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 Unpublished letters cannot be returned.

Reversible Renal Insufficiency and AngiotensinConverting Enzyme Inhibitor Therapy To the Editors: Toto and colleagues (1) reported a relatively high incidence of reversible renal insufficiency (19%) in patients with hypertensive nephrosclerosis and chronic renal insufficiency treated with enalapril and "conventional" antihypertensive agents. Renal insufficiency was associated only with a significant decrease in blood pressure and did not occur in patients treated with only "conventional" antihypertensive agents. This observation makes sense physiologically and, if confirmed, will make an important contribution to the literature. A major point of contention is the investigators' proposal that enalapril may cause reversible renal insufficiency in patients with chronic renal parenchymal disease but without renal artery stenosis. We do not believe that the investigators definitively excluded renal artery stenosis. To exclude this condition, they used noninvasive duplex scanning of the renal arteries in five patients and renal arteriography in only three patients; yet, arteriography remains the gold standard for diagnosis of renal artery stenosis (2, 3). Duplex scanning is extremely difficult technically and has a long learning curve. In the best hands, it correlates with arteriography only 93% of the time, and 12% of patients studied cannot be adequately evaluated because of excess bowel gas or obesity (4). The main renal arteries are easier to visualize, but polar renal arteries (which may occur in up to 20% of the general population) are difficult to visualize. At best, duplex ultrasound of the renal arteries can only be considered a screening test for renal artery stenosis. To describe a newly recognized phenomenon (such as renal insufficiency secondary to treatment with angiotensinconverting enzyme inhibitors in patients without renal artery stenosis, the investigators must definitely rule out renal artery stenosis, even though all patients who developed reversible renal insufficiency were black and such stenosis is rare in blacks (5). The status of the renal arteries in the three patients who developed end-stage renal disease and in the patient who had accelerated hypertension would be of interest. The overall proportion of black patients in their study population also would be of interest. Black patients may be more prone than white patients to enalapril-associated reversible renal insufficiency just as they are to end-stage renal disease associated with hypertensive nephrosclerosis. Such an observation would have obvious important practical implications.

James J. Glazier, MD Jeffrey W. Olin, DO The Cleveland Clinic Foundation Cleveland, OH References 1. Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA. Reversible renal insufficiency due to angiotensin-converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med. 1991;115:513-9. 2. Working Group on Renovascular Hypertension. Detection, evaluation, and treatment of renovascular hypertension. Arch Intern Med. 1987;147:820-9. 3. Olin JW, Novick AC. Renovascular disease. In: Young JR, Graor RA, Olin JW, Bartholomew JR, eds. Peripheral Vascular Diseases. St. Louis: Mosby Year Book; 1991:267-84. 4. Taylor DC, Kettler MD, Moneta GL, et al. Duplex ultrasound scanning in the diagnosis of renal artery stenosis: a prospective evaluation. J Vase Surg. 1988;7:363-9. 5. Keith TA. Renovascular hypertension in black patients. Hypertension. 1982;4:438-43.

To the Editors: All eight patients who developed renal insufficiency in the study by Toto and colleagues (1) were black, had long-standing moderate-to-severe hypertension, were receiving diuretics, and had blood pressures measured in the supine position. The investigators noted a positive correlation of renal insufficiency with relative hypotension. The patients may have been saved from their reversible state of renal insufficiency by the simple expedient of measuring blood pressure in the standing position. Had an unusual orthostatic hypotensive component been found, the drug may have been withdrawn or the dose reduced, and the renal failure would never have occurred. Baruch Hurwich, MD Shaare Zedek Medical Center 91-031 Jerusalem, Israel Reference 1. Toto RD, Mitchell HC, Lee H-C, Milam C, Pettinger WA. Reversible renal insufficiency due to angiotensin-converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med. 1991;115:513-9.

