2C9. J Altern Complement Med. 2005;11:433-9. CrossRef
64. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment
of botanical supplementation on human cytochrome P450
phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle,
and saw palmetto. Clin Pharmacol Ther. 2004;76:428-40.
CrossRef
65. Yue QY, Jansson K. Herbal drug curbicin and anticoagulant
effect with and without warfarin: possibly related to the
vitamin E component. J Am Geriatr Soc. 2001;49:838.
CrossRef
66. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and
benefits of estrogen plus progestin in healthy postmenopausal
women: principal results From the Women’s Health Initiative
randomized controlled trial. JAMA. 2002;288:321-33.
CrossRef
67. Piersen CE. Phytoestrogens in botanical dietary supplements:
implications for cancer. Integr Cancer Ther. 2003;2:120-38.
CrossRef
68. Howes LG, Howes JB, Knight DC. Isoflavone therapy for
menopausal flushes: a systematic review and meta-analysis.
Maturitas. 2006;55:203-11. CrossRef
69. Tempfer CB, Bentz EK, Leodolter S, et al. Phytoestrogens
in clinical practice: a review of the literature. Fertil Steril.
187
2007;87:1243-9. CrossRef
70. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden
J, Brown J. Phytoestrogens for menopausal vasomotor
symptoms. Cochrane Database Syst Rev. 2013;12:CD001395.
CrossRef
71. Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S,
Di Renzo GC. Endometrial effects of long-term treatment
with phytoestrogens: a randomized, double-blind, placebocontrolled study. Fertil Steril. 2004;82:145-8, quiz 265. CrossRef
72. Kakehashi A, Tago Y, Yoshida M, et al. Hormonally active doses
of isoflavone aglycones promote mammary and endometrial
carcinogenesis and alter the molecular tumor environment in
Donryu rats. Toxicol Sci. 2012;126:39-51. CrossRef
73. Ollberding NJ, Lim U, Wilkens LR, et al. Legume, soy,
tofu, and isoflavone intake and endometrial cancer risk in
postmenopausal women in the multiethnic cohort study.
J Natl Cancer Inst. 2012;104:67-76. CrossRef
74. Bélisle S, Blake J, Basson R, et al. Canadian Consensus
Conference on menopause, 2006 update. J Obstet Gynaecol
Can. 2006;28:S7-94.
75. Anderson GD, Rosito G, Mohustsy MA, Elmer GW. Drug
interaction potential of soy extract and Panax ginseng. J Clin
Pharmacol. 2003;43:643-8. CrossRef
76. Cambria-Kiely JA. Effect of soy milk on warfarin efficacy.
Ann Pharmacother. 2002;36:1893-6. CrossRef
77. Centers for Disease Control and Prevention (CDC). Botulism
associated with home-fermented tofu in two Chinese
immigrants–New York City, March-April 2012. MMWR
Morb Mortal Wkly Rep. 2013;62:529-32.
78. Kudo T. Warfarin antagonism of natto and increase in serum
vitamin K by intake of natto. Artery. 1990;17:189-201.
79.Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E,
Vermeer C. Effect of vitamin K intake on the stability of
oral anticoagulant treatment: dose-response relationships in
healthy subjects. Blood. 2004;104:2682-9. CrossRef
80. Le Bars PL, Katz MM, Berman N, Itil TM, Freedman
AM, Schatzberg AF. A placebo-controlled, double-blind,
randomized trial of an extract of Ginkgo biloba for dementia.
North American EGb Study Group. JAMA. 1997;278:1327-32.
CrossRef
81. Ernst E, Stevinson C. Ginkgo biloba for tinnitus: a review.
Clin Otolaryngol Allied Sci. 1999;24:164-7. CrossRef
82. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment
of intermittent claudication: a meta-analysis of randomized
trials. Am J Med. 2000;108:276-81. CrossRef
83. Birks J, Grimley Evans J. Ginkgo biloba for cognitive
impairment and dementia. Cochrane Database Syst Rev.
2009;(1):CD003120. CrossRef
84. Sierpina VS, Wollschlaeger B, Blumenthal M. Ginkgo biloba.
Am Fam Physician. 2003;68:923-6.
85. Cho HJ, Nam KS. Inhibitory effect of ginkgolide B on platelet
aggregation in a cAMP- and cGMP-dependent manner by
activated MMP-9. J Biochem Mol Biol. 2007;40:678-83.
CrossRef
86. Lamant V, Mauco G, Braquet P, Chap H, Douste-Blazy L.
Inhibition of the metabolism of platelet activating factor
(PAF-acether) by three specific antagonists from Ginkgo
biloba. Biochem Pharmacol. 1987;36:2749-52. CrossRef
87.Kim YS, Pyo MK, Park KM, et al. Antiplatelet and
antithrombotic effects of a combination of ticlopidine and
ginkgo biloba ext (EGb 761). Thromb Res. 1998;91:33-8.
CrossRef
88.Matthews MK Jr. Association of Ginkgo biloba with
intracerebral hemorrhage. Neurology. 1998;50:1933-4.
CrossRef
89. Meisel C, Johne A, Roots I. Fatal intracerebral mass bleeding
associated with Ginkgo biloba and ibuprofen. Atherosclerosis.
2003;167:367. CrossRef
90. Rosenblatt M, Mindel J. Spontaneous hyphema associated
with ingestion of Ginkgo biloba extract. N Engl J Med.
1997;336:1108. CrossRef
91. Fessenden JM, Wittenborn W, Clarke L. Gingko biloba: a case
report of herbal medicine and bleeding postoperatively from a
laparoscopic cholecystectomy. Am Surg. 2001;67:33-5.
92. Hauser D, Gayowski T, Singh N. Bleeding complications
precipitated by unrecognized Gingko biloba use after liver
transplantation. Transpl Int. 2002;15:377-9. CrossRef
93. Jiang X, Williams KM, Liauw WS, et al. Effect of ginkgo
and ginger on the pharmacokinetics and pharmacodynamics
of warfarin in healthy subjects. Br J Clin Pharmacol.
2005;59:425-32. CrossRef
94. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10
and Ginkgo biloba on warfarin dosage in stable, long-term
warfarin treated outpatients. A randomised, double blind,
placebo-crossover trial. Thromb Haemost. 2002;87:1075-6.
95. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and
perioperative care. JAMA. 2001;286:208-16. CrossRef
96.Lifeline to Modern Medicine. Herbal supplements and
anesthesia.
http://www.asahq.org/lifeline/anesthesia%20
topics/herbal%20supplements%20and%20anesthesia.
Accessed July 23, 2015.
97. Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba
extract: mechanisms and clinical indications. Arch Phys Med
Rehabil. 2000;81:668-78. CrossRef
98. Lin YY, Chu SJ, Tsai SH. Association between priapism and
concurrent use of risperidone and Ginkgo biloba. Mayo Clin
Proc. 2007;82:1289-90. CrossRef
99. Kupiec T, Raj V. Fatal seizures due to potential herb-drug
interactions with Ginkgo biloba. J Anal Toxicol. 2005;29:755-8.
CrossRef
100.Galluzzi S, Zanetti O, Binetti G, Trabucchi M, Frisoni GB.
Coma in a patient with Alzheimer’s disease taking low dose
trazodone and gingko biloba. J Neurol Neurosurg Psychiatry.
2000;68:679-80. CrossRef
101.Wiegman DJ, Brinkman K, Franssen EJ. Interaction of Ginkgo
biloba with efavirenz. AIDS. 2009;23:1184-5. CrossRef
102.
Zhao J, Lahiri-Chatterjee M, Sharma Y, Agarwal R.
Inhibitory effect of a flavonoid antioxidant silymarin on
benzoyl peroxide-induced tumor promotion, oxidative
stress and inflammatory responses in SENCAR mouse skin.
Carcinogenesis. 2000;21:811-6. CrossRef
103.Milić N, Milosević N, Suvajdzić L, Zarkov M, Abenavoli
L. New therapeutic potentials of milk thistle (Silybum
marianum). Nat Prod Commun. 2013;8:1801-10.
104.Katiyar SK, Korman NJ, Mukhtar H, Agarwal R. Protective
effects of silymarin against photocarcinogenesis in a mouse
skin model. J Natl Cancer Inst. 1997;89:556-66. CrossRef
105.Fuhr U, Beckmann-Knopp S, Jetter A, Lück H, Mengs U.
The effect of silymarin on oral nifedipine pharmacokinetics.
Planta Med. 2007;73:1429-35. CrossRef
106.Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, et al.
Inhibitory effects of silibinin on cytochrome P-450 enzymes in
human liver microsomes. Pharmacol Toxicol. 2000;86:250-6.
CrossRef
Review
107.Strunets A, Mirza M, Sra J, Jahangir A. Novel anticoagulants
for stroke prevention in atrial fibrillation: safety issues in
the elderly. Expert Rev Clin Pharmacol. 2013;6:677-89.
CrossRef
108.Burdette JE, Liu J, Chen SN, et al. Black cohosh acts as a
mixed competitive ligand and partial agonist of the serotonin
receptor. J Agric Food Chem. 2003;51:5661-70. CrossRef
109.Qiu SX, Dan C, Ding LS, et al. A triterpene glycoside from
black cohosh that inhibits osteoclastogenesis by modulating
RANKL and TNFalpha signaling pathways. Chem Biol.
2007;14:860-9. CrossRef
110.Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K,
Guiltinan J. Treatment of vasomotor symptoms of menopause
with black cohosh, multibotanicals, soy, hormone therapy, or
placebo: a randomized trial. Ann Intern Med. 2006;145:869-79.
CrossRef
111.Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for
menopausal symptoms. Cochrane Database Syst Rev.
2012;9:CD007244. CrossRef
112.Davis VL, Jayo MJ, Ho A, et al. Black cohosh increases
metastatic mammary cancer in transgenic mice expressing
c-erbB2. Cancer Res. 2008;68:8377-83. CrossRef
113.Whiting PW, Clouston A, Kerlin P. Black cohosh and other
herbal remedies associated with acute hepatitis. Med J Aust.
2002;177:440-3.
114.Naser B, Schnitker J, Minkin MJ, de Arriba SG, Nolte
KU, Osmers R. Suspected black cohosh hepatotoxicity: no
evidence by meta-analysis of randomized controlled clinical
trials for isopropanolic black cohosh extract. Menopause.
2011;18:366-75. CrossRef
115.Mahady GB, Low Dog T, Barrett ML, et al. United States
Pharmacopeia review of the black cohosh case reports of
hepatotoxicity. Menopause. 2008;15:628-38. CrossRef
116.Linde K, Barrett B, Wölkart K, Bauer R, Melchart D.
Echinacea for preventing and treating the common cold.
Cochrane Database Syst Rev. 2006;(1):CD000530. CrossRef
117.Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA,
D’Alessio D. Treatment of the common cold with unrefined
echinacea: a randomized, double-blind, placebo-controlled
trial. Ann Intern Med. 2002;137:939-46. CrossRef
118.Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi JD.
An evaluation of Echinacea angustifolia in experimental
rhinovirus infections. N Engl J Med. 2005;353:341-8.
CrossRef
119.Gorski JC, Huang SM, Pinto A, et al. The effect of echinacea
(Echinacea purpurea root) on cytochrome P450 activity in
vivo. Clin Pharmacol Ther. 2004;75:89-100. CrossRef
120.Huntley AL, Thompson Coon J, Ernst E. The safety of
herbal medicinal products derived from Echinacea species: a
systematic review. Drug Saf. 2005;28:387-400. CrossRef
121.Gurley BJ, Swain A, Williams DK, Barone G, Battu SK.
Gauging the clinical significance of P-glycoprotein-mediated
herb-drug interactions: comparative effects of St. John’s
wort, Echinacea, clarithromycin, and rifampin on digoxin
pharmacokinetics. Mol Nutr Food Res. 2008;52:772-9.
CrossRef
122.Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment
of CYP2D6-mediated herb-drug interactions in humans:
effects of milk thistle, black cohosh, goldenseal, kava
kava, St. John’s wort, and Echinacea. Mol Nutr Food Res.
2008;52:755-63. CrossRef
123.Abdul MI, Jiang X, Williams KM, et al. Pharmacokinetic and
Review
pharmacodynamic interactions of echinacea and policosanol
with warfarin in healthy subjects. Br J Clin Pharmacol.
2010;69:508-15. CrossRef
124.Kocaman O, Hulagu S, Senturk O. Echinacea-induced severe
acute hepatitis with features of cholestatic autoimmune
hepatitis. Eur J Intern Med. 2008;19:148. CrossRef
125.Abebe W. Herbal medication: potential for adverse interactions
with analgesic drugs. J Clin Pharm Ther. 2002;27:391-401.
CrossRef
126. Hypericum Depression Trial Study Group. Effect of Hypericum
perforatum (St. John’s wort) in major depressive disorder:
a randomized controlled trial. JAMA. 2002;287:1807-14.
CrossRef
127.Linde K, Berner MM, Kriston L. St. John’s wort for major
depression. Cochrane Database Syst Rev. 2008;(4):CD000448.
CrossRef
128.Moore LB, Goodwin B, Jones SA, et al. St. John’s wort induces
hepatic drug metabolism through activation of the pregnane
X receptor. Proc Natl Acad Sci U S A. 2000;97:7500-2.
CrossRef
129.Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon
J. Indinavir concentrations and St. John’s wort. Lancet.
2000;355:547-8. CrossRef
130.Ernst E. Second thoughts about safety of St. John’s wort.
Lancet. 1999;354:2014-6. CrossRef
131.Crowe S, McKeating K. Delayed emergence and St. John’s
wort. Anesthesiology. 2002;96:1025-7.
132.Yue QY, Bergquist C, Gerdén B. Safety of St. John’s wort
(Hypericum perforatum). Lancet. 2000;355:576-7. CrossRef
133.Sarino LV, Dang KH, Dianat N, et al. Drug interaction between
oral contraceptives and St. John’s Wort: appropriateness of
advice received from community pharmacists and health
food store clerks. J Am Pharm Assoc (2003). 2007;47:42-7.
CrossRef
134.Goey AK, Meijerman I, Rosing H, et al. The effect of St.
John’s wort on the pharmacokinetics of docetaxel. Clin
Pharmacokinet. 2014;53:103-10. CrossRef
135.
Breidenbach T, Hoffmann MW, Becker T, Schlitt H,
Klempnauer J. Drug interaction of St. John’s wort with
cyclosporin. Lancet. 2000;355:1912. CrossRef
136.Ernst E. St. John’s Wort supplements endanger the success of
organ transplantation. Arch Surg. 2002;137:316-9. CrossRef
137.Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I.
Impact of St. John’s wort treatment on the pharmacokinetics of
tacrolimus and mycophenolic acid in renal transplant patients.
Nephrol. Dial Transplant. 2003;18:819-22. CrossRef
138.Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute
heart transplant rejection due to Saint John’s wort. Lancet.
2000;355:548-9. CrossRef
139.Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St.
John’s wort (Hypericum perforatum): drug interactions and
clinical outcomes. Br J Clin Pharmacol. 2002;54:349-56.
CrossRef
140.Jiang X, Williams KM, Liauw WS, et al. Effect of St.
John’s wort and ginseng on the pharmacokinetics and
pharmacodynamics of warfarin in healthy subjects. Br J Clin
Pharmacol. 2004;57:592-9. CrossRef
141.Uygur Bayramiçli O, Kalkay MN, Oskay Bozkaya E, et al. St.
John’s wort (Hypericum perforatum) and warfarin: Dangerous
liaisons! Turk J Gastroenterol. 2011;22:115.
142.Patel S, Robinson R, Burk M. Hypertensive crisis associated
with St. John’s Wort. Am J Med. 2002;112:507-8. CrossRef
189
143.Moses EL, Mallinger AG. St. John’s Wort: three cases
of possible mania induction. J Clin Psychopharmacol.
2000;20:115-7.
144.Hammerness P, Basch E, Ulbricht C, et al. St. John’s wort: a
systematic review of adverse effects and drug interactions for
the consultation psychiatrist. Psychosomatics. 2003;44:271-82.
CrossRef
145.Qi LW, Wang CZ, Yuan CS. American ginseng: potential
structure-function relationship in cancer chemoprevention.
Biochem Pharmacol. 2010;80:947-54. CrossRef
146.Henderson GL, Harkey MR, Gershwin ME, Hackman RM,
Stern JS, Stresser DM. Effects of ginseng components on
c-DNA-expressed cytochrome P450 enzyme catalytic activity.
Life Sci. 1999;65:PL209-14. CrossRef
147.Bilgi N, Bell K, Ananthakrishnan AN, Atallah E. Imatinib
and Panax ginseng: a potential interaction resulting in liver
toxicity. Ann Pharmacother. 2010;44:926-8. CrossRef
148.Mateo-Carrasco H, Gálvez-Contreras MC, Fernández-Ginés
FD, Nguyen TV. Elevated liver enzymes resulting from
an interaction between Raltegravir and Panax ginseng: a
case report and brief review. Drug Metabol Drug Interact.
2012;27:171-5. CrossRef
149. Gurley BJ, Gardner SF, Hubbard MA, et al. Clinical assessment
of effects of botanical supplementation on cytochrome P450
phenotypes in the elderly: St. John’s wort, garlic oil, Panax
ginseng and Ginkgo biloba. Drugs Aging. 2005;22:525-39.
CrossRef
150.Kuo SC, Teng CM, Lee JC, Ko FN, Chen SC, Wu TS.
Antiplatelet components in Panax ginseng. Planta Med.
1990;56:164-7. CrossRef
151.Park HJ, Lee JH, Song YB, Park KH. Effects of dietary
supplementation of lipophilic fraction from Panax ginseng on
cGMP and cAMP in rat platelets and on blood coagulation.
Biol Pharm Bull. 1996;19:1434-9. CrossRef
152.Teng CM, Kuo SC, Ko FN, et al. Antiplatelet actions of
panaxynol and ginsenosides isolated from ginseng. Biochim
Biophys Acta. 1989;990:315-20. CrossRef
153.Janetzky K, Morreale AP. Probable interaction between
warfarin and ginseng. Am J Health Syst Pharm. 1997;54:692-3.
154.Rosado MF. Thrombosis of a prosthetic aortic valve disclosing
a hazardous interaction between warfarin and a commercial
ginseng product. Cardiology. 2003;99:111. CrossRef
155.Yuan CS, Wei G, Dey L, et al. Brief communication: American
ginseng reduces warfarin’s effect in healthy patients: a
randomized, controlled trial. Ann Intern Med. 2004;141:23-7.
CrossRef
156.Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. Interaction
between warfarin and Panax ginseng in ischemic stroke
patients. J Altern Complement Med. 2008;14:715-21.
CrossRef
157.Lee YH, Lee BK, Choi YJ, Yoon IK, Chang BC, Gwak
HS. Interaction between warfarin and Korean red ginseng
in patients with cardiac valve replacement. Int J Cardiol.
2010;145:275-6. CrossRef
158.Izzo AA, Ernst E. Interactions between herbal medicines and
prescribed drugs: a systematic review. Drugs. 2001;61:2163-75.
