Letters and Corrections
Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request.
Kirk V. Shepard, MD Roxane Laboratories, Inc. Columbus, OH 43216-6532 References 1. Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med. 1989;111:947-9. 2. Burnett RJ. Sodium poly sty rene-sorbitol enemas. Ann Intern Med. 1990;112:311-2. 3. Product Information: Sodium Polystyrene Sulfonate Suspension. Roxane Laboratories, Columbus, Ohio, 1988. [Available from Roxane Laboratories, Inc., P.O. Box 16532, Columbus, OH 43216-6532.] 4. Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101:266-72.
5. Flanigan RC, Reckard CR, Lucas BA. Colonic complications of renal transplantation. J Urol. 1988;139:503-6. Antibiotics for Urinary Tract Infections in Women
Cleansing Enemas after Sodium Polystyrene Sulfonate Enemas To the Editor: An article by Wootton and colleagues (1) in a recent issue concerned a patient who had necrosis of the colon after he was administered a sodium polystyrene sulfonate suspension enema. A subsequent letter to the Editor by Burnett (2) questioned whether cleansing enemas had been administered to the patient before and after the sodium polystyrene sulfonate suspension enema, as is stated in bold type on the product insert, on the product label, and on the carton (3). In a discussion with one of the authors of this case report, I was told that the patient was not given cleansing enemas. Another paper by Lillemoe and colleagues (4), published in 1987, described five patients who had similar complications after sodium polystyrene sulfonate suspension enemas were administered. Subsequent discussions with one of these authors revealed that these patients also were not administered a cleansing enema. The six patients mentioned in these two articles are the only patients reported to us as having had this complication after the administration of sodium polystyrene sulfonate enemas. All six patients had the product administered improperly, and not in accordance with the product insert, product label, and product carton. This complication has never been reported when the product is administered properly according to the insert and label. The authors of the case report (1) attempted to implicate the inclusion of sorbitol in the sodium polystyrene sulfonate suspension enema as the agent causing necrosis of the colon. Because sodium polystyrene sulfonate suspension enemas are usually administered only to very ill patients with hyperkalemia, these case reports do not provide conclusive evidence that sorbitol causes the complications in the colon. There are also other theories, such as the disease itself or other medications, that have been suggested by experts as to why these colonic complications occur (5). The important point is that conclusions reached from research, especially from case reports, on the effects of therapy are inappropriate when the product is administered improperly and not according to the product insert and label.
To the Editor: I read with great interest the fine paper by Johnson and Stamm (1), updating proper diagnosis and treatment of urinary tract infections in women. Their otherwise comprehensive review of a complex subject was slightly marred by the inclusion of nonequivalent doses in some of their comparative tables (Tables 3 and 9). In a footnote, the authors do provide the caveat that in certain patients it may be preferable to use different doses or intervals. Nevertheless, Table 3 seems to indicate (based on the cost per day column) that the choices as given are comparable. This is not the case. As an illustration, a maximal dose of ceftazidime (2 g every 8 hours) is given whereas an agent with a roughly similar half-life and spectrum, aztreonam, is given at half the dose and therefore at seemingly half the cost per day. Similarly, ticarcillinclavulanate usage is for a near maximal dose with a resultant high cost whereas ampicillin-sulbactam and ureidopenicillins are shown for moderate doses and thus appear to be significantly cheaper. The same problem is found in the aminoglycoside grouping and with other betalactams and quinolones. The uninitiated, looking at the cost per day, may draw improper conclusions regarding the optimal cost-effective agent to use. It would be more appropriate to have chosen doses and intervals reflecting clinical usage of the agents for the same type of patient rather that having certain agents listed at a maximal dose (for "sicker" patients) compared with others listed at a minimal dose (for less severely ill patients). Finally, the authors state "in uncomplicated cases a single broad-spectrum intravenous agent can be used initially" and in Table 9 list ampicillin as a possible (albeit not the preferred) choice. Earlier in the article, however, the authors accurately state that increasing frequency of resistance to ampicillin among even community-acquired Escherichia coli strains has greatly diminished the attractiveness of ampicillin as part of an empiric regimen. Therefore, it would have been better to delete ampicillin as a (sole) initial choice for intravenous therapy for acute pyelonephritis. Aaron E. Glatt, MD Nassau County Medical Center East Meadow, NY 11554 Reference 1. Johnson JR, Stamm WE. Urinary tract infections in women: diagnosis and treatment. Ann Intern Med. 1989;111:906-17.
