Hyponatremia and Myelinolysis Pregnancy

Transcription

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Hyponatremia and Myelinolysis
To the Editor: Drs. Laureno and Karp suggest that in humans,
"rapid" correction of symptomatic hyponatremia may have detrimental sequelae, such as myelinolysis (1), despite overwhelming
evidence to the contrary (2, 3). Although absolute correction of
hyponatremia in laboratory animals by more than 25 mmol/L in
48 hours can lead to cerebral demyelinating lesions, the "rate" of
correction of plasma sodium concentrations in both humans and
laboratory animals has been shown to be irrelevant (2, 4). Most
patients who have brain damage associated with hyponatremic
encephalopathy are menstruant women who have had a hypoxic
episode (4). Among 117 patients with brain damage secondary to
hyponatremic encephalopathy, 96% had a hypoxic episode secondary to delayed onset of therapy and only 4% had brain
damage that might have been related to overcorrection (4). In
the past, the picture might have been distorted by the increased
likelihood of brain damage after an increase of plasma sodium in
patients with end-stage liver disease. The authors (1) unfortunately conclude that respiratory arrest leading to hypoxic encephalopathy in hyponatremic young women "rarely occurs," even
though in the study they cite, most patients with hyponatremia
were not included in the computer survey. To ascertain that most
patients who have brain damage associated with hyponatremia
are young women who have hypoxic events (4), the authors need
look no further than Table 1 in the article by Steele and colleagues (5) in the same issue of Annals in which their review
appears.
In summary, brain damage from hyponatremic encephalopathy
due to delayed onset of therapy is at least 24 times more likely
than brain damage due to improper therapy. Most patients who
have brain damage secondary to hyponatremic encephalopathy
are young (menstruant) women (4), whereas those who have
brain damage from a change in plasma sodium concentration
usually have end-stage liver disease.
/. Carlos Ayus, MD
Baylor College of Medicine
Houston, TX 77024
Allen I. Arieff, MD
University of California Medical Center
San Francisco, CA 94143
References
1. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia.
Ann Intern Med. 1997;126:57-62.
2. Sarnaik AP, Meert K, Hackbarth R, Fleischmann L. Management of
hyponatremic seizures in children with hypertonic saline: a safe and
effective strategy. Crit Care Med. 1991;19:758-62.
3. Tien R, Arieff AI, Kucharczyk W, Wasik A, Kucharczyk J. Hyponatremic encephalopathy: is central pontine myelinolysis a component? Am J
Med. 1992;92:513-22.
4. Ayus JC, Arieff AI. Brain damage and postoperative hyponatremia: role
of gender. Neurology. 1996;46:323-8.
5. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman RD,
Halpern ML. Postoperative hyponatremia despite near-isotonic saline
infusion: a phenomenon of desalination. Ann Intern Med. 1997;126:20-5.
In response: Rapid correction of hyponatremia can cause myelinolysis. This iatrogenic illness has been well documented in
humans (1, 2) and in controlled experiments in three mammalian
species (3-5).
Drs. Ayus and Arieff state that the rate of correction of plasma
sodium concentration is "irrelevant," yet they warn that a rate of
correction of "more than 25 mmol/L in 48 hours can lead to
cerebral demyelinating lesions." These statements are contradictory. The authors then discuss one possible outcome of symptomatic hyponatremia. We have always recognized that neurologic complications are associated with both hyponatremia and its
correction. We hope that Drs. Ayus and Arieff will soon recognize the amassed data showing that rapid correction of hyponatremia may cause myelinolysis.
We advise that the increase in serum sodium concentration be
limited, whenever possible, to a rate of less than 10 mmol/L in
any 24-hour period.
Barbara I. Karp, MD
National Institutes of Health
Bethesda, MD 20892
Robert Laureno, MD
Washington Hospital Center
Washington, DC 20010
References
1. Karp BP, Laureno R. Pontine and extrapontine myelinolysis. A neurological disorder following rapid correction of hyponatremia. Medicine
(Baltimore). 1993;72:359-73.
2. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurological sequelae
after treatment of severe hyponatremia: a multicenter perspective.
J Am Soc Nephrol. 1994;4:1522-30.
3. Illowsky BP, Laureno R. Encephalopathy and myelinolysis after rapid
correction of hyponatremia. Brain. 1987;110:855-67.
4. Laureno R. Central pontine myelinolysis following rapid correction of
hyponatremia. Ann Neurol. 1983;13:232-42.
5. Verbalis J, Martinez AJ. Neurological and neuropathological sequelae
of correction of chronic hyponatremia. Kidney Int. 1991;39:1274-82.
Pregnancy-Related Thromboembolism
To the Editor: I read with interest the informative article by
Friederich and colleagues (1) and the editorial by Lee (2) on
thromboembolic disease and pregnancy. Low-molecular-weight
heparin, recommended by Friederich and colleagues and Lee,
has been effectively and safely used for thromboprophylaxis during pregnancy (3, 4). However, no information seems to be
available about the drug's safety in relation to breast feeding, and
drug companies advise against its use during the puerperium in
15 July 1997 • Annals of Internal Medicine • Volume 127 • Number 2
163
breast-feeding patients. I would appreciate the authors' comments on this issue.
Arumugam Manoharan, MD
St. George Hospital
Kogarah, Sydney, Australia
References
1. Friederich PW, Sanson BJ, Simioni P, Zanardi S, Huisman MV, Kindt
I, et al. Frequency of pregnancy-related venous thromboembolism in
anticoagulant factor-deficient women: implications for prophylaxis. Ann
Intern Med. 1996;125:955-60.
2. Lee RV. Thromboembolic disease and pregnancy: are all women equal?
[Editorial] Ann Intern Med. 1996;125:1001-3.
3. Manoharan A. Use of low-molecular weight heparin during pregnancy
[Letter]. J Clin Pathol. 1994;47:94-5.
4. Sturridge F, de Swiet M. The use of low-molecular weight heparin for
thromboprophylaxis in pregnancy. Br J Obstet Gynaecol. 1994;101:69-71.
To the Editor: We would like to point out a critical error by
Friederich and associates (1) and to report on what we believe is
the largest population study of the incidence of deep venous
thrombosis and pulmonary embolism in the setting of delivered
pregnancies (4 weeks postpartum). Our data suggest that the
incidence is not only low but is similar to the incidence in closely
age-matched nonpregnant women in another study (2).
The annual 1.8% frequency of deep venous thrombosis in
nonpregnant women 20 to 40 years of age cited by Friederich
and colleagues is inaccurate. As listed in the original report (2),
the correct frequency is 0.018%.
We reviewed records of delivered pregnancies and postpartum
periods during which deep venous thrombosis and pulmonary
embolism occurred from January 1985 through January 1996 in
the northern California region of Kaiser Permanente (a health
maintenance organization serving 2.5 million members). A total
of 280 793 deliveries occurred; among these, 251 charts were
identified by International Classification of Diseases codes with
concomitant diagnoses of delivered pregnancy/postpartum and
thromboembolic disease. Patients were included in our study if
deep venous thrombosis or pulmonary embolism was documented by venography, Doppler ultrasonography, ventilationperfusion scanning, or pulmonary angiography. Eighty-one patients met these criteria (67 with deep venous thrombosis and 14
with pulmonary embolism); thus, the incidence of documented
deep venous thrombosis or pulmonary embolism in this population was 0.029%.
As cited in Friederich and colleagues' study, previous studies
have reported frequencies of these conditions of 1.3% to 7%
during pregnancy and 6.1% to 23% during the postpartum period
(1). Our incidence suggests a much lower frequency, as does the
0.055% frequency reported in the second largest population
study of these two conditions in women giving birth; like ours,
this study required objective documentation of thromboembolism
(3). Most noteworthy, in nonpregnant women 20 to 40 years of
age, the annual frequency of thromboembolism has been observed to be 0.018% (2). By using the Fisher exact test, we found
no statistically significant difference between this incidence and
the incidence of deep venous thrombosis or pulmonary embolism
in our study population (P > 0.2).
In response: Dr. Manoharan addresses the important issue of
the use of a drug when there is no formal knowledge of safety in
a specific situation. The experience with low-molecular-weight
heparin in pregnancy was obtained while the pharmaceutical
companies advised against use of the drug during pregnancy (1,
2). One report has indicated that low-molecular-weight heparin,
like unfractionated heparin, does not appear in breast milk (3).
Moreover, heparin is not easily absorbed and thus when given
orally is unlikely to cause any adverse effects.
We thank Brickner and colleagues for pointing out a mathematical error that escaped our attention when we reviewed the
galley proofs of our article. The numbers in the second paragraph of the introduction should read 0.018%, 0.013% to 0.07%,
and 0.061% to 0.23%, respectively. Thus, Brickner and colleagues' findings agree with the existing literature on the incidence of pregnancy-related venous thromboembolism in the general population.