In response: Renal arteriograms were obtained for two patients who developed severe renal insufficiency while taking enalapril (case 1, maximum creatinine, 1193 /xmol/L, and change in creatinine, -1-911 /xmol/L; case 3, maximum creatinine, 1158 /xmol/L, and change in creatinine, -I- 1017 /xmol/L) and for one patient who developed intermediate renal insufficiency (case 2, maximum creatinine, 583 /xmol/L, and change in creatinine, -I- 371 /xmol/L). These technically adequate studies showed entirely normal renal arteries. The remaining five patients had mild to intermediate renal insufficiency (case 4, maximum creatinine, 592 /xmol/L, and change in creatinine, 1239 /xmol/L; case 6, maximum creatinine, 239 /xmol/L, and change in creatinine, -I- 106 /xmol/L; case 7, maximum creatinine, 336 /xmol/L, and change in creatinine, + 97 /xmol/L; case 8, maximum creatinine, 345 /xmol/L, and change in creatinine, + 106 /xmol/L). Because of our growing familiarity with the syndrome, we thought that renal arteriography was not necessary or indicated and substituted noninvasive duplex scanning for detecting renal artery stenosis. All patients had technically excellent duplex studies performed by our senior technician. Eidt and colleagues (2)

15 April 1992 • Annals of Internal Medicine

Downloaded from https://annals.org by Tulane University user on 01/23/2019

• Volume 116 • Number 8

697

Table 1. Supine and Sta nding Blood Presisure Levels with Maximum Renal Insuffi ciency Patient

Supine at 5 Minutes*

Standing at 2 Minutes*

mm Hg 1 2 3 4 5 6 7 8

61/44 121/51 102/79 122/62 91/50 101/70 106/67 119/77

Serum Creatinine Level /xmol/L

61/44 122/88 101/80 129/68 109/61 107/75 116/79 73/62

1158 583 1193 575 380 239 336 327

* Data are the averages of three readings.

from our center have reported data comparing renal arteriography to duplex ultrasound scanning of the renal arteries in the diagnosis of renal artery stenosis. The overall diagnostic accuracy was 86% (sensitivity, 80%; specificity, 87%) in 49 patients with technically satisfactory duplex scans. We agree with Drs. Glazier and Olin that renal arteriography is the gold standard for the diagnosis of renal artery stenosis. However, based on our clinical findings, the high sensitivity and specificity in diagnosing renal vascular hypertension by duplex scanning in our center, the high risk for contrast medium-induced renal insufficiency in our patients, and the absence of recurrence of renal insufficiency after restarting therapy with the angiotensin-converting enzyme inhibitor, we believe that our conclusions are warranted. In our study, 89% of the patients were black. Blood pressure was taken in the standing position each time it was taken in the supine position. It was not reported in table 2 of our paper (4) for lack of space and because it was not revealing. A brief comparison of supine and standing pressures at maximum renal insufficiency in our patients is shown in Table 1. Only patient 8 (see Table 1) had impressive evidence of an orthostatic component. In patients 5 and 7, the standing pressure was considerably higher than the supine pressure. A drop in diastolic pressure may be noted at the time of renal insufficiency but is not always present. Robert D. Toto, MD Southwestern Medical Center Dallas, TX 75235-9030 References 1. Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA. Reversible renal insufficiency due to angiotensin-converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med. 1991;115:513-8. 2. Eidt JF, Fry RE, Clagett GP, Fisher DF, Alway C, Fry WJ. Postoperative follow-up of renal artery reconstruction with duplex ultrasound. J Vase Surg. 1988;8:667-73.

Studies within Studies To the Editors: Drs. Toto and colleagues (1) recently described eight patients who had reversible renal insufficiency that was attributed to the use of an angiotensin-converting enzyme inhibitor. They noted that these eight patients were identified during a randomized trial, which was annotated as their reference 9 (2). They further noted that three of the eight cases had been partially reported in their reference 10 (3). They described the randomized trial: seventy-three patients were treated with various antihypertensive agents and were randomized to receive an angiotensin-converting inhibitor or a placebo. Reference 9, however, appears to report a different randomized trial. In that study, patients were randomized to one of two groups. One was treated intensively to maintain a diastolic blood pressure of less than 80 mm Hg, and the other was treated to maintain a diastolic pressure of 90 to 95 mm Hg. Reference 9 makes no note of randomization to either an angiotensin-converting enzyme inhibitor or placebo. 698

15 April 1992 • Annals of Internal Medicine

Reference 9 reports the cases of the first 22 patients (of 79 patients; whether the trial was stopped at that time or not is unclear. Reference 10 notes that 5 patients (of 77 patients) developed manifestations of what the investigators termed "pseudo renal artery stenosis syndrome." Apparently four of these five patients were given the angiotensin-converting enzyme inhibitor. My confusion relates to the study design. Were there two randomized trials? If so, were these patients enrolled in both? If so, what was the justification for potentially treating the patients with a drug to which they had already had an adverse reaction? If, on the other hand, there was only one randomized trial, how did the design change so dramatically? Ronald L. Koretz, MD UCLA School of Medicine Sylmar, CA 91342-1495 References 1. Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA. Reversible renal insufficiency due to angiotensin-converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med. 1991;115:513-8. 2. Pettinger WA, Lee HC, Reisch J, Mitchell HC. Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension. 1989;13:766-72. 3. Pettinger WA, Mitchell HC, Lee HC, Redman HC. Pseudo renal artery stenosis (PRAS) syndrome. Am J Hypertens. 1989;2:349-51.