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In response: We thank Dr. Glatt for his warm reception of our paper (1) and appreciate the opportunity to respond to his specific comments. Determining equivalent doses for different antimicrobial agents can be problematic. We agree that it is desirable for doses and intervals shown in tables comparing drug costs to reflect actual clinical usage of the agents. In preparing the tables in our study (1), we considered the regimens used in published clinical trials of these newer agents and the dosing recommendations by authorities in the field (2). Dr. Glatt is concerned that we chose too high a dose for ceftazidime in comparison with the dose chosen for aztreonam, thereby exaggerating the difference in cost between these agents. We concur that the dose we selected for ceftazidime is at the high end although it is not inconsistent with clinical practice. As Dr. Glatt suggests, a fairer cost comparison with aztreonam might be obtained using half the given dose of ceftazidime; however, ceftazidime would still cost more. Although aztreonam doses ranging from 1 to 6 g daily have been used in clinical trials (reference 72 of [1]), most patients in these studies received 1 g every 6 or 8 hours (reference 71 of [1]). The dose of 1 g every 8 hours shown in our table reflects this experience. Dr. Glatt is concerned that we selected a "near maximal" dose for ticarcillin plus clavulanate, but only "moderate" doses for the ureidopenicillins. For ticarcillin plus clavulanate, however, the dose we used (3.1 g every 6 hours) is only half of the maximal dose listed in one source (2) and is entirely consistent with doses studied in several clinical trials (references 48-50 of [1]). For the ureidopenicillins, the dose we used (2 g every 6 hours) is not low in the context of doses used in recent trials (references 48 and 61 of [1]), and is even higher (for mezlocillin) than that recommended for urinary tract infections in one source (2). The doses we showed for the aminoglycosides (4.5 mg/ kg • d; 15 mg/kg • d for amikacin) are standard. We suggested a twice-daily dose of 400 mg for norfloxacin and 250 mg for ciprofloxacin because most of the published clinical experience with these agents in urinary tract infection has been with these doses (3). It should be noted that preparation and administration charges add $10 to $15 to the cost of each dose of antibiotic administered. Thus, actual total daily costs for antibiotic therapy depend not only on the total amount of drug given (as shown in our tables [1]) but on the number of doses administered, with shorter dosing intervals leading to markedly increased costs exclusive of the cost of the agent itself. Additionally, the prices shown in our tables (1) reflect manufacturers' average wholesale prices; actual costs may be lower with competitive bidding. We join with Dr. Glatt in discouraging the use of intravenous ampicillin alone for the initial therapy of acute pyelonephritis. As indicated in a footnote to Table 9(1), any initial regimen for acute pyelonephritis should cover all likely pathogens; it is clear from Table 2(1) that ampicillin fails badly in this respect if not combined with a more broadly active agent. We included ampicillin in Table 9 because ampicillin is currently among the most commonly used agents in the treatment of acute pyelonephritis, especially during pregnancy, and because intravenous ampicillin alone is acceptable once the isolate has been shown to be susceptible to it. James R. Johnson, MD University of Minnesota Minneapolis, MN 55455 Walter E. Stamm, MD University of Washington Harborview Medical Center Seattle, WA 98104
References 1. Johnson JR, Stamm WE. Urinary tract infections in women: diagnosis and treatment. Ann Intern Med. 1989;111:906-17. 2. Sanford JP. Guide to Antimicrobial Therapy. West Bethesda, Maryland: Antimicrobial Therapy, Inc.; 1988:44-59.
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3. Naber KG. Use of quinolones in urinary tract infections and prostatitis. Rev Infect Dis. 1989;ll(Suppl 5):S1321-7.
