EDITORIALS

Editorials

I NSULIN AND S YNDROME

THE

P OLYCYSTIC O VARY

HE cardinal clinical manifestations of the polycystic ovary syndrome are hirsutism and anovulation, oligomenorrhea, or amenorrhea. About half the women with this syndrome are obese, and some have diabetes mellitus. Underlying these clinical abnormalities is an array of biochemical abnormalities that have defied simple explanation. Among them, the most important are increased serum concentrations of total and free testosterone, decreased serum sex hormonebinding globulin concentrations, increased serum luteinizing hormone concentrations, and hyperinsulinemia. Not all affected women have all these biochemical abnormalities, but in the aggregate, these findings, along with the clinical abnormalities, are characteristic of the syndrome.1 Anatomically, most of the women have polycystic ovaries, as detected by ultrasonography, but because some normal women do also, the diagnosis should not be based on anatomical findings alone. The fundamental abnormality in women with the polycystic ovary syndrome is increased ovarian production of androgens, particularly testosterone. In the ovaries of normal women, progesterone is converted to 17a-hydroxyprogesterone and then androstenedione in theca cells by the actions, respectively, of 17a-hydroxylase and 17,20-lyase, both derived from cytochrome P450c17a. The androstenedione is rapidly converted to testosterone in the same cells, and it, in turn, is converted to estradiol in the granulosa cells. In polycystic ovaries, the activity of 17ahydroxylase and, to a lesser extent, 17,20-lyase is increased2; the net effect is an increase in testosterone production. Some of the excess testosterone acts locally to cause premature follicular atresia and anovulation, and some reaches the circulation, causing the small increases in serum testosterone concentrations that characterize the syndrome. Thus, increased ovarian androgen production has both local and systemic effects. The bilateral nature of the ovarian disease implies that extraovarian factors are in part responsible for maintaining, if not initiating, excess ovarian androgen production. One important factor is luteinizing hormone. This hormone is a potent stimulator of theca-cell growth and androgen production, and when its secretion is inhibited the serum testosterone concentration decreases. The small increases in serum luteinizing hormone concentrations in women with the polycystic ovary syndrome have been attributed to positive feedback effects of both estro-

gen and androgen and also to a direct stimulatory effect of insulin. A second ovary-stimulating hormone in women with the polycystic ovary syndrome is insulin. In vitro, insulin increases testosterone production in stromal tissue removed from women with this syndrome.3 Conversely, their serum testosterone concentrations decrease when insulin secretion is reduced by the administration of diazoxide (which inhibits insulin secretion directly) or by diet or the administration of metformin (which cause reductions in insulin resistance and secondarily in insulin secretion).4-6 The study reported by Nestler and Jakubowicz in this issue of the Journal was designed to clarify the linkage between insulin and the increased activity of cytochrome P450c17a that characterizes the polycystic ovary syndrome.7 The investigators administered metformin or placebo for four to eight weeks to a group of obese, hyperinsulinemic women with the polycystic ovary syndrome. Both insulin secretion and P450c17a activity (the latter measured both basally and in response to an increase in serum luteinizing hormone stimulated by the gonadotropin-releasing hormone analogue leuprolide) decreased in the women who received metformin, as did basal and leuprolide-stimulated luteinizing hormone secretion. Serum free testosterone concentrations decreased, as a result of both a decrease in testosterone production and an increase in serum sex hormonebinding globulin concentrations. Were the decreases in serum 17a-hydroxyprogesterone and testosterone concentrations the result of decreased insulin secretion or decreased luteinizing hormone secretion? Probably both. Was the decrease in serum luteinizing hormone concentrations also the result of decreased insulin secretion, or was it caused by the decrease in ovarian steroid secretion? Again, probably both. The evidence that insulin directly stimulates ovarian function is stronger than the evidence that it stimulates luteinizing hormone secretion, but the existence of a stimulatory action of insulin on luteinizing hormone secretion would help to explain the elevated serum luteinizing hormone concentrations that are so typical of the syndrome. The decrease in serum sex hormonebinding globulin concentrations reflects another action of insulin in women with this syndrome: to decrease hepatic production of the binding protein,8 which magnifies the effect of the increase in testosterone secretion by reducing the fraction of the hormone in serum that is bound. Hyperinsulinemia, therefore, is a key component of the polycystic ovary syndrome. It is caused by insulin resistance more specifically, resistance to the hypoglycemic actions of insulin. In this sense, the hyperinsulinemia in these women is like that which occurs in obese but otherwise normal women. It differs, however, in several important respects. Both
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The New England Journal o f Me d i c i n e