In response: Some patients in this trial had been previously enrolled in an earlier blood pressure control trial (1). Thus, there were two randomized trials; most, but not all, patients were enrolled in both. The moderate to severe renal insufficiency in three cases referred to in references 2 and 3 occurred on only one occasion. The other five cases of renal insufficiency had not been previously reported. Seven of the eight patients received enalapril later, as we described in our article (2). During this study, eight patients developed reversible renal insufficiency (2). These patients were not arbitrarily assigned to a group. We thought that the characteristics of these patients were of sufficient interest to be reported now rather than delayed for several years because blinded patients were still being followed. When these cases were reported, a majority of patients had been unblinded because of study completion or because of side effects. We analyzed only the unblinded patients but, because 16 patients remained blinded, we estimated that there would be 8 additional patients in each group. These additional patients would change the percentage of patients that developed the complication. Thus, we stated that 8 of 42 patients (34 known and 8 expected) receiving enalapri developed reversible renal insufficiency and that none of 31 (23 known and 8 expected) receiving placebo developed renal insufficiency (1). One can use either figure as the denominator. Robert D. Toto, MD Southwestern Medical Center Dallas, TX 75235-9030 References 1. Pettinger WA, Lee HC, Reisch J, Mitchell HC. Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension. 1989;13:766-72. 2. Toto RD, Mitchell HC, Lee HC, Milam C, Pettinger WA. Reversible renal insufficiency due to angiotensin-converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med. 1991;115:513-8. 3. Pettinger WA, Mitchell HC, Lee HC, Redman HC. Pseudo renal artery stenosis (PRAS) syndrome. Am J Hypertens. 1989;2:349-51.

Anticoagulation before Cardioversion for Atrial Fibrillation To the Editors: The article addressing the question of which subgroups of patients with atrial fibrillation need anticoagulation by Albers and colleagues (1) is a welcome addition to the medical literature. However, the implied advice about managing patients with paroxysmal atrial fibrillation may be misleading. Atwood (2) states that, "Unlike patients with chronic

• Volume 116 • Number 8

Downloaded from https://annals.org by Tulane University user on 01/23/2019

atrial fibrillation, patients with acute atrial fibrillation of less than 3 days duration do not require anticoagulant therapy before cardioversion." (Here, I equate each new paroxysm of atrial fibrillation with "acute atrial fibrillation.") In support of this statement, he cites an article by Bjerkelund and Orning (3); however, this article contains no data that support this statement. As pointed out by Albers (1), whether stroke risk is lower in paroxysmal atrial fibrillation is uncertain. In the absence of definitive data, making an unequivocal recommendation to withhold this treatment when episodes of atrial fibrillation last less than 72 hours is premature. Michael B. Jacobs, MD The Stanford University Clinic Stanford, CA 94305 References 1. Albers GW, Atwood JE, Hirsh J, Sherman DG, Hughes RA, Connolly SJ. Stroke prevention in nonvalvular atrial fibrillation. Ann Intern Med. 1991;115:727-36. 2. Atwood JE. Cause, evaluation, and management of atrial fibrillation. In: Albers GW, moderator. Stroke prevention in nonvalvular atrial fibrillation. Ann Intern Med. 1991;115:727-36. 3. Bjerkeland CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to d.c. electrical conversion of atrial fibrillation. Am T Cardiol. 1969;23:208-16.