CrossRef
159.Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng
(Panax quinquefolius L) reduces postprandial glycemia
in nondiabetic subjects and subjects with type 2 diabetes
mellitus. Arch Intern Med. 2000;160:1009-13. CrossRef
160.Caron MF, Hotsko AL, Robertson S, Mandybur L, Kluger J,
White CM. Electrocardiographic and hemodynamic effects of
Panax ginseng. Ann Pharmacother. 2002;36:758-63. CrossRef
161.Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2,
CYP2D6 and CYP3A4 by six trade herbal products in
cultured primary human hepatocytes. Basic Clin Pharmacol
Toxicol. 2007;100:23-30. CrossRef
162.McRae S. Elevated serum digoxin levels in a patient taking
digoxin and Siberian ginseng. CMAJ. 1996;155:293-5.
163.Punnonen R, Lukola A. Oestrogen-like effect of ginseng.
Br Med J. 1980;281:1110. CrossRef
164.Palmer BV, Montgomery AC, Monteiro JC. Gin Seng and
mastalgia. Br Med J. 1978;1:1284. CrossRef
165.Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream
and unexplained vaginal bleeding. Am J Obstet Gynecol.
1988;159:1121-2. CrossRef
166. Jones BD, Runikis AM. Interaction of ginseng with phenelzine.
J Clin Psychopharmacol. 1987;7:201-2. CrossRef
167.Hammond TG, Whitworth JA. Adverse reactions to ginseng.
Med J Aust. 1981;1:492.
168.Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular
consumption of grapefruit juice on the pharmacokinetics of
simvastatin. Br J Clin Pharmacol. 2004;58:56-60. CrossRef
169.Pillai U, Muzaffar J, Sen S, Yancey A. Grapefruit juice and
verapamil: a toxic cocktail. South Med J. 2009;102:308-9.
CrossRef
170.Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman
DJ, Bend JR. Grapefruit-felodipine interaction: effect of
unprocessed fruit and probable active ingredients. Clin
Pharmacol Ther. 2000;68:468-77. CrossRef
171.Tomlinson B, Chow MS. Stereoselective interaction of
manidipine and grapefruit juice: a new twist on an old tale.
Br J Clin Pharmacol. 2006;61:529-32. CrossRef
172.Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition
of amiodarone metabolism induced by grapefruit juice.
Br J Clin Pharmacol. 2000;49:373-8. CrossRef
173.Taniguchi K, Ohtani H, Ikemoto T, Miki A, Hori S, Sawada
Y. Possible case of potentiation of the antiplatelet effect of
cilostazol by grapefruit juice. J Clin Pharm Ther. 2007;32:
457-9. CrossRef
174.Brandin H, Myrberg O, Rundlöf T, Arvidsson AK, Brenning
G. Adverse effects by artificial grapefruit seed extract products
in patients on warfarin therapy. Eur J Clin Pharmacol.
2007;63:565-70. CrossRef
175.U.S. Congress. Act S. 784 (passed Aug. 13, 1994). http://www.
gpo.gov/fdsys/pkg/BILLS-103s784es/pdf/BILLS-103s784es.
pdf. Accessed September 20, 2015.
176.
U.S. Food and Drug Administration. Questions and
answers on dietary supplements. http://www.fda.gov/Food/
DietarySupplements/QADietarySupplements/default.htm.
177.
U.S. Food and Drug Administration. Current good
manufacturing practices (CGMPs). http://www.fda.gov/food/
guidanceregulation/cgmp/default.htm. Accessed September
20, 2015.
178.Ashar BH. The dietary supplement health and education act:
time for a reassessment: comment on “acute selenium toxicity
associated with a dietary supplement.” Arch Intern Med.
2010;170:261-3. CrossRef
179.Bouchard NC, Howland MA, Greller HA, Hoffman RS,
Nelson LS. Ischemic stroke associated with use of an ephedrafree dietary supplement containing synephrine. Mayo Clin
Proc. 2005;80:541-5. CrossRef
Review
180.Gershwin ME, Borchers AT, Keen CL, Hendler S, Hagie F,
Greenwood MR. Public safety and dietary supplementation.
Ann N Y Acad Sci. 2010;1190:104-17. CrossRef
181.Mills E, Wu P, Johnston BC, Gallicano K, Clarke M, Guyatt G.
Natural health product-drug interactions: a systematic review
of clinical trials. Ther Drug Monit. 2005;27:549-57. CrossRef
182.Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event
profile of Crataegus spp.: a systematic review. Drug Saf.
2006;29:523-35. CrossRef
183.González-Stuart A. Herbal product use by older adults.
Maturitas. 2011;68:52-5. CrossRef
184.Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome
P450 phenotypic ratios for predicting herb-drug interactions
in humans. Clin Pharmacol Ther. 2002;72:276-87. CrossRef
185.Institute of Medicine (US) Committee on the Use of
Complementary and Alternative Medicine by the American
Public. Complementary and alternative medicine in the
United States. Washington, DC: National Academies Press
(US), 2005.
186.Hu Z, Yang X, Ho PC, et al. Herb-drug interactions: a literature
review. Drugs. 2005;65:1239-82. CrossRef
187.Boon HS, Kachan N. Natural health product labels: is more
information always better? Patient Educ Couns. 2007;68:
193-9. CrossRef
188.Siegel RK. Ginseng abuse syndrome. Problems with the
panacea. JAMA. 1979;241:1614-5. CrossRef
189.Wanwimolruk S, Wong K, Wanwimolruk P. Variable inhibitory
effect of different brands of commercial herbal supplements
on human cytochrome P-450 CYP3A4. Drug Metabol Drug
Interact. 2009;24:17-35. CrossRef
190.
Newmaster SG, Grguric M, Shanmughanandhan D,
Ramalingam S, Ragupathy S. DNA barcoding detects
contamination and substitution in North American herbal
products. BMC Med. 2013;11:222. CrossRef
191.Kaplan S. GNC, Target, Wal-Mart, Walgreens accused of
selling adulterated ‘herbals’ (Feb. 3, 2015) http://www.
washingtonpost.com/news/morning-mix/wp/2015/02/03/gnctarget-wal-mart-walgreens-accused-of-selling-fake-herbals/.
Accessed February 5,2015.
192.
Consumer Reports. Alert: protein drinks (July 2010).
http://www.consumerreports.org/cro/magazine-archive/
2010/july/food/protein-drinks/overview/index.htm.
Accessed February 5, 2015.
193.
U.S. Food and Drug Administration. Steam dietary
supplement (updated Aug. 24, 2009). http://www.
f d a . g o v / S a f e t y / M e d Wa t c h / S a f e t y I n f o r m a t i o n /
SafetyAlertsforHumanMedicalProducts/ucm174339.htm.
Accessed July 23, 2015.
194.Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not
mean innocuous: ten cases of severe hepatotoxicity associated
with dietary supplements from Herbalife® products. J Hepatol.
2007;47:521-6. CrossRef
195. Torp-Pedersen C, Caterson I, Coutinho W, et al. Cardiovascular
responses to weight management and sibutramine in highrisk subjects: an analysis from the SCOUT trial. Eur Heart J.
2007;28:2915-23. CrossRef
196.Food and Drug Administration Office of Criminal
Investigations. Two New Jersey dietary supplement companies
and their principals found guilty of criminal contempt (June
2, 2011). http://www.fda.gov/ICECI/CriminalInvestigations/
ucm257815.htm. Accessed February 5, 2015.
197.Morris CA, Avorn J. Internet marketing of herbal products.
Review
JAMA. 2003;290:1505-9. CrossRef
198.Office of Inspector General, U.S. Department of Health &
Human Services. Dietary supplements: structure/function
claims fail to meet federal requirements (Oct. 2, 2012).
https://oig.hhs.gov/oei/reports/oei-01-11-00210.asp.
199.Office of Inspector General, U.S. Department of Health
& Human Services. Adverse event reporting for dietary
supplements. An inadequate safety valve (April 2001).
http://oig.hhs.gov/oei/reports/oei-01-00-00180.pdf. Accessed
February 5, 2015.
200.Alherbish A, Charrois TL, Ackman ML, Tsuyuki RT,
Ezekowitz JA. The prevalence of natural health product use
in patients with acute cardiovascular disease. PLoS One.
2011;6:e19623. CrossRef
201.Bailey DG, Dresser GK. Interactions between grapefruit
juice and cardiovascular drugs. Am J Cardiovasc Drugs.
2004;4:281-97. CrossRef
202.Harrigan JT. Patient disclosure of the use of complementary
and alternative medicine to their obstetrician/gynaecologist.
J Obstet Gynaecol. 2011;31:59-61. CrossRef
203.Suchard JR, Suchard MA, Steinfeldt JL. Physician knowledge
of herbal toxicities and adverse herb-drug interactions. Eur J
Emerg Med. 2004;11:193-7. CrossRef
204.Cellini M, Attipoe S, Seales P, et al. Dietary supplements:
physician knowledge and adverse event reporting. Med Sci
Sports Exerc. 2013;45:23-8. CrossRef
205.Gardiner P, Sarma DN, Low Dog T, et al. The state of dietary
supplement adverse event reporting in the United States.
Pharmacoepidemiol Drug Saf. 2008;17:962-70. CrossRef
206.U.S. Food and Drug Administration. Reporting serious
problems to FDA (MedWatch, updated Feb. 11, 2014).
h t t p : / / w w w. f d a . g o v / m e d w a t c h / r e p o r t / h c p . h t m .
207.Harris Interactive®. Harris poll shows widespread public
ignorance of supplement regulation (Dec. 23, 2002). http://
www.supplementquality.com/news/Harris_survey.html.
208.Fox S, Rainie L, Horrigan J, et al. The online health care
revolution: how the Web helps Americans take better care of
themselves (Nov. 26, 2000). http://www.pewinternet.org/files/
old-media//Files/Reports/2000/PIP_Health_Report.pdf.pdf.
209.Nazeri A, Massumi A, Wilson JM, et al. Arrhythmogenicity
of weight-loss supplements marketed on the Internet. Heart
Rhythm. 2009;6:658-62. CrossRef
210.Reinert A, Rohrmann S, Becker N, Linseisen J. Lifestyle and
diet in people using dietary supplements: a German cohort
study. Eur J Nutr. 2007;46:165-73. CrossRef
211.Cheung CK, Wyman JF, Halcon LL. Use of complementary
and alternative therapies in community-dwelling older adults.
J Altern Complement Med. 2007;13:997-1006. CrossRef
212.Kwan D, Hirschkorn K, Boon H. U.S. and Canadian
pharmacists’ attitudes, knowledge, and professional practice
behaviors toward dietary supplements: a systematic review.
BMC Complement Altern Med. 2006;6:31. CrossRef
213.Glisson JK, Rogers HE, Abourashed EA, Ogletree R, Hufford
CD, Khan I. Clinic at the health food store? Employee
recommendations and product analysis. Pharmacotherapy.
2003;23:64-72. CrossRef
191
The Role of Traditional Chinese Medicine in the
Management of Chronic Pain: A Biopsychosocial Approach
John Burns, DPT, MSOM,1 Tiffany A. Mullen, DO2
1
2
Acupuncture Clinical Services, Aurora Health Care, Milwaukee, WI
Department of Integrative Medicine, Aurora Health Care, Milwaukee, WI
AbstractThe National Institute of Medicine revealed that chronic pain affects more than 100 million adults in
the United States, citing chronic pain as the leading reason patients seek medical care. Pain is also an
extremely costly problem, with $635 billion per year spent nationally, more than cancer, heart disease
and diabetes combined. The biomedical model of chronic pain management has largely revolved
around the use of narcotic analgesics for pain control. Unfortunately, this corresponds to a growth
in the rate of abuse, misuse and overdose of these drugs. Additionally, there is an inherent failure
rate to the myriad procedures used to control pain, such as spinal epidural injections and insertion of
indwelling narcotic delivery systems, largely because these procedures fail to comprehensively address
the multiple facets of pain generation. With its roots in the biopsychosocial model of pain management,
traditional Chinese medicine may be a useful systematic or adjunct approach in the management of
chronic pain. (J Patient-Centered Res Rev. 2015;2:192-196.)
Keywords
chronic pain, biopsychosocial, traditional Chinese medicine, acupuncture, tai chi
A National Institute of Medicine report revealed that
chronic pain affects more than 100 million adults in the
United States.1 According to this report, chronic pain is
the leading reason patients seek medical care with an
estimated $635 billion per year spent nationally.1 The
cost of care for chronic pain exceeds that of cancer, heart
disease and diabetes combined, largely because “the costs
of unrelieved pain can result in longer hospital stays,
increased rates of rehospitalization, increased outpatient
visits, and decreased ability to function fully leading to
lost income and insurance coverage.”2 Excessive costs
aside, chronic pain exacts a more personal cost on the
pain sufferer, that of risk of abuse, misuse and overdose
of narcotic medications, a problem that has dramatically
increased over the last several years.3 Despite use of
narcotics as a mainstay of management of chronic pain
in this country, it is well-documented that an “estimated
40% of patients with chronic pain do not achieve
adequate pain relief.”2 Similarly, invasive procedures
such as spinal epidural steroid injections and implantable
Correspondence: John Burns, DPT, MSOM,
1020 N. 12th Street, 4th Floor, Milwaukee, WI, 53233,
T: 414-219-5910, F: 414-219-5914,
time-release narcotic delivery devices not only haven’t
delivered consistent benefit to patients but also come at
potentially significant risk to the patient.2,3
Definition of Pain: Acute vs. Chronic
The International Association for the Study of Pain
defines pain as an “unpleasant sensory and emotional
experience associated with actual or potential tissue
damage, or described in terms of such damage.”2 Pain
can be further categorized as acute or chronic.
Acute Pain: Acute pain is a normal physiologic response,
usually time-limited, to a noxious stimulus that enhances
survival by warning the individual of impending or
potential injury or progression of disease. If the noxious
stimulus persists, changes in the peripheral tissues and
both the central and peripheral nervous systems can
lead to sensitization that worsens and prolongs the pain.
Appropriate management of acute pain may prevent the
onset of the pathophysiologic processes that change the
spinal cord and brain and lead to chronic pain.
Chronic Pain: Chronic pain continues beyond the
normal time expected for healing and is associated with
the onset of pathophysiologic changes in the central
nervous system that may adversely affect an individual’s
Review
emotional and physical well-being, cognition, level
of function and quality of life. Chronic pain serves no
apparent useful purpose for the individual and may
be diagnostically and therapeutically approached as
a chronic disease process. The experience of pain, in
general, is highly subjective and notoriously difficult to
quantify or measure. For the purposes of this narrative
review, we will focus only on the management of
chronic pain.
The Biopsychosocial Model
Chronic pain is widely recognized as a biopsychosocial
disorder.4,5 The biopsychosocial model is differentiated
from the biomedical model in that the biopsychosocial
model supports the concept that biological, psychological
and social variables should be recognized as key factors
in causing pain, disease and disabilities.6 To limit our
treatment of pain to addressing only biological functions
and biochemical mediators largely ignores one of the
most disruptive features of pain that patients experience:
emotional distress.7
The influence of social influence (both positive and
negative) on chronic pain management is also wellrecognized. For example, a study on family support
and chronic pain was performed one year after patients
completed an outpatient pain program.8 This study
revealed that patients who reported having nonsupportive
families used more pain descriptors when discussing
their pain, relied more on medication and reported more
pain sites. Conversely those patients who described their
families as supportive reported having significantly less
intensity of pain, greater activity levels and less reliance
on medication.
Similarly, the doctor-patient relationship can influence
the course of a pain condition.4 When patients perceive
a physician as being supportive, they report decreased
levels of distress.4 This relationship is often referred to
as a “therapeutic alliance.” Other health care providers
can form therapeutic alliances as well. One study found
that when there is a strong therapeutic alliance between
physical therapists and patients with chronic low back
pain, this supportive relationship was consistently a
predictor of successful outcomes.9
Traditional Chinese Medicine
According to the National Institutes of Health, traditional
Chinese medicine (TCM) incorporates a broad range
Review
of treatment practices that includes the relatively wellknown practices of both acupuncture and tai chi to treat
or prevent health problems.10 TCM’s view of health
places less emphasis on anatomical structures and more
emphasis on interactions, or relationships, among the
body, mind, emotions and environment, or the social
interactions of an individual. From this perspective,
health is defined as a harmonious interaction of these
entities and the outside world. The origin of TCM and
the modalities of acupuncture and mind-body exercises
date back more than 2,000 years.11 At the core of all
TCM interventions is the appreciation that the physical
and psychological aspects of each patient must be
addressed to influence health and disease.11 Classical
acupuncture is based on the theory that vital energy,
called qi, flows through the body along pathways
called meridians. There are specific points along these
meridians, called acupuncture points, at which the qi
may be accessed. Inserting needles into these points
permits the practitioner to restore harmony to the system
by rebalancing the flow of qi.12
In the biomedical model, acupuncture is thought to
relieve pain through the gate-control mechanism or
through the release of neurochemicals.13 Pomeranz and
Berman13 described the possible neural mechanisms
of acupuncture analgesia as follows: small-diameter
muscle afferents are stimulated, sending impulses to the
spinal cord, which then activates three centers (spinal
cord, midbrain and pituitary) to release neurochemicals
(endorphins and monoamines) that block pain messages.
While acknowledging that there is some debate,
Pomeranz and Berman concluded that the evidence
supporting the endorphin hypothesis is very convincing.
The authors asserted on the basis of supporting evidence
from several studies that midbrain monoamines
(serotonin and norepinephrine) are also involved in
acupuncture analgesia; however, the role of the pituitary
is less clear.13 Identifying possible mechanisms of action
that fit within the paradigm of Western medicine has
helped make acupuncture more acceptable in the United
States.
The mind-body benefits of both acupuncture and tai chi
are believed to be associated with their direct effects on
the autonomic nervous system, which is involved in an
individual’s thoughts, emotions and behavior.11 From
a TCM perspective, a person’s emotional state, called
shen in TCM, plays a crucial role in their behavior as
193
well as a pivotal role in the development or exacerbation
of disease and disability.11 This ancient understanding
of the mind and body connection was addressed in the
first line of an ancient text on utilizing acupuncture to
alleviate pain, which stated: “The acupuncture method
is rooted in the shen.”14
Evidence for TCM in Pain Management
There are numerous studies that have demonstrated that
TCM interventions, specifically acupuncture and tai chi,
should be considered as viable modalities for treating
chronic pain and emotional disorders.15,16 A meta-analysis
of acupuncture’s effectiveness on chronic pain concluded,
“Acupuncture is effective for the treatment of chronic
pain and is therefore a reasonable referral option.”17
Another meta-analysis was conducted on the use of
auricular acupuncture to treat both acute and chronic
pain conditions. Findings showed an overall significant
improvement in pain scores for those patients receiving
acupuncture versus controls. The authors concluded the
evidence suggests that auricular acupuncture may be an
effective treatment for chronic pain.18
Several studies on chronic pain and disability due to
osteoarthritis also were evaluated. Osteoarthritis is the
most common form of arthritis and the eighth leading
cause of disability globally.19 In a meta-analysis of 10
randomized controlled trials with 1,456 participants,
the authors concluded that “acupuncture is an effective
treatment for pain and physical dysfunction associated
with osteoarthritis of the knee.”
