Letters
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send with the letter a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified only if their letter is accepted. Unpublished letters cannot be returned.
in a previous study (2), no beneficial effect of aminophylline as compared with placebo in relieving bronchospasm in patients already receiving other standard bronchodilator therapy was found. The decision on hospital admission, therefore, lies entirely with the house officer assigned to the emergency room. Although the authors have given preexisting guidelines for admission established for the emergency department, they did not discuss how these guidelines were adhered to by the house officer or what constitutes "independent clinical assessment." Although the study was double-blinded at the investigators' level, the house officers might have had knowledge of certain factors (that is, theophylline level) other than those presented in the report (3). This knowledge could play a major role in changing the rate of hospital admission. In short, it is hard to believe there was a threefold difference in the hospital admission rate, given the same objective and subjective findings for the aminophylline-treated group and the placebo group.
Aminophylline in the Emergency Department To the Editors: Wrenn and colleagues (1) are to be congratulated for their important contribution to the emergency management of bronchospasm. Further study of aminophylline's clinical action, however, is necessary before changing emergency-room practice. How aminophylline prevents admissions is mysterious, because the drug decreases neither the severity of bronchospasm nor its symptoms (2). Subdividing exacerbations into "infectious, inflammatory, or allergic" categories, as the authors suggest, might identify predictors of admission and help explain the drug's mechanism. The authors should consider measuring pulmonary function through the patient's emergency-room stay. Although improvement appears to level off after 2 hours, substantial airway obstruction remains. Additional gains in peak flow may well occur by the average of 4 hours later when admission decisions are made. Repeat measurements might show that aminophylline continues to decrease bronchospasm. Because Grady Memorial Hospital's emergency department uses discrete criteria for admission (recent relapse, failure to clear, failure to reach pre-exacerbation status, respiratory failure, or the inability to walk 100 feet), simply asking house officers why they admitted their patients may show how aminophylline provided benefit or, at least, may guide further study. Mark D. Siegel, MD Pennsylvania Hospital Philadelphia, PA 19107 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. McFadden ER Jr. Methylxanthines in the treatment of asthma: the rise, the fall, and the possible rise again. Ann Intern Med. 1991 ;115: 323-4. To the Editors: Wrenn and colleagues (1) recently reported the beneficial role of aminophylline therapy in reducing the rate of hospital admission in a randomized, double-blind, placebo-controlled intervention study. The authors showed a threefold decrease in the hospital admission rate for the aminophylline-treated group as compared with the placebo group. Despite no difference in objective (as measured by spirometry) or subjective (as estimated by patient satisfaction) findings, as 910
Thanh Nguyen-Dinh, MD Howard University Medical Service D.C. General Hospital Washington, DC 20003 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Siegel D, Sheppard D, Galb A, Weinberg PF. Aminophylline increases the toxicity but not the efficiency of an inhaled beta-adrenergic agonist in the treatment of acute exacerbation of asthma. Am Rev Respir Dis. 1985;132:283-6. 3. McFadden ER Jr. Methylxanthines in the treatment of asthma: The rise, the falls, and the possible rise again. Ann Intern Med. 1991; 115:323-4. To the Editors: Wrenn and colleagues (1) propose that the use of aminophylline for patients with acute exacerbations of bronchospastic disease in the emergency department setting may be justified because the drug reduces the hospital admission rate for these patients. The lack of concordance between hospital admission rates and any other index of improvement is worrisome. To support their findings, the authors cite a previous study of methylprednisolone in the emergency-room treatment of acute asthma (2). This study, however, did show a clinically important trend with respect to the difference between treatment groups of forced expiratory volume in 1 second (P = 0.068), forced vital capacity (P = 0.076), subjective symptom score (P = 0.026), and hospital admission rate (P = 0.003); the latter finding remained statistically significant after applying the Bonferroni correction. An isolated finding of decreased hospitalizations without physiologic or subjective improvement suggests a spurious statistical result. We are concerned that the single significant P value reported by Wrenn and colleagues (1) may be an artifact of multiple comparisons (3). The authors used statistical tests to determine the effect of aminophylline therapy on three spirometric variables, five side effects, patient satisfaction, patient improvement, duration of therapy, and admission status. Of these twelve variables, only one reached conventional levels of statistical significance. Applying the Bonferroni method, we find that the corrected threshold of statistical significance for hospital admission is 0.05/12 = 0.0042, not 0.0125, as reported by Wrenn and colleagues (1). Although the Bonferroni method is regarded as
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overly conservative by some, the P value of 0.016 reported for hospital admission exceeds the corrected threshold for statistical significance by almost fourfold. Overall, we commend the authors for attempting to resolve an important clinical controversy. Like the authors, we are also "unable to explain why treatment with aminophylline seems to have a measurable clinical effect in the absence of an objective improvement in pulmonary function as measured by spirometry." Based on this study's results, it is premature to recommend aminophylline for the emergency-room treatment of all patients with acute bronchospastic disease. David A. Katz, MD Veterans Affairs Medical Center White River Junction, VT 05001 Benjamin Littenberg, MD Dartmouth-Hitchcock Medical Center Hanover, NH 03756 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2. 3. Cupples LA, Heeren T, Schatzkin A, Colton T. Multiple testing of hypotheses in comparing two groups. Ann Intern Med. 1984; 100: 122-9. To the Editors: Wrenn and colleagues (1) should be commended on their recent randomized trial of intravenous aminophylline in the emergency-room treatment of acute bronchospasm. In the face of recent reports suggesting methylxanthine's lack of efficacy in the treatment of asthma, it is provocative to see opposing evidence further kindle the debate (2). Unfortunately, we are not yet willing to accept methylxanthine as a proven beneficial therapy for the emergencyroom treatment of acute bronchospasm until these data are confirmed by trials with longer follow-up. At our institution we not uncommonly see patients recently treated for acute bronchospasm in an emergency room who present several days later requiring retreatment. The authors state that follow-up data on their patients were obtained by examination of 4tbilling records." These records showed that only three patients returned within 72 hours of treatment, one in the aminophylline-treated group and two in the placebo group. However, hospital billing records would not include any patient who reported to another institution or a physician's office for retreatment. Wrenn and colleagues (1) are not alone. A similar study focusing on the use of methylprednisolone in acute asthma shares this methodologic flaw (3). Although more vigorous attempts were made to contact study participants, follow-up data were obtained for only 58% of participants. This level of follow-up is well below accepted standards for examining the clinical course of a disease (4). Studies on the emergency-room treatment of acute bronchospasm cannot be considered definitive until adequate follow-up data are analyzed and the whole story is known. Tim Richardson, MD Franz Fisher, MD Daniel Castro, MD Jerry L. Pettis Memorial Veterans Affairs Medical Center Loma Linda, CA 92357 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Littenberg B. Aminophylline treatment in severe, acute asthma: A meta-analysis. JAMA. 1988;259:1678-84. 3. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2. 4. Department of Clinical Epidemiology and Biostatistics, McMaster Uni-