In response: We appreciate Dr. Jacobs's interest in our article and the opportunity to clarify our recommendations (1). The important issue of subgroup analysis in atrial fibrillation has been addressed numerous times with highly variable results. Most recently, evidence from the Stroke Prevention in Atrial Fibrillation Study (2) suggests that the stroke risk of patients with paroxysmal nonvalvular atrial fibrillation does not differ significantly from that of patients with chronic nonvalvular atrial fibrillation. Thus, this variable may not be helpful when deciding whether to use chronic anticoagulant therapy. In our section on cardioversion, we did not mean to imply that patients with paroxysmal atrial fibrillation should have electrocardioversion without anticoagulant therapy. On the contrary, in general, we recommend prophylactic anticoagulation in this situation. The recommendation we made was for patients with new-onset atrial fibrillation of brief duration and is based on current recommendations from the American College of Chest Physicians (3). This recommendation is based on the assumption that "thrombus formation in the atria in the presence of fibrillation takes at least several days" (3). However, we agree with Dr. Jacobs that there are minimal data to support this assumption. Therefore, although it is not a standard recommendation, anticoagulation of patients with newonset atrial fibrillation of short duration before electrocardioversion is certainly not unreasonable. Gregory W. Albers, MD J. Edwin Atwood, MD Stanford University Medical Center Palo Alto, CA 94304 References 1. Albers GW, Atwood JE, Hirsh J, Sherman DC, Hughes RA, Connolly SJ. Stroke prevention in nonvalvular atrial fibrillation. Ann Intern Med. 1991;115:727-36. 2. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: I. clinical features of patients at risk. Ann Intern Med. 1992;116:1-5. 3. Dunn M, Alexander J, de Silva R, Hildner F. Antithrombotic therapy in atrial fibrillation. Chest. 1989;95:118S-25S.

Clinical Trials: To Terminate or Not To Terminate To the Editors: Laupacis and colleagues (1) are to be commended on their excellent analysis of the influence of completed studies on ongoing clinical trials. Their decision to stop the trial and perform the final analysis was ethical and courageous. "Aborting" a mission to which considerable time,

money, and patient participation have been devoted is frustrating in many ways. Two points are worthy of further comment. They refer to the desirability of a "meta-analysis when different groups are evaluating a similar problem." However, different groups should not be evaluating a similar problem. Better mechanisms are needed to organize large multicentered studies to study a similar problem. Such studies have several advantages over multiple smaller studies: The dilemma addressed by Laupacis and colleagues (1) can be avoided if only one trial is being conducted; greater statistical power is achievable; scarce resources can be better focused; diverse experience and intellect can be pooled to create a "best-possible" study; the results are more generalizable to general clinical practice; patient subgroups can be more easily studied; spurious results unique to a specific institution or patient population are diluted; and the recent practice of using meta-analysis to compare multiple similar but slightly different trials can be minimized. The last point is very important because meta-analysis of three 100subject trials is usually inferior to regular analysis of one 300-subject trial. Meta-analysis is usually considered when several similar studies show conflicting results. The reasons for these differences are many (for example, differences in patient selection), but the differences inevitably weaken the practical conclusion. Laupacis and coworkers (1) also stated that "In general, the result of one positive trial is not sufficient to change clinical practice." Why not? If a single, well-done trial shows convincing results in favor of therapy, it is difficult to justify enrolling patients in additional trials randomizing them to another seemingly inferior therapy. A major reason that the results of a single trial do not change clinical practice is that the trial was not convincing for the reasons outlined. James R. Gossage, MD Vanderbilt University Nashville, TN 37232-2650. Reference 1. Laupacis A, Connolly SJ, Gent M, Roberts RS, Cairns J, Joyner C, for the CAFA Study Group. How should results from completed studies influence ongoing clinical trials? The CAFA study experience. Ann Intern Med. 1991;115:818-22.

To the Editors: Laupacis and coworkers (1) described the deliberations of their steering committee when two other trials that were similar to their own terminated and released results. They noted that both of the other studies were stopped early because the planned data analyses reached the boundaries for interim statistical significance. When those studies were stopped, their own steering committee considered the following options: continuing recruitment and follow-up as planned; providing current data to an external safety- and efficacymonitoring committee for analysis; stopping recruitment but continuing follow-up of patients in the group to which they were assigned; stopping the trial immediately and performing the final analysis; performing a meta-analysis of all current data. Laupacis and colleagues (1) argued that, in view of the results obtained by the other studies, continuing recruitment and follow-up as planned might have been unethical, even though important questions remained unanswered. There is a sixth option, which we used in a similar circumstance (2). We were conducting a multicenter trial of zidovudine when the National Institutes of Health (NIH) announced early termination of similar studies (3, 4). Our data- and safety-monitoring board recommended that we continue our trial but that we first provide our participants with a new informed consent form, describing for them the NIH's reported results and outlining the risks and benefits of their continued participation (including the benefit of their providing additional data). The board also recommended that we offer participants the choice of continuing to receive blinded study treatment or switching to openlabel zidovudine treatment (2). The majority of patients who were still receiving blinded therapy elected to continue to do so until the scheduled conclusion. A prematurely terminated clinical trial is likely to overesti-