Myocardial Infarction during Cocaine Withdrawal To the Editor: Nademanee and colleagues (1) demonstrated ST segment changes of silent ischemia during Holter monitoring in 8 of 21 chronic cocaine abusers who had stopped taking the drug an average of 8.5 days before testing. These patients had normal exercise treadmill tests and were presumed free of significant coronary atherosclerosis. The authors of this interesting study proposed the dopamine depletion hypothesis to explain the coronary vasoconstriction (spasm) observed in these subjects. We report a case of myocardial infarction during cocaine withdrawal and postulate an alternative hypothesis to explain this phenomenon. A 42-year-old male chronic cocaine (crack) smoker was hospitalized for severe chest pain that occurred with strenuous exercise 3 days after he stopped using cocaine. The patient was alert, diaphoretic, and agitated. His lungs were clear and heart sounds were normal. The electrocardiogram showed ST elevations in III and AVF. The creatine kinase level was 738 U/L with an MB fraction of 7.5%. Cocaine metabolites were absent in the blood but present in the urine. A cardiac angiogram showed normal coronary arteries and inferior-wall hypokinesis. An exercise stress test done before discharge was normal. We believe our case is the first report of a myocardial infarction during cocaine withdrawal. Previously reported cases of cocaine-related myocardial infarction have been attributed to a direct effect of the drug (2). Because of cocaine's short half-life, however, it is likely that many infarctions were not caused by the drug itself. The dopamine depletion hypothesis may explain the psychologic abnormalities and the central system effects induced by cocaine (3). Nevertheless, there is no convincing evidence that presynaptic dopamine receptors play a significant role in adrenergic neurotransmision (4). It is known, however, that chronic cocaine abuse induces catecholamine depletion and paradoxic upregulation of postsynaptic receptors (2). We suspect that, during abstinence, progressive replenishment of catecholamine may occur in the setting of increased adrenergic receptors. This transient imbalance can provide the context for a disproportionate sympathetic response to an adrenergic stimulus such as exercise. The potential for ischemic complications would be determined by the degree of adrenergic stimulation and by the presence of other known risk factors. Cesar Del Aguila, MD Howard Rosman, MD Henry Ford Hospital Detroit, MI 48202-2689
References 1. Nademanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111:876-80. 2. Frishman WH, Karpenos A, Molloy TJ. Cocaine-induced coronary artery disease: recognition and treatment. Med Clin North Am. 1989; 73:475-86. 3. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev. 1985;9:1-9. 4. Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol Rev. 1980;32:337-62.
Visual Symptoms after Atenolol Therapy for Migraine To the Editor: Chronic headache is common in the general population. Ten to twenty percent of chronic headaches are migraine. Beta blockers have been used widely to prevent both common and classic migraine for more than 20 years. In studies documenting the effectiveness of propranolol and other beta blockers, including atenolol, timolol, nadolol, and metoprolol, in preventing migraine, the reported side effects have been drowsiness, fatigue, nightmares, and depression. We report a patient who developed marked visual symptoms consisting of
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scotoma and scintillations in the absence of headache after treatment of her migraine with atenolol. A 37-year-old woman was seen in our headache clinic with a history of migraine from age 17. Her headaches initially occurred two to three times a year but had increased to three to five times a month during the last 5 years. Scotoma and scintillations occurred only once or twice a year. After being evaluated, she was started on atenolol, 50 mg/d. After 3 weeks of treatment, she noted a marked reduction in the frequency and severity of her headaches. At the same time, she noticed visual symptoms consisting of scotoma and scintillations that occurred two to three times a week, lasted for 20 to 30 minutes, and were followed rarely by a headache. Atenolol was withdrawn and she was started on timed-release verapamil, 240 mg/d. Since then, she has not had any visual symptoms or migraine. During further discussion of her visual symptoms and their likely relationship to atenolol therapy, the patient recalled having had similar symptoms during treatment with nadolol several years ago. The mechanism by which beta blockers prevent migraine is not well defined. They are known, however, to decrease cerebral blood flow. During the aura of a migraine attack, cerebral blood flow is reduced. By further reducing the cerebral blood flow during the aura, beta