versity Health Sciences Center. How to read clinical journals: III. To learn the clinical course and prognosis of disease. Can Med Assoc J. 1981;124:869-72. In response: Dr. Siegel's suggestions seem appropriate and should be included in any future study of the question of aminophylline's efficacy. Dr. Nguyen-Dinh would have us better define what constitutes clinical assessment. We cannot. He raises the question of house-officer bias. We sincerely doubt that knowledge of theophylline levels influenced the house officers in their decision to admit patients because, at the time of the study, we were teaching the house officers that there was no evidence to suggest aminophylline had any use in the care of patients with bronchospasm in the emergency department. Drs. Katz and Littenberg would have us use a P value of 0.0042 as the threshold of significance. This value strikes us as unrealistic. No well-designed, randomized, double-blind, placebo-controlled clinical trial includes less than 5 to 15 variables. Littenberg and Gluck (1), in their study on the use of methylprednisolone, did not apply the Bonferroni correction despite having studied at least 13 variables, including admission rate, FEV,, FVC, subjective symptom score, follow-up care, early readmission, whether patients required endotracheal intubation or mechanical ventilation, time in the clinic, the use of three other agents, and side effects. If they looked for only four side effects, then the statistical significance of all their results would be in question according to the Bonferroni rule (P < 0.003 required to significance). In fact, they claim statistical significance for a difference in the subjective symptom score at P = 0.026 (1). We feel the Bonferroni correction does not apply to a prospective trial such as ours because it is used primarily to avoid "data dredging," which may occur in retrospective studies. To apply the correction, as Katz and Littenberg suggest, would routinely lower the P value for statistical significance to unrealistic levels. Finally, it is inappropriate to group all the variables they list as outcome variables. As to the questions raised by Richardson and colleagues, our study focussed on the short-term response. Ours is the only inner city hospital serving an indigent population, and the emergency department is the asthma treatment center. Thus, billing records probably are a good surrogate for follow-up. We agree, however, about the need for well-developed long-term follow-up studies of asthma treatment. We stand by our discussion as written. We were surprised by the statistically and, more important, clinically significant reduction in the admission rate of patients receiving aminophylline. We look forward to a large multicenter trial to test this agent's efficacy in the emergency department. We do not advocate the use of theophylline compounds as first-line agents in the emergency department, but feel, based on our data, that there may be some use for aminophylline in certain settings (for example, a lack of inpatient hospital beds) or situations (for example, failure to clear quickly with /3-agonist, steroids, and anticholinergic agents). In the final analysis, each physician must decide about the use of a drug in each situation. Keith D. Wrenn, MD Corey M. Slovis, MD University of Rochester Medical Center Rochester, NY 14642 Reference 1. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2.
Prevention of NSAID-induced Gastric Ulcer To the Editors: Agrawal and coworkers (1) described a prospective, randomized controlled trial comparing sucralfate and misoprostol in the treatment of patients with nonulcer pain associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). They observed that patients treated with misoprostol had a five- to ten-fold decrease in the incidence of subse-
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quent gastric ulceration. The implication is that misoprostol is the preferred agent. The development of a gastric ulcer was the primary end point of the study. The occurrence of any serious complications (for example, hemorrhage or perforation) of ulcer disease was not reported. Other observations indicated a greater percentage of patients receiving misoprostol had diarrhea (26% compared with 5%, P < 0.01). These patients may also have experienced somewhat less pain relief; 76% of patients receiving sucralfate and 68% of patients receiving misoprostol reported resolution of dyspepsia (P = 0.1). After reading the paper, I wondered which agent I would have preferred, had I been a study patient. In short, ulcers occurred more frequently in the group of patients who also had fewer symptoms. I think I would have opted for fewer symptoms, even at the cost of more signs. The patients who received misoprostol probably felt in poorer health during the course of the trial. Any additional long-term benefits that these patients might have received (for example, fewer ulcer-related complications) are only speculative, as the authors noted. As a physician, I might prefer not to worry whether patients would have these more serious gastrointestinal problems. I could easily lull myself into a (perhaps false) sense of security by assuming that fewer ulcers must mean fewer complications. The "mild or moderate 1 ' diarrhea and the perhaps slightly poorer pain relief would be prices I could find easy to pay (especially if I were not the one experiencing these symptoms). The recent proliferation of sophisticated diagnostic technology has allowed us to identify more abnormal signs. Often, however, these signs are dissociated from symptoms. Symptoms, not signs, are the things from which patients seek relief; we cannot make asymptomatic patients feel better. Clinical trials should use as end points factors that improve or worsen the quality of patients 1 lives, regardless of physicians' anxieties. From this perspective, the data of Agrawal and colleagues would suggest that sucralfate is the preferred agent. Further study using a placebo group may show that the absence of treatment would have been as effective.
Charles M. Farr, MD UCSF-Fresno Medical Education Program Fresno, CA 93720 References 1. Agrawal NM, Roth S, Graham D, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200. 2. Soil AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl J Med. 1990;322:913-4. 3. Soil AH, Kvrata J, McGuigan JE. Ulcers, nonsteroidal anti-inflammatory drugs and related matters. Gastroenterology. 1989;96:568. To the Editors: The study by Agrawal and colleagues (1) raises issues of cost and risk, which remain unanswered in clinical practice. Although aspirin may have a more important localized effect on gastric mucosa than do other NSAIDs (especially those taken in pro-drug form), enteric coated aspirin is associated with a low incidence of gastric erosion and ulceration (2). The study by Lanza and associates (3) shows a rate of erosion with enteric coated aspirin of 20% compared with 100% for plain aspirin during a 7-day period in a small-sample endoscopic study. In a study somewhat more comparable to that of Agrawal and associates, Silvoso and colleagues (4) found a 6% incidence of gastric ulcer in asymptomatic patients who received long-term therapy with enteric coated aspirin compared with 23.3% in patients who received plain aspirin. The fact that some patients enrolled in this study of aspirin were receiving one additional NSAID may have resulted in an overestimate of the rate of gastric ulcer in patients treated with enteric coated aspirin alone. No clear differences in efficacy have been shown among NSAIDs (5). Patients with osteoarthritis, as in this study, and patients with rheumatoid arthritis may respond as well to acetaminophen as to NSAIDs (5).
Ronald L. Koretz, MD Olive View Medical Center Sylmar, CA 91342
Table 1. Nonsteroidal Anti-inflammatory pared by Dosage and Cost
Reference 1. Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200.