15 April 1992 • Annals of Internal Medicine • Volume 116 • Number 8

Downloaded from https://annals.org by Tulane University user on 01/23/2019

699

mate the magnitude of a treatment effect (5), because estimates (observations) of the treatment effect vary around the true underlying value. At the time of an interim analysis, if an estimate by chance happens to be greater than the true effect, it is more likely to exceed the stopping boundary than if it is not (5). After the completion of a trial, clinicians should, however, know not only whether, statistically, a treatment provides benefit for patients but also the magnitude of these benefits, especially when an alternative treatment is available or substantial toxicity may occur. The best estimate of benefit and toxicity is achieved when multiple trials are carried out to completion. As this is being done, however, the autonomy of participants (their right to make informed decisions) must be respected. The mechanism that protects patient autonomy and voluntary participation in a research study is the consent form. There is no generally accepted method for the transmittal of pertinent outside data to patients during the course of a clinical trial. Periodic letters, information sheets, and discussions between investigators and study participants can serve this purpose, and, where necessary, a new informed consent might be obtained. Michael S. Simberkoff, MD Pamela M. Hartigan, PhD John D. Hamilton, MD The VA Cooperative Studies Group on AIDS References 1. Laupacis A, Connolly SJ, Gent M, Roberts RS, Cairns J, Joyner C, for the CAFA Study Group. How should results from completed studies influence ongoing clinical trials? The CAFA study experience. Ann Intern Med. 1991;115:818-22. 2. Simberkoff MS, Hartigan PM, Hamilton JD. Ethical dilemma in continuing a zidovudine-placebo trial in symptomatic HIV infection. Clin Res. 1991;39:315A. 3. Fischl MA, Kith man DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med. 1990;112:727-37. 4. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med. 1990;322:941-9. 5. Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Controlled Clinical Trials. 1989; 10: 209S-21S.

In response: Dr. Gossage argues that a large multicenter trial has many advantages over several smaller studies and that different groups should not be concurrently evaluating a similar problem. Many of the points he raises are valid. However, the practicalities associated with mounting such large trials can be formidable. Problems include being aware that other groups are interested in a similar question, disagreeing about the appropriate protocol, and coordinating funding from various granting agencies. In addition, protocols often differ when various groups embark on their own studies. The importance of these differences can subsequently be explored in a way that is not possible when a common protocol is used. Most large trials have external safety review committees who are charged with the responsibility of stopping a study before its planned conclusion if there is convincing evidence of benefit. Therefore, it is unlikely that sufficient patients would ever be entered into a positive trial to allow the evaluation of subgroup effects with any power. However, such evaluation may be possible with several concurrent studies. For example, data from the five concurrent trials of warfarin in atrial fibrillation are currently being combined into one common database that will provide considerable power in defining which patients are at low and which are at high risk for either stroke or warfarin side effects. We disagree with the statement "Meta-analysis is usually considered when several similar studies show conflicting results." Rather, meta-analysis has repeatedly shown that results that appear to differ quantitatively are in fact compatible with each other and that apparent differences most likely result from chance (1). 700

15 April 1992 • Annals of Internal Medicine

Simberkoff and colleagues suggest that before stopping our trial (2), we should have presented our patients with a new consent form describing the data from the other trials and should have offered them the option of continuing in our study. The mechanism for protecting patient autonomy and voluntary participation in a study is not the consent form itself, but rather the reasoning that goes into its development and how the investigators verbally present its content to the patients. In our case, our steering committee, which had overall responsibility for the conduct of the study, was convinced that the question of the efficacy of warfarin in nonvalvular atrial fibrillation had been answered. Continuing to enter patients into a trial to address this question therefore seemed inappropriate. Andreas Laupacis, MD, FRCPC Stuart J. Connolly, MD, FRCPC Michael Gent, DSc Ottawa Civic Hospital Ottawa, Ontario K1Y 4E9, Canada References 1. Yusaf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1958;27:335-71. 2. Laupacis A, Connolly SJ, Gent M, Roberts RS, Cairns J, Joyner C, for the CAFA Study Group. How should results from completed studies influence ongoing clinical trials? The CAFA Study experience. Ann Intern Med. 1991;115:818-22.