blockers could potentially produce cerebral ischemia or infarction. This hypothesis is supported by case reports of patients with classic and hemiplegic migraine who had strokes while on propranolol therapy (1-3). In a controlled trial (4) of the prophylactic effect of metoprolol on patients with classic migraine, scintillations occurred more often in patients on metoprolol therapy than on placebo. However, patients in this study were reported to have symptoms of aura without a headache. Our patient appears to be unique because she had prominent visual symptoms without the headache, a side effect of therapy not previously reported. Because of the pathophysiology of migraine and reports of occurrence of strokes during treatment with beta blockers, we believe that beta blockers should not be used in patients with complicated migraine and only with caution in classic migraine. Similarly, ergotamines, which have a vasoconstrictive effect on cerebral circulation, should be considered as contraindicated in such patients. Calcium channel blockers may increase the cerebral blood flow and thus may be the agents of choice in such patients (5). Kusum L. Kumar, MD Thomas G. Cooney, MD Oregon Health Sciences University Veterans Affairs Medical Center Portland, OR 97207
Clinical trials of acute stroke should be based on rational, clinically testable hypotheses and therapeutic approaches. For rational hypothesis testing, the pathogenesis of acute cerebral focal ischemia in a given patient may need to be known. The time-consuming nature of such investigations has been shown in well-conducted studies of the very early acute use of fibrinolytic agents after the onset of thrombotic stroke, at highly motivated and efficient centers in three countries. In all cases, computed tomographic (CT) scans and angiographic procedures were required immediately after the patient arrived to identify the symptomatic occlusion. The intervals from symptom onset to treatment averaged 7.6 ± 5.6 h (2) and 4.3 ± 2.9 h (3) in carotid territory stroke, and less than 24 h in one study (4) of vertebrobasilar territory stroke. In one cohort of patients entered into the ongoing t-PA/Acute Stroke Study Group trial (5), the average interval from hospital arrival to completion of CT scan and angiography has been 2.38 ± 0.74 h. The hypotheses to be tested in each case were that acute intervention with thrombolytic agents is feasible and produces reperfusion of documented symptomatic arterial thrombotic occlusions, and that vascular reperfusion by such agents is safe. In this setting early entry alone does not compensate for not knowing the cause of the stroke (that is, whether a thrombus is present). In addition, spontaneous neurologic recovery after focal stroke may occur without intervention as late as 6 hours after the onset of symptoms, often obscuring the relation between unproven "therapies" and outcome. Hence, many questions remain regarding the minimum and maximum intervals necessary for successful stroke intervention and their relation to the therapy being tested. Although early treatment of stroke remains a pursued and laudable goal, a "trauma-style approach" will not be feasible until we develop rational therapeutic strategies based on pathophysiology, and test them in randomized clinical trials. There is little question of the need for rational hypotheses and relevant testable agents and approaches in concert with well-directed, national and community-based patient education. Gregory J. del Zoppo, MD Scripps Clinic and Research Foundation La Jolla, CA Anthony Furlan, MD The Cleveland Clinic Foundation Cleveland, OH Werner Hacke, MD Universitat Heidelberg Heidelberg, Federal Republic of Germany
References 1. Gilbert GJ. An occurrence of complicated migraine during propranolol therapy. Headache. 1982;22:81-3. 2. Bard well A, Trott J A. Stroke in migraine as a consequence of propranolol. Headache. 1987;27:381-3. 3. Prendes JL. Considerations on the use of propranolol in complicated migraine. Headache. 1980;20:93-5. 4. Hedman C, Andersen AR, Andersson PG, et al. Symptoms of classic migraine attacks: modifications brought about by metoprolol. Cephalalgia. 1988;8:279-84. 5. Solomon GD. Comparative efficacy of calcium antagonist drugs in the prophylaxis of migraine. Headache. 1985;25:368-71.
Treatment of Acute Stroke To the Editor: We read with admiration the recent editorial of Barsan and colleagues (1) regarding their experience with "trauma-style" approaches to early treatment for acute ischemic stroke. Clearly, entry of patients within 90 minutes of symptom onset requires an efficient and labor-intensive accrual system, currently available in few communities. Although we agree that "early treatment should be a priority in future treatment trials of acute ischemic stroke," several significant and practical limitations revealed by recent acute stroke trials should not be overlooked.