Drug
To the Editors: In their recent article, Agrawal and colleagues (1) reported the results of a prospective, randomized, single-blind multicenter trial comparing misoprostol with sucralfate in the prevention of NSAID-induced gastric ulcer. The frequency of gastric ulcers of 0.5 cm or greater in patients receiving misoprostol was 0.8% compared with 9.2% in patients randomized to receive sucralfate. The authors conclude that misoprostol is superior to sucralfate in the prevention of gastric ulcer in patients receiving long-term NSAID therapy. What is the clinical significance of these observations? It is known that ulcers can resolve spontaneously, despite ongoing use of NSAID (2). The gastric lesions in this study were endoscopically graded by size, making it difficult to distinguish superficial erosions from ulcers that extend into the submucosa. Unfortunately, no studies have yet examined the impact of ulcer size, depth, and chronicity on clinical outcome; however, one presumes that these factors are important to the risk for ulcer complication. Whether prophylaxis with misprostol can prevent the complications of peptic ulcer compared with prophylaxis using sucralfate or an H2 antagonist remains to be determined. The data in this study add little new information to the challenging problem of NSAID-induced ulcer disease. Future studies should include end points such as rates of bleeding, perforation, and hospitalization. As pointed out by Soil and colleagues (3), clinical trials might also include a placebo arm using patients who have no recognized risk factors for NSAID-associated ulcer complications. 912
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Dosage
Cost per month $
Ibuprofen Naproxen Piroxicam Misoprostol Sucralfate Enteric aspirin Acetaminophen
600 mg four times daily 375 mg twice daily 20 mg daily 200 ^g four times daily 1 g four times daily 325 mg; 3 tablets, four times daily 500 mg; 2 tablets, four times daily
20.13 48.80 41.20 80.59 68.81 13.20 9.58
The comparative costs of several NSAIDs are listed in Table 1. Because Agrawal and colleagues did not report the doses of NSAIDs used in their study, I present the mid-range of recommended doses in the Physicians' Desk Reference. I also provide the least expensive generic dose as well as the cost of generic enteric coated aspirin at the dose recommended by Lanza and colleagues (3). Thus, the cost of the least expensive NSAID plus misoprostol is $100.32 per month, whereas the comparative cost of enteric coated aspirin is $13.20 per month, and that of acetaminophen is $9.58 per month. Until the more expensive approach is shown to be of sufficient benefit to justify its cost, it would seem reasonable to initiate therapy with enteric coated aspirin or acetaminophen and to adjust the aspirin dosage based on salicylate levels. If these less expensive regimens fail at therapeutic doses or if patients develop symptoms or signs of gastric irritation, or are at high risk for ulcer, other NSAIDs plus misoprostol may be indicated.
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Drugs Com-
Roger A. Renfrew, MD 46 South Factory Street Skowhegan, ME 04976 References 1. Agrawal NM, Roth S, Graham D, White RH, Germain B, Brown J, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200. 2. Soil AH, et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991;114:307-19. 3. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med. 1980;303:136-8. 4. Silvoso GR, Ivey KJ, Butt JH, Lockard OO, Holt SD, Sisk C, et al. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med. 1979;91:517-20. 5. Brooks PM, Day RO. Nonsteroidal anti-inflammatory drugs—differences and similarities. N Engl J Med. 1991;324:1716-25. In response: The main thrust of the comments regarding our paper (1) concerns the misunderstanding that ulcers induced by NSAIDs are trivial events. In addition, because we have not observed any serious ulcer-related complications (for example, hemorrhage and perforation), it is believed that these complications are overstated. Gastrointestinal complications associated with NSAID therapy frequently result in hospitalization. We have recently established that about one third of patients with gastrointestinal bleeding hospitalized at two major centers in New Orleans had a positive history of NSAID ingestion (2). Further, the increasing concern about the gastrointestinal toxicity of NSAIDs has prompted the Food and Drug Administration (FDA) to impose a class warning on the risks for NSAID-induced gastrointestinal damage, claiming a 2% to 4% annual incidence of serious gastrointestinal reactions (3). Complications related to NSAID use are being reported in epidemic proportions. The NSAID-induced ulcers may go undetected because patients do not frequently complain of ulcer symptoms. The response to symptoms did not differ for the two drugs in our study, and we noted a high degree of relief of dyspeptic symptoms with placebo (4). Thus, the assumption that sucralfate might be better for symptoms is incorrect. The concern about adverse reactions is overstated. The diarrhea associated with misoprostol was not as serious as believed. It was transient and disappeared spontaneously despite continued therapy with misoprostol. Few patients dropped out of the study because of this diarrhea. Further, sucralfate had not shown any efficacy in preventing NSAID-induced ulcers. The extent of ulcer incidence associated with sucralfate is similar to that obtained with placebo (5). Our study did not address the issue of prevention of complications, although such studies are now ongoing. Our study does show, however, that misoprostol is superior to other agents, if prophylaxis is considered. Worldwide experience, to date, indicates that misoprostol is the only drug that affects prevention of NSAID-induced gastric and duodenal ulcers (5). The use of any other antiulcer drugs for the prevention of NSAID-induced ulcer is not indicated. Naurang M. Agrawal, MD Tulane University School of Medicine New Orleans, LA 70112 David Y. Graham, MD Baylor Health Science Center Houston, TX 77211 References 1. Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Annals Intern Med. 1991;115:195-200. 2. Agrawal NM, Patel R, Mahatma M, Dajani EZ. Nonsteroidal antiinflammatory drugs and acute upper gastrointestinal bleeding: A prospective study. J Am Acad Min Phys. 1991;2:64-6. 3. FDC reports. Chevy Chase, Maryland. 30 November 1988. 4. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with the synthetic prostaglandin, misoprostol. A multi-
center, double-blind, placebo-controlled trial. Lancet. 1988;2:127780. 5. Graham DY, Stromatt SC, Jaszewski R, et al. Prevention of duodenal ulcer in arthritics who are chronic NSAID users: a multicenter trial of the role of misoprostol. Gastroenterology. 1991;100:A75.
Octreotide and Loss of Scalp Hair To the Editors: The use of the somatostatin analog octreotide is an established treatment in selected cases of acromegaly. Well-known side effects of octreotide are impaired glucose tolerance, development of gallstones, and diarrhea. We report diffuse loss of scalp hair as a possible new side effect, not previously described. We have treated nine patients with acromegaly (7 women, 2 men, 32 to 75 years of age). Seven patients had a poor response to previous external irradiation (46 to 50 Gy) with octreotide for 2 to 21 months. Three patients developed gallstones (ultrasound), one developed diabetes mellitus, and all had diarrhea or abdominal cramps. Four women (41 to 64 years of age), who were treated with conventional external irradiation 2 to 7 years earlier, spontaneously reported diffuse scalp hair loss 3 to 9 months after beginning octreotide treatment (100 /Ltg, 2 to 3 times daily). Extreme thinning of the hair was detected by clinical observation. Their remaining body hair was unchanged. All patients had pituitary insufficiency in differing degrees and required hormone substitution (thyroxine, 0.1 mg; cortisone, 37.5 mg daily). During octreotide treatment, all patients were euthyroid. After the octreotide treatment was withdrawn in three of the four patients, hair loss diminished. Four months later there was a complete recovery of scalp hair. The fourth patient, who continued octreotide treatment, still shows diffuse scalp hair loss. Anders Jons son, MD Per Manhem, MD University of Lund Malmo, Sweden S-214 01 Acute Doxorubicin Overdoses To the Editors: Twelve accidental acute doxorubicin overdoses (range, 3 to 10 times intended dose) have been reported to Adria Laboratories (Columbus, Ohio) since 1977. Nine patients (75%) received doxorubicin as part of a multidrug regimen. Of these, three patients were also simultaneously overdosed with other antineoplastic agents. Eight patients (67%) were given overdoses during the first administration of doxorubicin. Leukopenia or pancytopenia was universal. Mucositis, generally