Another important study compared acupuncture with
“usual care” (medication and psychotherapy) for pain
associated with depression that showed those patients
treated with acupuncture did better than the usual care
group.20 The findings showed that participants with
moderate-to-extreme pain at baseline did better at
3 months if they received acupuncture (mean 6.0-point
reduction from baseline 6.0 [95% confidence interval
(CI): 5.0–7.1] in Patient Health Questionnaire [PHQ-9]
depression score and a mean 11.2-point reduction from
baseline [95% CI: 7.1–15.2) in the Short Form Health
Survey [SF-36] bodily pain score 11.2) compared to
the mean improvements seen in those who received
counseling (4.3 [95% CI: 3.3–5.4], 7.6 [95% CI: 3.6–
11.6], respectively) or usual care (2.7 [95% CI: 1.50–
4.0], 7.2 [95% CI: 2.3–12.1], respectively).20
Similarly, tai chi is recognized as a mind-body
intervention that incorporates the principles of TCM.21
Tai chi is defined as an ancient martial art that is now
widely practiced for its health benefits of improving
physical and emotional well-being.22 According to
a meta-analysis conducted by the Department of
Veterans Affairs, the practice of tai chi was found to
be an effective nonpharmacologic modality to reduce
both pain23 and depression24 in veterans experiencing
these conditions. Yet another meta-analysis suggested
that practicing tai chi helped patients suffering from
fibromyalgia in that it reduced their pain and improved
both physical function and well-being.25 In the same
study, a subanalysis of low back pain also showed that
tai chi was beneficial for pain relief and disability in
this population.25
As a movement therapy, tai chi is associated with
promoting both physiological and psychological
adaptations by modulating parasympathetic tone
and the limbic system for improving functional
abilities and for reducing emotional distress.21 These
benefits are believed to be derived from tai chi’s
practice principles, which include meditation, visual
imagery, slow rhythmic movements and coordinated
breathing.24 This mind-body control modulates
multiple aspects of health, including mood, pain and
functions of the immune and peripheral autonomic
nervous systems.
Ancient Meets Modern: Combining the
Biomedical Model with TCM
There are several articles in the medical literature
that examine the outcomes resulting from the use of
both established biomedical models of chronic pain
management and TCM treatment modalities. One metaanalysis compared management strategies for sciatica
wherein the authors provided “new data to assist
shared decision-making” with findings that supported
the effectiveness of nonopioid medications, epidural
injections, spinal manipulation and acupuncture.26
Another study addressed the use of acupuncture in the
primary care setting alongside traditional approaches
to chronic pain. This study suggested that acupuncture
appeared to be a cost-effective clinically relevant
intervention with “short- and long-term benefits for
low back pain, knee osteoarthritis, chronic neck pain
and headache.”27
Review
Knowing that all approaches to the management of
chronic pain, whether biomedical or nontraditional
(from a Western perspective), have some validity
with respect to the literature, the most comprehensive
approach to pain management we can offer patients
may be to offer the best of both. In a clinical update
by the International Association for the Study of Pain
titled “Integrative Pain Medicine: A Holistic Model of
Care,” the author concluded the report by stating, “We
cannot afford to ignore these realities: it is imperative
that as health care providers we have an open mind
to low-cost, low-risk integrative strategies that our
patients are already embracing.”28
Limitations
There are many limitations in the area of TCM
research. Both acupuncture and tai chi studies have
an inherent problem to control for the placebo effect.24
A Cochrane review of acupuncture determined that
due to patient bias and expectations to positive
outcomes, the placebo effect could not be ruled out
as a major contributing factor to the observed benefits
associated with acupuncture interventions for a wide
range of conditions.29 The use of “sham” acupuncture
(the insertion of needles into points on the body not
associated with any particular therapeutic effect) has
been used as a means to circumvent this issue by
providing a “control” for many acupuncture studies.
It is also reported that tai chi studies similarly post a
conundrum for researchers to discern specific versus
nonspecific effects.30 Researchers have suggested
that tai chi cannot be scientifically studied with a
reductionist research framework that does not take into
account the complexity of tai chi as a multicomponent
intervention.31
Blinding also proves to be a difficult issue to solve
in the TCM research literature. Of the nonspecific
effects that are often underappreciated as contributing
factors in treatment outcomes, within both research
and clinical settings, is the recognition of importance
of patient expectations32 and the therapeutic alliance
developed between provider and patient.33 This new
appreciation of patient expectations and the providerpatient relationship directly acknowledges the
biopsychosocial model. When a patient’s thoughts,
emotions and beliefs (their shen) are addressed,
treatment outcome and healing may be enhanced.15
Review
This is germane to TCM practice. Accounting for this
effect in research is confounding, making it difficult
not only to “double-blind” the TCM practitioner, but to
want to blind them at all in order to draw appropriate
conclusions in the TCM paradigm.
Another limitation to the widespread adoption of
TCM in the management of chronic pain is cost.
While the delivery of TCM pain management is
significantly less costly dollar-for-dollar compared
with biomedical approaches, the cost nearly always
falls to the patient. It is helpful that the Affordable
Care Act (ACA) inserted language stating insurers
may not discriminate with regards to the coverage
of care offered by nontraditional versus traditional
practitioners;34 however, this aspect of the ACA has
yet to be legally implemented. With more attention
to the efficacy of chronic pain management using
less costly (to the health care system) options such as
TCM continuing to appear in the medical literature,
it is the hope of this review’s authors that TCM will
earn its place on the roster of covered benefits to all
insured patients.
Conclusions
A major responsibility of medical practitioners of
all kinds is to relieve suffering. When it comes to
relieving the suffering associated with chronic pain,
a strictly biomedical approach is not only limited but
at best not comprehensive and at worst potentially
dangerous. As an evidence-based approach to chronic
pain that exemplifies the biopsychosocial approach,
TCM should be strongly considered for delivering
truly patient-centered care.
• Current biomedical approaches to managing
chronic pain are associated with high failure rates
and a recent spike in narcotics abuse.
• The authors found growing evidence that
acupuncture or tai chi, two forms of traditional
Chinese medicine (TCM), can be used to
effectively treat chronic pain.
• Given its overall cost-effectiveness, physicians
should consider TCM as systematic or adjunct
therapy to alleviate their patents’ chronic pain.
195
None.
References
1. Committee on Advancing Pain Research, Care, and Education;
Board on Health Sciences Policy, Institute of Medicine.
Relieving Pain in America: A Blueprint for Transforming
Prevention, Care, Education, and Research. Washington, DC:
The National Academies Press, 2011.
2.International Association for the Study of Pain: IASP
taxonomy. http://www.iasp-pain.org/Taxonomy#Pain. Accessed
September 9, 2015.
3. American Academy of Family Physicians. Pain management
and opioid abuse: a public health concern—executive summary
(July 2012). http://www.aafp.org/dam/AAFP/documents/
patient_care/pain_management/opioid-abuse-position-paper.
pdf. Accessed September 9, 2015.
4. Bruns D, Disorbio JM. Chronic pain and biopsychosocial
disorders. Pract Pain Manag. 2005;5(7):2-9.
5.Gallagher RM. Biopsychosocial pain medicine and
mind-brain-body science. Phys Med Rehabil Clin N Am.
2004;15:855-82. CrossRef
6. Goodman CC, Fuller KS (eds). Pathology: Implications
for the Physical Therapist, Third Edition. St. Louis, MO:
Saunders Elsevier, 2009.
7. Linton SJ, Shaw WS. Impact of psychological factors in the
experience of pain. Phys Ther. 2011;91:700-11. CrossRef
8. Jamison RN, Virts KL. The influence of family support on
chronic pain. Behav Res Ther. 1990;28:283-7. CrossRef
9. Ferreira PH, Ferreira ML, Maher CG, Refshauge KM, Latimer
J, Adams RD. The therapeutic alliance between clinicians and
patients predicts outcome in chronic low back pain. Phys Ther.
2013;93:470-8. CrossRef
10.National Center for Complementary and Integrative Health.
Traditional Chinese medicine. https://nccih.nih.gov/health/
whatiscam/chinesemed.htm. Accessed September 10, 2015.
11.Kaptchuk TJ. The Web That Has No Weaver: Understanding
Chinese Medicine, Second Edition. New York, NY:
Contemporary Books (McGraw-Hill), 2000.
12.Wisneski LA, Anderson L. The Scientific Basis of Integrative
Medicine. Boca Raton, FL: CRC Press, 2005.
13.Pomeranz B, Berman B. Scientific basis of acupuncture. In:
Stux G, Berman B, Pomeranz B (eds). Basics of Acupuncture,
Fifth Edition. Berlin, Germany: Springer, 2003, pp. 7-86.
14.Mi HF. The Systematic Classic of Acupuncture and
Moxibustion, First Edition. Boulder, CO: Blue Poppy Press, 1994.
15.NIH Consensus Development Program, Office of Disease
Prevention. Acupuncture. NIH Consensus Statement Online.
1997;15(5):1-34.
16.Hempel S, Taylor SL, Solloway MR, et al. Evidence map
of tai chi. VA Evidence-Based Synthesis Program Reports.
Washington, DC: U.S. Department of Veterans Affairs,
September 2014.
17.Vickers AJ, Cronin AM, Maschino AC, et al. Acupuncture
for chronic pain: individual patient data meta-analysis. Arch
Intern Med. 2012;172:1444-53. CrossRef
18.Asher GN, Jonas DE, Coeytaux RR, et al. Auricular therapy
for pain management: a systematic review and meta-analysis
of randomized controlled trials. J Altern Complement Med.
2010;16:1097-108. CrossRef
19.Selfe TK, Taylor AG. Acupuncture for osteroarthritis of
the knee: a review of randomized, controlled trials. Fam
Community Health. 2008;31:247-54. CrossRef
20.Hopton A, MacPherson H, Keding A, Morley S. Acupuncture,
counseling or usual care for depression and comorbid pain:
secondary analysis of a randomized controlled trial. BMJ
Open. 2014;4:e004964. CrossRef
21.Rakel D (ed). Integrative Medicine. Philadelphia, PA: WB
Saunders, 2003.
22.Wang C, Bannuru R, Ramel J, Kupelnick B, Scott T, Schmid
CH. Tai Chi on psychological well-being: systematic review
and meta-analysis. BMC Complement Altern Med. 2010;10:23.
CrossRef
23.Hall A, Maher C, Latimer J, Ferreira M. The effectiveness
of Tai Chi for chronic musculoskeletal pain conditions:
a systematic review and meta-analysis. Arthritis Rheum.
2009;61:717-24. CrossRef
24.Wang F, Lee EK, Wu T, et al. The effects of tai chi on
depression, anxiety, and psychological well-being: a
systematic review and meta-analysis. Int J Behav Med.
2014;21:605-17. CrossRef
25.Peng PW. Tai chi and chronic pain. Reg Anesth Pain Med.
2012;37:372-82. CrossRef
26. Lewis RA, Williams NH, Sutton AJ, et al. Comparative clinical
effectiveness of management strategies for sciatica: systematic
review and network meta-analysis. Spine J. 2015;15:1461-77.
CrossRef
27.Mao JJ, Kapur R. Acupuncture in primary care. Prim Care.
2010;37:105-17. CrossRef
28.Tick H. Integrative pain medicine: a holistic model of care.
Pain: Clinical Updates. 2014;22(2):1-6.
29.Ernst E. Acupuncture: what does the most reliable evidence
tell us? J Pain Symptom Manage. 2009;37:709-14. CrossRef
30.Wayne PM, Kaptchuk TJ. Challenges inherent to t’ai chi
research: part I–t’ai chi as a complex multicomponent
intervention. J Altern Complement Med. 2008;14:95-102.
CrossRef
31.Wayne PM, Kaptchuk TJ. Challenges inherent to t’ai chi
research: part II—defining the intervention and optimal
study design. J Altern Complement Med. 2008;14:191-7.
CrossRef
32.Linde K, Witt CM, Streng A, et al. The impact of patient
expectations on outcomes in four randomized controlled
trials of acupuncture in patients with chronic pain. Pain.
2007;128:264-71. CrossRef
33.Fuentes J, Armijo-Olivo S, Funabashi M, et al. Enhance
therapeutic alliance modulates pain intensity and muscle
pain sensitivity in patients with chronic low back pain: an
experiment controlled study. Phys Ther. 2014;94:477-89.
CrossRef
34.Centers for Medicare & Medicaid Services, The Center
for Consumer Information & Insurance Oversight.
Affordable Care Act Implementation FAQs – Set 15: provider
non-discrimination. https://www.cms.gov/CCIIO/Resources/
FAct-Sheets-and-FAQs/aca_implementation_faqs15.html.
Review
Should Primary Care Physicians Address Sleep to Improve
Weight Loss in Obese Patients? A Clin-IQ
Kjersti E. Knox, MD
Department of Family Medicine, Aurora Sinai Medical Center, Aurora University of Wisconsin Medical Group, Aurora
Health Care, Milwaukee, WI
AbstractObesity is a commonly encountered problem in the primary care setting. Simultaneously, sleep is seen
to hold an increasingly important role in many components of health and wellness. A review of the
literature was performed to determine if improving sleep positively impacts weight loss in obese adults.
The evidence reviewed suggests that improving patients’ sleep may initially improve patient weight loss;
however, current studies do not show a sustained statistically significant impact. Until higher powered
and higher quality studies are completed, there are no clear evidence-based guidelines for primary care
physicians to follow regarding sleep and obesity. (J Patient-Centered Res Rev. 2015;2:197-200.)
Keywords
obesity, sleep, weight loss, primary care
Clinical Question
In obese adults, does improving sleep improve weight
loss?
Answer
Inconclusive. The evidence reviewed supports that
improving sleep initially improves weight loss;
however, in the setting of limited sample sizes,
specialized recruitment and limited follow-up,
statistically significant weight loss was not shown.
Date answer was determined: June 2015.
Level of evidence: B.
Inclusion criteria: Clinical trials searchable in PubMed
from the last 10 years (June 2005–June 2015).
Exclusion criteria: Incomplete/ongoing studies; no
matched comparison or control group described;
proposed intervention could not be performed by a
primary care provider in an outpatient clinic; patient
population was not recruited from the general
Correspondence: Kjersti E. Knox, MD, 1020 N. 12th Street,
Milwaukee, WI, 53233, T: 414-219-5259, F: 414-219-5960,
Topic Synopsis
population; patients were not overweight or obese at
study start; outcomes were not reported in body mass
index (BMI) change or weight loss; a validated sleep
assessment tool was not used.
Summary of the Problem
Obesity affects more than 30% of adults in the United
States and has remained at this level for over a decade.1
Additionally, obesity has far-reaching health effects,
including decreased quality of life and increased risk
for comorbid disease.2 Primary care physicians (PCPs)
are challenged with treating obese patients with the
tools now available. Empowering PCPs with evidencebased strategies to address obesity in the primary care
setting is essential to prevent further increases in
obesity and to treat existing disease.
Treatment of disordered sleep is emerging as a
low-risk intervention targeting multiple important
health problems, including obesity. Evidence shows
that changes in caloric intake,3 brain activation4
and biochemical processing5 occur with less sleep.
Collectively these studies suggest that sleep may have
an integral role in the development and treatment of
obesity. Sleep has increasingly gained importance in
integrative medicine and has been placed on par with
topics such as nutrition, exercise and stress as pillars of
wellness.6 Counseling and supporting patients in good
sleep hygiene is easily done in a primary care setting
197
through short motivational interviewing sessions
–– the foundational tool of the PCP.7 Motivational
interviewing lends itself to collaboration with patients
for patient-centered, holistic care. Additionally,
integrative methods such as mindfulness sleep
induction, progressive muscle relaxation, guided
imagery and over-the-counter supplements (e.g.
melatonin) have been suggested to improve sleep8 and
can be taught to patients in a primary care setting.
Summary of the Evidence
Of the initial 67 clinical trials identified by our search
strategy, two studies satisfied the inclusion/exclusion
criteria.9,10 Both suggested a relationship between
sleep and weight loss without ultimately showing
significance (Table 1). Each of these two studies
recruited participants from the general population,
used the self-reported Pittsburgh Sleep Quality Index
(PSQI) to assess sleep, measured percent weight loss
for participants, and had short follow-up periods
(24 months or less). Neither study separated individuals
who were overweight (BMI 25–30) from those who
were obese (BMI ≥ 30) or used formal sleep study
evaluation.
In the first study, Logue et al.9 recruited patients
from a family medicine clinic if they had BMI of
25.0–39.9 kg/m2, were 18–84 years old, were not
pregnant or two months postpartum and had no known
history of: vascular and endocrine comorbidities,
bariatric surgery, use of weight loss medications,
sleep disorders/ongoing sleep disruption (i.e. shift
work) or psychiatric comorbidities. The PSQI and
Sleep Timing Questionnaire were used. A total of
46 patients were randomized to either the Better Weight
(BW) intervention, which included diet, exercise and
development of coping skills, or to the Better Weight/
Better Sleep (BWBS) intervention, which provided the
same intervention as the BW group with additional sleep
counseling. Patient sleep was assessed three times over
12 weeks. Intention-to-treat analysis was performed.
Dropout rates were similar in both groups, with 23
patients (12 BW, 11 BWBS) completing the intervention.
Patients randomized to the two groups had similar
distribution of BMI and poor overall sleep quality
at baseline as well as similar employment and
socioeconomic status. Age distribution, education and
race differed between the groups, with more middleaged participants in the BW arm (60.9%), a higher
percentage of individuals completing more than
12 years of education (60.9% vs. 82.6%) in the BWBS
arm and also a higher percentage of African Americans
(39.1% vs. 60.9%) in the BWBS group. Importantly,
the BWBS group ate significantly fewer added sweets
(P=0.009) and added fats (P<0.0001) at baseline.9
Table 1. Summary of evidence
BW vs. BWBS9
Sleep association10
Trial format
Randomized control trial, single site
Embedded cohort, multicenter
No. at start (completed)
46 (23)
245 (198)
Duration
12 weeks
24 months
Measurement
Percent weight loss
Percent weight loss
Intervention
Sleep counseling
n/a
Outcome
Significantly increased weight loss in
intervention group at 12 weeks; however,
results were nonsignificant when adjusted
for sweets and fats intake at baseline
Significantly improved weight loss in group
with longer sleep duration and better quality
of sleep at 6 months, but results were
nonsignificant by 24 months
Limitations
Small sample size; length of follow-up
Recruitment methodology; length of follow-up
BW, better weight; BWBS, better weight/better sleep; n/a, not applicable.
Topic Synopsis
The authors found that the BWBS group’s mean
percentage of weight loss was significantly more than
the BW group (P=0.04). However, when controlling
for differences in intake of sweets and fats at
baseline, the sample size became too small to show
statistical significance (P=0.06). Interestingly, sleep
efficiency increased equally in both groups (P=0.52).