Martin H. Prins, MD, PhD
Academic Medical Center, University of Amsterdam
Amsterdam, the Netherlands
References
1. Rasmussen C, Wadt J, Jacobsen B. Thromboembolic prophylaxis with
LMWH during pregnancy. Int J Gynecol Obstet. 1994;47:121-5.
2. Melissari E, Parker CJ, Wilson NV, et al. Use of LMWH in pregnancy.
Thromb Haemost. 1992;68:652-6.
3. Harenberg J, Leber G, Zimmermann R, Schmidt W. Thromboembolieprophylaxe mit niedermolekularem Heparin in der Schwangerschaft.
Geburtsh u Frauenheilk. 1987;47:15-8.
To the Editor: In his editorial on thrombosis prophylaxis during
pregnancy in women with hereditary or acquired thrombophilia,
Lee (1) rightly asks whether all women entering reproductive life
should be screened for coagulation deficiencies. For factor V
Leiden, we have already answered in the negative: If mass
screening for factor V Leiden were followed by routine anticoagulation prophylaxis, even a short course (say, 6 weeks) of oral
anticoagulation during the puerperium might cause the death of
as many young mothers as, or even more than, would have died
of pulmonary emboli resulting from their thrombophilic condition (2). The recommendation that attention be paid to the
personal and family history of thrombosis is borne out by the
important paper by Friederich and colleagues (3), whose results
pertain to women who already have one or more relatives with
venous thrombosis and a coagulation defect. Lee mentions that a
fear of litigation in the United States might lead to defensive
testing for thrombophilia and prescribing of anticoagulation during the entire pregnancy. We hope that this will be counterbalanced by a fear of hemorrhagic side effects (although we, as
Europeans, are not sure whether such side effects might also lead
to litigation) (4).
Prescribers should not forget that there are different modes of
prophylaxis. For example, it might be worthwhile to investigate
prophylaxis with elastic stockings during or after pregnancy
(alone or in combination with a very low dose of pharmacologic
anticoagulation). In a meta-analysis of prophylaxis in patients
having hip surgery, elastic stockings proved to be only slightly
less effective than pharmacologic anticoagulation and certainly
caused no bleeding (5).
Leslea A. Brickner, MD
Kate A. Scannell, MD
Lynn Acker son, PhD
Kaiser Permanente
Oakland, CA 94611
Ian P. Vandenbroucke, MD, PhD
Frits R. Rosendaal, MD
Leiden University Hospital
2300 RD Leiden, the Netherlands
References
Intern Med. 1996;125:955-60.
2. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective
study of the incidence of deep-vein thrombosis within a defined urban
population. J Intern Med. 1992;232:155-60.
3. Rutherford S, Montoro M, McGehee W, Strong T. Thromboembolic
disease associated with pregnancy: an 11-year review [Abstract]. Am J
Obstet Gynecol. 1991;164(Suppl):286.
References
1. Lee RV. Thromboembolic disease and pregnancy: are all women equal?
[Editorial] Ann Intern Med. 1996;125:1001-2.
2. Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, Rosendaal FR.
Factor V Leiden: should we screen oral contraceptive users and pregnant women? Br Med J. 1996;313:1127-30.
Intern Med. 1996;125:955-60.
4. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding
164
15 July 1997 • Annals of Internal Medicine
• Volume 127 • Number 2
Table.
Guide to Clinical Decisions about Prophylaxis of
Thromboembolism in Pregnant Women
History of
Thromboembolism?
Personal
No
Yes
No
Yes
Screen for
Thrombophilia?
Family
No
No
Yes
Yes
No
Maybe
Yes
Yes
Pharmacologic Prophylaxis?
Antepartum
Intrapartum or
Postpartum
No
Maybe
Maybe
Probably
No
Yes
Yes
Yes
complications in oral anticoagulant therapy: an analysis of risk factors.
Arch Intern Med. 1993;153:1557-62.
5. Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous
thromboembolism following total hip replacement. JAMA. 1994;271:
1780-5.
In response: I thank Drs. Vandenbroucke and Rosendaal for
reinforcing the importance of old-fashioned history taking as a
screening strategy for thrombophilic predisposition. In a litigious
venue, unfortunately, the availability of a quantifiable test often
means that the new technique supplants the old and becomes the
standard. And after the presence of thrombophilia has been
identified, doing nothing during pregnancy (a condition highly
publicized as a hypercoagulable state) is risky even when doing
something like anticoagulation has clearly defined risks. In light
of new studies of genetic thrombophilic conditions, neither the
older literature about pregnancy and thromboembolism nor the
literature that deals exclusively with thromboembolic disease in
nonpregnant patients is a reliable source of guidance.
There should be no debate about adequate heparinization for
women who have thromboembolism during pregnancy or the
postpartum period. There should also be no debate about the
universal utility of prophylactic postural and mechanical procedures (such as use of elastic stockings) for pregnant women.
Which pregnant women need pharmacologic prophylaxis, how
much prophylaxis is necessary, and when prophylaxis should be
administered need to be further elucidated. Any clinical decisions
and studies must be stratified according to the personal and
family histories of thromboembolic events and according to the
results of evaluation for thrombogenic predisposition (Table).
I am not aware of any prospective studies examining the
outcome in terms of prevention of thromboembolism with varying doses of heparin during gestation. I agree with Drs. Vandenbroucke and Rosendaal that, given the coagulation changes of
pregnancy, a small amount of heparin should go a long way.
Studies of heparin metabolism indicate that to treat active
thromboembolism during pregnancy, a larger dose than expected
may be necessary. However, we do not know whether this applies
to prophylaxis in a patient with a personal or familial history of
thromboembolic disease.
Richard V. Lee, MD
State University of New York at Buffalo
Buffalo, NY 14222
Update in Infectious Diseases
To the Editor: In the Update in Infectious Diseases, Bartlett
(1) states that "worldwide, about 1.7 billion persons currently
have tuberculosis...." This statement implies that these persons
have clinical tuberculosis. In 1991, Kochi (2) estimated that approximately 1.7 billion persons were infected with Mycobacterium
tuberculosis. This figure reflected the prevalence of tuberculous
infection, not tuberculosis itself.
In Table 2, "incidence" is defined as "the number of deaths
per epidemic period, unless otherwise noted." I assume that this
is a typographical error and that incidence is referring to the
number of cases rather than the number of deaths.
In Table 5, the frequency of administration of trimethoprimsulfamethoxazole for prevention of Pneumocystis carinii pneumonia and toxoplasmosis was not included.
Richard I Frankel, MD, MPH
University of Hawaii at Manoa
Honolulu, HI 96813
References
1. Bartlett JG. Update in infectious diseases. Ann Intern Med. 1997;126:
48-56.
2. Kochi A. The global tuberculosis situation and the new control strategy
of the World Health Organization. Tubercle. 1991;72:1-6.
In response: Dr. Frankel is correct about the incidence of
tuberculosis. The estimate of 1.7 billion refers to the number of
patients who are infected with M. tuberculosis, not the number of
patients with tuberculosis itself.
In Table 2, the footnote for "Incidence" is mislabeled. This
refers to the number of patients infected rather than the number
of deaths. The number of deaths is given in the next column.
With regard to Table 5, trimethoprim-sulfamethoxazole is administered once daily except as otherwise stated.
lohn G. Bartlett, MD
Johns Hopkins University School of Medicine
Baltimore, MD 21205
The Illusion of Deterministic Rules
To the Editor: The recent article by Glassman and colleagues
(1) contains several errors and may mislead readers about the
promises and limitations of cost-effectiveness analysis.
First, their Table 2 reflects a 2.5% risk for rupture with aneurysms 3.5 to 3.9 cm in diameter, but their text reports a figure
of 0.25%. Second, their Table 3, from which most of their
conclusions are drawn, is inaccurate. A common mistake in calculating lives saved is not using a fixed reference point. In this
case, a reasonable reference point is the number of patients who
would die if no patients had surgery for aneurysms. Using their
example, 2900 of 40 000 patients would die under those circumstances (3080 if the 2.5% risk for rupture is used for aneurysms
<4 cm rather than the 0.25% we used). In either case, the
number of lives saved for each threshold at each of the three
hospital networks is calculated relative to this reference point.
We believe that the correct figures are presented in the Table on
page 166.
Many of the authors' conclusions are not preserved with this
new table. For example, the authors' view that the three hospital
networks differ little in total number of lives saved at the 5-cm
threshold for surgery is no longer supported. Similarly, although
the authors' table suggested that increasing numbers of lives are
saved at the 6-cm threshold as one moves from network A to
network C, our table reveals the opposite. The authors' result
could never be achieved given the different surgical mortality
rates. In the new table, network A not only saves more lives at
the 4-cm threshold, it saves each life at a lower cost than network
B or C.