References 1. Barsan WG, Brott TG, Olinger CP, Marler JR. Early treatment for acute ischemic stroke. Ann Intern Med. 1989;111:449-51. 2. del Zoppo GJ, Ferbert A, Otis S, et al. Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study. Stroke. 1988; 19:307-13. 3. Mori E, Tabuchi M, Yoshida T, Yamadori A. Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke. 1988;19:802-12. 4. Hacke W, Zeumer H, Ferbert A, Bruckmann H, del Zoppo GJ. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988;19:1216-22. 5. An open multicenter study of the safety and efficacy of various doses of rt-PA in patients with acute stroke: preliminary results The t-PA/Acute Stroke Study Group. [Abstract]. Stroke. 1988;19:134.
Lovastatin, Pravastatin, and Serum Lipoprotein(a) To the Editor: Genetically determined high concentrations of lipoprotein(a) [Lp(a)] have been strongly associated with premature cardiovascular disease (1), myocardial infarction (2), and cerebrovascular disease (3) in men. Until now, none of the classic hypolipidemic drugs has clearly been shown to influence this risk factor (4). There are controversial findings regarding the new class of HMG-CoA (3-hydroxy-3-methylglu-
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taryl coenzyme A) reductase inhibitors. Berg and Leren (5) reported unchanged serum Lp(a) concentrations in 30 patients with familial hypercholesterolemia treated with lovastatin, whereas Jurgens and colleagues (6) found an increased Lp(a) level during treatment with lovastatin in 8 patients. We therefore studied the effect of two HMG-CoA reductase inhibitors (lovastatin and pravastatin) on the serum levels of Lp(a) in 35 patients with severe hypercholesterolemia. During a 16-week period, 17 patients (10 women, 7 men) were treated consecutively with 20 mg, 40 mg, and 80 mg of lovastatin daily, whereas 18 patients (6 women, 12 men) were given 20 mg and 40 mg of pravastatin daily for 16 weeks. The lovastatin group did not differ significantly from the pravastatin group in mean age (50 compared with 51 years); body-mass index (25.6 compared with 24.5 kg/m2); total serum cholesterol before treatment (373 ± 14 compared with 373 ± 17 mg/dL); low-density lipoprotein (300 ± 13 compared with 307 ± 17 mg/dL); high-density lipoprotein (45 ± 3 mg/dL in both groups); triglycerides (152 ± 19 compared with 136 ± 14 mg/ dL); and Lp(a) (17.6 ± 3.1 compared with 23.7 ± 4.3 mg/dL). (The Lp[a] level was determined using a radioimmunometric assay [Pharmacia, Uppsala, Sweden].) Additionally, another group of 8 patients (3 women, 5 men) who were being treated with cholestyramine, 16 g daily, was followed for 16 weeks (initial Lp[a] level, 11.9 ± 2.9 mg/dL). Lovastatin and pravastatin (in terms of milligrams of drug given daily) showed marked and similar effects on the reduction of total cholesterol, low-density lipoprotein, and apolipoprotein B. However, pretreatment Lp(a) values did not differ significantly from those observed during therapy (week 16, 16.9 ± 3.5 mg/dL [-4%] in the lovastatin group; 25.3 ± 5.0 mg/dL [-1-7%] in the pravastatin group). Studying only the patients with higher Lp(a) values (exceeding 30 mg/dL) we observed no significant change in Lp(a) values with therapy, especially no increase. As shown previously (4), cholestyramine alone also had no effect on serum Lp(a) in the group of 8 patients (week 16, 12.8 ± 4.0 mg/dL; +8%). After 16 weeks on HMG-CoA reductase inhibitor therapy, cholestyramine, 8 g/d, was added to the regimen for these patients. Six of the patients receiving combined therapy with lovastatin and cholestyramine and 13 of the patients receiving pravastatin and cholestyramine were followed for over 1 year. Even after this long treatment period, neither of the two HMGCoA reductase inhibitors was able to influence the Lp(a) level (lovastatin plus cholestyramine, 17.7 ± 9.5 compared with 17.4 ± 9.2 mg/dL; pravastatin plus cholestyramine, 21.8 ± 6.4 compared with 20.4 ± 6.4 mg/dL). We conclude that HMGCoA reductase inhibitors do not exert any unfavorable effect on Lp(a) serum levels. Bernd G. Jacob, MD Werner O. Richter, MD Peter Schwandt, MD University of Munich 8000 Munich 70 Federal Republic of Germany
References 1. Dahlen GH, Guyton JR, Attar M, Farmer J A, Kautz JA, Gotto AM Jr. Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation. 1986;74:758-65. 2. Rhoads GG, Dahlen GH, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA. 1986; 256:2540-4. 3. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M. Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction. Atherosclerosis. 1986;59:199-204. 4. Kostner G, Klein G, Krempler F. Can serum Lp(a) concentrations be lowered by drugs and/or diet? In: Carlson LA, Olsson AG, eds. Treatment of Hyperlipoproteinemia. New York: Raven Press; 1984: 151-6. 5. Berg K, Leren TP. Unchanged serum lipoprotein(a) concentrations with lovastatin [Letter]. Lancet. 1989;2:812. 6. Jurgens G, Ashy A, Zenker G. Raised serum lipoprotein during treatment with lovastatin [Letter]. Lancet. 1989;1:911-2.