Limitations of the study were largely sample size,
participant completion rate and short study length
(12 weeks).9
In the second study, Thomson et al.10 used an embedded
cohort in an ongoing randomized control trial. Patients
from the general population were recruited to a
multicenter, multistate trial through flyers, email, radio
and survey of electronic medical records. Participants
were randomized to take part in a commercial weight
loss program or to receive counseling from a dietician;
all were followed for 24 months. Participants were
≥ 18 years old, had BMI 25–40 kg/m2 and were at least
15 kg overweight. Patients were excluded based
on current pregnancy or intended pregnancy in the
subsequent two years after study start, history of eating
disorders or food restrictions, inability to perform
baseline fitness testing, and any psychiatric illness
or “any other condition that, in the investigator’s
judgment, would interfere with participation in the
trial.”10
This embedded study was an ancillary cohort study that
started after initial patient recruitment for the parent
randomized control trial. The original randomization
was not used; instead, cohorts were built from
participants in the parent study who had lost 1 or more
kg at 6 months. A total of 245 female patients qualified
for the embedded study, with 198 completing the full
24-month follow-up. Cohort outcomes were compared
based on: 1) patient-reported hours slept at baseline
> 7 or ≤ 7, and 2) poor quality of sleep based on a
component sleep score of 0 (good sleep) or ≥ 1 (poor
sleep). Groups were adjusted for confounders of
age, BMI, race/ethnicity and intervention arm in the
parent study. The two groups differed based on age
and menopausal status (with longer sleep duration
associated with younger, premenopausal participants,
consistent with previously established norms).
Sleep quality was assessed using the PSQI at 0 and
6 months.10
Topic Synopsis
The authors found a significant difference in ability
to obtain weight loss > 10% of baseline weight at
6 months in the “good sleep” group (adjusted risk ratio:
0.67) and in women sleeping > 7 hours/night (adjusted
risk ratio: 0.70). This pattern was continued at 12, 18
and 24 months; however, the effect decreased and was
nonsignificant at 24 months. Limitations of this study
include the nonrepresentative volunteer sample of the
original randomized control trial, subsequent lack of
clarity on exclusion criteria and its limiting to patients
with successful weight loss at 6 months. The study
sample also differed in accepted patterns of spectrum
of sleep duration, with very few participants in this
study sleeping > 9 hours at baseline.
Conclusions
Obesity treatment and prevention is an ongoing
challenge for adult patients and their primary care
physicians. Initial evidence suggests that improving
patient sleep may improve patient weight loss, however,
a sustained statistically significant effect has not been
shown in current studies. The question of whether
PCPs should emphasize sleep in the treatment of obese
patients remains unanswered. Further research efforts
–– including appropriately powered, high-quality
randomized control trials with systematic recruitment
and attention to specific demographics (e.g. sex, age,
and race) –– are needed.
• Preventing and treating obesity is an ongoing
challenge for patients and their primary care
physicians.
• The authors asked whether current evidence
indicates improved sleep leads to weight loss in
obese patients.
• They found that while improving a patient’s
sleep pattern may result in initial weight loss, a
sustained effect has not been sufficiently proven
by published clinical trials.
• Further research is needed before physicians can
be instructed to emphasize sleep when treating
obesity.
199
Acknowledgments
The Clin-IQ teaching materials used for this project
were provided by Oklahoma Shared Clinical &
Translational Resources, funded by grant number
NIGMS U54GM104938 (National Institute of General
Medical Sciences, National Institutes of Health).
None.
References
1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of
childhood and adult obesity in the United States, 2011-2012.
JAMA. 2014;311:806-14. CrossRef
2. U.S. Department of Health and Human Services, National
Institutes of Health. Managing overweight and obesity in
adults. Systematic evidence review from the obesity expert
panel, 2013. https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.
gov/files/obesity-evidence-review.pdf. Accessed June 27,
2015.
3. Calvin AD, Carter RE, Adachi T, et al. Effects of experimental
sleep restriction on caloric intake and activity energy
expenditure. Chest. 2013;144:79-86. CrossRef
4. St-Onge MP, McReynolds A, Trivedi ZB, Roberts AL, Sy
M, Hirsch J. Sleep restriction leads to increased activation
of brain regions sensitive to food stimuli. Am J Clin Nutr.
2012;95:818-24. CrossRef
5. Achike F, To NH, Wang H, Kwan CY. Obesity, metabolic
syndrome, adipocytes and vascular function: A holistic
viewpoint. Clin Exp Pharmacol Physiol. 2011;38:1-10.
CrossRef
6. Arizona Center for Integrative Medicine. Sleep & health
(curriculum from Integrative Medicine in Residency program).
http://integrativemedicine.arizona.edu/program/2011_
IMR_3_Year/sleep_health/sleep_health/1.html.
Accessed
June 30, 2015.
7. VanBuskirk KA, Wetherell JL. Motivational interviewing
with primary care populations: a systematic review and metaanalysis. J Behav Med. 2014;37:768-80. CrossRef
8. Rakel D. Improving and maintaining a healthy sleep-wake
cycle (patient handout from the Integrative Medicine Program,
Department of Family Medicine, University of Wisconsin
School of Medicine and Public Health). http://www.fammed.
wisc.edu/sites/default/files/webfm-uploads/documents/
outreach/im/handout_sleep.pdf. Accessed June 30, 2015.
9. Logue EE, Bourguet CC, Palmieri PA, et al. The better
weight-better sleep study: a pilot intervention in primary care.
Am J Health Behav. 2012;36:319-34. CrossRef
10.Thomson CA, Morrow KL, Flatt SW, et al. Relationship
between sleep quality and quantity and weight loss in women
participating in a weight-loss intervention trial. Obesity (Silver
Spring). 2012;20:1419-25. CrossRef
Topic Synopsis
Call for papers!
Journal of Patient-Centered Research and Reviews (JPCRR)
is currently seeking manuscript submissions for two theme
issues scheduled for publication in 2016.
The first theme issue will focus on the topic
of INFECTIOUS DISEASES. Please note the
deadline for papers to be considered for this
special issue is January 1, 2016. Submissions
are strongly encouraged in advance of the
deadline to ensure timely publication.
JPCRR also will publish a theme issue on
CARDIOVASCULAR AGING, which refers to
changes in the heart’s structure and function
that occur over time. The deadline to submit
papers for this special issue, to be guest edited by
cardiovascular expert Arshad Jahangir, MD, is July 1, 2016.
A peer-reviewed quarterly journal founded by Aurora Health Care, JPCRR features
scientific articles from a broad spectrum of disciplines. Issues include original research,
state-of-the-art reviews, and editorials on controversial topics.
For a complete list of article types and author instructions,
or to submit a manuscript, please visit our website:
Don’t miss this great opportunity to publish in your field. For questions, contact
Editor-in-Chief Dennis J. Baumgardner, MD, at [email protected].
201
The following abstracts were presented at the 41st annual Aurora Scientific Day research symposium, held May 20,
2015, at Aurora Health Care Conference Center in Milwaukee, Wisconsin. Aurora Scientific Day provides a forum
for original research conducted by residents, fellows, students, teaching and research faculty, and other allied health
professionals at Aurora Health Care, a private nonprofit health care provider with 15 hospitals, 150 clinics and 70
pharmacies integrated throughout eastern Wisconsin and northern Illinois.
FIRST PLACE ORAL PRESENTATION
Model Assessment and Development of Risk
Stratification of Surgical Site Infection Following
Cesarean Delivery for a High-Risk, Urban Population
Dakisha N. Lewis, Nicole P. Salvo, Kiley A. Bernhard,
Danielle M. Greer
Department of Obstetrics and Gynecology, Aurora
Sinai Medical Center and Aurora UW Medical Group;
Center for Urban Population Health
Background: Surgical site infection (SSI) remains a major
cause of morbidity despite efforts aimed at prevention
and treatment. Risk stratification tools identify patients
at greatest risk of SSI. Two models of stratification are:
1) the Centers for Disease Control and Prevention’s National
Healthcare Safety Network SSI Risk Index (NHSN), which
assigns risk based on surgery duration, surgical wound
contamination and physical status; and 2) the New Risk
Stratification Schema (NRSS). The NRSS aimed to improve
upon NHSN by incorporating five variables: diabetes
control, body mass index (BMI), chorioamnionitis, methods
of placental extraction and skin closure.
Purpose: Our objectives were to: 1) compare and evaluate
NHSN and NRSS in terms of risk stratification outcomes
in a high-risk urban population; and 2) develop a risk
stratification model appropriate for assessing SSI risk in our
population.
Methods: Data-related risk factors were gathered through
chart review of all women who underwent cesarean delivery
from September 2012 to October 2013. Using NHSN
and NRSS models, we classified patients by risk of SSI
following cesarean delivery. Logistic regression model
effects represented 12 a priori risk factors in SSI, including
BMI, diabetes, chorioamnionitis, delivery indication,
use of chlorhexidine, preoperative antibiotics, timing of
antibiotics, manual placental removal, antibiotic re-dosing,
incision closure via staples, number of people present and
surgery duration. Model-derived predicted values of SSI
were used to stratify patients into low-, moderate- and
high-risk categories. Strength of associations between SSI
outcome and classified risks were examined. Agreement in
risk classification between NHSN and NRSS, and each with
our model, were assessed.
Results: Patients were normally distributed across the
low- (21.3%), moderate- (55.9%) and high-risk (22.9%)
categories of NHSN, but under NRSS were restricted to
moderate- (33.6%) and high-risk (66.4%) categories. While
both methodologies produced results strongly associated
with SSI (P<0.0001), agreement in SSI risk occurred
for only 46.3% of patients. Modeling efforts established
chorioamnionitis, BMI and surgery duration as the three
most significant predictors of SSI.
Conclusion: While both NHSN and NRSS produced results
strongly associated with SSI, distribution of patients was
shifted toward high-risk in the NRSS arm. Our stratification
model is a simplification of the NRSS, utilizing only three
highly significant predictors: chorioamnionitis, BMI and
surgery duration.
SECOND PLACE ORAL PRESENTATION
Operating Room First Start Efficiency Throughout
a Large Urban Hospital System
Callie Cox Bauer, Kiley A. Bernhard, Danielle M. Greer,
Scott Kamelle
Department of Obstetrics and Gynecology, Aurora
Sinai Medical Center; Center for Urban Population
Health; Gynecologic Oncology, Aurora Health Care
Background: Operating room delays decrease health care
system efficiency and increase hospital costs. Data on delays
in a multihospital system are sparse.
Purpose: In an effort to improve our operating room
efficiency, we investigated operating room delays, the causes
and the impending financial impact.
Methods: A retrospective analysis on first case-of-the-day
surgeries at three hospitals during 2013 was conducted.
Delays were defined as in-room time being after scheduled
surgery start time. Length of delay and causes were recorded.
Patient demographics, body mass index, hospital facility,
total number of procedures, provider specialty and time of
patient arrival were incorporated into a logistic regression
model to identify significant variables. Hosmer-Lemeshow
was used to measure goodness-of-fit and predictive power.
Cost was calculated using published estimates.
Results: 5,607 cases were examined and 88% were delayed.
Surgeons (21%), anesthesiologists (6.17%), patients
(5.42%), staff (3.60%), facility (2.10%) and other (2.35%)
were identified as causes. Mean time for patient arrival to
surgery was 104.57 min. Mean time between arrival and
Supplement
room placement was 127.38 min. The average delay time
from scheduled surgery start was 24.26 min. Logistic
regression identified hospital facility (P<0.0001), surgical
specialty (P<0.0001), patient age (P=0.0004) and late
patient arrival (P=0.0005) as significant predictors of delay.
Operating room delays were responsible for $444,074 in lost
revenue.
Conclusion: In our study, 88% of first start cases were
delayed, the majority of which were caused by the surgeon.
However, hospital facility, surgical subspecialty, patient age
and arrival time also significantly affected delays. Correction
of operating room delays can significantly reduce hospital
costs.
THIRD PLACE ORAL PRESENTATION
Assessing the Effectiveness of Implementation of
Unified Workflow in Improvement of Medication
Reconciliation for Aurora St. Luke’s Family Medicine
Residency Outpatients
Katherine Meyers, Jessica Konarske, Jessica J.F. Kram,
Dennis J. Baumgardner
Department of Family Medicine, Aurora UW Medical
Group, Aurora Health Care; Center for Urban Population
Health
Background: Medication errors are the most common errors
occurring in hospitals. Preventable adverse drug events are
linked with 1 in 5 injuries or deaths; 23% of medication errors
in primary care occur due to inaccuracies in the medication list.
Quality improvement projects designed to improve accuracy
of outpatient medication reconciliations may decrease the
number of medication errors and increase patient safety by
preventing adverse drug events.
Purpose: To determine whether a unified workflow
for medication reconciliation improves the accuracy of
ambulatory, electronic medical record (EMR)-based patient
medication records.
Methods: Retrospective study of random sample of patients
from Aurora Family Medicine Residency Clinics before
(prior to March 31, 2014) and after (December 10, 2014)
improvements to the medication reconciliation process (n=80
and n=77, respectively). Aurora pharmacy medication lists
were obtained and compared to that of the EMR. To preserve
patient and caregiver confidentiality, charts were assigned
arbitrary identifiers. Two-sample t-tests were used to compare
pre- and post-medication reconciliation. An additional
patient chart audit on pre- (n=51) and post- (n=45) workflow
implementation to assess utilization of workflow was
conducted; Fisher’s exact tests were used to gauge changes
(P<0.05).
Results: When comparing pre- and post-medication
reconciliation implementation, there was a significant decrease
in the number of EMR medications not on the pharmacy
list (mean 0.475 vs. 0.208; P=0.022). Number of providers
reviewing the EMR medication record improved significantly
by 30.4% (P=0.045). A downward trend in the number of
Supplement
unintentional medication duplicates also was observed by a
13.3% decrease (P=0.07).
Conclusion: Implementation of systematic workflow and
care team education led to overall improvement in accuracy
of EMR medication reconciliation. This quality improvement
project led to identification of multiple barriers to accuracy.
Future areas of focus would include continued education
around current workflow and additional attention to
medication compliance via out-of-date prescriptions.
FIRST PLACE POSTER (tie)
Using an Automated Model to Identify Older Patients
at Risk for 30-Day Hospital Readmission and 30-Day
Mortality
Ariba Khan, Mary L. Hook, Maharaj Singh, Marsha
Vollbrecht, Aaron Malsch, Michael L. Malone
Department of Geriatrics, Aurora UW Medical Group;
Knowledge-Based Nursing Department, Aurora Health
Care; Aurora Research Institute, Aurora Health Care;
Senior Services, Aurora Health Care
Background: A real-time electronic health record (EHR)
predictive model that identifies older patients at risk for
readmission and mortality may assist the health care team in
improved patient care.
Purpose: This study was performed to generate an automated
30-day readmission and 30-day mortality risk model using
data from the EHR in hospitalized older adults.
Methods: This was a retrospective cohort study. Included
were patients age 65 years and older admitted to the hospital
from July 2012 to December 2013. An automated predictive
model was derived from variables collected from the EHR
including socioeconomic factors, medical diagnoses and
health care utilization. The study sample was randomly
divided into derivation (70%) and validation (30%) cohorts.
Multiple logistic regression analysis was performed to derive
a prediction model. A scoring system was developed for
estimating risk of 30-day readmission.
Results: The study included 11,223 patients in one hospital, of
which 46% were male, 20% were age > 85 years, 6.2% were
black, 60% required emergency admission, 2.8% required an
ICU stay and 62.7% were discharged home. Overall 30-day
readmission and mortality rates were 13.7% and 1.5%. The
risk model predicted 30-day readmission, with c-statistics
of 0.62 (95% confidence interval [CI]: 0.61–0.64) and 0.62
(95% CI: 0.60–0.65) in the derivation and validation cohorts,
respectively. A readmit risk score was developed that ranged
from 0 to 20. The readmission rate increased as the score
increased: score 0–4, readmission rate=8.38%; score 5–9,
readmission rate=13%; and score >10, readmission rate 20%
(P<0.0001) in the derivation cohort. Results were similar for
validation cohort. The risk model predicted 30-day all-cause
mortality with c-statistics of 0.81 (95% CI: 0.77–0.86) and
0.73 (95% CI: 0.66–0.81) in the derivation and validation
cohorts. The variables associated with mortality included
discharge to nursing home, urgent admission status, social
203
worker consultation and diagnoses of respiratory issues and
dementia.
Conclusion: A promising automated model generated by
EHR data to predict 30-day readmissions and mortality
among hospitalized older adults, these findings will be used
by the health care system to incorporate a real-time alert into
physician workflow. Efforts to improve care will include
interventions targeted at the highest-risk group.
FIRST PLACE POSTER (tie)
See page 217 for citation.
SECOND PLACE POSTER
See page 217 for citation.
THIRD PLACE POSTER
Echocardiographic Predictors of Admission
Among Patients With Heart Failure With Reduced
Ejection Fraction
Chi C. Cho, Yang Shi, Robyn Shearer, Nasir Z.
Sulemanjee, Dianne L. Zwicke, T. Edward Hastings,
Omar M. Cheema, Vinay Thohan
Aurora Research Institute, Aurora Health Care; Aurora
Cardiovascular Services, Aurora Health Care
Background: Congestive heart failure afflicts 5.7 million
people in the United States with annual incidence of 600,000
and mortality of 280,000. Heart failure accounts for greater
than 1 million hospitalizations annually and the single largest
inpatient Medicare expense. As the U.S. population ages and
greater emphasis is placed on population health as a means
to bend projected health care expenditures, large health care
organizations will need to develop algorithms to identify
patients at high risk with heart failure and possibly preempt
hospitalizations. Doppler echocardiography is routinely
performed in clinical assessment of severe heart failure.
Purpose: We sought to determine echocardiographic
parameters that predict 1-year cardiac events among
ambulatory patients diagnosed with heart failure with
reduced ejection fraction.
Methods: A retrospective single-institution investigation
identified 485 patients aged < 75 years with left ventricular
ejection fraction < 35%. Kaplan-Meier method was used to
identify parameters that corresponded with primary endpoint
of hospitalization, emergency room visit or death.
Results: High risk of primary endpoint could be segregated
into four groups by presence of one or more of the following
parameters (0, 1, 2, 3): mitral inflow E/A ratio > 1.5, mitral
E-wave deceleration time < 160 ms or peak tricuspid
regurgitant (TR) velocity > 3 m/s. Event-free survival was
significantly lower in high-risk group compared to low-risk
group (P=0.002). The 30-day hospitalization rates among
those with all three factors compared to those without was
37.5% and 17.3%, P=0.018.
Conclusion: Presence of routine echocardiographic
parameters, including E/A ratio > 1.5, E-wave deceleration
time < 160 ms and TR velocity > 3 m/s, is associated with high
cardiovascular event rates among nonhospitalized ambulatory
patients with reduced ejection fraction heart failure.
RIESELBACH DISTINGUISHED PAPER #1
Cardiopulmonary Exercise Testing-Based Algorithm
and Its Usefulness in Clinical Cardiology
Mirza Nubair Ahmad, Syed Hasan Yusuf, Rafath Ullah,
Mary Ellis, Haroon Yousaf, Timothy E. Paterick, Khawaja
Afzal Ammar
Aurora Cardiovascular Services, Aurora Health Care;
Division of Pulmonary and Critical Care Medicine,
Medical College of Wisconsin
Background: Only cardiopulmonary exercise (CPX) testing
provides information on the ability of the cardiovascular
system to meet the body’s metabolic demands in terms
of oxygen consumption (VO2 ) and carbon dioxide
production (VCO2 ). However, CPX testing is underutilized
by cardiologists due to complex diagnostic algorithms
involving up to 30 variables as well as lack of validation
studies. In addition, CPX also provides oxygen (O2 ) pulse
as a continuous measure of stroke volume, which is its
superiority to other stress modalities in which systolic
function is measured at peak stress and rest. In the literature,
it has been recommended that a composite criterion
(combining peak O2 pulse with O2 pulse curve pattern)
should be used to assess the cardiac function. Furthermore,
the operating test characteristics and optimal cutoff of O2
pulse for distinguishing cardiac from noncardiac causes of
exercise limitation also are unknown.