Finally, we agree that cost-effectiveness analyses often involve
tradeoffs and that those tradeoffs can be hard to balance. But
hard-to-balance tradeoffs are not an argument against using costeffectiveness analyses to develop decision rules. An important
purpose of cost-effectiveness analysis is to make these tradeoffs
explicit. Sometimes, these analyses reveal that some strategies
are clearly better than others. The miscalculations by Glassman
and colleagues understate the persuasiveness of quantitative
health policy analysis. After this analysis, for example, who would
consider using a 4-cm threshold at network B or C? More lives
could be saved, at a lower cost, by using a 6-cm threshold at
network A. Similarly, a 5-cm threshold at network C is clearly
worse than a 6-cm threshold at network A or B.
We believe that few could support using the 4-cm threshold at
network A after viewing this analysis. Although this strategy
165
Table.
Corrected Values for Lives Saved, Intervention
Cost, and Cost per Life Saved
Variable
Hospital
Network A
Aneurysm >4 cm
Total lives saved, n
Total intervention cost, $
Cost per life saved, $
Aneurysm >5 cm
Cost per life saved, $
Aneurysm > 6 cm
Cost per life saved, 5
2280
1 200 000 000
526316
Hospital
Network B
Hospital
Network C
1680
1080
900 000 000 600 000 000
535714
555556
2240
1840
1440
800 000 000 600 000 000 400 000 000
357 143
326 087
277 778
1720
1520
1320
400 000 000 300 000 000 200 000 000
232 558
197368
151515
carries an average cost of $526 316 per life saved, the relative
extravagance of this strategy is most evident when one considers
that the 40 additional lives saved at this threshold, compared
with the 5-cm threshold at the same network, increase costs by
$400 000 000. In other words, each additional life saved costs
$10 000 000.
Although the authors created their example to illustrate the
limitations of cost-effectiveness analysis, the correct figures ironically reveal how much these analyses contribute. The virtue of
these analyses is that they often reveal which strategies are
dominated, which are extravagant, and which are truly close calls.
David A. Asch, MD, MBA
John C. Hershey, PhD
University of Pennsylvania
Philadelphia, PA 19104
Reference
1. Glassman PA, Model KE, Kahan JP, Jacobson PD, Peabody JW. The
role of medical necessity and cost-effectiveness in making medical decisions. Ann Intern Med. 1997;126:152-6.
To the Editor: The analytical model proposed by Glassman and
colleagues (1) is an excellent example of how better definitions
can help clarify what is really important to consider in developing
decision rules. Although I agree that cost-effectiveness as a basis
for clinical choices is questionable, I think that "medical necessity" is an important factor in clinical decision-making processes.
From a public health standpoint, medical necessity justifies the
need for such actions as quarantining. It would be hard, for
example, to require that children be immunized against most
known infectious diseases if there were no medical reason for
this immunization. Although it can be argued that herd immunity
would not require all children to be immunized in order for a
community to derive a benefit from such intervention, having all
children immunized would be the right step toward eradicating
the disease.
Second, as the authors note, what may be necessary may not
be reimbursable by health insurance. This does not mean that the
definitions used by health insurers are appropriate bases for
defining medical necessity. Furthermore, as long as the courts are
called on to define situations in which physicians are held accountable or liable for actions that may be considered negligent,
medical necessity will remain a crucial consideration in prioritizing clinical actions.
Finally, it is understandable why medical necessity has lost its
urgency as the management of chronic diseases becomes more
common. In such cases, clinical outcomes are no longer as
straightforward as matters of life and death. Rather, disease is
measured by its impact on a patient's quality of life, which is
uninsurable.
Betty C. Jung, RN, MPH
Guilford, CT 06437
166
Reference
1. Glassman PA, Model KE, Kahan JP, Jacobson PD, Peabody JW. The
role of medical necessity and cost-effectiveness in making medical decisions. Ann Intern Med. 1997;126:152-6.
In response: Drs. Asch and Hershey point out two errors, one
arithmetic and one conceptual. The arithmetic error, transposing
a decimal point (turning 0.25% into 2.5%), does not affect the
model. Thus, we focus here on the conceptual error: We added
lives saved (by not performing surgery) for patients who were not
being considered for intervention in the first place. We concur
with the calculations of Asch and Hershey but do not concur that
our miscalculations understate the persuasiveness of quantitative
health policy. When the calculations of Asch and Hershey are
used, cost-effectiveness still fails to act as a deterministic decision
point. Network A provides the most cost-effective point for the
4-cm threshold, but it no longer does so for the 5-cm threshold.
Asch and Hershey agree that few could support using the 4-cm
threshold at network A after viewing the associated costs, even
though doing so would improve societal outcome. This underscores our main point, which is that perverse decisions (such as
choosing a network of lesser quality) can occur if one focuses on
cost-effectiveness without considering other important factors.
Rigorous cost-effectiveness analyses have a role in health care
decisions, but we are not convinced that the needed rigor will
always be present within a competitive marketplace where coverage decisions may be influenced by financial incentives.
Ms. Jung's comments bring out the varied uses of medical
necessity. However, we do not share her view that medical necessity is a strong factor in clinical decision making. First, there
is little to suggest that providers routinely incorporate the concept of medical necessity in their clinical decisions. Second, medical necessity decisions are primarily made by payers and are
often predicated on contractual requirements rather than on
clinical judgment. Third, medical necessity does not always correlate with good public policy; this is true, for example, for
immunization to prevent re-emergence of an infectious disease,
such as diphtheria. Finally, interpretations by courts and payers
vary, and medical necessity is thus not currently a viable foundation on which to prioritize clinical actions. Whether it can be
is controversial, and some have argued that cost-effectiveness
should become the basis for coverage decisions (1).
We believe that cost-effectiveness will not readily solve the
medical necessity conundrum. Nonetheless, developing better
methods to target those who truly need a medical service and
those who do not is paramount. Our primary concern was to
demonstrate the intrinsic problems that arise when medical necessity and cost-effectiveness are used. We hope that our model
was helpful in this regard.
Peter Glassman, MBBS, MSc
John Peabody, MD, PhD
West Los Angeles Veterans Affairs Medical Center
Los Angeles, CA 90073
Karyn Model, PhD
National Economic Research Associates
Los Angeles, CA 90017
Reference
1. Eddy DM. Clinical decision making: from theory to practice. Benefit
language: criteria that will improve quality while reducing costs. JAMA.
1996;275:650-7.
Hantavirus Antibodies in New York
To the Editor: To clarify an association between end-stage
renal disease and antibodies to hantavirus (1, 2), we examined
serum samples from patients seen in a dialysis facility and an
emergency department in New York City.
Serum samples were screened by enzyme-linked immunosorbent assay (ELISA) using previously described protocols (1). To
confirm the ELISA results, a Western blot analysis of tentatively
positive samples was done. Samples with antibodies directed
against nucleocapsid protein (3) were considered seropositive.
Of 546 samples screened by ELISA, 292 were controls obtained from the emergency department population and 254 were
obtained from patients undergoing hemodialysis. Overall, 28 samples (5.13%) were positive by ELISA. Of these, 4 (1.37%) were
from the emergency department population and 24 (9.45%) were
from the dialysis population. This difference was statistically significant (odds ratio, 7.5 [95% CI, 2.4 to 25.9]; P < 0.001).
Western blot analysis could not confirm many ELISA-positive
results. Of the 4 ELISA-seropositive samples obtained from the
emergency department population, only 1 (0.34%) was confirmed; of the 24 ELISA-seropositive samples obtained from
patients undergoing dialysis, only 5 (1.97%) were confirmed. The
latter patients tended to be infected with hantavirus more often
than did the former (odds ratio, 5.8 [CI, 0.7 to 277.3]; P = 0.07).
Our data corroborate the observation (1) that patients undergoing hemodialysis tend to have antibodies to hantavirus more
frequently than do control patients. The seroprevalences in the
control group and dialysis group were similar to those observed
in Baltimore (0.34% and 0.25% compared with 1.97% and
2.80%, respectively). These results also indicate a need to interpret ELISA results with some caution because 22 of 28 ELISApositive samples were negative according to Western blot analysis. This suggests that uremic serum samples have nonspecific
reactions to ELISA reagents. It is unclear whether results of the
serologic tests for hantavirus represent infection or cross-reactive
autoantibodies to shared epitopes. This question may be resolved
by prospective studies of patients with acute hemorrhagic fever
with the renal syndrome, who may develop hypertensive renal
disease (4). As an alternative, the presence of viral antigen or
nucleic acids in these patients would provide critical supporting
evidence of ongoing viral infection.
Walter G. Wasser, MD
North General Hospital
New York, NY 10035
Cindy A. Rossi, MA
U.S. Army Research Institute of Infectious Diseases
Frederick, MD 21701
Gregory E. Glass, PhD
Johns Hopkins School of Public Health
Baltimore, MD 21205
References
1. Glass GE, Watson AJ, LeDuc JW, Kelen GD, Quinn TC, Childs JE.
Infection with a ratborne hantavirus in US residents is consistently
associated with hypertensive renal disease. J Infect Dis. 1993;167:61420.