requiring 2 to 6 weeks for resolution, was reported in six of the seven (86%) patients who recovered, but in only one of the five (20%) patients who died. Two patients developed heart failure before death, but no other cardiac toxicities occurred in any patient. Other adverse effects included cracked nails, transient peripheral numbness, rash with desquamation, an elevated serum creatinine level, and an isolated seizure. The doxorubicin doses in the five patients who died ranged from 150 to 333 mg/m2 body surface area (3 to 10 times intended dose), and death occurred from less than 24 hours to 16 days after the overdose. One patient, who received 333 mg/m2 of doxorubicin (a 10-fold overdose), has been reported (1). The autopsy report given to the drug manufacturer showed lung edema, bilateral pleural effusions, and a strikingly pale myocardium with a markedly dilated left ventricle. A 10-fold overdose also occurred in a patient who received 230 mg/m2 (300 mg) and was treated with two 4-hour Amberlite (Rohm and Haas Co., Philadelphia, Pennsylvania) hemoperfusions. The patient recovered completely within 2 weeks. In other published clinical studies, 1.5- to 3-hour hemoperfusions have been done during and after the intra-arterial administration of up to 150 mg, or 2 mg/kg body weight, of doxorubicin (2-4). Rapid reduction in doxorubicin serum or plasma levels followed. The high protein-binding affinity of
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doxorubicin suggests that hemoperfusion is practical only if begun within minutes after an overdose. In this series, the most common cause of overdose was the misinterpretation of dosing orders when written as the total dosage divided over several days. In 5 cases (42%), this dosage was administered repeatedly. Stating the intended individual dosage and schedule rather than the total dosage to be administered should minimize the possibility of error. Charles F. Curran, PhD Adria Laboratories Columbus, OH 43216
Reducing Scutwork To the Editors: In their recent article, Hay ward and coworkers (1) define scutwork, list examples of scut cited by their residents, and note that the effect of such chores is to decrease job satisfaction among house officers. The study results suggest that both the faculty and residents feel that scutwork should be minimized, but the authors recognize that "it may prove difficult to identify persons who can do these tasks." We have been able to identify such persons and to minimize scut by appointing "health technicians" to each of the six ward teams at the McClellan Veterans Administration Hospital, a major teaching site for our house officers and medical students. Their duties are virtually identical to the examples of scutwork cited by the residents surveyed by Hayward and associates. Our health technicians had worked previously as ward clerks or nursing assistants or had been health technicians while on military service. Before assuming their duties, they underwent a 2- to 3-week period of training, during which they learned the technique of venipuncture, the methods of test and appointment scheduling, the mechanics of various hospital procedures, and the preparation of consultation requests and other forms. In addition, they served a 1-week preceptorship under the tutelage of an administrative assistant who had previously established a similar health-technician program and who continues to supervise their activities. Interviews with these persons indicate that they find their work stimulating and rewarding. They are recognized as members of the ward team by patients. House officers and medical students welcome their presence. Residents have more time for educational activities, and patient care is expedited. When one weighs the cost of providing this type of support against the effect of scutwork on housestaflf morale, patient care, and the educational role of the residency and clerkship, the balance is highly favorable. At our other teaching center, the university hospital, phlebotomy teams draw blood specimens and ward nursing staffs start intravenous infusions. At both hospitals, traditional night call has been replaced by a night-float system. Scutwork can be controlled and residency can be made a more humane and educational experience. George L. Ackerman, MD University of Arkansas for Medical Sciences Little Rock, AR 72205 1 December 1991 • Annals of Internal Medicine
Reference 1. Hayward RS, Rockwood K, Sheehan GJ, Bass EB. A phenomenology of scut. Ann Intern Med. 1991;115:372-6.
Service Versus Education in Residency
References 1. Anonymous. Inquests. The Pharmaceutical Journal. 1977;219:139. 2. Harada T, Ohmura H, Nishizawa O, Tsuchida S. Efficacy and side effects of the regional arterial infusion of anti-cancer drugs combined with direct hemoperfusion in malignancies of the urinary tract. J Urol. 1982;128:524-7. 3. Kamidono S, Fujii A, Hamami G, Nakano Y, Umezu K, Oda Y, et al. New preoperative chemotherapy for bladder cancer using combination hemodialysis and direct hemoperfusion: preliminary report. J Urol. 1984;131:36-40. 4. Kihara T, Nakazawa H, Agishi T, Honda H, Ota K. Superiority of selective bolus infusion and simultaneous rapid removal of anticancer agents by charcoal hemoperfusion in cancer treatment. Transactions of the American Society of Artificial Internal Organs. 1988;34:581-4.
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Louis L. Sanders, MD John L. McClellan Veterans Affairs Medical Center Little Rock, AR 72205
To the Editors: In their recent article, Hayward and colleagues (1) address the balance between service and clinical education in residency training by examining characteristics of "burdensome non-medical chores" (2) known as "scutwork." They successfully defined numerous procedural and clerical duties, which were viewed by residents as having little educational value and as being peripheral to their physician role. As anticipated, there were differences between faculty and residents' perceptions of scutwork, with faculty tending to underestimate scut content and to overestimate educational merit. Interestingly, for residents, the scut content of a service often depended on the clinical context and specific person requesting the task. Other physicians (2, 3) have called for the need to minimize the "educationally irrelevant" (4) workload of residents. Many have blamed rigorous night-call schedules for the stress and sleep deprivation that negatively affect resident learning skills and quality of patient care. Additionally, frequent paging during clinics, conferences, and rounds limits residents' pursuit of available educational opportunities (5). Nevertheless, making changes has not been easy. Current approaches to lessening resident scutwork include using fellows for routine overnight admissions, expanding phlebotomy and intravenous catheter services, and increasing use of nonphysician personnel such as physician assistants and extended-role nurses. For various reasons, this last approach has been slow to gain acceptance in academic medicine despite widespread use in other fields. Certainly, replacing a "cheap" labor force with salaried nonphysician personnel is a major financial deterrent. Many competitive residency programs have adopted a resident "night-float" system. This system theoretically allows for increased sleep for the on-call resident by transferring the bulk of night-time scut to a night-float intern. Despite some initial success, it is not clear whether, through the course of a residency, this method will solve or merely dilute the problem. Today in medicine there is momentum toward reducing resident work hours. Given the ever-expanding body of clinical knowledge, residency program directors should restructure the clinical training to relieve residents of time-consuming, noneducational activities. This change should be pursued aggressively and collectively to ensure both the quality and number of internists through the next decade. Providing high-quality patient care and meeting health care needs of the future may be at stake. Jon S. Du Bois, MD New England Medical Center Hospitals Boston, MA 02111 References 1. Hayward RS, Rockwood K, Sheehan GJ, Bass EB. A phenomenology of scut. Ann Intern Med. 1991;115:372-6. 2. Association of Program Directors in Internal Medicine. Response to the New York State Advisory Committee on Emergency Services: Position Paper. Washington, D.C.: Association of Program Directors in Internal Medicine; 1987. 3. Wallice EZ. Service vs education in internal medicine residency: need for a solution. Arch Intern Med. 1988; 148:1296. 4. Squires BP. Fatigue and stress in medical students, interns and residents: it's time to act. Can Med Assoc J. 1989;140:18-9. 5. Katz MH, Schroeder SA. The sounds of the hospital: paging patterns in three teaching hospitals. N Engl J Med. 1988;319:1585-9.