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The Myelodysplastic Syndrome and Bronchiolitis Obliterans To the Editor: We have identified bronchiolitis obliterans with organizing pneumonia as a cause of refractory hypoxemia, infiltrates, and relentless fever in a patient with the myelodysplastic syndrome. A 58-year-old white man with a 40-pack-year smoking history presented with a 6-week history of fever, productive cough, dyspnea, and a weight loss of 4 kg. He also had pancytopenia. The total leukocyte count was 2700/mm3; the hemoglobin, 10.0 g/dL; and the platelet count, 73 x 103/ mm3. A bone marrow biopsy specimen showed refractory anemia with excess blasts-a myelodysplastic syndrome. Physical examination showed the following: blood pressure, 125/65 mm Hg; pulse, 95/min; respiratory rate, 21/min; and temperature, 38.3 °C. There were bibasilar rales with egophony in both midlung fields. The initial chest roentgenogram showed bilateral infiltrates. The room air arterial blood gas analysis showed the following: Pao^, 62 mm Hg; Pacc^, 35 mm Hg; and pH, 7.43. Despite several courses of broad-spectrum antibiotics and amphotericin over 3 weeks, daily fever (38.3 °C to 39.4 °C) continued, and hypoxemia worsened (Pac^, 72 mm Hg with 50% Fio2). A repeat chest roentgenogram showed some clearing of the left lung infiltrate, but a progressive alveolar consolidation appeared on the right side. All surveillance cultures and special stains from both bronchoalveolar lavage and transbronchial biopsy specimens were negative for pathogens. A biopsy specimen obtained during the thoracotomy showed peribronchial and interstitial lymphoplasmacytic inflammation, poorly formed histiocytic granulomas with intrabronchiolar necrosis, distal focal collections of alveolar neutrophils, and edema in a patchy distribution consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia. All antibiotics were withdrawn, and prednisone was started at 1.5 mg/kg body weight daily. All symptoms and hypoxemia resolved within 4 days. Although bronchiolitis obliterans with organizing pneumonia was first described in 1901, the first large clinical study and classification of this disease occurred only recently (1). It presents as a cough and flu-like illness that lasts 4 to 10 weeks in most cases. The cough is severe in 75% of the patients, whereas dyspnea dominates the symptom complex in about 50% of the cases. Lung examination shows crackles in 70%, and wheezing occurs only in a few patients (10% to 20%). The disease affects men and women equally (1). The roentgenographic patterns vary; progressive focal or peripheral lesions can result in amorphous opacification with air bronchograms, patchy ground-glass densities, or diffuse nodular infiltrates. Honeycombing is not a feature of the disease (2). Pulmonary function tests show restriction of lung volumes and decreased diffusing capacity. Bronchiolitis obliterans with organizing pneumonia is different from bronchiolitis obliterans with irreversible obstruction seen in transplant patients. It is often confused with idiopathic pulmonary fibrosis, but the pathologic findings, as in the case of our patient, are distinctive (3). The diagnosis of bronchiolitis obliterans with organizing pneumonia cannot be considered if the pathologic findings include eosinophilic pneumonia, features of allergic alveolitis, aspiration, the bronchial sequelae of long-term smoking, or the post-obstructive effects associated with endobronchial tumors (1). Our patient had a total neutrophil count of less than 1200/ mm3 throughout the course of his illness. Considerable debate occurred regarding the cause of his illness and the mechanism of immunologic response in this immunosuppressed host. The granulomatous changes persuaded some to continue antifungal therapy. It was only with the initiation of prednisone therapy that his progressive hypoxemia and disabling febrile course were reversed. The recognition of bronchiolitis obliterans with organizing pneumonia in all settings, including the immunocompromised host, is most critical because of the complete clinical and physiologic recovery seen in 65% of patients treated with prednisone. Recovery should begin within a few days. Although relapses occur with 3-month treatment, most patients respond to extended therapy (3 to 12 months).