Antibiotic-resistant Enterobacter Cephalosporins

To the Editors: The results of a recent study conducted by Chow and colleagues (1) indicated that newer-generation cephalosporins should be used cautiously in treating Enterobacter bacteremias. They showed an associated higher risk for subsequent infection with a strain that is resistant to multiple beta-lactam antibiotics and the greater mortality associated with these strains (1). Although Chow and coworkers (1) showed a relation between presence in the intensive care unit at time of the initial blood culture and mortality, they did not explore the potentially important relation between hospitalization in the intensive care unit and use of newer cephalosporins. These agents provide a selective pressure that favors colonization and infection with Enterobacter spp. over other Enterobacteriaceae, which do not have protective cephalosporinases (2). Second, in their prospective evaluation of emergence of resistance to antimicrobials during therapy, Chow and colleagues (1) used 118 as the study denominator (that is, the number of persons from whose blood Enterobacter was isolated and who were followed through therapy for subsequent development of multiresistant Enterobacter). Eleven additional patients who received inappropriate therapy were excluded. The 118, however, includes 37 patients whose initial blood culture isolate was a multiresistant Enterobacter and whose risk for development of an even more resistant phenotype was likely to be less than that of patients whose initial isolate was a sensitive strain. The exclusion of these patients would result in a still greater incidence of emergence of multiresistant Enterobacter spp. during antibiotic therapy. Finally, the prospective nature of the study design allowed an opportunity to evaluate other potential risk factors, such as dose and duration of antibiotic therapy (for example, prolonged exposure to potentially subinhibitory doses of antibiotics) and site of initial infection (for example, pneumonia involving a high concentration of organisms compared with a wound infection or urinary tract infection in which the concentration of organisms is likely to be lower) (1). Such associations would have important clinical implications concerning the use of third generation cephalosporins. Ellen J. Mangione, MD, MPH John M. Douglas, MD University of Colorado Health Sciences Center Denver, CO

• Volume 116 • Number 8

Downloaded from https://annals.org by Tulane University user on 01/23/2019

and the Newer

References 1. Chow JW, Fine MJ, Shales DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585-90. 2. Sanders C. New beta-lactams: new problems for the internist. Ann Intern Med. 1991;115:650-1.

In response: Drs. Mangione and Douglas raise several interesting issues: First, 35% of patients who were in the intensive care unit had initially multiresistant Enterobacter compared with 23% of patients who were not in the intensive care unit (P = 0.13) (Chow JW, Fine MJ, Shales DM. Unpublished results). Patients in intensive care units usually receive multiple courses of antibiotics, including cephalosporins, which select for colonization with multiresistant organisms. Second, we agree that the emergence rate of 6% (7 of 118 patients) is an underestimate because the denominator contains all patients treated with various appropriate antibiotics. Table 4 in our article gives more precise data (1). For example, 19% of patients who received third-generation cephalosporin therapy developed resistance to these same agents. Third, although dose and duration of antibiotic therapy are likely associated with the emergence of resistance to antibiotic therapy, this assessment was logistically difficult to perform; dosing must take into account renal and hepatic function. An association was not seen between site of initial infection and the seven cases of emergence of resistance to antibiotic therapy: In 3 of 45 cases (6.7%), the abdomen was the portal of entry; in 1 of 13 cases (7.7%), an intravascular catheter was the portal; in 1 of 11 cases (9.1%), the respiratory tract was the portal; in 1 of 8 cases (12.5%), a wound was the portal; and in 1 case, the portal of entry was unknown (Chow JW, Fine MJ, Shales DM. Unpublished data). This lack of an association may be a result of several confounding factors. For example, because all patients were bacteremic, a relatively high concentration of organisms was likely in most patients. Also, a case of a mild unilobar pneumonia may actually have fewer organisms than a wound infection with an abscess. Joseph W. Chow, MD Marilyn M. Wagener, MS Victor L. Yu, MD University of Pittsburgh Pittsburgh, PA

Finally, in going beyond the binary problem of deciding whether myocardial infarction is present or absent, what new difficulties does Dr. Baxt anticipate in constructing a network for the differential diagnosis of chest pain? How large a training set might be necessary for, say, a 20-output network? Alan P. Zelicoff, MD Sandia National Laboratories—Division 9241 Albuquerque, NM 87185 References 1. Baxt W. Use of an artificial neural network for the diagnosis of myocardial infarction. Ann Intern Med. 1991;115:843-8. 2. McClelland J, Rumelhard DE, eds. Parallel Distributed Processing: Explorations in the Microstructure of Cognition. Cambridge, Massachusetts: MIT Press; 1986.