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The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send with the letter a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified only if their letter is accepted. Unpublished letters cannot be returned.
in a previous study (2), no beneficial effect of aminophylline as compared with placebo in relieving bronchospasm in patients already receiving other standard bronchodilator therapy was found. The decision on hospital admission, therefore, lies entirely with the house officer assigned to the emergency room. Although the authors have given preexisting guidelines for admission established for the emergency department, they did not discuss how these guidelines were adhered to by the house officer or what constitutes "independent clinical assessment." Although the study was double-blinded at the investigators' level, the house officers might have had knowledge of certain factors (that is, theophylline level) other than those presented in the report (3). This knowledge could play a major role in changing the rate of hospital admission. In short, it is hard to believe there was a threefold difference in the hospital admission rate, given the same objective and subjective findings for the aminophylline-treated group and the placebo group.
Aminophylline in the Emergency Department To the Editors: Wrenn and colleagues (1) are to be congratulated for their important contribution to the emergency management of bronchospasm. Further study of aminophylline's clinical action, however, is necessary before changing emergency-room practice. How aminophylline prevents admissions is mysterious, because the drug decreases neither the severity of bronchospasm nor its symptoms (2). Subdividing exacerbations into "infectious, inflammatory, or allergic" categories, as the authors suggest, might identify predictors of admission and help explain the drug's mechanism. The authors should consider measuring pulmonary function through the patient's emergency-room stay. Although improvement appears to level off after 2 hours, substantial airway obstruction remains. Additional gains in peak flow may well occur by the average of 4 hours later when admission decisions are made. Repeat measurements might show that aminophylline continues to decrease bronchospasm. Because Grady Memorial Hospital's emergency department uses discrete criteria for admission (recent relapse, failure to clear, failure to reach pre-exacerbation status, respiratory failure, or the inability to walk 100 feet), simply asking house officers why they admitted their patients may show how aminophylline provided benefit or, at least, may guide further study. Mark D. Siegel, MD Pennsylvania Hospital Philadelphia, PA 19107 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. McFadden ER Jr. Methylxanthines in the treatment of asthma: the rise, the fall, and the possible rise again. Ann Intern Med. 1991 ;115: 323-4. To the Editors: Wrenn and colleagues (1) recently reported the beneficial role of aminophylline therapy in reducing the rate of hospital admission in a randomized, double-blind, placebo-controlled intervention study. The authors showed a threefold decrease in the hospital admission rate for the aminophylline-treated group as compared with the placebo group. Despite no difference in objective (as measured by spirometry) or subjective (as estimated by patient satisfaction) findings, as 910
Thanh Nguyen-Dinh, MD Howard University Medical Service D.C. General Hospital Washington, DC 20003 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Siegel D, Sheppard D, Galb A, Weinberg PF. Aminophylline increases the toxicity but not the efficiency of an inhaled beta-adrenergic agonist in the treatment of acute exacerbation of asthma. Am Rev Respir Dis. 1985;132:283-6. 3. McFadden ER Jr. Methylxanthines in the treatment of asthma: The rise, the falls, and the possible rise again. Ann Intern Med. 1991; 115:323-4. To the Editors: Wrenn and colleagues (1) propose that the use of aminophylline for patients with acute exacerbations of bronchospastic disease in the emergency department setting may be justified because the drug reduces the hospital admission rate for these patients. The lack of concordance between hospital admission rates and any other index of improvement is worrisome. To support their findings, the authors cite a previous study of methylprednisolone in the emergency-room treatment of acute asthma (2). This study, however, did show a clinically important trend with respect to the difference between treatment groups of forced expiratory volume in 1 second (P = 0.068), forced vital capacity (P = 0.076), subjective symptom score (P = 0.026), and hospital admission rate (P = 0.003); the latter finding remained statistically significant after applying the Bonferroni correction. An isolated finding of decreased hospitalizations without physiologic or subjective improvement suggests a spurious statistical result. We are concerned that the single significant P value reported by Wrenn and colleagues (1) may be an artifact of multiple comparisons (3). The authors used statistical tests to determine the effect of aminophylline therapy on three spirometric variables, five side effects, patient satisfaction, patient improvement, duration of therapy, and admission status. Of these twelve variables, only one reached conventional levels of statistical significance. Applying the Bonferroni method, we find that the corrected threshold of statistical significance for hospital admission is 0.05/12 = 0.0042, not 0.0125, as reported by Wrenn and colleagues (1). Although the Bonferroni method is regarded as
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overly conservative by some, the P value of 0.016 reported for hospital admission exceeds the corrected threshold for statistical significance by almost fourfold. Overall, we commend the authors for attempting to resolve an important clinical controversy. Like the authors, we are also "unable to explain why treatment with aminophylline seems to have a measurable clinical effect in the absence of an objective improvement in pulmonary function as measured by spirometry." Based on this study's results, it is premature to recommend aminophylline for the emergency-room treatment of all patients with acute bronchospastic disease. David A. Katz, MD Veterans Affairs Medical Center White River Junction, VT 05001 Benjamin Littenberg, MD Dartmouth-Hitchcock Medical Center Hanover, NH 03756 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2. 3. Cupples LA, Heeren T, Schatzkin A, Colton T. Multiple testing of hypotheses in comparing two groups. Ann Intern Med. 1984; 100: 122-9. To the Editors: Wrenn and colleagues (1) should be commended on their recent randomized trial of intravenous aminophylline in the emergency-room treatment of acute bronchospasm. In the face of recent reports suggesting methylxanthine's lack of efficacy in the treatment of asthma, it is provocative to see opposing evidence further kindle the debate (2). Unfortunately, we are not yet willing to accept methylxanthine as a proven beneficial therapy for the emergencyroom treatment of acute bronchospasm until these data are confirmed by trials with longer follow-up. At our institution we not uncommonly see patients recently treated for acute bronchospasm in an emergency room who present several days later requiring retreatment. The authors state that follow-up data on their patients were obtained by examination of 4tbilling records." These records showed that only three patients returned within 72 hours of treatment, one in the aminophylline-treated group and two in the placebo group. However, hospital billing records would not include any patient who reported to another institution or a physician's office for retreatment. Wrenn and colleagues (1) are not alone. A similar study focusing on the use of methylprednisolone in acute asthma shares this methodologic flaw (3). Although more vigorous attempts were made to contact study participants, follow-up data were obtained for only 58% of participants. This level of follow-up is well below accepted standards for examining the clinical course of a disease (4). Studies on the emergency-room treatment of acute bronchospasm cannot be considered definitive until adequate follow-up data are analyzed and the whole story is known. Tim Richardson, MD Franz Fisher, MD Daniel Castro, MD Jerry L. Pettis Memorial Veterans Affairs Medical Center Loma Linda, CA 92357 References 1. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-7. 2. Littenberg B. Aminophylline treatment in severe, acute asthma: A meta-analysis. JAMA. 1988;259:1678-84. 3. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2. 4. Department of Clinical Epidemiology and Biostatistics, McMaster Uni-