2. Peter JB, Patnaik M, Gott P, Weins B, Souw PT. Antibodies to different strains of hantavirus in end-stage renal disease in USA and Japan.
Lancet. 1994;343:181.
3. Schmaljohn CS, Jennings GB, Jay J, Dalrymple JM. Coding strategy of
the S genome segment of hanta virus. Virology. 1986;155:633-43.
4. Kleinknecht D, Rolin PE. Hypertension after hemorrhagic fever with
renal syndrome. Nephron. 1993;61:121.
Paraneoplastic Autoimmune Xerostomia
To the Editor: An 18-year-old man was hospitalized with intense thirst, polyuria, polydypsia, and weight loss. The oral mucosa appeared slightly dry, and mild hepatosplenomegaly was
present. The physical examination was otherwise unremarkable.
Diabetes mellitus and insipidus were ruled out by laboratory tests
and imaging of the head. Fever and pancytopenia, in the absence
of signs of disease other than xerostomia, prompted us to take a
biopsy specimen from the bone marrow. Lymphoblastic lymphoma was diagnosed, polychemotherapy produced complete remission, and xerostomia disappeared. Two relapses were heralded by xerostomia that disappeared after remission was
obtained through salvage protocols. The patient died of aspergillotic pneumonia during drug-induced pancytopenia. His salivary
Figure. A. Normal histologic appearance of the patient's salivary gland
(hematoxylin and eosin stain; original magnification, x40). B. The patient's
serum immunostains monkey salivary ducts on indirect immunofluorescence
(original magnification, X40). (Courtesy of Drs. E. Bosi and A. M. Girardi.) C.
The patient's IgG levels are detectable in the ductal and acinar cells of his
parotid gland on direct immunocytochemistry (original magnification, x40).
D. The patient's IgG reacts preferentially with the cytoplasm of the acinar
cells of his parotid gland, leaving nuclei unstained (direct immunocytochemistry; original magnification, x80).
glands were clinically and histologically (Figure, panel A) normal,
and no antinuclear antibodies were present in his serum, thus
excluding the Sjogren syndrome (1).
To investigate the nonfortuitous relation between xerostomia
and lymphoma, we looked for autoantibodies to the salivary
glands in the patient's serum. Circulating autoantibodies against
the ductal cells of monkey salivary glands were demonstrated by
indirect immunofluorescence at each relapse and during the second remission (Figure, panel B). The presence of autoantibodies
was shown by direct immunocytochemistry in the patient's parotid gland (Figure, panels C and D).
Autoantibodies directed against cellular antigens are present in
patients with a malignant condition (2). Although rarely pathogenic (3), autoantibodies can be considered markers of an impending tumor because they can precede the appearance of
clinically detectable cancer (4, 5). To our knowledge, paraneoplastic autoimmune xerostomia has never been reported. Although the cellular target of these autoantibodies is unknown, we
hypothesize that they might play a pathogenic role inhibiting
salivary secretion.
We suggest that the sudden appearance of xerostomia together
with autoantibodies to the salivary glands—after exclusion of the
Sjogren syndrome, direct infiltration of the salivary glands by
neoplasia, and primary disorders of water balance—should
prompt a careful search for occult cancer.
Franco Folli, MD, PhD
Maurilio Ponzoni, MD
Aurelio M. Vicari, MD
Istituto di Ricovero e Cura a Carattere Scientifico
20132 Milano, Italy
167
Table.
References
1. Moutsopolous HM. Sjogren's syndrome. In: Isselbacher KJ, Braunwald
E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrison's Principles of Internal Medicine. 13th ed. New York: McGraw-Hill; 1994:
1661-4.
2. Agarwala SS. Paraneoplastic syndromes. Med Clin North Am. 1996;80:
173-84.
3. Lennon VA, Lambert EH. Autoantibodies bind solubilized calcium
channel-omega conotoxin complexes from small cell lung carcinoma: a
diagnostic aid for Lambert-Eaton myastenic syndrome. Mayo Clin Proc.
1989;64:1498-553.
4. Posner JB. Paraneoplastic syndromes. Neurol Clin. 1991;9:919-36.
5. Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, et al.
Autoantibodies to a 128-kd synaptic protein in three women with the
stiff-man syndrome and breast cancer. N Engl J Med. 1993;328:546-51.
Intracranial Hypertension and Minocycline
To the Editor: We report a case of intracranial hypertension
with permanent visual damage after minocycline treatment.
A 19-year-old healthy woman was treated with minocycline,
100 mg/d, for acne vulgaris. Two weeks after treatment began,
the patient presented with severe headache, nausea, and visual
disturbance. Ophthalmologic examination revealed severe bilateral papilledema with visual field damage. A computed tomographic scan of the brain was normal. After minocycline therapy
was discontinued and acetazolamide was administered, the papilledema disappeared. However, the patient's visual fields and
visual acuity are permanently damaged.
Tetracyclines, especially minocycline, are widely used to treat
acne vulgaris. Despite the listed side effects of the tetracycline
groups, therapy with these agents is safe. Intracranial hypertension or pseudotumor cerebri is well known in infants but rare in
adults (1). Intracranial pressure is also common in patients
treated by both tetracyclines and retinoids (2). Among the few
cases reported in the literature, elevated intracranial pressure
was more common in women; neurologic and ophthalmologic
symptoms developed 1 month after therapy began; and, in most
cases, neurologic and ophthalmologic symptoms and signs were
alleviated after discontinuation of minocycline therapy (1, 3). In
some patients, however, visual acuity was permanently damaged
(4). One patient required lumboperitoneal bypass (5).
Minocycline is known to penetrate into the central nervous
system and to have good lipoid solubility. The mechanism by
which minocycline increases intracranial pressure is unknown.
Awareness of this cause of headache and visual obscuration may
prevent severe, permanent neurologic damage.
Joseph Shiri, MD
Boaz Amichai, MD
Tel-Nordoy Clinic
Tel-Aviv, Israel
References
1. Lubetzki C, Sanson M, Cohen D, et al. Benign intracranial hypertension and minocycline. Rev Neurol Paris. 1988;144:218-20.
2. Delaney RA, Narayanswamy TR, Wee D. Pseudo-tumor cerebri and
acne. Mil Med. 1990;155:511.
3. Le-Bris P, Glacet-Breard A, Coscas G, et al. Papilledema caused by
minocycline: apropos of a case. J Fr Ophthalmol. 1988;11:681-4.
4. Lander CM. Minocycline-induced benign intracranial hypertension. Clin
Exp Neurol. 1989;26:161-7.
5. Donnet A, Dufour H, Graziani N, et al. Minocycline and benign intracranial hypertension. Biomed Pharmacother. 1992;46:171-2.
Thyrotoxicosis Factitia Veterinarius
To the Editor: We describe a case of "thyrotoxicosis factitia
canis."
A 50-year-old woman presented with new-onset nervousness
and dizziness. Her medical history was notable for hypertension
treated with enalapril, 10 mg four times daily. Further questioning revealed that the patient's dog, who "had no thyroid," was
168
Day
1
13
49
74
Results of Follow-Up in a Patient with
Thyrotoxicosis Factitia Veterinarius*
Thyroxine
Radioimmunoassayt
Triiodothyronine
RU*
Triiodothyronine
Radioimmunoassay§
TSH ||
Ixg/dL
%
Ixg/mL
mU/L
21.7
8.5
6.9
33.9
33.8
33.8
2.69
1.49
1.19
<0.03
0.03
0.88
1.83
* TSH = thyroid-stimulating hormone,
t Normal range, 4.5 to 12.0 jug/dl_.
* Normal range, 25% to 40%.
§ Normal range, 0.8 to 2.0 ng/mL
|| Normal range, 0.32 to 5.0 mU/L.
being treated with L-thyroxine, 0.6 mg four times daily (a typical
canine dosage). It seems that, at some point, the patient may
have inadvertently switched her medication with her dog's medication. The results of physical examination were normal except
for tremor. The pulse was 72 beats/min and regular. The patient
was followed after correction of her regimen; results of this
follow-up are shown in the Table.
Further search for diagnostic clues to the diagnosis, such as a
low uptake on I 123 scanning or a suppressed thyroglobulin level,
was considered unnecessary in this case because of the careful
history. Interim treatment with j3-blockers may be needed in
some cases but was not in this one.
We suggest that a pet history should be taken when puzzling
symptoms are present in previously healthy patients.
Sheila Feit, MD
Syosset, NY 11791
Helen Feit, MD
Villanova, PA
Mycobacteriosis in the Pliocene
To the Editor: Recognition of disease in antiquity is predicated
on the uniformity of the character of disease over time. Although
bone can manifest only a limited spectrum of reaction to any
"insult," the pattern of skeletal involvement is often highly specific (1). One such pattern—vertebral destruction with partial
collapse, minimal reactive bone formation, but fusing affected
adjacent vertebrae (producing a coalesced, acutely angulated vertebral appearance)—is highly specific for mycobacterial disease,
such as tuberculosis (1, 2). Observation of such a phenomena in
a Pliocene macropod stimulated this analysis.