normal-weight and obese women with the polycystic ovary syndrome are more resistant to insulin than normal-weight and obese women without it.9 The greater insulin resistance in women with the syndrome is unexplained, but it is not due to hyperandrogenemia. The nonhypoglycemic actions of insulin also differ in the two groups, in that most insulin-resistant women do not have menstrual abnormalities or any of the other clinical, biochemical, or anatomical features of the syndrome. The most attractive explanation for the ovary-stimulating action of insulin in women with the polycystic ovary syndrome is that the post-receptor mechanism of action of insulin in the ovary is augmented in some way, perhaps by an abnormality of intracellular insulin signaling or an abnormality in P450c17a activity that renders the enzyme complex more sensitive to insulin. This explanation is supported by evidence that there is familial clustering of the polycystic ovary syndrome,10 as well as by the fact that hyperinsulinemia does not cause hyperandrogenemia in most women with insulin resistance. This hypothesis does not, however, account for the sensitivity to hyperinsulinemia of sex hormonebinding globulin production by the liver and luteinizing hormone secretion by the pituitary. These changes, like ovarian hyperresponsiveness, imply some gain of function, because they are not present in other women with similar degrees of hyperinsulinemia. Finally, the insensitivity of normalweight as well as obese women with the polycystic ovary syndrome to the hypoglycemic actions of insulin must be explained. The most parsimonious hypothesis is that these three actions two reflecting increased insulin sensitivity (in the liver and pituitary) and one reflecting decreased sensitivity (in muscle and adipose tissue) are a result of interactions between insulin and testosterone or estrogen (or both) in these tissues. What do these new results mean with respect to the treatment of women with the polycystic ovary syndrome? Currently, treatment consists of weight reduction for women who are obese. For those who wish to conceive, clomiphene may be given; if that is unsuccessful, assisted-reproduction procedures or partial ovarian resection may be tried. For the remaining women, administration of an oral contraceptive, an antiandrogen such as spironolactone or cyproterone, or both, may reduce the clinical manifestations of androgen excess and restore regular menstrual bleeding. The results reported by Nestler and Jakubowicz7 indicate that drugs like metformin that increase insulin sensitivity and decrease hyperinsulinemia can reduce androgen secretion and, by raising serum sex hormonebinding globulin concentrations, also limit the action of androgen; the risk of hypoglycemia is minimal, because insulin secretion is decreased. Although the goal of this study was to provide some
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insight into the pathophysiology of the polycystic ovarian syndrome, it also points the way to new therapy. If the prolonged administration of metformin, which is safe in patients with non-insulin-dependent diabetes mellitus, proves not only to reduce androgen secretion but also to restore cyclic pituitary gonadal function and improve fertility, as already reported in a few women,6 it could represent a substantial advance in treatment for women with the polycystic ovary syndrome.
ROBERT D. UTIGER, M.D. REFERENCES
1. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333: 853-61. 2. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 1992;327:157-62. 3. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62:904-10. 4. Nestler JE, Barlascini CO, Matt DW, et al. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1989;68:102732. 5. Holte J, Bergh T, Berne C, Wide L, Lithell H. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1995;80:2586-93. 6. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54. 7. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-23. 8. Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72: 83-9. 9. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257-66. 10. Carey AH, Chan KL, Short F, White D, Williamson R, Franks S. Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 1993;38:653-8. 1996, Massachusetts Medical Society.

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EDITORIALS

P HARMACOTHERAPY FOR O BESITY D O THE B ENEFITS O UTWEIGH THE R ISKS ?

N association between appetite-suppressant drugs and primary pulmonary hypertension is reported by Abenhaim et al. in this issue of the Journal.1 This important finding requires careful assessment, because the prevalence of obesity is increasing and sustained weight reduction has been difficult to achieve without drug treatment. Moreover, the appetite-suppressant drug dexfenfluramine (Redux) has recently become available in the United States. The current receptive climate for pharmacotherapy reflects a paradigm shift: obesity is now recognized as a chronic disease that requires long-term treatment. Obesity results from a complex interaction of genetic, behavioral, and environmental factors. Because exercise, diet, and behavioral modification alone are usually not sufficient to maintain longterm weight loss, there has been renewed interest in drug therapy. Given the benefits of weight loss among the obese, how is the small risk of primary pulmonary hypertension associated with appetitesuppressant drugs (28 cases per million person-years) to be interpreted? Obesity is the second leading cause of preventable death in the United States, exceeded only by cigarette smoking.2 It is a major risk factor for cardiovascular disease, diabetes mellitus, and some cancers in both men and women, and it contributes to 300,000 deaths annually in the United States.2 Obesity affects 58 million people in the nation, and its prevalence is increasing.3 It is a major determinant of premature mortality: among more than 115,000 women followed for 16 years in the Nurses Health Study, the risk of death was 60 to 70 percent higher among those who had body-mass indexes between 29 and 32 (as calculated by dividing the weight in kilograms by the square of the height in meters) than among those with body-mass indexes between 25 and 27.4 These figures translate into 1260 excess lives lost per million women per year as a consequence of an average weight difference of only 13 kg. Even small degrees of weight loss are consistently associated with improvements in blood pressure, serum lipid values, and glucose tolerance.5,6 Intentional weight loss by women with coexisting conditions, primarily diabetes and hypertension, is associated with a 20 percent reduction in mortality.7 Despite the dire health consequences of obesity, traditional interventions to reduce body weight have usually been ineffective, especially in the long term.5 Data from clinical trials demonstrate the value of drug therapy for obesity. In one 12-month trial of 404 obese patients treated with dexfenfluramine, 64 percent lost 5 percent or more of their body weight8:

more than 20 percent lost at least 15 percent, 20 percent lost 10 to 14 percent, and another 20 percent lost 5 to 9 percent of their initial weight. Using these results and extrapolating from data on mortality according to body-mass index in the Nurses Health Study,4 we can estimate that at least 280 deaths could be prevented per million obese persons treated per year. In addition, more than 400 nonfatal myocardial infarctions and cerebrovascular events could be prevented. It is in the context of these benefits of weight reduction that the risk of primary pulmonary hypertension must be interpreted. The investigators in the International Primary Pulmonary Hypertension Study intensively sought all cases of primary pulmonary hypertension seen over a 25-month period at 220 referral hospitals in four countries.1 Only 95 eligible patients were found, underscoring the rarity of the disease. Thirty of them had been treated with appetite-suppressant drugs, as compared with only 26 of 355 control patients. The principal finding of the study was an odds ratio of 23 for primary pulmonary hypertension associated with the use of appetite-suppressant drugs for more than three months. Multiplying this ratio by a background risk of about 1.2 per million person-years among persons unexposed to such drugs gives an absolute risk of primary pulmonary hypertension of about 28 cases per million person-years of exposure. This is close to the magnitude of the risk of death from penicillin-induced anaphylaxis or oral-contraceptiveassociated venous thromboemboli and myocardial infarction. Assuming a 50 percent mortality rate for patients with primary pulmonary hypertension and combining the result with the benefits of weight loss, treatment with appetite-suppressant drugs would yield 14 deaths from primary pulmonary hypertension and a benefit:risk ratio of 20:1 (280 lives saved as compared with 14 deaths caused by the drugs per million person-years of treatment). Several biases may have inflated the estimates of risk in the study by Abenhaim et al. In France and Belgium, where 81 percent of the patients with primary pulmonary hypertension were treated, there was considerable publicity about a possible association between appetite-suppressant drugs and primary pulmonary hypertension9,10; this publicity is likely to have increased the referral of patients treated with such drugs to the study hospitals. Although the severity of the pulmonary hypertension was similar in the case patients and the controls, this similarity does not fully alleviate our concern about detection bias. In addition, differences between the case patients and the controls in their recall of drug treatment (a recall bias) could have affected the results despite the investigators attempts to minimize such bias. Given the small numbers of patients with primary pulmonary hypertension and control patients, the effect of these two biases on the odds ratios is
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The New England Journal o f Me d i c i n e