versity Health Sciences Center. How to read clinical journals: III. To learn the clinical course and prognosis of disease. Can Med Assoc J. 1981;124:869-72. In response: Dr. Siegel's suggestions seem appropriate and should be included in any future study of the question of aminophylline's efficacy. Dr. Nguyen-Dinh would have us better define what constitutes clinical assessment. We cannot. He raises the question of house-officer bias. We sincerely doubt that knowledge of theophylline levels influenced the house officers in their decision to admit patients because, at the time of the study, we were teaching the house officers that there was no evidence to suggest aminophylline had any use in the care of patients with bronchospasm in the emergency department. Drs. Katz and Littenberg would have us use a P value of 0.0042 as the threshold of significance. This value strikes us as unrealistic. No well-designed, randomized, double-blind, placebo-controlled clinical trial includes less than 5 to 15 variables. Littenberg and Gluck (1), in their study on the use of methylprednisolone, did not apply the Bonferroni correction despite having studied at least 13 variables, including admission rate, FEV,, FVC, subjective symptom score, follow-up care, early readmission, whether patients required endotracheal intubation or mechanical ventilation, time in the clinic, the use of three other agents, and side effects. If they looked for only four side effects, then the statistical significance of all their results would be in question according to the Bonferroni rule (P < 0.003 required to significance). In fact, they claim statistical significance for a difference in the subjective symptom score at P = 0.026 (1). We feel the Bonferroni correction does not apply to a prospective trial such as ours because it is used primarily to avoid "data dredging," which may occur in retrospective studies. To apply the correction, as Katz and Littenberg suggest, would routinely lower the P value for statistical significance to unrealistic levels. Finally, it is inappropriate to group all the variables they list as outcome variables. As to the questions raised by Richardson and colleagues, our study focussed on the short-term response. Ours is the only inner city hospital serving an indigent population, and the emergency department is the asthma treatment center. Thus, billing records probably are a good surrogate for follow-up. We agree, however, about the need for well-developed long-term follow-up studies of asthma treatment. We stand by our discussion as written. We were surprised by the statistically and, more important, clinically significant reduction in the admission rate of patients receiving aminophylline. We look forward to a large multicenter trial to test this agent's efficacy in the emergency department. We do not advocate the use of theophylline compounds as first-line agents in the emergency department, but feel, based on our data, that there may be some use for aminophylline in certain settings (for example, a lack of inpatient hospital beds) or situations (for example, failure to clear quickly with /3-agonist, steroids, and anticholinergic agents). In the final analysis, each physician must decide about the use of a drug in each situation. Keith D. Wrenn, MD Corey M. Slovis, MD University of Rochester Medical Center Rochester, NY 14642 Reference 1. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314: 150-2.
Prevention of NSAID-induced Gastric Ulcer To the Editors: Agrawal and coworkers (1) described a prospective, randomized controlled trial comparing sucralfate and misoprostol in the treatment of patients with nonulcer pain associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). They observed that patients treated with misoprostol had a five- to ten-fold decrease in the incidence of subse-
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quent gastric ulceration. The implication is that misoprostol is the preferred agent. The development of a gastric ulcer was the primary end point of the study. The occurrence of any serious complications (for example, hemorrhage or perforation) of ulcer disease was not reported. Other observations indicated a greater percentage of patients receiving misoprostol had diarrhea (26% compared with 5%, P < 0.01). These patients may also have experienced somewhat less pain relief; 76% of patients receiving sucralfate and 68% of patients receiving misoprostol reported resolution of dyspepsia (P = 0.1). After reading the paper, I wondered which agent I would have preferred, had I been a study patient. In short, ulcers occurred more frequently in the group of patients who also had fewer symptoms. I think I would have opted for fewer symptoms, even at the cost of more signs. The patients who received misoprostol probably felt in poorer health during the course of the trial. Any additional long-term benefits that these patients might have received (for example, fewer ulcer-related complications) are only speculative, as the authors noted. As a physician, I might prefer not to worry whether patients would have these more serious gastrointestinal problems. I could easily lull myself into a (perhaps false) sense of security by assuming that fewer ulcers must mean fewer complications. The "mild or moderate 1 ' diarrhea and the perhaps slightly poorer pain relief would be prices I could find easy to pay (especially if I were not the one experiencing these symptoms). The recent proliferation of sophisticated diagnostic technology has allowed us to identify more abnormal signs. Often, however, these signs are dissociated from symptoms. Symptoms, not signs, are the things from which patients seek relief; we cannot make asymptomatic patients feel better. Clinical trials should use as end points factors that improve or worsen the quality of patients 1 lives, regardless of physicians' anxieties. From this perspective, the data of Agrawal and colleagues would suggest that sucralfate is the preferred agent. Further study using a placebo group may show that the absence of treatment would have been as effective.
Charles M. Farr, MD UCSF-Fresno Medical Education Program Fresno, CA 93720 References 1. Agrawal NM, Roth S, Graham D, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200. 2. Soil AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl J Med. 1990;322:913-4. 3. Soil AH, Kvrata J, McGuigan JE. Ulcers, nonsteroidal anti-inflammatory drugs and related matters. Gastroenterology. 1989;96:568. To the Editors: The study by Agrawal and colleagues (1) raises issues of cost and risk, which remain unanswered in clinical practice. Although aspirin may have a more important localized effect on gastric mucosa than do other NSAIDs (especially those taken in pro-drug form), enteric coated aspirin is associated with a low incidence of gastric erosion and ulceration (2). The study by Lanza and associates (3) shows a rate of erosion with enteric coated aspirin of 20% compared with 100% for plain aspirin during a 7-day period in a small-sample endoscopic study. In a study somewhat more comparable to that of Agrawal and associates, Silvoso and colleagues (4) found a 6% incidence of gastric ulcer in asymptomatic patients who received long-term therapy with enteric coated aspirin compared with 23.3% in patients who received plain aspirin. The fact that some patients enrolled in this study of aspirin were receiving one additional NSAID may have resulted in an overestimate of the rate of gastric ulcer in patients treated with enteric coated aspirin alone. No clear differences in efficacy have been shown among NSAIDs (5). Patients with osteoarthritis, as in this study, and patients with rheumatoid arthritis may respond as well to acetaminophen as to NSAIDs (5).
Ronald L. Koretz, MD Olive View Medical Center Sylmar, CA 91342
Table 1. Nonsteroidal Anti-inflammatory pared by Dosage and Cost
Reference 1. Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200.