Purpose: We tested whether a 6-variable algorithm would
discriminate cardiac from noncardiac causes of dyspnea
when compared with comprehensive CPX testing to promote
its use by cardiologists. We also tested several cutoff points
along with the composite criterion against the clinical
standard to define the optimal O2 pulse cutoff point.
Methods: Consecutive patients (n=54) referred for dyspnea
underwent CPX test consisting of pulmonary (VO2, VCO2,
22 additional variables and invasive measurement of lactate
and blood gases at peak and baseline) and cardiac (exercise
ECG, heart rate and blood pressure response) components as
well as medical record evaluation. Patients were categorized
as normal or abnormal by an experienced pulmonologist.
Abnormal patients were further categorized according to
cause of dyspnea (cardiac, pulmonary, deconditioning, poor
effort and miscellaneous). Subsequently, the 6-variable
algorithm was applied by a cardiologist blinded to all
of the information from CPX tests, and the patients were
categorized similarly. The 6 variables used were peak O2
uptake, peak respiratory exchange ratio, O2 pulse, heart
rate reserve, breathing reserve (1 – [peak ventilation (VE) /
maximal voluntary ventilation]) and ventilatory efficiency
(VE/VCO2). Seven O2 pulse reference cutoff points
Supplement
included nongender-based (<15 ml/beat), gender-based
(<15 ml/beat for males and <10 ml/beat for females) and
< 80% of O2 pulse based on five different definitions of
predicted VO2 max. The optimal cutoff obtained was then
used to create the composite criterion. For the purpose of
evaluating this composite criterion, the study population was
recategorized as: noncardiac group (n=18), normal patients
according to the composite criterion; or cardiac group (n=13),
abnormal patients according to the composite criterion.
Patients who were normal by only one component of the
composite criterion were categorized as borderline (n=23).
Data were analyzed against the comprehensive CPX test by
first excluding the borderline patients and then by including
them with either the cardiac or noncardiac group.
Results: The 6-variable algorithm performed well against
comprehensive CPX test in discriminating cardiac from
noncardiac causes of dyspnea, with 94% sensitivity, 92%
specificity, 84% positive predictive value (PPV), 97% negative
predictive value (NPV) and 93% accuracy. The results remained
consistent for gender and referral source. O2 pulse, as defined
by Wasserman, had the highest accuracy, specificity and PPV
and therefore was used to define the composite criterion. The
composite criterion had an accuracy of 87%, PPV of 77%,
NPV of 94%, sensitivity of 91% and specificity of 85%, when
borderline patients were excluded. Including borderline patients
in the cardiac group (n=36) improved sensitivity (94%) and
maintained NPV (94%) but greatly decreased specificity (46%),
PPV (44%) and accuracy (61%), whereas including these
patients in the noncardiac group (n=41) improved specificity
(92%) and maintained similar PPV (77%) and accuracy (81%)
but decreased sensitivity (59%) and NPV (83%).
Conclusion: This is the first study to validate a diagnostic
algorithm for patients undergoing CPX testing as well as
demonstrate that a simplified 6-variable algorithm applied
by a cardiologist without prior CPX experience is quite
accurate to evaluate the optimal O2 pulse value at peak stress
for discrimination of cardiac and noncardiac causes, and to
provide the operating test characteristics for the common
clinical practice of using composite criterion to diagnose
cardiac versus noncardiac causes of dyspnea.
RIESELBACH DISTINGUISHED PAPERS #2–4
See page 217 for citations.
SELECT ABSTRACTS
participant in the American College of Cardiology’s National
Cardiovascular Data Registries, submitting data to its ICD
Registry™ since 2005. Our system’s implantable cardioverterdefibrillator (ICD) procedure volume averages 930 cases
annually. During 2012 we experienced an increase in
in-hospital mortality/morbidity for ICD cases.
Purpose: A single-center study examining in-hospital
mortality/morbidity post-ICD implant before and after
changes in practice and patient selection.
Methods: ICD implants and generator changes discharged
from January 1, 2009, to December 31, 2012, were included
in developing a risk model predicting in-hospital mortality/
morbidity. The risk score was shared with physicians for
clinical input. A point system was developed, including
those factors with highest risk. Using the defined factors,
a risk score > 14 was used to indicate those at highest risk
for morbidity/mortality. The risk score model was fit on the
development group (2009–2012), and then re-run for the
intervention cohort from January 1, 2013, to June 30, 2014.
Logistic regression was used in the risk model development
and validation. Continuous variables were compared using
Student’s t-test, and categorical variables were compared
using chi-square test.
Results: From 2009 to 2012, 3,417 ICD implants and
generator changes were performed and included in risk model
development. Of those, 200 (5.9%) patients were indicated as
high risk with a score > 14. From January 2013 to June 2014,
1,057 implants and generator changes were performed, with
41 (3.4%) patients indicated as high risk with a score > 14. In
the development phase, mean age was 67 years and 70% of
patients were male. Post-model development, mean age was
66 years with 72% male. For patients indicated as high risk,
in-hospital mortality/morbidity dropped from 20 (10%) to
2 (4.9%), though the decrease was not statistically significant
(P=0.39).
Conclusion: Awareness of high-risk patients and changes
in patient selection can lead to improvement in in-hospital
mortality/morbidity among those high-risk patients. Although
the improvement was not statistically significant, this was
most likely due to low volumes and we will continue to
monitor outcomes among these patients.
Geographic Distribution of Infant Death During Birth
Hospitalization and Maternal Group B Streptococcus
Colonization: Eastern Wisconsin
Score Big for Decreasing Mortality: ICD Risk Score
Model
Jessica J.F. Kram, Dennis J. Baumgardner, Kiley A.
Bernhard, Melissa A. Lemke
Linda Francaviglia, Rachel Petersen, Maria Stone, M.
Eyman Mortada
Center for Urban Population Health; Department of
Family Medicine, Aurora UW Medical Group; TRIUMPH,
University of Wisconsin-Madison
Departments of Cardiovascular Data Services and
Quality Management, Aurora Cardiovascular Services,
Aurora Health Care
Background: Aurora Health Care, a system of 14 acute
care hospitals in eastern Wisconsin, has been a long-time
Supplement
Background: Neonatal death rate in the United States is
4/1,000 live births; infant death rate is 6/1,000. Group B
Streptococcus (GBS) may be transmitted from a colonized
mother (rates vary from 15% to 35%) to the newborn during
a vaginal delivery, and may contribute to neonatal death.
205
Purpose: To explore the geographic distribution and
associated risk factors for maternal GBS colonization and
infant death prior to discharge in eastern Wisconsin births.
Methods: Retrospective study of institutional data from
PeriData.net, a comprehensive birth registry, utilizing data
from 2007 through 2013 at all Aurora medical centers.
Categorical variables were analyzed with chi-square tests,
and ordinal or continuous variables by Mann-Whitney
or two-sample t-tests. Binary regression was used for
multivariate modeling.
Results: Population demographics (N=99,305) were mean
age 28 years, 59% married, 64% white, 42% governmentinsured, 39% nulliparous, mean prepregnancy body mass
index (BMI) of 27, gestational age of 39 weeks, birth weight
of 3,296 g and 26% C-section rate. The GBS colonization
rate was 22.3%. Among ZIP codes with > 100 subjects,
8 ZIP codes had a GBS-positive rate > 30% (7 in Milwaukee,
1 in Kohler). GBS colonization was higher in blacks (34%)
than whites (20%; P<0.0001), in unmarried women (26%
vs. 20%; P<0.0001), with increasing BMI (mean BMI 27.3
if GBS-positive vs. 26.6; P<0.0001) and based on ZIP code
group (P<0.0001); and was predictive of neonatal antibiotics
for sepsis (26% if GBS-positive vs. 22%; P<0.0001). In
multivariate analysis, unmarried status, higher BMI, race and
ZIP code were predictive of GBS colonization. Rate of infant
death during birth hospitalization was 0.57% (n=558) and
varied by ZIP code group. GBS colonization was negatively
associated with infant death (0.25% in GBS-positive vs.
0.66%; P<0.0001; N=98,065 with lethal anomalies and
stillbirths excluded). This association remained when
controlling for gestational age. In multivariate analysis,
death rate was associated with one ZIP code group, no
prenatal care, preterm labor, vaginal bleeding, hydramnios,
oligohydramnios, lower gestational age and maternal GBS
(negative predictor).
Conclusion: Geographic characteristics are associated
with infant death during birth hospitalization and maternal
GBS colonization. Demographic characteristics are only
associated with maternal GBS colonization. It is unclear if
maternal GBS colonization is “protective” against infant
demise due to increased surveillance.
An Automated Model Using Electronic Health
Record Data to Identify Delirium Among Hospitalized
Older Adults: A Pilot Project
Ariba Khan, Maharaj Singh, Hina Singh, Ayesha Maria,
Michelle Simpson
Department of Geriatrics, Aurora UW Medical Group
and Aurora Sinai Medical Center; Aurora Research
Institute, Aurora Health Care
Background: Delirium is a serious change in mental status
with adverse outcomes, but remains underrecognized.
The electronic health record (EHR) may assist in the
identification of delirium.
Purpose: This study was performed to generate an
automated delirium identification model using data from the
EHR among hospitalized older adults.
Methods: Inpatients 65 years and older were included in
this cross-sectional study. The researchers used “confusion
assessment method” as the gold standard to identify delirium.
Four categories of variables were obtained from the EHR
on the day of and the day prior to researcher assessment:
1) hypoactive delirium (any one of the following: nurse’s
assessment of motor retardation or reduced level of
consciousness or decline in activities of daily living [ADL]
score); 2) hyperactive delirium (any one of the following:
use of restraints or antipsychotic medications or nurse’s
assessment noting a change in mental status or poor attention
or motor agitation or poor thought process or anxiety);
3) patient factors (any one of the following: dementia,
age, mean blood urea nitrogen and serum creatinine); and
4) health care-associated factors (any one of the following:
urinary catheter, surgical procedure, brain imaging).
Relationships were analyzed using chi-square or Fisher’s
test as appropriate. Statistical significance was set at P<0.05.
Results: Ninety-two participants in three hospitals were
included in the analysis. Of these, mean age was 77 ± 8.8
years and 54% were female, 70% had a Morse fall score
> 45, and mean ADL score was 10 of 12. The prevalence
of delirium was 17%. In the univariate analysis, variables
associated with delirium included abnormal mental status
(94% vs. 41%; P<0.0001); reduced level of consciousness
(69% vs. 9%; P<0.0001), motor retardation (50% vs.
13%; P<0.0007), motor agitation (38% vs. 7%; P=0.004)
abnormal attention (81% vs. 12%; P<0.0001), abnormal
thought process (56% vs. 11%; P<0.001), dementia (31%
vs. 11%; P=0.03), age (82 vs. 72 years; P=0.02), number
of medications (10 vs. 12; P=0.0313), use of antipsychotic
medication (31% vs. 7%; P=0.004), mean Braden score
(15 vs. 18; P=0.0038) and Morse fall score > 45 (94% vs.
59%; P=0.02). In the multivariate analysis, factors associated
with delirium included reduced level of consciousness and
abnormal attention (area under curve 0.920).
Conclusion: This pilot study demonstrates that variables
present in the EHR may be used to develop an automated
model to identify delirium in hospitalized older adults. These
findings need to be validated in a larger study and define if
the model performs well in predicting clinical outcomes.
Prognostic Indices for Hospitalized Older Adults:
A Meta-Analysis and Systematic Review
Ariba Khan, Ayesha Maria, James Hocker, Maharaj
Singh, Michelle Simpson
Department of Geriatrics, Aurora UW Medical Group
and Aurora Sinai Medical Center; Aurora Research
Institute, Aurora Health Care
Background: A prognostication predictive model
incorporated into the electronic health record (EHR) may
be useful in assisting the health care team in accurately
predicting mortality and may be used in appropriately
Supplement
allocating palliative care services.
Purpose: To systematically review and summarize current
medical literature regarding the factors predictive of
mortality in an inpatient population above 65 years of age.
Methods: Nondisease-specific prognostication indices
that predict 1-year mortality in an inpatient population of
adults over age 65 were included. We excluded studies that
estimated intensive care unit, disease-specific or in-hospital
mortality. A MEDLINE, CINAHL, Ovid and Cochrane
literature search of English-language articles that developed
and/or validated a prognostication index to predict mortality
was performed. Review of 3,600 citations revealed 53
articles that reported variables associated with mortality.
Based on the inclusion criteria, 9 studies were included in the
final analysis. Data was extracted from the 9 studies using
the following parameters: adequate method of description
of population, nonbiased selection of patients, low loss
to follow-up, adequate prognostic factor measurements,
adequate outcome measurements and methods of validation.
We performed qualitative analysis on 5 studies and 4 studies
were pooled for a quantitative meta-analysis.
Results: The 1-year mortality rate for the 21,338 patients
included in all the studies was 31% (95% confidence
interval [CI]: 31.3–32.6); mean age was 80.6 years. Factors
significantly associated with mortality included male sex
(odds ratio [OR]: 1.25, 95% CI: 1.09–1.42; P<0.001),
congestive heart failure (OR: 0.41, 95% CI: 0.37–0.45;
P<0.001), chronic obstructive pulmonary disease (OR:
3.2, 95% CI: 0.42–24.9; P=0.26), myocardial infarction
(proportion 0.39; P<0.001), and cerebrovascular disease
(proportion 0.38, 95% CI: 0.32–0.44; P<0.001).
Conclusion: One-year mortality for inpatients aged >
65 years was high and associated with male sex, chronic
obstructive pulmonary disease and congestive heart failure.
Generalization of these findings to all older adults should
be made with caution because of insufficient published
information. In the future, our results may be used to
develop a prognostication tool that draws patient data in real
time from the EHR to identify vulnerable older adults in the
hospital with end-of-life needs.
Chronic Illness Management in Teams of Urban
Multidisciplinary Scholars (CIMTUMS) –– Part II
John R. Brill, Diane Ames, Christine B. Groth, Helen Yu
Academic Affairs, Aurora UW Medical Group; Concordia
University; Pharmacy, Aurora Health Care; University of
Background: Diabetes is a major contributor to morbidity
and mortality as well as the single most expensive health
care condition in the world. Numerous interventions have
attempted to improve control of this disorder and reduce
its complications. Traditional care for diabetes centers on
an individual clinician. More recently, recognition of the
central role of the patient has come into vogue. Payors,
including Medicare, now cover up to 13 hours of diabetes
Supplement
self-management and education programs annually. Patientcentered medical home efforts add an aspect of inclusiveness,
but retain a medical focus and are being increasingly
advocated and trained. To date, no research has focused on
the use of interprofessional learning teams simultaneously
delivering care and learning to work together.
Purpose: This project contributes to the development
and training of interprofessional learner teams to enhance
patient care. Intended outcomes include learner attitude and
behavior changes and improvement in diabetic patients’
biomarkers, empowerment and satisfaction.
Methods: Teams of 6–9 learners from eight fields and three
universities work with cohorts of 6–21 African-American
diabetic patients. The project includes team training,
implementation of a diabetes self-management education
(DSME) program and weekly telephone coaching. Learners
complete the Centers for Disease Control and Prevention’s
TeamSTEPPS teamwork attitude questionnaire pre- and
postintervention. Patients are recruited from the Aurora
Midtown Clinic, which serves a largely Medicare/Medicaid
population in Milwaukee’s central city. Registries are
searched for patients who fall out of quality goals; they are
recruited by team members, with a target of 25 to 30 willing
patients to complete the five DSME sessions and 4-week
phone coaching around SMART goals. Patient biomarker
data is tabulated, and pre- and postintervention Diabetes
Empowerment Scale completed.
Results: Three cohorts of 42 patients and 23 students
have completed the program. Patients demonstrated high
attendance rates, improved diabetes knowledge and selfmanagement skills, and a trend in improvement in diabetes
control compared to age/gender-matched controls. Students
did not show a change in interprofessional attitude.
Conclusion: Challenges included coordinating schedules,
demonstrating change of attitude in self-selected students,
and discipline-specific supervision requirements. These
programs demonstrated feasibility of concept for an
interprofessional student-led DSME program to enhance
patient care, with high student interest and engagement.
A Meta-Analysis of Incidence and Risk Factors
of Trastuzumab-Induced Cardiotoxicity in Breast
Cancer
Zeeshan Ali Jawa, Ruth M. Perez, Lydia Garlie, Maharaj
Singh, Rubina Qamar, Bijoy K. Khandheria, Arshad
Jahangir, Yang Shi
Internal Medicine, Medical College of Wisconsin; Aurora
Research Institute, Aurora Health Care; University of
Wisconsin-Madison; Medical Oncology, Aurora Health
Care; Aurora Cardiovascular Services, Aurora Health
Care; Sheikh Khalifa bin Hamad Al Thani Center for
Integrative Research on Cardiovascular Aging, Aurora
Health Care
Background: A monoclonal antibody, trastuzumab targets
the human epidermal growth factor receptor 2 (HER2)
207
oncogene that is overexpressed in 25–30% of breast cancers.
In combination with first-line therapy, trastuzumab resulted
in significant improvement in survival outcomes for
those with HER2-positive metastatic breast cancer. Due
to its improvement in outcome and prolonged survival,
trastuzumab has been established as standard of care in
both adjuvant and metastatic settings. However, along with
common adverse events, trastuzumab has been found to be
associated with cardiotoxicity. An estimated 1–4% of patients
treated with trastuzumab will develop heart failure and ~10%
of patients will experience a reduction in left ventricular
ejection fraction (LVEF). Many studies have published on
the risk factors of trastuzumab-induced cardiotoxicity (TIC),
with some discrepancy. Whereas one study found that of
all risk factors accounted for (age, hypertension, LVEF,
radiotherapy) only age was significantly associated with
TIC, another found that LVEF was the sole factor, and others
found that a combination of these were indicative of TIC.
Purpose: This paper aims to consolidate the data and
identify potential risk factors from combined data.
Methods: A computer-based literature search using
MEDLINE database was executed using the keywords
trastuzumab/Herceptin, risk factors, outcomes, cardiac,
cardiotoxicity, cardiomyopathy, LVEF and chemotherapy.
Only prospective/retrospective human studies were included,
with additional studies excluded if they reported a baseline
LVEF > 68, a cohort < 50 patients, and/or results were not
stratified based on cadiotoxic events.
Results: Data was collected from 17 articles, capturing
6,527 patients. A familial history of cardiac disease (odds
ratio [OR]: 3.31, 95% confidence interval [CI]: 1.80–6.08;
P<0.01), diagnoses of hypertension (OR: 1.61, 95% CI:
1.14–2.26; P<0.01), diabetes (OR: 1.62, 95% CI: 1.1–2.38;
P=0.014), and previous anthracycline use (OR: 2.14, 95%
CI: 1.17–3.92; P=0.013) were all shown to be associated
with TIC. Age (P=0.013) also was a risk factor.