Fused proximal caudal macropod (kangaroo) vertebrae
(Queensland F178989), discovered on the Chinchilla Rifle Range
in southeastern Queensland, Australia, consisted of one partially
collapsed vertebra, angulated 90 degrees in juxtaposition to a
second and associated with extensive new bone formation. The
first vertebra had an irregular spinal canal with several speculations and was fused with the subjacent two vertebrae. There was
an oval-shaped, slightly expansile lytic lesion in the right transverse process of the third vertebra. Three-dimensional computed
tomographic reconstruction (done by Southwoods Radiology,
Youngstown, Ohio, and Carol Scott, St. Joseph Hospital, Warren, Ohio) revealed classic collapse and fusion with no significant
new bone formation (Figure).
Disruption of vertebral centra with subsequent angulation and
fusion is characteristic of Mycobacterium tuberculosis in humans
(1, 2) and of M. avium in macropods (1, 3, 4). Trauma and
osteoporotic compression fractures do not produce lytic lesions
(1, 2). Cancer produces lytic lesions but not fusion. Spondyloarthropathy produces vertebral fusion but not transverse process
lytic lesions or vertebral collapse. Brucellosis and fungal disease
Figure. Three-dimensional reconstruction of computed tomographic images of affected vertebrae. The left and middle panels reveal reconstructed radiologic images. The image in the upper right panel is slightly oblique. The images in the center and the bottom right panels have been manipulated
to remove overlapping structures. Draining sinuses are especially visible on the bottom right image. The vertebral pedicle and spinous processes have been
removed to allow visualization of the posterior aspect of the vertebral body. General disorganization of bone with collapse, minimal new bone formation, and
draining sinuses are notable.
(such as that caused by Blastomycosis species) can produce lytic
lesions, but collapse with fusion has not been observed (2).
Thus, mycobacterial disease seems to be the most reasonable
diagnosis. The earliest previous example (5) was in a 6000-yearold Egyptian mummy. Queensland F178989 substantially extends
the antiquity of mycobacterial infection (existent in contemporary
macropods) to 5 million years and seems to represent the earliest
notation of this infection (1).
Bruce M. Rothschild, MD
Arthritis Center of Northeast Ohio
Youngstown, OH 44512
Ralph E. Molnar, MD
Queensland Cultural Centre
South Brisbane, Queensland, Australia
Jeno I. Sebes, MD
University of Tennessee Center for Health Sciences
Memphis, TN 28117
References
1. Rothschild BM, Martin L, eds. Paleopathology: Disease in the Fossil
Record. London: CRC Pr; 1993.
2. Resnick D, Niwayama G, eds. Diagnosis of Bone and Joint Disorders.
2d ed. Philadelphia: WB Saunders; 1989.
3. Kennedy S, Montali RJ, James AE, Bush M. Bone lesions in three tree
kangaroos. J Am Vet Med Assoc. 1978;173:1094-8.
4. Mann PC, Montali RJ, Bush M. Mycobacterial osteomyelitis in captive
marsupials. J Am Vet Med Assoc. 1982;181:1331-3.
5. Strouhal E. La Tuberculose Vertebrate en Egypte et Nubie Anciennes.
Bulletins et Memoires Societe de la dAnthropologic de Paris. 1987; 14:
261-70.
Protracted Cholestatic Hepatitis after the Use of
Prostata
To the Editor: One reason for the growing popularity of herbal
medicines is the perception that these compounds are safe and
free of side effects. We report a case of acute hepatitis caused by
Prostata (Gero Vita International), an herbal preparation used to
treat prostatic hypertrophy.
A 65-year-old man with nocturia and hesitancy began taking
Prostata, which had been ordered from a catalogue. Two weeks
later, he developed jaundice and severe pruritus and stopped
taking the medication. His abdomen was not tender, and his liver
and spleen were not palpable. Biochemical findings were as
follows: bilirubin level, 8.2 mg/dL; aspartate aminotransferase
level, 1238 IU/L; alanine aminotransferase level, 1364 IU/L; alkaline phosphatase level, 179 IU/L (normal <108 IU/L); y-glutamyl transferase level, 391 IU/L; hematocrit, 0.41; leukocyte
count, 3.3 X l^/mm 3 (polymorphonuclear count, 1.6 X KP/mm3);
lymphocyte count, 1.2 X 103/mm3; monocyte count, 0.4 X 103/
mm3; eosinophil count, 0.1 X 103/mm3); and platelet count,
153 000 cells/mm3. Serum total protein level was 6.3 g/dL (albumin level, 3.6 g/dL), and the carcinoembryonic antigen level was
less than 2 mg//nL. Computed tomography of the abdomen revealed a normal liver, pancreas, and biliary system. Results of
serologic testing were negative for hepatitis A virus IgM, hepatitis B surface antigen, cytomegalovirus IgM, and antibodies to
hepatitis C virus; hepatitis C virus RNA was undetectable by
polymerase chain reaction. The patient was positive for antimitochondrial antibodies (titer, 1:320) and negative for antinuclear
antibodies and anti-smooth-muscle antibody. Liver enzyme levels
remained abnormal for more than 3 months before completely
returning to normal. Because of slow resolution of disease, liver
biopsy done 2 months after presentation showed a parenchymal
infiltrate of neutrophils and lymphocytes that involved the portal
tracts, early bridging, and mild periportal fibrosis. No evidence
showed cirrhosis, granulomas, or bile duct damage.
Prostata is a combination of zinc picolinate, pyridoxine, Lalanine, glutamic acid, apis mellifica pollen, silica, hydrangea
extract, panex ginseng, serenoa serrulata, and pygeum africanum.
Serenoa (saw palmetto) is presumably the most active ingredient,
providing an estrogenic and antiandrogenic effect through direct
stimulation of estrogen receptors and inhibition of testosterone5-alpha-reductase (1).
Both estrogens and antiandrogens can be hepatotoxic. Estrogens interfere with bromosulfophthalein and bilirubin excretion
(2), and cholestasis of pregnancy may be a manifestation of
exaggerated responsiveness to cholestatic effects of high estrogen
levels (3). Fulminant hepatitis has been reported with the antiandrogenic drugs flutamide and cyproterone acetate (4). Flutamide competitively inhibits binding of dihydrotestosterone to
androgen receptors and increases plasma concentrations of estrogen and testosterone in the rat by blocking the inhibitory
feedback of testosterone on production of luteinizing hormone
(5). The cholestatic hepatitis observed with flutamide is postulated to result from testosterone-mediated cholestasis.
169
Saeed Hamid, MD
Sergio Rojter, MD
John Vierling, MD
Southwestern Medical Center
Dallas, TX 75235-9151
References
1. Champault M, Patel JC, Bonnard AM. A double-blind trial of an
extract of the plant serenoa repens in benign prostatic hyperplasia. Br J
Clin Pharmacol. 1984;18:461-2.
2. Kottra LL, Kappas A. Effect of estradiol on plasma disappearance rate
of sulfobromophthalein in man. Arch Intern Med. 1966;117:373-5.
3. Haemmerli HU. Jaundice during pregnancy. In: Schiff L, ed. Diseases
of the Liver. 4th ed. Philadelphia: JB Lippincott; 1975:1336-48.
4. Dankoff JS. Near fatal liver dysfunction secondary to administration of
flutamide for prostate cancer. J Urol. 1992;148:1914.
5. Marchetti B, Labrie F. Characteristics of flutamide action on prostate
and testicular functions in the rat. J Steroid Biochem. 1988;29:691-8.
Fatal Phenformin-Associated Lactic Acidosis
To the Editor: The popularity of metformin has renewed interest in biguanide hypoglycemic agents. The association between
phenformin and fatal lactic acidosis, particularly in patients with
renal failure, led to the withdrawal of phenformin from the U.S.
market in 1977 (1). We describe a patient who recently died of
phenformin-associated lactic acidosis.
A 64-year-old Haitian woman with diabetes, hypertension, and
consequent renal insufficiency presented with profound lactic acidosis (pH, 7.15; bicarbonate level <5.0 mmol/L; lactic acid level,
54.5 mmol/L). She had been hospitalized on four previous occasions for unexplained severe lactic acidosis. After recovery from
such an episode, muscle biopsy had disclosed normal structure on
light and electron microscopy and normal in vitro mitochondrial
enzymatic function (pyruvate dehydrogenase complex, dihydrolipoamide dehydrogenase, and electron transport chain complexes
I to IV). Mitochondrial DNA contained no rearrangements or
known point mutations.