To the Editors: I had some problems with the statistics used in the article by Baxt (1). Although I don't have access to the journal Technometrics (his reference 22), none of the methods that I know for calculating confidence intervals (CIs) would give a 95% CI of 97.2% to 97.5% (incredibly precise!) when 35 of 36 are correct. The values I obtained using the F test method (2) are 28/36 = 78% (61% to 90%) 35/36 = 97% (85% to 99.9%) 250/295 = 85% (80% to 88%) 284/295 = 96% (93% to 98%) I also get different values (though still "significant") when using the McNemar test to compare the sensitivities of the two methods (assuming the discordant pair is 7 and 0). Warren S. Browner, MD, MPH University of California, San Francisco San Francisco, CA 94121 References 1. Baxt W. Use of an artificial neural network for the diagnosis of myocardial infarction. Ann Intern Med. 1991;115:843-8. 2. Zar J H . Biostatistical Analysis. 2d ed. 1984:378-9.

Reference 1. Chow JW, Fine MJ, Shales DM, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115:585-90.

Myocardial Infarction Prediction by Artificial Neural Networks To the Editors: Baxt's (1) successful use of neural networks in accurately diagnosing myocardial infarction in an emergency room setting illustrates the vast potential utility of this technique for medical decision making. Unfortunately, despite an apparently straightforward mathematical foundation, much of the design and training of neural networks remains an intuitive art. Network theory provides very little guidance for optimizing network structure, including optimizing the depth of hidden layers and the number of nodes in those layers, which are important determinants of computing resources necessary for training the network (2). Such considerations are paramount in large input nets and in networks with complex logistic functions for node outputs. I therefore would like to know whether Dr. Baxt can explain the process of his network design. Specifically, what was his experience with a single hidden layer network for the myocardial infarction problem? Did he use other training techniques before settling on back-propagation based on the generalized delta rule? If so, why does he think that one optimization technique is superior to another for this particular application? Was pruning the large initial network possible as a result of training?

To the Editors: The report of Dr. Baxt (1) concerning the potential of artificial neural networks in clinical medicine was refreshing. Because artificial neural networks learn by example, how the variables used to train the network are chosen is very important. Was selection based on previous studies of patient records, previous experience with artificial neural networks trained to recognize myocardial infarction, or simply trial and error? A significant amount of " a r t " is still involved in designing and training artificial neural networks (for example, deciding the appropriate number of layers of hidden units and the number of elements per hidden layer) (2). Therefore, before these devices can be used widely in clinical medicine, a better understanding of the design process as an engineering matter is necessary. Back propagation networks are best at predicting current or future states based on past occurrences. Another type of artificial neural network that may have widespread use in clinical medicine is the Kohonen self-organizing network (3). Kohonen networks are simpler in design than back propagation networks and have two traits that the latter do not have: continuous learning and statistical modeling capability (3). These two characteristics make Kohonen nets excellent candidates for applications in which the investigators wish to assess whether a collection of data is hiding any significant statistical relationships. A Kohonen network used in this manner might also be used to help identify the variables that should be used to train a back propagation network. Their continuous learning capability helps to assure that the network's "knowledge" reflects the most recent data. Thus, a Kohonen network given data on hospital admissions could note trends in admitting diagnoses or

15 April 1992 • Annals of Internal Medicine

Downloaded from https://annals.org by Tulane University user on 01/23/2019

• Volume 116 • Number 8

701

physician utilization patterns—very important for clinicians and administrators today. Jerome H. Carter, MD Morehouse School of Medicine Atlanta, GA 30310-1495 References 1. Baxt WG. Use of an artificial neural network for the diagnosis of myocardial infarction. Ann Intern Med. 1991;115:843-8. 2. Caudill M. Neural network primer, part III. AI Expert. 1988;3:53-9. 3. Simpson PK. Artificial Neural Systems: Foundations, Paradigms, Applications and Implementations. New York: Pergamon Press; 1990:85-94.