Conclusion: Additional measures need to be set in place
for monitoring cardiac performance in women treated with
trastuzumab. Being aware of the potential risk factors along
with careful attention to symptoms/LVEF can hopefully
minimize the occurrence of TIC in this population.
baseline and after the educational intervention. Data collected
included observation by a geriatrician attending weekly
interdisciplinary rounds to note any mention by nurses of
delirium or confusion. The patient’s electronic health record
(EHR) was reviewed to note delirium assessment by “confusion
assessment method for the intensive care unit (Vanderbilt)”
(CAM-ICU) by the nurses for 2 days prior to the team
meeting. The numbers of positive and total attempted CAMICU were recorded. Use of antipsychotics or benzodiazepines
was reported as a “delirium marker.” Diagnosis of delirium
and dementia was obtained from the problem list in the EHR.
The educational intervention included Just-in-Time Teaching
during weekly Acute Care for Elders rounds during a 1-month
period.
Results: In month 1, before intervention, CAM-ICU was
performed 140 times in 2 days on 32 patients with an average
CAM-ICU performed 2.2 times per patient/day. There were
3 concerning quotes for confusion during team rounds and 0
for delirium by nurses during team rounds. EHR review noted
7 patients had dementia, 2 had a positive CAM-ICU and 3
had a diagnosis of delirium. In month 2, after intervention,
CAM-ICU was performed 163 times in 2 days on 35 patients
with an average CAM-ICU performed 2.35 times per patient/
day. There were 6 concerning quotes regarding confusion and
1 regarding delirium by nurses during team rounds. EHR
review noted 1 patient had dementia, 0 had a positive
CAM-ICU and 0 patients with delirium diagnosis.
Conclusion: This quality improvement project using Justin-Time Teaching by a geriatrician during weekly rounds
resulted in a modest increase in number of times CAMICU was performed, increased discussion of delirium
during rounds, but no increase in delirium recognition using
CAM-ICU. Areas for improvement include involving more
physicians and nursing staff along with more structured
delirium education.
Delirium Recognition in Hospitalized Older Patients:
A Quality Improvement Project
Aurora Research Institute, Aurora Health Care
Jodi Punke, Ariba Khan, Michael L. Malone
Background: Stent thrombosis is an infrequent but
catastrophic complication of percutaneous coronary
intervention (PCI). Many studies usually involve few
stent thrombosis patients, generally less than 60, given its
prevalence. While dual antiplatelet therapy has decreased
stent thrombosis significantly in the general population,
there are still patients who present with occurrence and
recurrence of stent thrombosis.
Purpose: We sought to define the prevalence of site-specific
stent thrombosis in a larger cohort of patients by specific
coronary territories and determine if this had an effect on
cardiovascular outcomes. In addition we sought to elucidate
the role of previous coronary artery bypass grafting (CABG)
Department of Geriatrics, Aurora Sinai Medical Center
and Aurora UW Medical Group
Background: We noted a low reported prevalence of delirium
(3%) in hospitalized older patients at a community teaching
hospital in north central Wisconsin.
Purpose: This was a quality improvement project to report
recognition of delirium by nurses before and after an
educational intervention.
Methods: This project was performed on one medical unit
in our hospital. Quality improvement data was collected at
Stent Thrombosis: Regional
Factors, and Outcomes
Prevalence,
Risk
Andrew M. Ayers, Chi C. Cho, Robyn Shearer, M. Fuad
Jan, Anjan Gupta
Supplement
and subsequent PCI to determine if there is increased
risk of stent thrombosis in specific post-CABG coronary
artery territories and if these altered overall cardiovascular
outcomes.
Methods: A retrospective review of our database on all
patients presenting with stent thrombosis over the last 5
years was performed. Patients were included based on the
accepted Academic Research Consortium definition of stent
thrombosis.
Results: From January 2009 to February 2014, 220 patients
were found to have had a stent thrombosis. Of these, 110
(50.0%) had left anterior descending (LAD) artery lesions,
82 (37.3%) had right coronary artery (RCA) lesions and
26 (11.8%) had a stent thrombosis in the left circumflex
artery (LCx). Prevalences of traditional risk factors were
essentially equivalent regardless of which coronary artery
developed stent thrombosis. All patients were on dual
antiplatelet prior to developing stent thrombosis. Further
analysis revealed 38 (17.3%) had a prior history of CABG. A
significant difference among the location of stent thrombosis
and the history of CABG (P=0.043) was seen; 30.8% (n=8)
of patients with LCx stent thrombosis had prior CABG
compared to 10.9% (n=12) and 22% (n=18) with LAD and
RCA stent thrombosis, respectively.
Conclusion: In a large cohort of patients with stent
thrombosis, LAD and RCA lesions were predominant, with
LAD lesions representing half of all stent thromboses. PCI
of these coronary territories thus infers a higher risk of
stent thrombosis even in the presence of optimal medical
therapy. Once stent thrombosis occurs, no significant
difference in outcomes is seen based on location of the
lesion alone. Additionally, patients who had prior CABG
were significantly more likely to have stent thrombosis in
the LCx and less likely in the LAD. This could be due to the
fact that the left internal mammary artery graft is more often
patent than vein grafts, which are more often anastomosed
to the LCx and RCA and are at higher risk of needing stent
placement after CABG.
expression and growth factor receptor (GFR)-mediated
signaling. NFκB and STAT3 are phosphorylated in response
to GFR activation and modulate gene expression, which
promotes cell growth and invasion. Activated NFκB and
STAT3 expression is associated with ccRCC pathogenesis.
Purpose: The dietary polyphenol curcumin is a welldocumented antitumor agent and a known inhibitor of NFκB
and STAT3 activation. Given the lack of effective therapies
that block ccRCC progression, our objective was to examine
whether curcumin could suppress the growth and migration
of ccRCC cells, and whether this suppression was mediated
via inhibition of NFκB and STAT3 activity.
Methods: Human ccRCC cell lines (769-p, 786-o, Caki-1,
ACHN and A-498 cells) were exposed to curcumin to assess
the impact of curcumin on ccRCC cell viability. To examine
the mechanism by which curcumin induced cell death, we
used 769-p cells, a highly aggressive human ccRCC cell line
that does not express functional von Hippel-Lindau protein.
The impact of curcumin on the phosphorylation status and
transcriptional activity of NFκB and STAT3, in 769-p cells,
was determined.
Results: Our results show that in ccRCC cells curcumin
decreased cell proliferation and cell viability, abolished
clonogenic property, induced apoptosis and blocked cellular
migration. The growth suppressive and proapoptotic effects
of curcumin were accompanied by decreased phosphorylation
and transcriptional activity of NFκB and STAT3.
Conclusion: The ability of curcumin to induce apoptosis and
inhibit migration of ccRCC cells justifies additional studies
that explore the potential of developing curcumin or other
NFκB and STAT3 inhibitors as novel therapeutic agents in
the management of ccRCC.
Triple Aim for Clinical Teachers (TACT): Faculty
Physician Perceptions on Their Ability to Balance
Clinical Quality, Trainee Learning, and Teaching
Efficiency
In Vitro Growth Suppression of Renal Carcinoma
Cells by Curcumin
Minuja Muralidharan, Anne Getzin, Kjersti E. Knox,
Bonnie L. Bobot, Marie M. Forgie, Nicole P. Salvo,
Deborah Simpson
Santhi D. Konduri, Madhavi Latha Yadav Bangaru, Phu
Thanh Do, Shenglin Chen, Jeffrey Woodliff, Sanjay
Kansra
Departments of Internal Medicine, Family Medicine,
Obstetrics and Gynecology, and Academic Affairs,
Aurora UW Medical Group
Aurora Research Institute, Aurora Health Care; Medical
College of Wisconsin
Background: A common challenge facing teaching
physicians is balancing high-quality student and resident
teaching with efficient, high-quality care and patient service.
Publicly accessible clinic performance reports increasingly
affect where patients seek care and demand that teaching
clinics rise to consumer expectations while training future
physicians to function in the modern health care workplace.
Limited information is available to guide physicians to
achieve the triple aim for clinical teachers (TACT): clinical
quality/patient experience, trainee learning, and teaching
efficiency.
Purpose: To understand clinical teachers’ TACT-related
Background: Malignant clear cell renal carcinoma
(ccRCC) is an aggressive tumor that is highly resistant to
chemotherapy and radiation. Current therapeutic approaches
to management of ccRCC have not significantly improved
patient survival, therefore novel therapies are needed. The
von Hippel-Lindau tumor suppressor gene is frequently
mutated in ccRCC resulting in unregulated transcriptional
activity of hypoxia-inducible factors (HIF) 1α and 2α. HIFmediated transcription leads to increased growth factor
Supplement
209
experiences, perceptions and preferences for how to learn
TACT-associated skill sets to improve their competence as
teachers.
Methods: A 7-question needs assessment survey was
distributed to teaching faculty members in family medicine,
internal medicine and ob/gyn in a health care system.
Ranking, rating and free-response item formats were used
to determine teachers’ prioritization of care management
and patient satisfaction metrics within medical education
and their perceived skills and limitations in incorporating
these factors into medical education. Data was analyzed
using descriptive statistics and narrative comments using
qualitative thematic analysis. This project was deemed “not
human subjects research” by Aurora Health Care.
Results: A 78% response rate was obtained (32/41).
Respondents’ top 3 teaching priorities were “Meeting
specific clerkship objectives/residency milestones,” “Impact
on your time/teaching efficiency” and “Service quality
priorities for the clinic.” Respondents ranked learner’s
evaluation of teaching among their lowest priorities.
63% of respondents reported that they involve learners in
improvement efforts (quality, safety, patient experience).
Respondents identified a variety of strategies for involving
learners in improvement efforts (medical students initiate
patient callback, follow up on lab tests, check/address health
maintenance items; residents identify a care management
target), although time was consistently identified as a barrier
to learner involvement.
Conclusion: Survey results confirmed that clinical teachers
place value on integrating efforts to enhance clinical quality/
patient experience as they teach yet face challenges to
TACT goal attainment. Findings will inform description of
successful TACT strategies, assessment of their effectiveness
and faculty development initiatives.
Reducing Readmission Rates in Acute Pancreatitis
Through Patient Education and Risk Assessment
Methods: Project was conducted out of Aurora’s Sinai,
St. Luke’s and West Allis Medical Centers with a total of
18 patients with acute pancreatitis admitted predominantly
to the internal medicine teaching service between February
2014 and October 2014. Patients were seen within 1–2
days of admission and provided one-on-one education
with a handout on acute pancreatitis. In addition, a
30-day pancreatitis readmission predictor (PRP) score was
used to classify patient as low (5%), moderate (17%) or
high (68%) risk for readmission via Epic health record’s
“Dot Phrase.” Subsequent readmissions, 14-day follow-up,
total hospitalizations and emergency department visits were
tracked through present. This was compared to readmission
rates of a randomly selected control group of 18 patients
admitted with acute pancreatitis.
Results: Patients had PRP scores ranging from 0 to 4, with
an average of 1 (rounded from 0.78). Of the 18 patients in
the study group, only 2 were readmitted within 30 days for
pancreatitis, or 11.1%. The control group had 3 (16.7%)
readmissions within 30 days. Patients with alcohol-related
pancreatitis were more likely to have a higher PRP (1.0) and
readmission rate (20%, 2/10).
Conclusion: A diagnosis of acute pancreatitis places
the patient at a significantly higher than average risk of
readmission. This project was able to reduce readmission
rates from 16.7% to 11.1% by simple patient education and
readmission risk assessment. Readmissions are detrimental
to both the patient and health care system. This project
serves as a starting point for reducing readmissions not only
in acute pancreatitis patients but potentially other diagnosisspecific readmission initiatives.
Tertiary Center Experience of Catheter-Directed
Thrombolysis for Immediately Threatened Acute
Lower Limb Ischemia of Native Vessels and Bypass
Graft Thrombosis
Jordan T. Vulcano
Hani Hashim, M. Fuad Jan, Maharaj Singh, Suhail
Allaqaband, Tanvir Bajwa, Anjan Gupta
Department of Internal Medicine, Aurora Sinai Medical
Center
Background: Early hospital readmissions are a direct burden
on both our patients’ well-being and health care system as a
whole. Acute pancreatitis is a top offender, with countless
30-day readmissions. Studies have showed a consistently
higher than average 30-day readmission rates in acute
pancreatitis, around 19%. This is significantly higher than
the average all-cause readmission rate at Aurora Health Care
hospitals. This quality improvement project aimed to reduce
the rate of acute pancreatitis 30-day readmission rates at
several Aurora hospitals through patient education and a
readmission risk assessment tool.
Purpose: To clarify some of the risk factors associated with
acute pancreatitis readmissions and reduce 30-day acute
pancreatitis readmission rates through patient education and
risk assessment to facilitate a safe discharge.
Background: Catheter-directed thrombolysis (CDT) is an
effective therapy and a class I indication for patients with
acute limb ischemia (ALI, Rutherford categories I and IIa)
of less than 14 days duration, and class IIb indication for
ALI (Rutherford category IIb) with symptoms more than
14 days duration. However, there is no consensus on the
initial management option for ALI (Rutherford category IIb)
with symptoms less than 14 days duration.
Purpose: To evaluate the safety, efficacy and outcome
of CDT, with or without bailout Angiojet mechanical
thrombectomy, in patients with immediately threatened
acute lower extremity ischemia (Rutherford category IIb)
as a minimally invasive alternative to emergent surgical
revascularization.
Methods: We retrospectively reviewed data on 69
Supplement
consecutive patients (mean age 67 ± 14.15 years, 50.72%
women) with ALI (Rutherford category IIb) who underwent
CDT only (57.9%) or CDT plus bailout Angiojet mechanical
thrombectomy (36.78%) at Aurora St. Luke’s Medical
Center from January 2004 to October 2014. Data were
collected from electronic medical records, procedures
reports, laboratory data and billing codes. Continuous
variables were expressed as means ± standard deviation and
range; categorical variables were expressed as frequency
count and percentage.
Results: Sites of target vessel for CDT were native vessel
arterial thrombosis (68.11%) and vascular bypass graft
thrombosis (27.5%). Reestablishment of blood flow and
clinical success was achieved in 75.4% of patients, while limb
salvage at 30 days was achieved in 87.1%. Amputation at
30 days occurred in 12.9%. Surgical embolectomy was
required in 15.9%, and lower extremity bypass surgery was
required in 8.7%. Time to lysis was 26.12 ± 18.6 hours.
Bleeding complications that required blood transfusion
occurred in 21% and hemorrhagic stroke in 1.44%.
Conclusion: Catheter-directed thrombolysis for acute limb
ischemia with symptoms less than 14 days (Rutherford
category IIb) in native artery or bypass graft thrombosis
has high immediate clinical success rate and very high
limb salvage rate at 30 days. CDT is a reasonable
minimally invasive alternative option to emergent surgical
revascularization.
PRACTC: Practice Readiness Academic Clinical
Training Collaborative –– Gap Analysis to Advance
Clinical Training for Nurse Practitioner Students
Jennifer Hartlaub, Mary Ann Muzi, M. Jamie Cairo,
John R. Brill, James Weese, Kristin Rivera, Susan
Hafemann, Ann M. Rohrer, Julia Schumacher, Terri L.
Vandenhouten
Departments of Family Medicine and Academic Affairs,
Aurora UW Medical Group; Departments of Oncology
and Medical Education, Aurora Health Care
Background: Multiple factors have created a perfect
storm of health care provider shortages in the United
States. Advanced practice registered nurses (APRNs),
long established as high-quality, cost-effective health care
providers, are meeting health care needs across the nation
in a variety of settings, and in Wisconsin will be needed
to augment the primary care workforce. With 5.7% of its
registered nurses credentialed as APRNs, Wisconsin lags
behind the national average of 8.7%. However, current
capacity to educate this workforce is strained, requiring
innovative data-driven clinical education models.
Purpose: To identify gaps in the current clinical educational
framework for nurse practitioner (NP) students within the
integrated health system.
Methods: Multiple data sources were used including
NP core learning goals achievement, current continuum
education/training experience models, health care system
Supplement
stakeholders’ perspectives, and advanced practice provider
hiring targets for 2015. NP-partnering universities’ curricula
and experiences of placing students within the integrated
health system were reviewed. Analysis was conducted by an
interprofessional team to identify gaps.
Results: Four gaps were identified: 1) structured learning
and assessments focused on value-based care models
(e.g. population, chronic disease) and tracking competencybased milestone achievement; 2) streamlined NP student
placement system and onboarding through centralized onestop infrastructure; 3) interdisciplinary education to emulate
the workplace in which practice-ready graduates will be placed;
and 4) number of preceptors with skills and knowledge
regarding NP educational curriculum and competencies.
Conclusion: Systematic gap analysis will guide NP student
placement and education at large Midwestern integrated
health system. A structured clinical academic partnership
with local university NP programs (PRACTC) that addresses
preclinical preparedness, a structured student placement
process, coordinated clinical experiences, preceptor
development strategies and a diversity strategy provides a
mechanism for accomplishing these goals.
β-Thujaplicin: A Soil Antifungal
Department of Family Medicine, Aurora UW Medical
Group; Center for Urban Population Health
Background: β-thujaplicin (β-Th), also known as hinokitiol,
naturally occurs in cedar mulch, is found in personal
care products and has in vitro antitumor activities. It is
antibacterial and antifungal, but has not been tested on
soil. Scedosporium apiospermum (Sce) is an emerging
“extremophile” fungal pathogen found in built outdoor
environments.
Purpose: Pilot β-Th as “natural” soil antimicrobial or for
isolation of extremophiles, and to explore β-Th resistance as
selective advantage to Sce in mulched landscape.
Methods: A variety of outdoor and indoor environments
were used for 2 sets of 24 paired soil samples. Soil/H20 slurry
(0.1 ml) was spread on Sabouraud dextrose agar with titrated
β-Th levels of 0, 25, 250 and 500 mg/L at 20° C. Fungal and
bacterial growth was semiquantitated with 4-point Likert
scale. Wilcoxon signed rank test was used for comparison.
A local soil Sce isolate was tested on each β-Th concentration.
Results: There was no significant inhibition of total
bacterial growth at β-Th 250 mg/L (mean 1.7/4) or 500 mg/L
(mean 1.7) compared to plain Sabouraud dextrose agar
(mean 1.6). Purple bacteria seemed to be selected for by
β-Th. Fungal inhibition was essentially complete, similar,
and significantly different from no β-Th (mean 3.4/4) at
levels of 250 (mean 0.1) and 500 mg/L (mean 0.0). There
was no significant fungal inhibition at 25 mg/L (mean 3.2,
second set samples). Similarly, Sce was completely inhibited
at 250 and 500 mg/L, but not inhibited at 25 mg/L.
Conclusion: In vitro, β-thujaplicin profoundly, but
211
nonselectively, inhibits fungal growth in soil samples at
moderately high levels. It does not appear likely that this
Scedosporium apiospermum strain employs β-Th resistance
for selective advantage in cedar mulched landscaping.