likely to be substantial. For example, if only five additional control patients had been treated with appetite suppressants, the crude odds ratios for primary pulmonary hypertension associated with treatment lasting more than three months would have been halved. In addition, the stratified and other statistical analyses performed did not entirely eliminate the possibility of confounding by obesity, because no data were obtained on weight fluctuations and the extent of weight loss. For these reasons, a causal relation with appetite-suppressant drugs is not established unequivocally by this study. The association of appetite-suppressant drugs with primary pulmonary hypertension is probably not limited to the fenfluramines. These drugs were by far the most widely used of the drugs in the study countries, however, which probably accounts for the preponderance of fenfluramine-treated patients in the study. The inclusion in the risk estimates of compound preparations whose contents were not standardized also makes it problematic to draw conclusions pertaining to specific drugs. The patients most likely to benefit from the use of appetite-suppressant drugs are those with body-mass indexes greater than 30 (or 27 if patients with coexisting conditions such as hypertension, diabetes, or hyperlipidemia are included) in whom nonpharmacologic interventions have been unsuccessful. These body-mass indexes correspond to body weights above 85 and 76 kg (186 and 167 lb), respectively, for a person 1.68 m (5 ft 6 in.) tall. Drugs should be considered as adjuncts to programs of diet and exercise and reserved for patients with medically important obesity. Because few data are available on patients treated for more than one year, further study of the benefits and risks of prolonged therapy will be important. Physicians must be vigilant to avoid overuse, misuse, and noncompliance with prescribing recommendations. Surveillance will be needed to ensure that the risks of primary pulmonary hypertension do not exceed those found in the present study, and patients should be advised about the need to report new or progressive dyspnea, chest pain, leg edema, or other symptoms of this disorder. To limit unwarranted exposure and risks, treatment with appetite-suppressant drugs should be continued only if the patient has an initial response; in the case of dexfenfluramine, this would amount to a loss of at least 1.8 kg (4.0 lb) in the first month of therapy. Obesity is an escalating problem in the United States, and the condition is notoriously difficult to treat. Because the associated health hazards are considerable, medications are needed that produce and maintain weight loss safely and effectively. Dexfenfluramine is an important new drug in the clinicians arsenal, but it is not free of risk. Although physicians and patients need to be informed, the possible risk of pulmonary hypertension associated with dexfen660
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fluramine is small and appears to be outweighed by benefits when the drug is used appropriately.
JOANN E. MANSON, M.D., DR.P.H.
Harvard Medical School Boston, MA 02115

GERALD A. FAICH, M.D., M.P.H.

University of Pennsylvania Philadelphia, PA 19104

REFERENCES
1. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:60916. 2. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA 1993;270:2207-12. 3. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994;272:205-11. 4. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85. 5. Daly PA, Solomon CG, Manson JE. Risk modification in the obese patient. In: Manson JE, Ridker PM, Gaziano JM, Hennekens CH, eds. Prevention of myocardial infarction. New York: Oxford University Press, 1996: 203-40. 6. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122: 481-6. 7. Williamson DF, Pamuk E, Thun M, Flanders D, Byers T, Heath C. Prospective study of intentional weight loss and mortality in never-smoking overweight US white women aged 4064 years. Am J Epidemiol 1995; 141:1128-41. 8. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P Turner , P International trial of long-term dexfenfluramine in obesity. Lancet 1989; . 1142-5. 9. Brenot F, Herve P Petitpretz P Parent F, Duroux P Simonneau G. Pri, , , mary pulmonary hypertension and fenfluramine use. Br Heart J 1993;70: 537-41. 10. Atanassoff PG, Weiss BM, Schmid ER, Tornic M. Pulmonary hypertension and dexfenfluramine. Lancet 1992;339:436. 1996, Massachusetts Medical Society.

ESCHERICHIA COLI AND THE H EMOLYTIC U REMIC S YNDROME

HE hemolyticuremic syndrome is characterized by nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure.1 Extrarenal manifestations, particularly neurologic signs, may be present, indicating that the disease process is not limited to the kidney. As in the closely related disorder of thrombotic thrombocytopenic purpura, the pathologic hallmark of the disease is thrombotic microangiopathy. The hemolyticuremic syndrome is the leading cause of acute renal failure in young children, but it occurs in adults as well, sometimes together with gastrointestinal infection and bloody diarrhea. Other forms of the syndrome in adults are related to pregnancy, the postpartum state, oral-contraceptive use, malignant hypertension, cancer and chemotherapy, transplantation and cyclosporine therapy, and human immunodeficiency virus infection. In some