During this final hospitalization, we discovered that the patient
had been taking Bidiabe (Laboratori Guidotti, Pisa, Italy), a
combination of chlorpropamide (125 mg) and phenformin hydrochloride (30 mg). Despite treatment with antibiotics, sodium
bicarbonate, insulin, and hemodialysis, the patient died. The
patient's serum phenformin concentration was 649 /ig/L at admission and 42 /ig/L at autopsy. Our patient had obtained Bidiabe without prescription in Haiti and had been taking it without
the knowledge of her physicians for several years.
It is not known why some patients develop lactic acidosis while
taking phenformin. We found no enzyme deficiency to explain
recurrent acidosis in our patient. However, skeletal-muscle electron microscopy done at autopsy revealed hyperplasia of mitochondria that had normal size, internal structure, and distribution
(Figure). Hepatocyte mitochondrial hyperplasia might reflect an
early compensatory response to adverse environmental stimuli, as
has been hypothesized in other settings (2).
The availability of metformin, a drug that has similar efficacy
but is associated with a lower risk for lactic acidosis, now renders
phenformin obsolete (3). Physicians, especially those serving immigrant communities, must remain aware of the availability of
phenformin.
Jonathan Rosand, MD
Jonathan W. Friedberg, MD
Jane M. Yang, MD
Massachusetts General Hospital
Boston, MA 02114
References
1. Misbin RI. Phenformin-associated lactic acidosis: pathogenesis and
treatment. Ann Intern Med. 1977;87:591-5.
2. Reznik-Schuller HM, Reuber MD. Ultrastructure of liver tumors induced in F344 rats by methapyrilene. J Environ Pathol Toxicol Oncol.
1986;7:181-96.
3. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574-9.
A Return to Farr and Nightingale
Figure. Electron micrograph obtained at autopsy shows hepatocyte cytoplasm densely filled with mitochondria {asterisks). The latter
are of normal size, shape, and internal structure. Arrow demarcates luminal
space, and the bar represents 1.9 ^m.
170
To the Editor: In her response to our defense of Farr and
Nightingale (1), Dr. Iezzoni fails to distinguish between two
issues: the correct calculation of the incidence rate and the
comparability of data across hospitals. In her original contribution, Dr. Iezzoni had accused Farr and Nightingale of using the
wrong method of calculation and thereby making the wrong
comparison (2).
We are amazed by the first part of her counterexample, the
myocardial infarction rate of 326%. We gave exactly this example
in our letter and at the same time indicated the solution: a 326%
death rate per patient-year amounts to 0.9 deaths per 100 patient-days, which is not confusing.
Next comes the comparability of incidence rates between hospitals. In 1948, Greenwood stated that even if one uses the right
denominator (as Farr and Nightingale did), comparisons between
hospital statistics remain hazardous (3). We have discussed this
problem elsewhere (4). One factor that Dr. Iezzoni mentions is a
difference in length of stay between hospitals. When length of
follow-up is related to mortality, which it almost always is, the
simple solution is to stratify by time. That is done routinely, for
example, by Cox proportional hazards models that estimate hazard rates (which are ratios of incidence rates by the day!). When
person-time denominators are used over longer periods of time,
follow-up is subdivided into "first week," "second week," and so
on. This adjustment for length of stay has nothing to do with the
calculation of incidence. Of course, the solution proposed by Dr.
Iezzoni—to use a fixed time interval—is an excellent one. It
permits one to calculate either incidence rates or cumulative
incidences afterward.
Did Farr and Nightingale have political motives? Of course
they did; they bore a grudge against certain hospitals with poor
ventilation and sanitation (5). In this, they resemble Dr. Iezzoni,
who militates (rightly) against the simplistic use of betweenhospital comparisons (5). Might Farr and Nightingale's zeal have
led them to throw caution to the wind when publishing comparisons that proved how right they were? Not unlikely. In the end,
were they right by insisting on reforms? Most probably. That,
and not the way in which they did their calculations, is the heart
of the argument.
Jan P. Vandenbroucke, MD, PhD
Leiden University
2300 RC Leiden, the Netherlands
Christina MJ.E. Vandenbroucke-Grauls, MD, PhD
University "Vrije Universiteit"
1081 HV Amsterdam, the Netherlands
References
1. Iezzoni LI. In defense of Farr and Nightingale [Letter]. Ann Intern
Med. 1996;125:1014.
2. Iezzoni LI, Ash AS, Shwartz M, Daley J, Hughes JS, Mackiernan YD.
Judging hospitals by severity-adjusted mortality rates: the influence of
the severity-adjustment method. Am J Public Health. 1996;86:1379-87.
3. Greenwood M. Some British Pioneers of Social Medicine. London:
Oxford Univ Pr; 1948:97-108.
4. Ierodiakonou K, Vandenbroucke JP. Medicine as a stochastic art. Lancet. 1993;341:542-3.
5. Eyler JM. Victorian Social Medicine. The Ideas and Methods of William Farr. Baltimore: Johns Hopkins Univ Pr; 1979:183.
In response: As I said in response to the first letter of Drs.
Vandenbroucke and Vandenbroucke-Grauls, their assertions are
reasonable. It all boils down to context: My comments were
framed by current state and regional initiatives to publish "report
cards" on hospitals. I cannot imagine the Pennsylvania Health
Care Cost Containment Council (1), New York's Cardiac Surgery
Reporting System (2), or Cleveland Health Quality Choice (3)
using the number of deaths per 100 days in-hospital in their
report cards on hospital mortality rates. Given the common
English meaning of the words "death rate," such figures would
not make intuitive sense to the average reader.
Lisa I Iezzoni, MD, MSc
Beth Israel Deaconess Medical Center
Boston, MA 02215
References
1. Pennsylvania Health Care Cost Containment Council. Focus on Heart
Attack in Western Pennsylvania. A 1993 Summary Report for Health
Benefits Purchasers, Health Care Providers, Policy-makers, and Consumers. Harrisburg, PA: Pennsylvania Health Care Cost Containment
Council; 1996.
2. Chassin MR, Hannan EL, DeBuono BA. Benefits and hazards of reporting medical outcomes publicly. N Engl J Med. 1996;334:394-8.
3. Rosenthal GE, Harper DL. Cleveland Health Quality Choice: a model
for collaborative community-based outcomes assessment. Jt Comm J
Qual Improv. 1994;20:425-42.
Twain: Differences of Opinion on the Worthiest of
All Occupations
To the Editor: I read with interest Dr. Ober's informative and
entertaining paper (1). Although the medical practices of the
19th century, particularly as viewed through the acerbic wit of
Mark Twain, appear crude and often dangerous, it seems inappropriate to state that "Nineteenth century medicine was as
stagnant as it was toxic; therapeutic bloodletting had been championed in James' Medicinal Dictionary of 1743, and it was still
being strongly advocated in 1892 by William Osier." In a broad
sense, the therapeutics of the 19th century saw the discovery of
emetine, chloral, pilocarpine, antipyrine, ephedrine, suprarenal
extract, general anesthesia, antisepsis, and radiation therapy—
hardly a stagnant period! Phlebotomy is currently used to treat
polycythemia, hemochromatosis, and porphyria.
William Osier's advocacy of venesection is somewhat overstated. Osier recognized the abuses of this technique when he
wrote on pneumonia (2):
In many cases the question comes up at the onset as to
the propriety of venesection. The reproach of Van
Helmont, that 'a bloody Moloch presides in the chairs
of medicine,' cannot be brought against the present
generation of physicians. During the first five decades
of this century, the profession bled too much, but
during the last decades we have certainly bled too
little.
In 1898, in his textbook, he quoted P.C.A. Louis's seminal
attack on bloodletting in pneumonia but continued to advocate
the practice (3).
Interestingly, Osier, when offered James's Medicinal Dictionary
by a bookseller in 1910, wrote that ".. .the James Dictionary I do
not care for, the only important thing about it now is that
Johnson wrote the Preface" (4). Although Samuel Johnson had a
hand in the book, modern scholars do not agree that he wrote
the preface.
As Mark Twain said, "It were not best that we should all think
alike; it is difference of opinion that makes horse races" (5).
Richard L. Golden, MD
State University of New York at Stony Brook School
of Medicine
Stony Brook, NY 11794
References
1. Ober KP. The pre-Flexnerian reports: Mark Twain's criticism of medicine in the United States. Ann Intern Med. 1997;126:152-6.
2. Osier W. The Principles and Practice of Medicine. New York: D.
Appleton; 1892:530.
3. Osier W. The Principles and Practice of Medicine. 3rd ed. New York:
D. Appleton; 1898:135.
4. Osier W. Typed letter signed to G. Gregory. Oxford: 25 July 1910.
5. Twain M. Pudd'nhead Wilson: a tale. In: Cardwell G, ed. Mississippi
Writings. Library of America; 1982:1029.
In response: I appreciate Dr. Golden's comments and have no
serious disagreement with any of them. Some of Twain's statements about 19th century medicine were almost certainly exaggerations, and he would have been the first to admit that he was
not above embellishing the facts to help make his point. However, other sources cited in my paper would tend to confirm that
19th century medicine for the average citizen was largely as
Twain reported it.