Mailed At-Home FIT Intervention to Increase
Colorectal
Screenings
at
Sixteenth
Street
Community Health Centers
Alexander V. Herrera, Brian Hilgeman, Michelle Buelow,
Melissa A. Lemke
TRIUMPH Program, University of Wisconsin School
of Medicine and Public Health; Internal Medicine and
Family Medicine, Sixteenth Street Community Health
Center
Background: Mailed at-home FIT intervention kits to
increase colorectal cancer screenings at Sixteenth Street
Community Health Centers (SSCHC).
Purpose: It is our goal to increase the current SSCHC
colorectal cancer baseline screening rate of 23% to 50%
within three years of full at-home FIT kit implementation.
Methods: Colon cancer is the second and third most common
cause of cancer death in the United States in Hispanic men
and women, respectively. Colonoscopy is the most common
method of colon cancer screening, even among low-income
patients. However, it has been shown in community health
centers that mailed FIT kits are a more effective outreach
method (40.7% completion) than colonoscopy outreach
(24.6%) or usual care (12.1%). We hope to increase colorectal
cancer screening in eligible patients at the SSCHC through
mailed at-home FIT kits that have FIT materials, instructions
and educational materials based on the Health Belief Model.
Results: A trial intervention will assess the potential for
annual implementation with hopes of full implementation to
all of SSCHC eligible patients in the future.
Conclusion: Application of culturally relevant interventions
can be a practical and inexpensive method of increasing
colorectal screening rates in community health centers with
predominantly Hispanic populations.
Maternal Intuition of Fetal Gender
Michael P. McFadzen, David P. Dielentheis, Ronda
Kasten
Department of Obstetrics, Aurora Sheboygan Clinic
Background: Many pregnant mothers feel they have a
perception or intuition as to the gender of their unborn baby.
There is very little published scientific literature regarding
this topic. The study’s goal is to determine accuracy of
mothers’ perceptions as to gender of their unborn babies.
Many scientists believe a pregnant woman could not
determine her baby’s gender by intuition, with a 50%
probability of correctly determining the gender. This study
should be considered fun science.
Purpose: To objectively measure a pregnant mother’s
perception as to the gender of her unborn baby and compare
to sonographically proved gender. The study also will
measure the percentage of pregnant patients who have this
intuition.
Methods: All patients will be presenting for their secondtrimester screening ultrasound in the Obstetrics Department
of Aurora Sheboygan Clinic and must be 17–23 weeks
pregnant. A medical sonographer will describe the ultrasound
exam and obtain appropriate consent and medical history.
The patient will be asked if they have perception as to the
fetal gender; their answer will be logged. Patients with
knowledge of fetal gender will be excluded from this study.
Results: Thus far, 128 patients have qualified for the study
(with an expected cohort of 400). Approximately one-third
of our patient population has “intuition” or “perception” on
the gender of their baby. Of these, 47% correctly indicated
fetal gender, 53% did not. Within this study, we’ve started
categorizing patients who have a strong intuition of fetal
gender. This cohort has correctly indicated gender with 90%
accuracy; however, there are not enough participants for
clinical relevancy at this point in the study.
Conclusion: Preliminary data indicates mom perception of
fetal gender is 47% accurate.
Disease-Management in Family Medicine Clinics
Through the Addition of a Health Coach: A Pilot
Study
Crystal Y. Cichon, Jessica J.F. Kram, Tiffany A. Mullen,
Pamela Voelkers, Kristin J. Magliocco, Kiley A. Bernhard,
Department of Family Medicine, Aurora Health Care;
Center for Urban Population Health; Aurora Advanced
Health Care; University of Wisconsin School of Medicine
and Public Health; Aurora UW Medical Group
Background: In the United States, more than 80% of health
care spending is focused on the management of chronic
illnesses such as hypertension, diabetes and hyperlipidemia.
Controlling these chronic diseases can lead to better health
outcomes and decrease the number of preventable deaths.
Patient self-management has shown to improve clinical
outcomes. In a primary care setting, a multidisciplinary
approach can more effectively educate patients on improving
their health.
Purpose: To assess the impact of a health coach in a primary
care setting as it relates to clinical outcomes.
Methods: Patients from two Aurora family medicine clinics
were referred to a health coach by primary care providers. A
total of 40 patients participated and paid out of pocket for the
health coaching sessions (intervention). Patients had at least
one scheduled session with the health coach that covered
topics such as healthy eating, weight loss and exercise.
Patient data, including glycohemoglobin, lipid panels and
blood pressures, were reviewed pre- and postintervention.
Supplement
Data were obtained 1 year before the intervention date and at
least 3 months after. Paired t-tests were used for comparisons.
Results: The study population was predominantly
Caucasian (90%) and female (90%) with a mean age of 54
years (range 25–79). The mean patient body mass index
(kg/m2) was 37 and ranged from 28 to 63. When comparing
pre- and postintervention clinical data, several improvements
in laboratory values were noted. Low-density-lipoprotein
cholesterol levels decreased from an initial mean of 114
preintervention to 105 postintervention, mean high-densitylipoprotein cholesterol levels increased from 47 to 58, and
mean glycohemoglobin levels decreased from 6.5 to 6.1.
All improvements in clinical data were not statistically
significant, but were clinically relevant.
Conclusion: Patients showed mild improvements in multiple
lab values after their first meeting with a health coach. This
pilot study was limited by the small number of patients who
chose to have a health coaching session. A limiting factor
for patient use of a health coach may be secondary to the
cost of each clinic visit and follow-up lab work. Cost may
have contributed to our demographic mix. To further assess
the impact and benefit of a health coach in a primary care
setting, a larger, more diverse patient population is needed.
Real-World Relevance of Manual Electrocardiography
QT Interval Measurement
Satish Velagapudi, Zahra Nur Khaled, Bilal Omery,
Firas Zahwe, Michael Anigbogu, Sarah Zukkoor,
Indrajit Choudhuri
Department of Cardiology, Aurora Health Care;
Department of Pharmacy, Aurora St. Luke’s Medical
Center; Aurora Cardiovascular Services, Aurora Health
Care
Background: Electrocardiography (ECG) QT interval
(QTI) prolongation independently predicts sudden death.
Hospitalized patients are commonly exposed to multiple
QT-prolonging drugs, and manual measurement of ECG QTI
based on identifying the intersection of isoelectricity with
the tangent to the terminal phase T-wave slope (QTTTT)
is advocated due to inaccuracies in automated detection
algorithms that may imprecisely identify QT duration.
Purpose: We evaluated the performance of QTTTT compared
to a standard automated (12SL, GE Healthcare) method
(QT-12SL).
Methods: Consecutively obtained ECGs of 250 hospitalized
patients were reviewed. The QTI in leads II, aVR, V5 and
V6 determined by QT-12SL and QTTTT were compared.
ECGs in which QT-12SL and QTTTT differed by > 10 ms
were further characterized.
Results: The T-wave end was not reliably identified in 6 ECGs
(2.4%). Of the remaining 244 ECGs (976 leads), QTTTT
differed from QT-12SL by < 10 ms in 52 ECGs (21.3%).
QT-12SL differed from QTTTT by > 10 ms in lead II in 140
leads (14.3%), V5 in 149 leads (15.3%), V6 in 152 leads
(15.6%) and aVR in 143 leads (14.7%). ECGs with mutually
Supplement
exclusive lead combinations in which QTTTT differed from
QT-12SL by > 10 ms were: 1) II, aVR, V5, V6 (39.8%);
2) V5, V6 (7.8%); 3) II, aVR (4.9%); and 4) II, V5, V6
(3.7%). The expected overestimation of QTI by QT-12SL
compared to QTTTT exceeded 10 ms in 105 leads (10.8%),
related to T-waves with “normal” appearance, or biphasic
(negative-to-positive) morphology; U-wave; and TP
segment voltage exceeding PR segment voltage. Compared
to QTTTT, QT-12SL underestimated QTI in 479 leads
(49.1%), in association with biphasic T-waves (positiveto-negative); atrial arrhythmias; downsloping baseline near
the T-wave end resulting in TP segment voltage less than
PR segment voltage; and slow return of T-wave terminus to
baseline.
Conclusion: Multiple clinical and electrical phenomena
impacted automated QTI determination. QT-12SL and
QTTTT were comparable across all analyzed leads in
only 1/5 of ECGs. Compared to QTTTT, QT-12SL QTI
determinations were discordant in 3/5 of all leads, and
underestimated QTI nearly half the time. Perhaps most
important, for a given ECG, manual review of any of the
analyzed leads identified these differences 2/3 of the time.
Aligning Asthma Education Across the Continuum
of Physician Education: Impact on Clinical Metrics
Lisa Sullivan Vedder, Deborah Simpson, Jacob L.
Bidwell, John R. Brill, Theresa Frederick
Departments of Family Medicine and Academic Affairs,
Aurora UW Medical Group; Office of Continuing and
Professional Development, Aurora Health Care
Background: All trainees entering family medicine
residency training programs after June 1, 2012, must
complete the same American Board of Family Medicine
(ABFM) Maintenance of Certification (MOC) requirements
as practicing physicians. These shared requirements provide
an opportunity to align physician education initiatives
across the continuum focused around a clinical care topic to
improve health care system metrics.
Purpose: To assess the initial effectiveness of an ABFM
Asthma Part IV approved MOC module, aligned to meet
residency and medical student program accreditation
requirements, on health care system metrics.
Methods: An ABFM Asthma Part IV MOC module was
implemented for family medicine physicians and residents
in April 2014 with open, rolling enrollment for all providers.
The module focused on a 20% asthma control test (ACT)
improvement as ACT is a potential driver for appropriate use
of asthma controller medications (ACM) in persistent asthma
and completion of the asthma action plan (AAP). Students
rotating on a required primary care clerkship received a
1-hour orientation to quality improvement principles and
their role in assuring that an ACT had been completed on
their patients. Care quality measures at baseline (January
2014) and 12 months later (December 2014) were compared:
ACT use, AAP completion, and percentage of patients on
213
ACM for two targeted family medicine residency teaching
clinics.
Results: Through February 2015, 29 providers systemwide
completed the module with 212 in progress. Data from
targeted clinics demonstrated system level increases in all
metrics over project period, with average increases of 21%
in ACT completion, 34% in use of AAP and 7% in ACM
use. Participants’ evaluations are strong: 80% of module
completers rate MOC training as yielding a high return
on their time investment; 100% of M3 students report
completing an ACT test and an associated impact on their
patient’s care. Participant comments include: “... since
completing this project I will strive to screen all my asthma
patients at every visit … [and] adjust their medications
based on it. [It’s] an extremely useful clinical tool”; and “I
plan on trying to use [the] ACT with more appointments as a
way to check up on asthma quickly. Score increased to 44%
with minimal intervention.”
Conclusion: Aligning physician education opportunities
across the continuum with health care system metrics meets
board (re)certification requirements, residency and medical
student accreditation requirements and improves care for
patients.
Incidence of Breast, Colorectal and Lung Cancers
and Mortality Among Women Within Midwestern
States
(122 per 100,000), Wisconsin women had a significantly
higher incidence (P<0.05). Within the Midwest, Wisconsin
had a higher incidence than Indiana (P<0.0005) as well
as higher mortality than Nebraska (P<0.05). However,
Wisconsin had lower incidence of breast cancer than
Minnesota and Ohio (P<0.01) and lower mortality than Ohio
(P<0.05). Wisconsin had both lower incidence and mortality
than Illinois, Indiana, Iowa and Nebraska (P<0.05) for
colorectal cancer. For lung cancer, Wisconsin had a higher
incidence and mortality than Minnesota and Nebraska
(P<0.005) and lower incidence than Indiana, Michigan and
Missouri (P<0.05). No significant differences were noted
between Wisconsin and other Midwestern states.
Conclusion: Though variations exist between Wisconsin
and other Midwestern states in incidence and mortality, there
are no consistent trends between these states and the three
most common cancers. As a whole, however, the Midwest
had statistically higher incidence and mortality rates than the
nation. Further investigations into the regional differences
between Wisconsin, the Midwest, and other states with
similar demographic composition will be explored.
Fair Weight Loss After Gastric Rebanding for
Slippage
Ahmed Dalmar, Maharaj Singh, Sara K. Roloff, Thomas
Y. Chua
Ruth M. Perez, Matthew Rappelt, Kathryn Kossow,
Maharaj Singh
Aurora Research Institute, Aurora Health Care;
Wisconsin Bariatrics
Background: Laparoscopic adjustable gastric banding
(LAGB) is one of the most common bariatric surgery
procedures performed in the United States. LAGB results in
safe and satisfactory weight loss, but it is often complicated
with slippage, a complication requiring rebanding
(reoperation). There is a paucity of studies and no uniform
consensus regarding weight loss after rebanding.
Purpose: This study assessed the effect of rebanding for
slippage after LAGB on weight loss up to five years.
Methods: This is a historical cohort study of 865 patients
who underwent LAGB from 2001 to 2011. Rebanding was
performed in 103 (11.9%) patients. Primary outcome of
interest was percent excess weight loss (% EWL), which
was categorized as fair (>25–50%) and failure (<25% EWL)
after rebanding. Of the 103 patients diagnosed with slippage,
23 were excluded from further analysis because either the
band was removed (n=15), or they were rebanded twice due
to recurrent slippage (n=2) or lack of enough data (n=6).
Of the remaining 80, 76 patients were matched with 76
controls without slippage using propensity matching. Paired
t-test was used to compare weights (initial, at reoperation,
and 1, 2, 3, 4 and 5 years before and after rebanding). Chisquare test was used to compare EWL rate between groups.
Multivariate logistic regression was performed to determine
predictive probability for propensity matching of slippage.
Results: The majority of patients were female (82.9%).
Mean age was 44.32 ± 11.3 years, mean preoperative body
Background: Breast, colorectal and lung cancers have
been shown to be the most common cancers as well as the
leading causes of cancer death among women. Previous
studies suggest that the Northeast had significantly higher
rates in incidence and mortality than the Midwest, South
and Western regions. However, new data indicates that
the Midwest now harbors the highest mortality rates. In
Wisconsin, the sixth largest state in the Midwest, cancer
is the leading cause of death. Differences in incidence and
mortality of breast, colorectal and lung cancers have been
observed between Wisconsin, other Midwestern states and
national data, warranting further investigation.
Purpose: To examine the incidence and mortality of
Wisconsin females across breast, colorectal and lung
cancers compared to that of the national average along with
the individual states that comprise the Midwest (ND, SD,
NE, KS, MN, IA, MO, IL, IN, OH and MI).
Methods: Female incidence and mortality rates were
retrieved from the Centers for Disease Control and
Prevention (CDC) National Program of Cancer registries for
the 2011 year, while census data was retrieved from the U.S.
Census Bureau for the nation, region and individual states.
Data was analyzed using two-sample z-test for proportions
with significance set at P<0.05.
Results: Compared to the national incidence of breast cancer
Supplement
mass index 48.62 ± 8.0 kg/m2 and mean preoperative excess
weight 171.28 ± 52.0 lbs. Median follow-up after LAGB was
63.63 months (range 0.0–162.4) for a total of 4,859 patientyears. During follow-up, 103 patients (11.9%) underwent
reoperation for slippage at a median of 54.26 months
(range 0.0–160.50) after LAGB. We found a significantly
lower weight at rebanding, and at 1, 2, 3, 4 and 5 years
after rebanding in patients with slippage compared to their
initial weight, and their weight at 1, 2, 3, 4 and 5 years after
LAGB. There was a significantly lower excess weight loss
failure rate in patients with slippage compared to matching
controls (40% vs. 60%, P=0.0006) after first year. There
were no differences in EWL rate between the two groups
after first year. In multivariate analysis only female gender
was significantly associated with slippage.
Conclusion: Failure rate of excess weight loss after
rebanding for slippage was lower or similar to the failure
rate after initial laparoscopic adjustable gastric banding.
Feasibility of Atrial Delivery and Tracking of Stem
Cells in a Porcine Model
Nina Garlie, Timothy Hacker, Eric G. Schmuck, Jill
Koch, Jayant Khitha, Amish Raval, Indrajit Choudhuri
Regenerative Medicine Center, Aurora Research
Institute, Aurora Health Care; Department of Medicine,
University of Wisconsin School of Medicine and Public
Health; Aurora Cardiovascular Services, Aurora Health
Care
Background: Many patients undergoing open heart surgery
have sinus node dysfunction and atrial fibrillation, leading
to adverse outcomes. Mesenchymal stem cells (MSC)
delivered at the time of surgery may have a reparative effect
on atrial tissue, thereby improving sinus node function and
reducing or preventing atrial fibrillation. Stem cell delivery
to the atrium is entirely unstudied. This is a significant gap in
medical research, as atrial disease contributes significantly
to health care costs.
Purpose: The purpose of this pilot study is to establish a
technique to deliver MSC to the atria through an open-chest
model, to assess the safety of this technique, and to evaluate
the acute retention of the delivered cells.
Methods: All in vivo animal experimentation was approved
by the University of Wisconsin Animal Care and Use
Committee and took place in the Cardiovascular Physiology
Core Facility at UW-Madison. MSC (3-5×106 in 50 μl per
site) were injected intramyocardially during an open-chest
procedure in anesthetized pigs. To track the cells in vivo,
MSC were labeled with 18FDG then visualized at 1 and 6
hours postinjection by PET/CT. Pigs were monitored for
intraoperative arrhythmia, bleeding and hypotension.
Results: By gently repositioning the heart, both atria were
accessible for the injections. The thickest part of each atrium
was isolated and stabilized briefly for the injection using
a hemostat. The injected cells were visible by PET/CT 1
and 6 hours postinjection. However, when the MSC were
Supplement
labeled with 10mCi 18FDG, the signal was too high, causing
a bloom around the areas of injection. So the dose was
lowered to 5mCi 18FDG, which resulted in a clear signal
at 1 hour in both atria. At 6 hours, the right atrial injection
was still easy to read, but the left injection was difficult to
resolve from background signal. All injections resulted in
cell leakage from the injection site and uptake of the signal
into the lungs. However, pulmonary function as measured by
SpO2 and EtCO2 was unchanged. Intraoperative arrhythmias
detected during the injections were caused by manipulation
of the heart. No additional arrhythmias were detected. No
bleeding or hypotension was observed as a result of the
injections.
Conclusion: This pilot study demonstrated that atrial
delivery of MSC is feasible and safe in an open-chest
porcine model and that MSC are retained for at least 6 hours
postinjection. Subsequent studies will determine the ability
of MSC to downregulate inflammation, decrease scarring
and prevent sinus node dysfunction.
Does the Expression of Ki-67, p16 and COX-2 at
Initial Diagnosis of Breast Atypia or Usual Ductal
Hyperplasia Predict a Second Clinically Significant
Event?
Judy A. Tjoe, Philippe Gascard, Jianxin Zhao, Gary
F. Neitzel, Maharaj Singh, Brittany Last, James Marx,
Thea Tlsty, Sanjay Kansra
Surgical Breast Oncology, Aurora Health Care;
Department of Pathology, University of California, San
Francisco; ACL Laboratories, Department of Pathology,
Aurora Health Care; Aurora Research Institute, Aurora
Health Care
Background: Women diagnosed with atypical ductal
hyperplasia (ADH) or atypical lobular hyperplasia (ALH)
have a fivefold increased risk of developing breast cancer.