In response: The initial variables tested were chosen from those shown in reported studies to predict myocardial infarction in patients presenting to an emergency department with anterior chest pain. Alternate training methods were not used but should be evaluated. None of the existing training methods appears to improve end-point network accuracy. Which method is used may affect the rapidity with which the network is trained. Our confidence intervals (CIs) were calculated using statistical software which was based on the method of Bailey (1). These CIs have been recalculated with the same results. However, CIs were also recalculated using the proportions method, which yielded a sensitivity for physicians of 77.8% (91.4% to 64.2%) and for the network of 97.2% (100.0% to 91.8%); and a specificity for physicians of 84.7% (88.8% to 80.6%) and for the network of 96.3% (98.5% to 94.1%). The CIs were also calculated using the method of Clopper and Pearson (2), which adjusts for very small sample sizes. This method yielded a sensitivity for physicians of 77.8% (89% to 61%) and for the network of 97.2% (100% to 91%); and a specificity for physicians of 84.7% (90% to 81%) and for the network of 96.3% (98% to 92%). Because these two methods and Dr. Browner's computation yielded similar and wider intervals, we conclude that the originally reported intervals were too narrow. The McNemar test was recalculated with the same P value as published. A single-layer network was initially used (3). It was found that, by adding the second layer, an approximate improvement of 5% in sensitivity was achieved on the original test sets with no improvement in specificity (3). Back-propagation was the only training method used for the reasons stated above. Other training techniques may be more effective. The initial network was pruned by the selective omission of variables and by the determination of any loss in sensitivity and specificity. The development of networks to deal with specific chief complaints and the possible disease states connected to these complaints is a definite goal. The size of the training sets as well as the number of input nodes would probably have to be considerably larger than those for a single disease. The specifics would depend on the chief disorders and disease states being studied.

15 April 1992 • Annals of Internal Medicine

Three-Legged Stool—The Quality of the Wood To the Editors: Dr. Barondess's article (1) was a sound description of the "wobbly" stool of academic medicine, supported by the three unbalanced legs of research, education, and patient care and public responsibility. I agree that we need better carpenters to reconstruct our stool, to balance its structure, and to secure its attachments. When I stand on a stool, however, my first concern is whether it was built with the proper materials. Dr. Barondess suggested that medical students and residents have no characteristics of their own—that they are shaped by instructors who, drawing from their own imperfect experience, fashion them into their own self images. If it is true, as the adage states, that a doctor is always a student of medicine, then choosing the best students implies not only building the best stools but also selecting the best raw materials. Before we head to the toolshed, we need to consider the maturity of the tree and the consistency, strength, and (moral) grain of the timber. Pamela Jo Harris, MD 1810 Calvert Street NW Suite 5 Washington, D.C. 20009 Reference 1. Barondess JA. The academic health center and the public agenda: whose three-legged stool? Ann Intern Med. 1991;115:962-7.

In response: Dr. Harris's extension of the analogy of the three-legged stool is much appreciated. In my observation over the years, there has been a fair consistency in the quality of entering medical students. A recent Alpha Omega Alpha survey (Barondess JA, Glaser RJ. Unpublished data) indicated that students attracted to the medical career are altruistic. Medical student characteristics have not concerned me as much as has the imprinting students receive in our educational and training institutions. Our process for selecting entering medical students could be improved; no one thinks that the process is perfect. At the same time, the educational enterprise in medicine has, in my judgment, sent a confusing message. My message was that more of us who have contributed, actively or passively, to the persistence of the traditional three-legged stool should raise our sights. Jeremiah A. Barondess, MD The New York Academy of Medicine New York, New York 10029

William G. Baxt, MD UCSD Medical Center San Diego, CA 92103-1990.

702

References 1. Bailey BJ. Large sample simultaneous confidence intervals for the multinominal probabilities based on transformations of the cell frequencies. Technometrics. 1980;22:583-9. 2. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26:404. 3. Baxt WG. Use of an artificial neural network for data analysis in clinical decision-making: the diagnosis of acute coronary occlusion. Neural Computation. 1991;2:480-9.

• Volume 116 • Number 8

Downloaded from https://annals.org by Tulane University user on 01/23/2019