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EDITORIALS

cases the hemolyticuremic syndrome remains idiopathic, and rare familial forms have been described.1 The link among all these manifestations of this disease is endothelial-cell injury, affecting predominantly but not exclusively endothelial cells of the kidney. In the past 15 years there has been substantial progress in our understanding of the pathophysiology of postinfectious hemolyticuremic syndrome, but clinical observation at the bedside and sophisticated bacteriologic studies in the laboratory may still provide new insights into this important disease. In this issue of the Journal,Tarr et al. report an unusual case of the hemolyticuremic syndrome in a six-year-old girl.2 The first unusual feature is that the syndrome was caused by Escherichia coli O103:H2. About three quarters of the cases of sporadic or epidemic hemorrhagic colitis complicated by the hemolyticuremic syndrome in the United States and Western Europe are caused by the O157:H7 serotype of E. coli.1 The reservoir of E. coli O157:H7, as of other enterohemorrhagic E. coli, is the intestinal tract of domestic animals, particularly cows, and the usual route of human contamination is the ingestion of unpasteurized milk or uncooked meat from these animals. Serotype O157:H7 is rare and produces large amounts of toxins previously called verotoxins (since they kill Vero cells in culture) or Shiga-like toxins and now called Shiga toxins, since they are similar to the toxins produced by Shigella dysenteriae type 1. Two main Shiga toxins, 1 and 2, are produced by enterohemorrhagic E. coli. In contrast to the Shiga-toxin gene of shigella, the E. coli genes encoding Shiga toxins 1 and 2 are located not on the bacterial chromosome but on bacteriophages that infect the bacteria. These bacteriophages may infect several different serotypes of E. coli, and hemorrhagic diarrhea and the hemolyticuremic syndrome have been reported with serotypes other than O157:H7, particularly in South America,3 but also in Ontario and Quebec.4 Serotype O103:H2 is not often isolated from humans but has been identified as a cause of diarrhea in rabbits. In a recent study in France, strains of E. coli O103:H2 were isolated from the stools of 6 of 69 children with the hemolyticuremic syndrome. Comparison of the human and rabbit strains suggested a common origin but found no evidence of horizontal transmission between the two species.5 Enteropathogenic E. coli cause diarrhea, but only enterohemorrhagic strains that produce Shiga toxins induce microvascular damage, hemorrhagic colitis, and the hemolyticuremic syndrome. Shiga toxins bind specifically through their B subunits to glycolipid receptors identified as ceramide trihexoside (globotriosylceramide).6 The toxins then enter the cell through clathrin-coated pits, and their A subunits are dissociated from the B subunits and proteolytically cleaved. The activated A subunits inhibit protein synthesis by inactivating ribosomal subunits,

which blocks the elongation of peptides and leads to cell death. In studies involving the intravenous injection of Shiga toxin 1 in rabbits, Zoja et al. demonstrated that microvascular lesions appeared in the central nervous system, colon, and lungs where endothelial cells express Shiga-toxin receptors.7 Unfortunately, endothelial cells of the rabbit kidney do not express ceramide trihexoside, so they cannot be used as a model for the hemolyticuremic syndrome. Conversely, Obrig et al. showed that in human cells, the basal levels of ceramide trihexoside were approximately 50 times higher in renal microvascular endothelial cells than in umbilical-vein endothelial cells in culture and that 1 pM Shiga toxin reduced protein synthesis and the viability of renal endothelial cells by 50 percent, whereas umbilical-vein cells were not even affected by much larger concentrations ( 1 nM).8 Glomerular endothelial cells from infants (children less than two years old) but not from adults have recently been reported to express Shiga-toxin receptors, suggesting that the greater frequency of the hemolyticuremic syndrome in children could be related to glomerular expression of ceramide trihexoside early in life.9 The sequence of events that follows the injury of renal endothelial cells by Shiga toxin in vivo is not well understood, mainly because of the lack of an animal model of the hemolyticuremic syndrome. Pathological studies of renal-biopsy specimens from patients with the syndrome have provided diagnostic and prognostic information.10 These studies have also revealed that platelets accumulate in this disorder, as a result of their adhesion to the subendothelium and activated endothelial cells, and that fibrin is deposited, indicating local generation of thrombin. There is indirect evidence of the activation of the functional thrombin receptor of renal endothelial cells.11 In addition, up-regulation of plasminogen-activator inhibitor type 1 and the receptor for urokinase-type plasminogen activator within the renal capillaries indicates an activated phenotype of endothelial cells during the repair process.12 Indeed, local fibrinolysis and regeneration of endothelial cells usually lead to complete or partial recovery of renal function after Shiga-toxininduced hemolytic uremic syndrome.13 However, precise control of hypertension is essential to prevent secondary vascular lesions induced by shear stress. A second unusual feature of the case reported by Tarr et al. is that the hemolyticuremic syndrome occurred after a urinary tract infection. This and a few previous reports show that Shiga toxins can enter the circulation through the inflamed urinary mucosa or pyelonephritic lesions, even if the strain responsible does not have the urovirulence traits usually expressed by E. coli strains that cause pyelonephritis.14 This route of entry would have been more firmly estab661

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The New England Journal of Me d i c i n e

lished if stool analysis had been negative for Shiga toxin, thereby excluding the possibility of a simultaneous intestinal infection with serotype O103:H2, O157:H7, or both.15 Although antibiotic therapy is not recommended for gastrointestinal infections due to Shiga-toxin producing E. coli, it is essential in cystitis and pyelonephritis to prevent sepsis. E. coli O157:H7 does not ferment sorbitol, and this characteristic has been extremely useful in pinpointing this serotype as the chief cause of sporadic or epidemic outbreaks of enterohemorrhagic colitis and the hemolyticuremic syndrome in North America and Western Europe. Other means of detecting Shiga toxin in stool and perhaps urine, such as an assay for ceramide trihexoside receptors or amplification of the Shiga-toxin gene by the polymerase chain reaction, will be required to identify the other E. coli serotypes that cause the hemolyticuremic syndrome, particularly in cases in which the syndrome is not preceded by diarrhea. It remains to be seen whether E. coli O103:H2 will emerge as an important new agent of the hemolyticuremic syndrome.
ERIC RONDEAU, M.D., PH.D. MARIE-NOLLE PERALDI, M.D.
Hpital Tenon 75020 Paris, France

REFERENCES
1. Remuzzi G, Ruggenenti P The hemolytic uremic syndrome. Kidney Int . 1995;48:2-19. 2. Tarr PI, Fouser LS, Stapleton AE, et al. Hemolyticuremic syndrome in a six-year-old girl after a urinary tract infection with Shiga-toxinproducing Escherichia coli O103:H2. N Engl J Med 1996;335:635-8.