Because ADH/ALH can be precursors or predictive markers
of a subsequent clinically significant event (SCSE), i.e.
atypia, in situ or invasive carcinoma, the clinical outcome
for these patients ranges anywhere from remission to
invasive malignancy. Currently we cannot predict which
atypical breast lesion is likely to be associated with
future cancer, resulting in aggressive management and,
possibly, overtreatment. Kerlikowske et al. reported that
a combination of three biomarkers (cell cycle regulator
p16INK4a, proliferation antigen Ki-67 and stress response
enzyme COX-2) predicted risk of progression for ~50% of
women diagnosed with ductal carcinoma in situ and treated
by lumpectomy alone.
Purpose: To evaluate whether expression levels of p16,
Ki-67 and COX-2 predict risk of development of a SCSE
in patients initially diagnosed with breast atypia (ADH or
ALH) or usual ductal hyperplasia (UDH).
Methods: Patients with an initial diagnosis of pure
ADH/ALH were identified by medical record review
and the lesion confirmed by a single pathologist blinded
215
to original diagnosis. Twelve women who developed a
SCSE (cases) were matched to 44 women who did not
(controls) at least 5 years after initial diagnosis. Archived
tissues were stained for p16INK4a, Ki67 and COX-2 using
“multiplex immunohistochemistry,” enabling simultaneous
interrogation of expression levels of the three biomarkers in
a single tissue section.
Results: Our multiplex analysis revealed that expression
levels of Ki-67, p16INK4a or COX-2, either in epithelial
cells within the lesion or in stromal cells adjacent to the
lesion, either individually or in combination, do not predict
the development of a SCSE in women initially diagnosed
with ADH/ALH or UDH. However, this analysis identified
double- or triple-positive cells in the vicinity of the lesions
in some cases and controls.
Conclusion: Expression of Ki-67, p16INK4a and COX-2 is
not predictive of a SCSE following initial diagnosis of ADH/
ALH or UDH. Further analysis is needed on a larger cohort
after longer follow-up after initial diagnosis to confirm our
findings and to investigate whether the presence of doubleor triple-positive cells (a signature predicted to correlate
with poor outcome) is predictive of progression regardless
of the expression status of the lesion.
The Effect of Percutaneous Closure of Large Atrial
Septal Defects on Right Ventricular Function in
Adults
Armaan Shaikh, Alejandro Lopez-Mas, Suhail
Allaqaband, Bijoy K. Khandheria, Abraham Getenet,
Matt M. Umland, Maharaj Singh, Tanvir Bajwa
Department of Internal Medicine, Aurora Sinai Medical
Center; Aurora Research Institute, Aurora Health Care
Background: Percutaneous closure of atrial septal defects
has been shown to be a safe alternative to surgery. Despite
this, past studies have largely been focused on either smallto medium-sized atrial septal defects or percutaneous closure
in children and young adults.
Purpose: Our study sought to examine if right ventricular
function and size improved after percutaneous closure of
large atrial septal defects in the adult population.
Methods: Over a 5-year span, 25 patients underwent
percutaneous closure of a secundum atrial septal defect
with an occluder device. A retrospective examination was
conducted for each patient, including both echocardiography
and chart review for postdevice complications/symptoms.
Results: Average patient age was 44.4 years, and mean
device size was 28 mm (range: 24–38 mm). Follow-up
echocardiography (mean of 134 days) showed tricuspid
annular plane systolic excursion was significantly improved
(2.11 vs. 2.33; P=0.013). There also was a significant
reduction in right ventricular diastolic chamber size (31.0
vs. 35.4; P<0.01). At 1-year postprocedure follow-up, zero
patients had experienced transient ischemic attack, stroke or
device perforation/embolization.
Conclusion: Percutaneous closure of large secundum atrial
septal defects in adults improves right ventricular function as
well as right ventricular chamber size. Percutaneous closure
of large atrial septal defects also is a safe, very low-risk
procedure in terms of future adverse neurologic, embolic or
perforation-related events.
Coronary Aorta Systolic and Diastolic Pressure
Indices: Two Novel Indicators for Predicting
Significant Coronary Stenosis –– A Validation
Against Fractional Flow Reserve
Mirza Mujadil Ahmad, Khawaja Afzal Ammar, Mirza
Nubair Ahmad, Arsalan Riaz, Fatima A. Husain, Syed
Shahab Kazmi, Imran Husain, Anjan Gupta
Aurora Cardiovascular Services, Aurora Health Care
Background: Since most of the coronary flow occurs in
diastole, either mean Pd/Pa or iFR has been used to measure
the hemodynamic significance of a coronary stenosis. We
have observed that a significant pressure gradient exists
in coronary stenosis even in systole, which is contrary to
general understanding but similar to ankle brachial index.
Furthermore, prior studies have evaluated baseline Pd/Pa
(mean coronary artery/mean aorta pressure) ratio as well as
iFR (instantaneous wave-free ratio obtained during entire
period of diastole) to predict fractional flow reserve (FFR) ≤
0.80. We hypothesized a simple end-systolic and -diastolic
pressure measurement in the coronary artery distal to
stenosis may perform adequately to predict FFR, obviating a
need to measure Pd/Pa or iFR.
Purpose: We sought to evaluate systolic and diastolic Pd/
Pa, and termed them coronary artery systolic pressure
index (CASPI) and coronary artery diastolic pressure index
(CADPI), respectively, against FFR ≤ 0.80.
Methods: After retrospectively identifying 555 moderate
stenotic lesions undergoing FFR measurement at a tertiary
care center over a 4-year period, we procured original
pressure tracings obtained during the cardiac catheterization
and manually measured systolic and diastolic pressures in
the aorta and in the coronary artery distal to the stenosis,
before and after adenosine infusion. Utilizing FFR ≤ 0.80,
operating test characteristics of CASPI and CADPI were
measured and compared to those of baseline Pd/Pa.
Results: In the 555 lesions, mean CASPI (0.97 ± 0.04) and
CADPI (0.95 ± 0.08) were similar to baseline Pd/Pa (0.95 ±
0.05). CASPI correlated well with baseline Pd/Pa (Spearman
r=0.81; P<0.0001). Similarly, CADPI was strongly correlated
with baseline Pd/Pa (0.86; P<0.0001). The area under the
receiver operating curve (AUC) was lower for CASPI and
CADPI, as compared to baseline Pd/Pa (0.80 vs. 0.82 vs. 0.89,
respectively), for predicting the FFR ≤ 0.80. For a CASPI <
0.88 there were no false positives with 100% specificity, and
for a CASPI > 1.02, there were no false negatives with 100%
sensitivity. Similarly, for a CADPI < 0.8 there were no false
positives with 100% specificity, and for CADPI > 1.16 there
were no false negatives with 100% sensitivity.
Supplement
Conclusion: These data demonstrate that contrary to the
popular belief, significant systolic and diastolic pressure
gradients distal to coronary stenosis exist with a reasonable
but lower predictive power towards FFR ≤ 0.80.
Contemporary Usage of Intra-Arterial CatheterDirected Thrombolytic (CDT) Power Pulse Spray
With Rheolytic Thrombectomy in Failed CDT Alone
for Acute Limb Ischemia
Hani Hashim, M. Fuad Jan, Maharaj Singh, Suhail
Allaqaband, Tanvir Bajwa, Anjan Gupta
tool for lower extremity acute limb ischemia that achieves
success in the vast majority of patients, is not associated
with higher complications when compared to successful
CDT alone, and obviates the need for emergent surgical
revascularization.
Additional Presentations
The following citations reflect additional 2015 Aurora
Scientific Day presentations, some of which have been
published as abstracts or articles in scientific journals.
________________________________________________
Background: Acute lower limb ischemia (ALI) caused
by arterial embolism, thrombosis of native vessels, and/
or grafts is a serious condition associated with substantial
morbidity and mortality. Peripheral arterial thrombolysis
utilizing catheter-directed thrombolytic (CDT) has become
established as a useful option in the management of ALI.
However, use and outcome of adjunctive power pulse
spray with rheolytic thrombectomy (PPSRT) following
unsuccessful CDT is underreported in the literature.
Purpose: To evaluate outcome of contemporary use of intraarterial CDT PPSRT as an adjunct to unsuccessful standard
CDT for ALI.
Methods: We reviewed 78 consecutive patients (mean age 69 ±
14.2 years, 48.8% female) who presented to Aurora St. Luke’s
Medical Center with less than 14 days of ALI from January 2004
to October 2014. All patients had percutaneous transluminal
angioplasty procedures as a standard revascularization option
for ALI. Data were collected from electronic medical records,
and billing codes. Continuous variables were expressed as
mean ± standard deviation and range, and categorical variables
as frequency count and percentage. Differences between the
groups were analyzed with t-tests or analysis of variance and
chi-square or Fisher’s test.
Results: 48 patients (Group 1) underwent CDT alone with
successful technical and clinical results, while 30 patients
(Group 2) who had unsuccessful CDT results underwent
adjunctive CDT with PPSRT. There was no statistical
significance among both groups in regard to their baseline
characteristics. In Group 1 and Group 2, respectively,
limb salvage was 87.5% and 86.6% (P=ns), amputation at
30 days 13% and 16% (P=ns), embolectomy 16.67% and
20% (P=ns), emergent bypass graft 8.3% and 13.33% (P=ns),
distal embolization 14.89% and 17.24% (P=ns), 30-day
compartmental syndrome 12.5% and 13.79% (P=ns), death
at 30 days 8.8% and 13.33% (P=ns), and bleeding requiring
blood transfusion 16% and 14% (P=ns). Hemorrhagic
stroke occurred in one patient of Group 1. Complete and
partial analysis achieved in (Group 2) 73.4%, length of
hospitalization was 10.6 ± 6.25 days (P=ns).
Conclusion: Adding intra-arterial CDT power pulse spray
with rheolytic thrombectomy to unsuccessful standard CDT
as an adjunctive procedure is a powerful revascularization
First Place Poster (tie): Ali Z, Greer DM, Shearer R, Alemu
A, Jahangir A. Androgen suppression effects on heart failure
and in patients with prostate cancer. J Am Coll Cardiol.
2015;65(10S):A887.
Supplement
Second Place Poster: Muluneh A, Nfor T, Bajwa T, Biru
NY, Parmar HS, Greer DM, Belete HM. Evaluating MACE
associated with temporary discontinuation of antiplatelets
for acute GI bleeding in patients with coronary stents. Poster
presented at Aurora Scientific Day, Milwaukee, WI, May 20,
2015.
Rieselbach Distinguished Paper #2: Forgie MM, Greer
DM, Kram JJF, Bernhard KA, Salvo NP, Siddiqui DS.
A randomized control trial of Foley catheter placement
for induction of labor: stylette versus no stylette. Orally
presented at Aurora Scientific Day, Milwaukee, WI, May
20, 2015.
Rieselbach Distinguished Paper #3: Yousaf H, Ahmad
MN, Ammar KA, Yusuf SH, Ellis MK. Operating
test characteristics of respiratory exchange ratio as a
noninvasive measure of anaerobic threshold. Circulation.
2013;128:A13761.
Rieselbach Distinguished Paper #4: Ali Z, Greer DM,
Shearer R, Gardezi AS, Chandel A, Jahangir A. Effects
of testosterone supplement therapy on cardiovascular
outcomes in men with low testosterone. J Am Coll Cardiol.
2015;65(10S):A1346.
Shi Y, Cho C, Garlie L, Perez R, Shearer R, Sulemanjee
N, Zwicke D, Hastings T, Cheema O, Thohan V.
Echocardiographic markers of implantable cardioverterdefibrillator therapy. J Am Coll Cardiol. 2015;65(10S):A913.
Honoris L, DeFranco A, Port S, Cho C, Li D, Nasir K,
Kronmal R, Barr RG, Budoff M. Correlation of coronary
artery calcium scoring on ungated computed tomography
compared to gated cardiac computed tomography scans
from the multi-ethnic study of atherosclerosis. J Am Coll
Cardiol. 2015;65(10S):A1063.
217
Battiola T, Cosic M, Holmuhamedov A, Negmadjanov U,
Holmuhamedov E, Jahangir A. Human cardiac fibroblasts
motility is predominantly supported by ATP from anaerobic
glycolysis. Orally presented at Aurora Scientific Day,
Milwaukee, WI, May 20, 2015.
Fink JT, Havens KK, Schumacher JA, Walker RE, Morris
GL 3rd, Nelson DA, Singh M, Cisler RA. Impact of the
Heart WATCH program on patients at risk of developing
metabolic syndrome, prediabetes or cardiovascular disease.
J Patient-Centered Res Rev. 2015;2:56-63.
Peterson L, Shafer M, Abugiazya A, Scoon C, Kramer D.
Telemedicine improves hospital system compliance with
lung-protective ventilation. Crit Care Med. 2014;42(12
Suppl 1):A1555.
Kazmi SS, Riaz A, Ahmad MN, Husain FA, Husain I, Yousaf
H, Shah S, Ammar KA, Gupta A. A baseline Pd/Pa of ≤ 0.86
obviates the need for FFR measurement and adenosine
infusion in intermediate coronary stenoses: a large tertiary
care experience. J Am Coll Cardiol. 2015;65(10S):A1738.
Andreeva A, Divan V, Maria A, Simpson M, Khan A,
Malone ML. Increasing delirium awareness in caregivers of
older hospitalized patients using an educational pamphlet:
a quality improvement project. Poster presented at Aurora
Scientific Day, Milwaukee, WI, May 20, 2015.
Hook ML, Badger MK, Gentile DL, Giannini RC, Hoffmann
ML, Ketchum BM, Martens M, Singh M. The impact of
electronic Knowledge-Based Nursing content and decisionsupport on nursing knowledge and use of evidence-based
practices. Poster presented at Aurora Scientific Day,
Milwaukee, WI, May 20, 2015.
Riaz A, Ahmad MN, Husain F, Kazmi SS, Husain I, Yousaf H,
Ammar KA, Gupta A. Prevalence of errors in fractional flow
reserve measurement in a high volume tertiary care center.
J Am Coll Cardiol. 2015;65(10S):A1879.
Rizvi F, Siddiqui R, DeFranco A, Jayaprakash A, Mirza
M, Emelyanova L, Ross G, Holmuhamedov E, O’Hair D,
Tajik AJ, Jahangir A. Simvastatin inhibits TGF-β1-induced
proliferation and activation of cardiac fibroblasts through
inhibition of SMAD pathway. Circ Res. 2014;115:A329.
Shanitkvitch Z, Amuzu B. Necessity of pathologic analysis
after tubal ligation by resection. Poster presented at Aurora
Cox Bauer C, Greer DM, Kram JJF, Kamelle SA. Tumor
diameter as a predictor of lymphatic dissemination in
endometrioid endometrial cancer. Poster presented at Aurora
Bauer LM. Program evaluation of the integrative health
coaching initiative at the Aurora Walker’s Point Community
Clinic: elucidating barriers to engagement and optimal health.
Poster presented at Aurora Scientific Day, Milwaukee, WI,
May 20, 2015.
Ross G, Holmuhamedov A, Cosic M, Rizvi F, Holmuhamedov
E, Jahangir A. Pro-proliferative effect of nifedipine, a L-type
Ca2+ channel blocker, in NIH-3T3 fibroblasts. Poster
presented at Aurora Scientific Day, Milwaukee, WI, May
20, 2015.
Negmadjanov U, Godic Z, Mirza M, Emelyanova L, Rizvi
F, Holmuhamedov E, Jahangir A. Transforming growth
factor-β1 increases resistance of fibroblasts to apoptotic cell
death. Circ Res. 2014;115:A268.
Aldag E, Farrell S, Pedersen R, Sahajpal A, Clendenon J,
Gunabushanam V, Kramer D. Evaluation of the effects of
N-acetylcysteine treatment in adult liver transplant recipients
[abstract]. Am J Transplant. 2015;15(S3). Available online
at http://www.atcmeetingabstracts.com/abstract/evaluationof-the-effects-of-n-acetylcysteine-treatment-in-adult-livertransplant-recipients/. Accessed May 4, 2015.
Pinninti M, Rivera C, Cho C, Thohan V, Hastings TE,
Cheema O, Downey FX, Crouch J, Weiss E, Sulemanjee
NZ. The effect of severity of renal dysfunction on clinical
outcomes in patients with continuous-flow left ventricular
assist device implantation. J Heart Lung Transplant.
2015;34(4 Suppl):S229.
Kumaravel V, Mahmoud M, Klyve D, Hernandez
LV, Guda NM. A prospective study on endoscopy for
luminal abnormalities on imaging and its impact on
clinical management. Gastrointest Endosc. 2015;81(5
Suppl):AB237-AB238.
Getzin A, Bobot B, Simpson D. Fueling the fire, sustaining
family physicians in urban underserved communities. Poster
presented at Aurora Scientific Day, Milwaukee, WI, May 20,
2015.
Erickson L, Sra J, Krum D, Ahmad MN, Majid T. Choudhuri
I, Rahman M, Djelmami-Hani M, Mortada ME, Kress D.
A retrospective analysis of hybrid ablation in patients with
long-standing persistent atrial fibrillation. Orally presented
at Aurora Scientific Day, Milwaukee, WI, May 20, 2015.
Klemm S, Cook M, Brummitt C, Ravenna V. Management
of Staphylococcus aureus bacteremia through pharmacist
prospective evaluation. Crit Care Med. 2014;42(12 Suppl
1):A1480.
Supplement
Join
us.
Be a life changer.
In 1981, Robyn Temkin lost her battle to malignant melanoma at the young age of 22.
But her spirit to fight this disease lives on today.
The launch of Journal of Patient-Centered Research and Reviews was made possible
through the generosity of the Robyn Temkin Memorial Fund, which provides new hope
to those facing melanoma. The fund also created the Robyn Temkin Memorial Garden
at Aurora Sinai Medical Center, and supports melanoma cancer research led by Marty
Oaks, PhD, at the Aurora Research Institute.
Thanks to the Robyn Temkin Memorial Fund, Aurora Health Care is able to share and
promote cutting-edge, life-saving research – that’s happening right here in Wisconsin.
Libby Temkin honors her daughter,
Robyn, through the creation of the
Robyn Temkin Memorial Garden at
Aurora Sinai Medical Center.
Learn more about how you can make a difference in the care we provide today –
and tomorrow. Visit Aurora.org/Foundation or call 877-460-8730. Because every
gift can change a life.
X48434a (01/14) ©AHC
Milwaukee, WI 53233
T: 414-219-7914
F: 414-219-3116

Fall 2015 issue - Aurora Medical Professionals

Transcription

Similar documents

Emerging African News

Aurora Shred Fest Flyer September 2015

AURORA SWIM CENTER SPRING 1 GROUP

E-Guidebook

View Fox Valley Park District`s Reservation Guide.

ICSU World Data System: Trusted Data Services for Global Science

Brochure - Treasure Hill Commercial

Building Upon Our Experience General Contracting

NEWSLETTER - The Aurora Project