Drug
To the Editors: In their recent article, Agrawal and colleagues (1) reported the results of a prospective, randomized, single-blind multicenter trial comparing misoprostol with sucralfate in the prevention of NSAID-induced gastric ulcer. The frequency of gastric ulcers of 0.5 cm or greater in patients receiving misoprostol was 0.8% compared with 9.2% in patients randomized to receive sucralfate. The authors conclude that misoprostol is superior to sucralfate in the prevention of gastric ulcer in patients receiving long-term NSAID therapy. What is the clinical significance of these observations? It is known that ulcers can resolve spontaneously, despite ongoing use of NSAID (2). The gastric lesions in this study were endoscopically graded by size, making it difficult to distinguish superficial erosions from ulcers that extend into the submucosa. Unfortunately, no studies have yet examined the impact of ulcer size, depth, and chronicity on clinical outcome; however, one presumes that these factors are important to the risk for ulcer complication. Whether prophylaxis with misprostol can prevent the complications of peptic ulcer compared with prophylaxis using sucralfate or an H2 antagonist remains to be determined. The data in this study add little new information to the challenging problem of NSAID-induced ulcer disease. Future studies should include end points such as rates of bleeding, perforation, and hospitalization. As pointed out by Soil and colleagues (3), clinical trials might also include a placebo arm using patients who have no recognized risk factors for NSAID-associated ulcer complications. 912
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Dosage
Cost per month $
Ibuprofen Naproxen Piroxicam Misoprostol Sucralfate Enteric aspirin Acetaminophen
600 mg four times daily 375 mg twice daily 20 mg daily 200 ^g four times daily 1 g four times daily 325 mg; 3 tablets, four times daily 500 mg; 2 tablets, four times daily
20.13 48.80 41.20 80.59 68.81 13.20 9.58
The comparative costs of several NSAIDs are listed in Table 1. Because Agrawal and colleagues did not report the doses of NSAIDs used in their study, I present the mid-range of recommended doses in the Physicians' Desk Reference. I also provide the least expensive generic dose as well as the cost of generic enteric coated aspirin at the dose recommended by Lanza and colleagues (3). Thus, the cost of the least expensive NSAID plus misoprostol is $100.32 per month, whereas the comparative cost of enteric coated aspirin is $13.20 per month, and that of acetaminophen is $9.58 per month. Until the more expensive approach is shown to be of sufficient benefit to justify its cost, it would seem reasonable to initiate therapy with enteric coated aspirin or acetaminophen and to adjust the aspirin dosage based on salicylate levels. If these less expensive regimens fail at therapeutic doses or if patients develop symptoms or signs of gastric irritation, or are at high risk for ulcer, other NSAIDs plus misoprostol may be indicated.
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Drugs Com-
Roger A. Renfrew, MD 46 South Factory Street Skowhegan, ME 04976 References 1. Agrawal NM, Roth S, Graham D, White RH, Germain B, Brown J, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Ann Intern Med. 1991;115:195-200. 2. Soil AH, et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991;114:307-19. 3. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med. 1980;303:136-8. 4. Silvoso GR, Ivey KJ, Butt JH, Lockard OO, Holt SD, Sisk C, et al. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med. 1979;91:517-20. 5. Brooks PM, Day RO. Nonsteroidal anti-inflammatory drugs—differences and similarities. N Engl J Med. 1991;324:1716-25. In response: The main thrust of the comments regarding our paper (1) concerns the misunderstanding that ulcers induced by NSAIDs are trivial events. In addition, because we have not observed any serious ulcer-related complications (for example, hemorrhage and perforation), it is believed that these complications are overstated. Gastrointestinal complications associated with NSAID therapy frequently result in hospitalization. We have recently established that about one third of patients with gastrointestinal bleeding hospitalized at two major centers in New Orleans had a positive history of NSAID ingestion (2). Further, the increasing concern about the gastrointestinal toxicity of NSAIDs has prompted the Food and Drug Administration (FDA) to impose a class warning on the risks for NSAID-induced gastrointestinal damage, claiming a 2% to 4% annual incidence of serious gastrointestinal reactions (3). Complications related to NSAID use are being reported in epidemic proportions. The NSAID-induced ulcers may go undetected because patients do not frequently complain of ulcer symptoms. The response to symptoms did not differ for the two drugs in our study, and we noted a high degree of relief of dyspeptic symptoms with placebo (4). Thus, the assumption that sucralfate might be better for symptoms is incorrect. The concern about adverse reactions is overstated. The diarrhea associated with misoprostol was not as serious as believed. It was transient and disappeared spontaneously despite continued therapy with misoprostol. Few patients dropped out of the study because of this diarrhea. Further, sucralfate had not shown any efficacy in preventing NSAID-induced ulcers. The extent of ulcer incidence associated with sucralfate is similar to that obtained with placebo (5). Our study did not address the issue of prevention of complications, although such studies are now ongoing. Our study does show, however, that misoprostol is superior to other agents, if prophylaxis is considered. Worldwide experience, to date, indicates that misoprostol is the only drug that affects prevention of NSAID-induced gastric and duodenal ulcers (5). The use of any other antiulcer drugs for the prevention of NSAID-induced ulcer is not indicated. Naurang M. Agrawal, MD Tulane University School of Medicine New Orleans, LA 70112 David Y. Graham, MD Baylor Health Science Center Houston, TX 77211 References 1. Agrawal NM, Roth S, Graham DY, White RH, Germain B, Brown JA, et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized controlled trial. Annals Intern Med. 1991;115:195-200. 2. Agrawal NM, Patel R, Mahatma M, Dajani EZ. Nonsteroidal antiinflammatory drugs and acute upper gastrointestinal bleeding: A prospective study. J Am Acad Min Phys. 1991;2:64-6. 3. FDC reports. Chevy Chase, Maryland. 30 November 1988. 4. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with the synthetic prostaglandin, misoprostol. A multi-
center, double-blind, placebo-controlled trial. Lancet. 1988;2:127780. 5. Graham DY, Stromatt SC, Jaszewski R, et al. Prevention of duodenal ulcer in arthritics who are chronic NSAID users: a multicenter trial of the role of misoprostol. Gastroenterology. 1991;100:A75.