3. Cordovez A, Prado V, Maggi L, et al. Enterohemorrhagic Escherichia coli associated with hemolytic-uremic syndrome in Chilean children. J Clin Microbiol 1992;30:2153-7. 4. Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 1985;151:77582. 5. Mariani-Kurkdjian P Denamur E, Milton A, et al. Identification of a , clone of Escherichia coli O103:H2 as a potential agent of hemolyticuremic syndrome in France. J Clin Microbiol 1993;31:296-301. [Erratum, J Clin Microbiol 1994;32:860.] 6. Waddell T, Cohen A, Lingwood CA. Induction of verotoxin sensitivity in receptor-deficient cell lines using the receptor glycolipid globotriosylceramide. Proc Natl Acad Sci U S A 1990;87:7898-901. 7. Zoja C, Corna D, Farina C, et al. Verotoxin glycolipid receptors determine the localization of microangiopathic process in rabbits given verotoxin-1. J Lab Clin Med 1992;120:229-38. 8. Obrig TG, Louise CB, Lingwood CA, Boyd B, Barley-Maloney L, Daniel TO. Endothelial heterogeneity in Shiga toxin receptors and responses. J Biol Chem 1993;268:15484-8. 9. Lingwood CA. Verotoxin-binding in human renal sections. Nephron 1994;66:21-8. 10. Morel-Maroger L, Kanfer A, Solez K, Sraer JD, Richet G. Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults. Kidney Int 1979;15:548-58. 11. Xu Y, Zacharias U, Peraldi MN, et al. Constitutive expression and modulation of the functional thrombin receptor in the human kidney. Am J Pathol 1995;146:101-10. 12. Xu Y, Hagge J, Mougenot B, Sraer JD, Rnne E, Rondeau E. Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney. Kidney Int (in press). 13. Van Dyck M, Proesmans W, Depraetere M. Hemolytic uremic syndrome in childhood: renal function ten years later. Clin Nephrol 1988;29: 109-12. 14. Johnson JR, Moseley SL, Roberts PL, Stamm WE. Aerobactin and other virulence factor genes among strains of Escherichia coli causing urosepsis: association with patient characteristics. Infect Immun 1988;56:40512. 15. Pai CH, Ahmed N, Lior H, Johnson WM, Sims HV, Woods DE. Epidemiology of sporadic diarrhea due to verocytotoxin-producing Escherichia coli: a two-year prospective study. J Infect Dis 1988;157: 1054-7. 1996, Massachusetts Medical Society.

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SOUNDING BOARD

Sounding Board

T HE L EGALIZATION OF P HYSICIAN -A SSISTED

S UICIDE

ITH the enactment of an Oregon statute permitting physician-assisted suicide,1,2 the recognition of a constitutional right to assisted suicide by two U.S. courts of appeals,3,4 discussed elsewhere in this issue of the Journal,5 and the acquittals of Dr. Jack Kevorkian,6,7 there appears to be a dramatic shift in right-to-die law. Although the law previously distinguished between the withdrawal of life-sustaining treatment and assisted suicide, these recent events suggest that the distinction is being abandoned and that the law is undergoing a profound change. I will argue here that this interpretation is mistaken. Instead of a shift in the law, these events reflect the continued application of principles that have driven the development of right-to-die law since the Quinlan case in 1976. For the same reasons that the law previously drew a distinction between the withdrawal of treatment and assisted suicide, it is now eliminating that distinction. Assisted suicide has been prohibited, in my view, not because it is meaningfully different from the withdrawal of life-sustaining treatment but because the distinction between assisted suicide and the withdrawal of life-sustaining treatment served as a useful proxy, or substitute, for distinguishing between morally acceptable and morally unacceptable decisions by patients to end their lives. Society commonly implements its principles through generally valid rules rather than case-by-case determinations, recognizing that the rules will not fit every case but that case-by-case determinations are not feasible. The distinction between assisted suicide and the withdrawal of treatment is an example of rule-based lawmaking that, in the view of the public and the courts, worked well for many years but is no longer working well. Accordingly, the distinction is being replaced and will continue to be replaced by new proxy distinctions that allow assisted suicide in certain situations.
ARGUMENTS FOR THE DISTINCTION BETWEEN ASSISTED SUICIDE AND THE WITHDRAWAL OF TREATMENT

The distinction between assisted suicide and the withdrawal of treatment has generally been justified by courts and scholars on the grounds that there is a moral difference between the two acts. On close examination, however, it becomes clear that the distinction must have rested on grounds other than some moral difference. Perhaps the most common justification for the dis-

tinction is that assisted suicide involves an act of killing, whereas the withdrawal of treatment permits the disease to take its natural course.8 As the Second3 and Ninth4 Circuit Courts observed, however, the withdrawal of treatment is no less an act of killing than suicide. If I entered an intensive care unit and shut off every patients ventilator, I would be charged with the murder of every patient who died. And it would be no defense that the patients deaths were caused by their underlying illnesses.9 It is true that I would have acted without the patients consent, but consent does not change the cause of a patients death. It serves only to justify the use of treatment withdrawal to cause the patients death.9 The issue, then, is not whether assisted suicide causes death but whether it is a justifiable way to cause death. Callahan10 and Pellegrino11 maintain that we distinguish between the withdrawal of treatment and assisted suicide because ceasing treatment will kill the patient only if he or she is suffering from a fatal illness, whereas suicide will kill both the sick and the healthy. This claim also does not survive scrutiny. It reflects the considerations that originally led society to acknowledge the right to refuse life-sustaining treatment. Although that right is now well established, it was not always clear that withdrawal of treatment was permissible. Twenty years ago, Karen Ann Quinlans family had to obtain permission from the New Jersey Supreme Court, in a landmark decision, before her ventilator could be withdrawn.12 Thirteen years ago, in the Barber case, two physicians were prosecuted for withdrawing life-sustaining treatment at the behest of the patients family, and an appellate-court decision was required to vacate the murder charges.13 At some point, society had to decide whether treatment withdrawal was unlawful killing, and it declined to do so, primarily because we think it permissible to let patients die when they are hopelessly ill and there is little benefit from treatment. As a California court observed in explaining why Elizabeth Bouvias right to refuse a feeding tube superseded the states interest in preserving life, Bouvia faced a life of painful existence, her condition [was] irreversible, and she had no choice but to lie physically helpless subject to the ignominy, embarrassment, humiliation and dehumanizing aspects created by her helplessness.14 All these decisions indicate that the relevant issue is whether the person is dying and beyond help, not whether the person dies as a result of treatment withdrawal or suicide. Accordingly, it should be acceptable to assist in the suicide of a dying patient and unacceptable to withdraw life-sustaining treatment from a patient who is not irreversibly ill. It is also often argued that assisted suicide is fundamentally inconsistent with the physicians role as a healer,15 and in the wake of the circuit-court deci663