Medical advances did indeed occur in the 1800s, but stagnation
also occurred in the sense that these improvements were not
readily translated into benefit for the patient; instead, the old
approaches continued to be favored. Twain was appalled that
James's Medicinal Dictionary of 1743 was still used by physicians
a century later (1):
In 1861 this deadly book was still working the cemeteries . . . For three generations and a half it had been
going quietly along, enriching the earth with its slain.
Up to its last free day it was trusted and believed in
and its devastating advice taken, as was shown by notes
inserted between its leaves.
The venesection issue is an interesting one. In 1890, Twain (1)
championed the application of evidence-based medicine by berating "the celebrated Bonetus" for the report of 12 headache
cases in the Medicinal Dictionary, all of whom died after being
bled:
171
Without enlarging upon the matter, I merely note this
coincidence—they all 'dy'd.' Not one of these people
got well; yet this obtuse hyena sets down every little
gory detail of the several assassinations as complacently as if he was doing a useful and meritorious work
in perpetuating the methods of his crimes.
In Osier's famous 1892 text (published 149 years after the
Medicinal Dictionary and 2 years after Twain's suggestion that a
0 in 12 survival rate for bled patients was not a good clinical
outcome), Osier himself did indeed suggest that venesection was
underused in the last half of the century. He then proceeded to
report on his own series of patients with pneumonia, which, by
coincidence, was the same size as Bonetus's headache series
(n = 12). Osier stated that "I urged free venesection, but in
twelve hospital patients bled under these circumstances only one
recovered" (2). Comparison of Bonetus's raw data with Osier's
suggests that the outcomes for these two series were probably
not statistically significantly different.
As I mentioned in my paper, Twain was very pleased with the
new scientific orientation of medicine in the late 19th century,
and he agreed with Dr. Golden's assessment by stating that "in
our day our physicians and surgeons work a thousand miracles—
prodigies which would have ranked as miracles fifty years ago"
(3). Finally, despite his criticisms, Twain continued to believe
that "the physician's is the highest and worthiest of all occupations" (3).
K. Patrick Ober, MD
Bowman Gray School of Medicine of Wake Forest University
Winston-Salem, NC 27157
References
1. Twain M. A majestic literary fossil. In: Neider C, ed. The Complete
Humorous Sketches and Tales of Mark Twain. Garden City, NY:
Doubleday; 1961:532-42.
2. Osier W. The Principles and Practice of Medicine: New York: D.
Appleton; 1892:530.
3. Friedlander WJ. Mark Twain, social critic, and his image of the doctor.
Ann Intern Med. 1972;77:1007-10.
On Bedside Teaching
To the Editor: I was delighted to read LaCombe's article on
bedside teaching (1). As he points out, it is a sorry state of affairs
that the use of bedside teaching at university hospitals has significantly decreased since the 1960s. This decrease, I think, results from the new imaging techniques that can make a diagnosis
for us. This diagnostic testing often escalates the cost of medical
care. A complete history followed by a thorough physical examination can help new physicians to order appropriate tests rather
than a battery of expensive tests. This cannot be achieved unless
physicians develop good bedside assessment skills.
In the United States, many young teachers of medicine are
products of this more laboratory-oriented teaching style and thus
have fewer bedside clinical skills. There is no doubt that these
teachers will have to sharpen their bedside clinical evaluation
abilities before they can impart their skills and knowledge to the
next generation of physicians.
Many of the Board examinations in the different branches of
medicine are basically written examinations. Very little of the
examinations actually involves patient assessment at the bedside.
In Canada, the Royal College of Physicians and Surgeons maintains an examination format that includes bedside assessment of
the patient. I think it is high time that bedside evaluation be
included in the different medical specialty examinations in the
United States. If this is not done, students will have little incentive to sharpen their bedside skills, nor will the physicians who
teach these skills.
IIP. Patil, MB, BS, FRCP(C)
Dalhousie University
Halifax, Nova Scotia, Canada
172
Reference
1. LaCombe MA. On bedside teaching. Ann Intern Med. 1997;126:217-20.
To the Editor: I read with interest Dr. LaCombe's comments
(1) on his perceptions of the increasing failure to teach the next
generation of physicians medicine at the bedside. I would like to
remind Dr. LaCombe that there remains one branch of medicine
in which the value of the bedside examination remains firmly
rooted, namely, neurology. The neurologic examination confirms
or negates the initial impressions of lesion localization drawn
from the elements of history. The nuances of the neurologic
examination are not readily conveyed in textbooks and must be
learned at the bedside. Every well-trained neurologist is mentored at the bedside. Although newer imaging techniques of the
brain and spinal cord have revolutionized our approach to many
disorders, they are no substitute for the careful neurologic examination. I am reminded of the words of the neurologist F.M.R.
Walshe (2): "The more resources we have, and the more complex they are, the greater are the demands upon our clinical skill.
These resources are calls upon judgment and not substitutes for
it. Do not, therefore, scorn clinical examination; learn it sufficiently to get from it all it holds, and gain in it the confidence it
merits."
Joseph R. Berger, MD
University of Kentucky
Lexington, KY 40536
References
2. Walshe FM. The changing and the unchanging face of medicine. Can
Med Assoc J. 1952;67:395-7.
To the Editor: As I read LaCombe's article on bedside teaching
(1), I reflected that the changes in medical economics may resurrect "the good old days." We academic internists have never
been busier and now need to continuously document our real
impact on patient care. There is no better way to do this than to
round daily with the housestaff, at which time they present new
and follow-up patients—at the bedside. We learn and teach each
other as we go while communicating at the bedside with patients
and families on a daily basis. We encourage nurses to join us,
and we always write our daily orders after the bedside presentation, assessment, and plan have been discussed. With the patients, their families, and the attending nurse there, the physician
of record, who is also the teacher, learns and verifies the facts,
communicates with the patients and families, and is present when
the daily diagnostic and therapeutic orders are written. All this is
done while the physician observes housestaff and students.
I am now evaluating a similar format for residents' primary
care clinics. When the residents are prepared to present within
the time frame allotted, they put a green flag up outside their
examining rooms. I enter for an "examining room presentation"
that is similar to the inpatient bedside presentation. The same
positive results occur in clinic as occur in the inpatient service.
The attendings are able to move relatively rapidly from one room
to the next while giving each patient a reasonable amount of
personal attention and educating the resident. We believe we can
run resident-based clinics with this operational design and still
adhere to reasonable managed care characteristics.
Clifford W. Zwillich, MD
University of Colorado Health Sciences Center
Denver, CO 80220
Reference
To the Editor: Thank you for publishing "On Bedside Teaching" (1). LaCombe nicely distinguishes between principles, to
which we allegedly adhere, and practice, which readily obscures
patients and their informal care givers behind a morass of figures. According to McKnight and Rockwood (2) "house staff
readily declaim weeks' worth of serial biochemistry but cannot
tell when a patient last walked unaided." One advantage of
practicing and teaching geriatric medicine is that one can take
the student to the most relevant bedside—the one in the patient's home.
Colin Powell, MD, FRCP
Dalhousie University
Halifax, Nova Scotia, Canada
References
2. McKnight C, Rockwood K. A hierarchical assessment of balance and
mobility. Age Aging. 1997;24:126-30.
To the Editor: I would like to thank Dr. LaCombe for bringing
us back to the basics (1). When I was at the University of
California, San Francisco, I tried to do as much bedside teaching
as possible but was frustrated by the disappearance of patients.
Probably half of the patients I went to visit were off somewhere
else, often in an imaging center awaiting a test. I sometimes took
the entire housestaff team down with me to the radiology suite
where, in less than adequate circumstances, we would at least get
a history and do a preliminary physical examination. The current
accelerated pace of diagnosis and treatment means that the early
stages of the workup are done much more quickly than in the
good old days. Making this fast pace more compatible with
bedside teaching is not easy. I don't think that simply informing
the nurses will suffice, especially because the attending physician
may not be the one who is doing the bedside teaching.
Stephen A. Schroeder, MD
The Robert Wood Johnson Foundation
Princeton, NJ 08543-2316
Reference
To the Editor: I was touched by the recent article on bedside
teaching (1). As a harried academic physician, I long to get back
to basics and spend more time doing bedside teaching but have
not been able to do so. The article correctly captured both the
costs and rewards of effective bedside teaching. I thank the
author for gently reminding all of us what we are missing.
Elise A. Olsen, MD
Duke University Medical Center
Durham, NC 27710
Reference
To the Editor: The article "On Bedside Teaching" (1) appeared
at exactly the right time for me. I am teaching a course on
physical diagnosis to a group of medical students at the University of Minnesota from March until May 1997. This represents a
return to teaching for me after an absence of more than 20 years.