Octreotide and Loss of Scalp Hair To the Editors: The use of the somatostatin analog octreotide is an established treatment in selected cases of acromegaly. Well-known side effects of octreotide are impaired glucose tolerance, development of gallstones, and diarrhea. We report diffuse loss of scalp hair as a possible new side effect, not previously described. We have treated nine patients with acromegaly (7 women, 2 men, 32 to 75 years of age). Seven patients had a poor response to previous external irradiation (46 to 50 Gy) with octreotide for 2 to 21 months. Three patients developed gallstones (ultrasound), one developed diabetes mellitus, and all had diarrhea or abdominal cramps. Four women (41 to 64 years of age), who were treated with conventional external irradiation 2 to 7 years earlier, spontaneously reported diffuse scalp hair loss 3 to 9 months after beginning octreotide treatment (100 /Ltg, 2 to 3 times daily). Extreme thinning of the hair was detected by clinical observation. Their remaining body hair was unchanged. All patients had pituitary insufficiency in differing degrees and required hormone substitution (thyroxine, 0.1 mg; cortisone, 37.5 mg daily). During octreotide treatment, all patients were euthyroid. After the octreotide treatment was withdrawn in three of the four patients, hair loss diminished. Four months later there was a complete recovery of scalp hair. The fourth patient, who continued octreotide treatment, still shows diffuse scalp hair loss. Anders Jons son, MD Per Manhem, MD University of Lund Malmo, Sweden S-214 01 Acute Doxorubicin Overdoses To the Editors: Twelve accidental acute doxorubicin overdoses (range, 3 to 10 times intended dose) have been reported to Adria Laboratories (Columbus, Ohio) since 1977. Nine patients (75%) received doxorubicin as part of a multidrug regimen. Of these, three patients were also simultaneously overdosed with other antineoplastic agents. Eight patients (67%) were given overdoses during the first administration of doxorubicin. Leukopenia or pancytopenia was universal. Mucositis, generally requiring 2 to 6 weeks for resolution, was reported in six of the seven (86%) patients who recovered, but in only one of the five (20%) patients who died. Two patients developed heart failure before death, but no other cardiac toxicities occurred in any patient. Other adverse effects included cracked nails, transient peripheral numbness, rash with desquamation, an elevated serum creatinine level, and an isolated seizure. The doxorubicin doses in the five patients who died ranged from 150 to 333 mg/m2 body surface area (3 to 10 times intended dose), and death occurred from less than 24 hours to 16 days after the overdose. One patient, who received 333 mg/m2 of doxorubicin (a 10-fold overdose), has been reported (1). The autopsy report given to the drug manufacturer showed lung edema, bilateral pleural effusions, and a strikingly pale myocardium with a markedly dilated left ventricle. A 10-fold overdose also occurred in a patient who received 230 mg/m2 (300 mg) and was treated with two 4-hour Amberlite (Rohm and Haas Co., Philadelphia, Pennsylvania) hemoperfusions. The patient recovered completely within 2 weeks. In other published clinical studies, 1.5- to 3-hour hemoperfusions have been done during and after the intra-arterial administration of up to 150 mg, or 2 mg/kg body weight, of doxorubicin (2-4). Rapid reduction in doxorubicin serum or plasma levels followed. The high protein-binding affinity of
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doxorubicin suggests that hemoperfusion is practical only if begun within minutes after an overdose. In this series, the most common cause of overdose was the misinterpretation of dosing orders when written as the total dosage divided over several days. In 5 cases (42%), this dosage was administered repeatedly. Stating the intended individual dosage and schedule rather than the total dosage to be administered should minimize the possibility of error. Charles F. Curran, PhD Adria Laboratories Columbus, OH 43216
Reducing Scutwork To the Editors: In their recent article, Hay ward and coworkers (1) define scutwork, list examples of scut cited by their residents, and note that the effect of such chores is to decrease job satisfaction among house officers. The study results suggest that both the faculty and residents feel that scutwork should be minimized, but the authors recognize that "it may prove difficult to identify persons who can do these tasks." We have been able to identify such persons and to minimize scut by appointing "health technicians" to each of the six ward teams at the McClellan Veterans Administration Hospital, a major teaching site for our house officers and medical students. Their duties are virtually identical to the examples of scutwork cited by the residents surveyed by Hayward and associates. Our health technicians had worked previously as ward clerks or nursing assistants or had been health technicians while on military service. Before assuming their duties, they underwent a 2- to 3-week period of training, during which they learned the technique of venipuncture, the methods of test and appointment scheduling, the mechanics of various hospital procedures, and the preparation of consultation requests and other forms. In addition, they served a 1-week preceptorship under the tutelage of an administrative assistant who had previously established a similar health-technician program and who continues to supervise their activities. Interviews with these persons indicate that they find their work stimulating and rewarding. They are recognized as members of the ward team by patients. House officers and medical students welcome their presence. Residents have more time for educational activities, and patient care is expedited. When one weighs the cost of providing this type of support against the effect of scutwork on housestaflf morale, patient care, and the educational role of the residency and clerkship, the balance is highly favorable. At our other teaching center, the university hospital, phlebotomy teams draw blood specimens and ward nursing staffs start intravenous infusions. At both hospitals, traditional night call has been replaced by a night-float system. Scutwork can be controlled and residency can be made a more humane and educational experience. George L. Ackerman, MD University of Arkansas for Medical Sciences Little Rock, AR 72205 1 December 1991 • Annals of Internal Medicine
Reference 1. Hayward RS, Rockwood K, Sheehan GJ, Bass EB. A phenomenology of scut. Ann Intern Med. 1991;115:372-6.
Service Versus Education in Residency
References 1. Anonymous. Inquests. The Pharmaceutical Journal. 1977;219:139. 2. Harada T, Ohmura H, Nishizawa O, Tsuchida S. Efficacy and side effects of the regional arterial infusion of anti-cancer drugs combined with direct hemoperfusion in malignancies of the urinary tract. J Urol. 1982;128:524-7. 3. Kamidono S, Fujii A, Hamami G, Nakano Y, Umezu K, Oda Y, et al. New preoperative chemotherapy for bladder cancer using combination hemodialysis and direct hemoperfusion: preliminary report. J Urol. 1984;131:36-40. 4. Kihara T, Nakazawa H, Agishi T, Honda H, Ota K. Superiority of selective bolus infusion and simultaneous rapid removal of anticancer agents by charcoal hemoperfusion in cancer treatment. Transactions of the American Society of Artificial Internal Organs. 1988;34:581-4.
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Louis L. Sanders, MD John L. McClellan Veterans Affairs Medical Center Little Rock, AR 72205
To the Editors: In their recent article, Hayward and colleagues (1) address the balance between service and clinical education in residency training by examining characteristics of "burdensome non-medical chores" (2) known as "scutwork." They successfully defined numerous procedural and clerical duties, which were viewed by residents as having little educational value and as being peripheral to their physician role. As anticipated, there were differences between faculty and residents' perceptions of scutwork, with faculty tending to underestimate scut content and to overestimate educational merit. Interestingly, for residents, the scut content of a service often depended on the clinical context and specific person requesting the task. Other physicians (2, 3) have called for the need to minimize the "educationally irrelevant" (4) workload of residents. Many have blamed rigorous night-call schedules for the stress and sleep deprivation that negatively affect resident learning skills and quality of patient care. Additionally, frequent paging during clinics, conferences, and rounds limits residents' pursuit of available educational opportunities (5). Nevertheless, making changes has not been easy. Current approaches to lessening resident scutwork include using fellows for routine overnight admissions, expanding phlebotomy and intravenous catheter services, and increasing use of nonphysician personnel such as physician assistants and extended-role nurses. For various reasons, this last approach has been slow to gain acceptance in academic medicine despite widespread use in other fields. Certainly, replacing a "cheap" labor force with salaried nonphysician personnel is a major financial deterrent. Many competitive residency programs have adopted a resident "night-float" system. This system theoretically allows for increased sleep for the on-call resident by transferring the bulk of night-time scut to a night-float intern. Despite some initial success, it is not clear whether, through the course of a residency, this method will solve or merely dilute the problem. Today in medicine there is momentum toward reducing resident work hours. Given the ever-expanding body of clinical knowledge, residency program directors should restructure the clinical training to relieve residents of time-consuming, noneducational activities. This change should be pursued aggressively and collectively to ensure both the quality and number of internists through the next decade. Providing high-quality patient care and meeting health care needs of the future may be at stake. Jon S. Du Bois, MD New England Medical Center Hospitals Boston, MA 02111 References 1. Hayward RS, Rockwood K, Sheehan GJ, Bass EB. A phenomenology of scut. Ann Intern Med. 1991;115:372-6. 2. Association of Program Directors in Internal Medicine. Response to the New York State Advisory Committee on Emergency Services: Position Paper. Washington, D.C.: Association of Program Directors in Internal Medicine; 1987. 3. Wallice EZ. Service vs education in internal medicine residency: need for a solution. Arch Intern Med. 1988; 148:1296. 4. Squires BP. Fatigue and stress in medical students, interns and residents: it's time to act. Can Med Assoc J. 1989;140:18-9. 5. Katz MH, Schroeder SA. The sounds of the hospital: paging patterns in three teaching hospitals. N Engl J Med. 1988;319:1585-9.
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