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The New England Journal of Me d i c i n e

sions, the American Medical Association reiterated its opposition to the practice. Treatment designed to cause death is not part of the medical armamentarium, according to this argument, and must therefore not be provided.16,17 Moreover, if physicians began to dispense lethal agents, patients would profoundly distrust the medical profession.16,18 However, physicians are providers of comfort as much as they are healers of illness.19,20 Indeed, if we view physicians fundamentally as relievers of discomfort or disease, with health promotion as part of that role, then assistance with suicide is not only compatible with the physicians role but quite possibly an obligation inherent in it. According to this view, what breeds distrust of physicians is not the possibility that they will dispense lethal agents but the possibility that they will refuse to do so.21 Patients fear that when they are suffering intolerably, they will be denied the drugs necessary to end their suffering. Another argument turns on the physicians intent. The withdrawal of treatment differs from assisted suicide, it is argued, because the intent is to remove an undesired treatment, not to kill the patient, and indeed the patient may not die. Karen Quinlan lived for nearly a decade after her ventilator had been withdrawn.22 Yet, as Jack Kevorkian successfully argued in his trials,23 the same claim can be made about assisted suicide. A lethal dose of a drug is prescribed not to kill the patient but to relieve the patients suffering. Moreover, the patient may not die. He or she may never take the pills, may take a sublethal dose of the drug, or may be revived before dying and then decide against subsequent suicide attempts. Some make the distinction that the refusal of treatment involves a negative right to be left alone, whereas the request for assistance with suicide involves a positive right to receive aid. This argument mischaracterizes the claim made by the proponents of assisted suicide. Their claim is not that a patient should have the right to insist that a physician provide assistance with suicide, but that the state should not interfere when a patient and a physician agree on assisted suicide. The right to assisted suicide, in other words, is also a negative right to be left alone. Still, it is argued, the right to refuse life-sustaining treatment reflects the laws traditional recognition of a right to be free of unwanted physical invasion. People denied assistance with suicide, on the other hand, are not subject to unwanted invasion and therefore are not denied any rights. In fact, however, rights with regard to treatment are not defined simply on the basis of whether the patient accepts or refuses a physical intrusion. About half the states have statutes permitting the imposition of treatment for tuberculosis,24 and courts have ordered pregnant women to accept medical treatment that would benefit their fetuses and themselves.25,26 There are also rights to receive treatment for example, the right to emer664
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gency medical care.27 More important, the reasons we prohibit physical invasion do not explain why we distinguish between assisted suicide and treatment withdrawal. Society recognizes a right to be free of unwanted physical intrusions because of the importance of self-determination and control over ones body. Yet we can also justify physician-assisted suicide in terms of the importance of self-determination and control over ones body. We are still left with the question why society has considered personal autonomy a more important principle in treatment withdrawal than in assisted suicide. There are also slippery-slope arguments against assisted suicide. Even though there might be some justifiable cases, it is argued, there is too great a risk that vulnerable patients will end their lives involuntarily or succumb to pressure from others to do so. Patients who choose suicide may have impaired competence as a side effect of medication or because of a treatable depression, and physicians responding to requests for assistance are often inadequately trained to distinguish rational requests from those driven by depression.28 Patients may also choose suicide to spare their families the financial and emotional burdens imposed by their illness.29 Furthermore, patients may choose to die because they have not received the pain relief or support services that would make them willing to stay alive. Physicians often do not treat physical or psychological pain aggressively enough. Finally, physicians may spend less time caring for their dying patients if assisted suicide is an option.30 It is emotionally draining and time-consuming to provide appropriate care for patients who are seriously ill31; if patients can choose suicide, physicians may be slower to respond to their patients needs. These risks are real, but as the Second Circuit Court of Appeals observed,3 they are just as real for patients who refuse life-sustaining treatment. Indeed, Larry McAfee,32 a Georgia man who was left quadriplegic and dependent on a ventilator after a motorcycle accident, did not exercise his court-authorized right to discontinue his ventilator, in part because wide publicity about his case brought forth support services that made his life more worthwhile to him.33
THE REAL BASIS FOR THE LEGAL DISTINCTION

I have tried to demonstrate that none of the traditional arguments can explain the legal distinction between the withdrawal of treatment and assisted suicide. For each of the arguments, there is an equally valid counterargument. Yet the law has drawn a distinction between assistance with suicide and withdrawal of treatment, and that distinction needs to be explained. I believe the distinction was drawn because it provided a useful proxy for separating morally valid and morally invalid requests by patients for help in

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SOUNDING BOARD

ending their lives. There may be no meaningful difference between the acts of treatment withdrawal and assisted suicide, but the distinction between the two has served an important functional role. As an example, consider the following two patients. One is 28 years old, despondent over the recent breakup of a romantic relationship, and because of an acute asthma attack, temporarily dependent on a ventilator. Apart from asthma, this person is in good health. The other patient is 82 years old, is wracked with pain from extensive metastatic cancer, and has only a few weeks to live. Assume that both persons wish to end their lives, the 28-year-old by refusing the ventilator and the 82-year-old by suicide. Under current law, the 28-year-old has the right to refuse the ventilator, whereas the 82-year-old generally lacks the right to assistance with suicide. Yet in terms of the reasons why we recognize a right to refuse life-sustaining treatment, it would be more justifiable to assist the 82-year-old patient with suicide than to accede to the 28-year-old patients refusal of the ventilator. As I noted earlier, the right to refuse life-sustaining treatment arose from the sense that hopelessly ill patients should be able to refuse treatment that provides minimal benefit and prolongs the process of dying. Societys interest in preserving life becomes attenuated when there is little left of the life to save and treatment is burdensome. In the same way, societys interest in preserving the life of the hypothetical 82-year-old becomes attenuated the patients remaining life is very short and characterized by severe suffering.4 On the other hand, refusing to withdraw the ventilator from the 28-year-old would result not in prolongation of the process of dying but in the continuation of a long life that the patient would probably come to value once again. Indeed, in cases in which a patients right to refuse life-sustaining treatment has been denied, the patient has been a young person whose health could readily be restored.25,34-36 Thus, although we think of assisted suicide as inherently worse than treatment withdrawal, this judgment largely reflects the fact that the typical suicide is less justifiable than the typical withdrawal of treatment.37,38 The despondent 28-year-old is the kind of person we think of when we think about those who choose suicide,4 and the 82-year-old person with metastatic cancer better fits our profile of the patient who asks that treatment be withdrawn. The relevant difference, then, is the context, not the act. This example suggests that, ideally, we would permit withdrawal of life-sustaining treatment and assisted suicide in some cases but prohibit them in others. Each case would be judged on its merits: someone would decide whether society should respect the patients decision that life is no longer worth living. It would be cumbersome, however, to make that judgment in every case. More important,