As I recall, my own education included a great deal of
hands-on teaching at the bedside. I was a little astonished and
distressed to learn that this practice has become relatively uncommon. I hope that I can emulate the method and skills outlined in LaCombe's essay and appreciate the references to the
literature on physical diagnosis. I do not think my skills have
atrophied too seriously, at least not in disorders of the heart and
lungs. They certainly can stand to be polished, however, especially if I am going to be showing them off in public.
Thomas F. Mulrooney, MD
Minnesota Lung Center
Minneapolis, MN 55407
task somewhat daunting and frightening; I have never performed
bedside teaching before, an embarrassing admission indeed.
However, I believe it will be a rewarding experience.
It is my hope that my residents and students and I will become
better diagnosticians. As has been noted so frequently, the art of
physical diagnosis is vanishing. I recently reviewed an article for
the, American Journal of Medicine in which the authors found that
cardiologists are not significantly better at diagnosing certain
cardiac murmurs than general internists or family practitioners.
Furthermore, it seems abundantly clear that a physician's physical diagnosis abilities do not improve much after the third year
of medical school. I find these facts quite shameful. I believe that
everyone will profit by taking rounds back to the bedside.
David M. Ennis, MD
Birmingham Baptist Medical Center
Birmingham, AL 35213-1944
Reference
In response: Dr. Patil illustrates the common belief among
academicians that "no one does bedside teaching but us." In
truth, the opening vignette in my essay, which begins "Some time
ago, when visiting a great university medical center..." and
which ends with the housestafiPs incredulous wonderment at what
bedside teaching really was, actually occurred at Dr. Patil's institution, Dalhousie University in Nova Scotia, when I was the
T.J. Murray Visiting Scholar in Medicine in 1994.
Dr. Berger illustrates another common misconception, the belief that "our specialty relies upon physical diagnosis as does no
other." I would have to say, after 20 years in practice, that
neurologists too have lost their edge where physical diagnosis is
concerned. I think that all practicing internists would agree with
me that when we ask for a neurology consultation, the first
question asked of us by the neurologist is, "what did the CAT
scan show?"
Drs. Zwillich and Powell point out that bedside teaching can
occur in the outpatient clinic and at the patient's home, something we must not forget. Dr. Schroeder's point is well taken and
deserves emphasis. To make certain that the patient will be there
when one returns to the bedside with the entourage takes considerable planning beforehand.
Finally, and perhaps most important, the comments by Drs.
Olsen, Mulrooney, and Ennis illustrate the concerns of academicians everywhere who wish to return to bedside teaching. The
pressures on academic physicians to see more patients and make
more money for the department erode the teaching of students
in general, the art of bedside teaching, and physician diagnosis
particularly. That is a secret to no one. The trepidation expressed
by Drs. Ennis and Mulrooney is common. Here is a trick for the
anxious bedside teacher: The night before your bedside rounds,
open Sapira (1) or DeGowin (2) and read all you can about the
physical findings you have already seen and know you can recognize. Ignore the findings you have never seen. Reading about
them will not help you there. But knowing the significance and
historical basis of Queen Anne's sign, for example, will give you
some confidence, and something to say, even if you begin with
only, "Well, she doesn't have Queen Anne's sign."
Michael A. LaCombe, MD
Bridgton, ME 04009
Reference
To the Editor: After reading "On Bedside Teaching" (1), I was
inspired to begin doing bedside teaching, especially because I am
currently attending on the General Medical Service. I find the
References
1. Sapira JD. The Art and Science of Bedside Diagnosis. Baltimore:
Williams & Wilkins; 1990.
2. DeGowin EL, DeGowin RL, Jochimsen PR, Theilen RO. DeGowin &
DeGowin's Bedside Diagnostic Examination. 5th ed. New York:
McGraw-Hill; 1993.
173
Doing the Little Things
To the Editor: As a former chief resident at a university medical center, I had a sense of nostalgia when reading Rinder's
essay, "Doing the Little Things" (1). Maintaining a laboratory for
the housestaff and students to use was a pleasure and brought
home the importance of both sample collection and the clinical
laboratory in the treatment of patients.
In our case, the housestaff laboratory had to be shut down
because it did not have the "quality control" systems demanded
by the Joint Commission on Accreditation of Hospitals (JCAH),
even though the tests were being done in parallel by the main
laboratory. Ironically, one of the best teaching methods was
eliminated in order to improve the hospital. The laboratory personnel were not too keen on the housestaff coming down to their
crowded workstations to do Gram stains or look at the CBCs the
laboratory prepared!
Personally, I miss showing up for morning report with purplestained fingers.
Howard Homier, MD
University of California, Davis, School of Medicine
Davis, CA 95616
Reference
1. Kinder MR. Doing the little things. Ann Intern Med. 1997; 126:247.
In response: Homler's sentiments are consistent with those of
many other respondents who have contacted me in the past
several months. Most respondents echo Homler's comments that
the housestaff laboratory provided a sense of accomplishment
while teaching students and housestaff the importance of interpreting test results. However, whereas Homier states that JCAH
issues have shut down his and other satellite laboratories, most
correspondents have indicated added frustration with housestaff
attitudes toward just examining specimens collected by others. It
is unclear whether this lack of motivation is a result of the access
problem, a failure of academic faculty to teach specimen examination, or simply a change in the way housestaff view their role
as care providers. I truly believe that motivated students and
house officers will find ways to examine specimens and persuade
administrative types to provide facilities for these activities.
Morton R. Rinder, MD
Washington University School of Medicine
St. Louis, MO 63110
Physician-Assisted Suicide
To the Editor: As pointed out by Drickamer and colleagues (1),
physician-assisted suicide is changing the physician-patient relationship. It is clear that physicians as a group are divided in their
willingness to assist suicide: Of 938 physicians in Washington,
40% were willing to help a patient to commit suicide but 39%
held that assisted suicide is never ethically justified (2). With the
reports from the Netherlands that involuntary euthanasia has
followed the legalization of voluntary euthanasia (3), concern will
increase among patients about what would happen to them if
they became too ill to participate in end-of-life decisions. Physi-
174
cians are unlikely to discuss their ethical views with patients, but
patients will increasingly want to know their physician's stand on
euthanasia and assisted suicide.
One way to address this issue is for physicians to document
their stand on euthanasia and assisted suicide and have this
position accessible for public review. A group of seven physicians
from six states has set up an Internet registry of physicians who
do not practice assisted suicide or euthanasia (http://www.wp
.com/JMV/Anti-Euthanasia). Members of the public have free
access to this registry, and physicians can have their names
included when they log onto the site.
Patrick Pullicino, MD, PhD
Buffalo General Hospital
Buffalo, NY 14203
References
1. Drickamer MA, Lee MA, Ganzini L. Practical issues in physicianassisted suicide. Ann Intern Med. 1997;126:146-51.
2. Cohen JS, Fihn SD, Boyko EJ, Jonsen AR, Wood RW. Attitudes toward
assisted suicide and euthanasia among physicians in Washington State.
N Engl J Med. 1994;331:89-94.
3. Van der Maas PJ, van der Wal G, Haverkate I, de Graaf CL, Kester
JG, Onwuteaka-Philipsen BD, et al. Euthanasia, physician-assisted suicide, and other medical practices involving the end of life in the
Netherlands, 1990-1995. N Engl J Med. 1996;335:1699-705.
In response: Voluntary euthanasia has not been legalized in the
Netherlands, although guidelines of acceptable practice and a
reporting system were established in 1991 (1). Contrary to Dr.
Pullicino's statements, evidence suggests that since the establishment of the guidelines and reporting system in the Netherlands,
the number of cases of involuntary euthanasia found on survey
has actually decreased (1).
We are not sure whether Dr. Pullicino's assertion that physicians are unlikely to discuss their ethical views with patients is
correct. One of the positive outcomes of the publicity focused on
the physician-assisted suicide issue seems to be an increase in
dialogue about all end-of-life issues (2), which we find heartening. A World Wide Web site is a good source of public information, but physician-patient communication is best done faceto-face. The timing and manner in which the physician's position
on assisted suicide is revealed are best determined within the
context of each individual physician-patient relationship. When a
patient does inquire about assisted suicide, we hope that the
physician will take that opportunity to explore the underlying
reasons for that patient's request.
Margaret A. Drickamer, MD
West Haven Veterans Affairs Medical Center
West Haven, CT 06516
Melinda A. Lee, MD
Linda Ganzini, MD
Portland Veterans Affairs Medical Center
Portland, OR 97207
References
1. Van der Maas PJ, van der Wal G, Haverkate I, de Graaf CL, Kester
JG, Onwuteaka-Philipsen RD, et al. Euthanasia, physician-assisted suicide, and other medical practices involving the end of life in the
Netherlands, 1990-1995. N Engl J Med. 1996;335:1699-705.
2. Lee MA, Ganzini L, Brummel-Smith K. When patients ask about
assisted suicide: a viewpoint from Oregon. West J Med. 1996;16:205-8.

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