someone would have to have authority for deciding whether to permit the withdrawal of treatment or assistance with suicide. Physicians or others would not be likely to embrace this authority, nor would we be likely to entrust it to physicians or others.10 The judgment that a persons life has insufficient value can be made only by that person. Accordingly, whereas the right to refuse life-sustaining treatment was once viewed as legitimate only when a patients prognosis was considered dim or the treatment was deemed particularly burdensome, that right has now become recognized for almost any patient and almost any treatment.39 Given the infeasibility of case-by-case judgments, we relied on the bright-line distinction between treatment withdrawal and assisted suicide, a categorical distinction that could be readily applied to specific cases and that generally produced results that would have occurred with individual assessments. For, in most cases, the withdrawal of life-sustaining treatment has been morally acceptable, and until recently, most suicides have been morally problematic. The typical case of treatment withdrawal has involved a patient who was suffering greatly and would have died shortly no matter what treatment was provided. On the other hand, many persons who have died by suicide led seemingly productive and fulfilling lives and could have lived for many more years. In short, the distinction between the withdrawal of life-sustaining treatment and assisted suicide has essentially been used as a proxy for distinguishing morally acceptable from morally unacceptable cases of physician-assisted death. I am not making a normative judgment about whether this distinction is good ethics or good law. Instead, I am explaining why I think the law is as it is. Categorical rules are often used in the law. For example, everyone gains the right to vote at the age of 18 years. We could assess adolescents individually to decide when they are mature enough to vote. However, it would be terribly burdensome for the government to make such judgments. Also, once we abandon bright-line rules for case-by-case determinations, we increase the chances of abuse by decision makers or of grievance if some people are treated differently from others whom they believe they are like. This is one reason why the civil service has fixed salaries.
WHY THE LAW IS CHANGING

In recent years, the usefulness of the distinction between the withdrawal of treatment and assisted suicide has been undermined. As a result of medical advances, there are many terminally ill persons who are suffering intractably but are not dependent on life-sustaining treatment, and a ban on assisted suicide thus prevents many suicides that can be justified on the same basis used to justify the withdrawal of treatment. If we assessed each case on its own
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The New England Journal of Me d i c i n e

merits, we would find that a number of persons who choose suicide have medical conditions similar to those in patients who request the withdrawal of treatment and have the same reasons for ending their lives.40 The decisions of the Second and Ninth Circuit Courts and the new law in Oregon address this category of patients. By redefining the right to die to include a right to assisted suicide for terminally ill persons, these changes in the law have brought societys legal rules more in line with societys moral reasoning. The opinions of the Second and Ninth Circuit Courts and the language of the Oregon statute indicate that their drafters were reformulating the categories of permitted and prohibited aid in dying to create a better proxy for the distinction between morally justified and morally unjustified cases of hastening death. The decisions and the statute all retain a categorical approach to distinguishing between permissible and impermissible deaths. All terminally ill patients may choose a lethal dose of medication whether or not they are suffering greatly.1,3,4 Conversely, no patients who are not terminally ill may choose to end their lives with a lethal dose of medication even if they are suffering greatly. In addition, as before, all patients have a right to the withdrawal of life-sustaining treatment whether or not they are suffering greatly. With the infeasibility of case-bycase determinations, the Second and Ninth Circuit Courts and Oregon have chosen a new proxy for the distinction between permissible and impermissible deaths, and the new proxy essentially reflects the view that the typical case in which a terminally ill patient chooses suicide is a case in which the patients death is morally justifiable. Moreover, the decisions and the statute reflect the sense that what is critical for the purpose of determining a patients right to die is the patients condition rather than whether death is the result of treatment withdrawal or suicide. According to the Second Circuit Court, the state has little interest in requiring the prolongation of a life that is all but ended or in requiring the continuation of agony when the result is imminent and inevitable.3 Moreover, the court found no meaningful distinction between treatment withdrawal and assisted suicide, observing that the ending of life by [the withdrawal of life support] is nothing more nor less than assisted suicide.3 The Ninth Circuit Court concluded that the strength of the patients right to hasten death is especially dependent on the individuals physical condition and that right is strongest when the patient is terminally ill and wishes to hasten death because his remaining days are an unmitigated torture.4 Accordingly, wrote the court, We see no ethical or constitutionally cognizable difference between a doctors pulling the plug on a respirator and his prescribing drugs which will permit a terminally ill patient to
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end his own life.4 Indeed, the Ninth Circuit Court expressed doubt that deaths resulting from terminally ill patients taking medication prescribed by their doctors should be classified as suicide.4 Similarly, the Oregon statute expressly states, Actions taken in accordance with this Act shall not, for any purpose, constitute suicide, assisted suicide, mercy killing or homicide.1 The steps taken by the two courts and by the state of Oregon are likely to be followed by other courts and states, because the new proxy reflects a widely shared sentiment. Public-opinion polls have consistently demonstrated that the majority of the public supports the right to assisted suicide for terminally ill patients.40 Surveys of physicians demonstrate the same majority support.41-43 In California and Washington, the rejection of referendums permitting assisted suicide probably reflected concern about the adequacy of safeguards and the scope of the proposed changes rather than opposition to assisted suicide itself.44,45 Laws permitting assisted suicide in limited circumstances are likely to be widely adopted, because such laws will once again bring societys legal rules in closer line with its moral values.
DAVID ORENTLICHER, M.D., J.D.
Indiana University School of LawIndianapolis Indianapolis, IN 46202-5194
Address reprint requests to Dr. David Orentlicher at the Center for Law and Health, Indiana University School of LawIndianapolis, 735 W. New York St., Indianapolis, IN 46202-5194.

I am indebted to Judy Failer for her contributions.

REFERENCES
1. Death with Dignity Act. 1995 Oregon Laws Ch. 3 (Initiative measure no. 16). 2. Alpers A, Lo B. Physician-assisted suicide in Oregon: a bold experiment. JAMA 1995;274:483-7. 3. Quill v. Vacco, 80 F.3d 716 (2d Cir. 1996). 4. Compassion in Dying v. Washington, 79 F.3d 790 (9th Cir. 1996). 5. Annas GJ. The promised end constitutional aspects of physicianassisted suicide. N Engl J Med 1996;335:683-7. 6. Lewin T. Ruling sharpens assisted-suicide debate. New York Times. March 8, 1996:A14. 7. Lessenberry J. Jury acquits Kevorkian in common-law case. New York Times. May 15, 1996:A14. 8. In re Conroy, 486 A.2d 1209, 1224 (N.J. 1985). 9. Brock DW. Voluntary active euthanasia. Hastings Cent Rep 1992; 22(2):10-22. 10. Callahan D. When self-determination runs amok. Hastings Cent Rep 1992;22(2):52-5. 11. Pellegrino ED. Doctors must not kill. J Clin Ethics 1992;3:95-102. 12. In re Quinlan, 355 A.2d 647 (N.J. 1976). 13. Barber v. Superior Court, 195 Cal Rptr 484 (Ct App 1983). 14. Bouvia v. Superior Court, 225 Cal Rptr 297 (Ct App 1986). 15. Kass LR. Neither for love nor money: why doctors must not kill. Public Interest 1989(94):25-46. 16. Gaylin W, Kass LR, Pellegrino ED, Siegler M. Doctors must not kill. JAMA 1988;259:2139-40. 17. Council on Ethical and Judicial Affairs. Physician-assisted suicide. Issues Law Med 1994;10(1):91-7. 18. Orentlicher D. Physician participation in assisted suicide. JAMA 1989; 262:1844-5.

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19. Emanuel EJ. Euthanasia: historical, ethical, and empiric perspectives. Arch Intern Med 1994;154:1890-901. 20. Weir RF. The morality of physician-assisted suicide. Law Med Health Care 1992;20(1-2):116-26. 21. Battin MP Ethical issues in suicide. Englewood Cliffs, N.J.: Prentice. Hall, 1995:206. 22. McFadden RD. Karen Ann Quinlan, 31, dies: focus of 76 right to die case. New York Times. June 12, 1985:A1. 23. Lessenberry J. In latest suicide trial, Kevorkian asserts duty as a doctor. New York Times. May 4, 1996:10. 24. Gostin LO. Controlling the resurgent tuberculosis epidemic: a 50state survey of TB statutes and proposals for reform. JAMA 1993;269:25561. 25. Jefferson v. Griffin Spalding County Hospital Authority, 274 S.E.2d 457 (Ga. 1981). 26. In re Jamaica Hospital, 491 N.Y.S.2d 898 (Sup Ct 1985). 27. Owens v. Nacogdoches County Hospital District, 741 F.Supp. 1269 (E.D. Tex. 1990). 28. Conwell Y, Caine ED. Rational suicide and the right to die reality and myth. N Engl J Med 1991;325:1100-3. 29. Kamisar Y. Are laws against assisted suicide unconstitutional? Hastings Cent Rep 1993;23(3):32-41. 30. Council on Ethical and Judicial Affairs, American Medical Association. Decisions near the end of life. JAMA 1992;267:2229-33. 31. Miles SH. Physicians and their patients suicides. JAMA 1994;271: 1786-8. 32. State v. McAfee, 385 S.E.2d 651 (Ga. 1989). 33. Associated Press. Larry McAfee, 39; sought right to die. New York Times. October 5, 1995:D23. 34. In re Caulk, 480 A.2d 93 (N.H. 1984).

35. John F. Kennedy Memorial Hosp v. Heston, 279 A.2d 670 (N.J. 1971). 36. Application of President & Directors of Georgetown College, Inc., 331 F.2d 1000 (DC Cir 1964). 37. Rachels J. Active and passive euthanasia. N Engl J Med 1975;292:7880. 38. Rubenfeld J. The right of privacy. Harvard Law Rev 1989;102:737807. 39. Orentlicher D. Physician-assisted dying: the conflict with fundamental principles of American law. In: Blank RH, Bonnicksen AL. Medicine unbound: the human body and the limits of medical intervention. New York: Columbia University Press, 1994:256-68. 40. Quill TE, Cassel CK, Meier DE. Care of the hopelessly ill proposed clinical criteria for physician-assisted suicide. N Engl J Med 1992;327: 1380-4. 41. 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. 42. Bachman JG, Alcser KH, Doukas DJ, Lichtenstein RL, Corning AD, Brody H. Attitudes of Michigan physicians and the public toward legalizing physician-assisted suicide and voluntary euthanasia. N Engl J Med 1996;334:303-9. 43. Lee MA, Nelson HD, Tilden VP Ganzini L, Schmidt TA, Tolle SW. , Legalizing assisted suicide views of physicians in Oregon. N Engl J Med 1996;334:310-5. 44. Carson R. Washingtons I-119. Hastings Cent Rep 1992;22(2):7-9. 45. Annas GJ. Death by prescription the Oregon Initiative. N Engl J Med 1994;331:1240-3. 1996, Massachusetts Medical Society.

Fountain, Rome

L.P. BALDONI, M.D.

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