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Michael F. Tenholder, MD V e t e r a n s Affairs Medical C e n t e r A u g u s t a , G A 30910 Gregory L. Becker, MD Manuel I. Cervoni, MD W a l t e r R e e d A r m y Medical C e n t e r W a s h i n g t o n , D C 20307-5001
References 1. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med. 1985; 312:152-8. 2. Bartter T, Irwin RS, Nash G, Balikian JP, Hollingsworth HH. Idiopathic bronchiolitis obliterans organizing pneumonia with peripheral infiltrates on chest roentgenogram. Arch Intern Med. 1989;149:273-9. 3. Guerry-Force ML, Muller NL, Wright JL, et al. A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis. 1987; 135:705-12.
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Hypocalcemia, and Hypomagnesemia To the Editor: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is currently being studied as a possible therapy for severe aplastic anemia, although the myelopoietic response to such therapy is usually only transient (1) and is often disappointing in patients with very severe neutropenia (2). Adverse metabolic effects associated with this treatment are rare, but hypokalemia in the setting of GM-CSF therapy has recently been described (3). We report a case of acute hypocalcemia and hypomagnesemia causing tetany in a patient with severe aplastic anemia who was treated with human recombinant mammalian glycosylate (rh) GM-CSF (Sandoz-Schering Plouth, Basel, Switzerland). A 4-year-old boy with idiopathic severe aplastic anemia (hemoglobin, 63 g/L; leukocyte count, 2.6 x 109/L, with all lymphocytes; and platelet count, 11 x 109/L at presentation) was initially treated with rabbit antilymphocyte globulin (Merieux, Lyons, France). He required blood and platelet transfusion support and broad-spectrum antibiotics including cefuroxime, tobramycin, and metronidazole for a persistent oral infection with Vincent organisms (a fusobacterium and a spirochete). Amphotericin B to 1 mg/kg body weight on alternate days was added because of a persisting pyrexia, and oral prednisolone, 1 mg/kg body weight daily, was required for a serum sickness reaction to the antilymphocyte globulin, which manifested as a florid rash and arthralgias. The oral infection did not improve and because of anticipated delay in response to the antilymphocyte globulin, a supply of rh GM-CSF was provided by Sandoz (Basel, Switzerland) for compassionate use. The patient has no siblings and a search for a matched, unrelated donor for possible allogeneic bone marrow transplantation is currently being conducted. Pretreatment assessments of serum creatinine, urea, potassium, calcium, magnesium, and albumin were normal. The rh GM-CSF was given by continuous intravenous infusion via a central line at a dose of 8 fxg/kg body weight daily for 14 days. Adverse effects included further arthralgias, edema of the legs and scrotum, and, on the final day of treatment, acute bilateral tetany of the hands. At this time, the serum albumin level was 27 g/L (normal, 33 to 35 g/L); corrected calcium, 0.99 mmol/L (normal, 2.25 to 2.70 mmol/L); and magnesium, 0.18 mmol/L (normal, 0.7 to 1.0 mmol/L). The serum potassium was also low (2.8 mmol/L [normal, 3.5 to 5.0 mmol/L]), but urea, creatinine, and phosphate remained normal. Urinalysis showed an inappropriately high renal magnesium and calcium loss. The patient responded to intravenous infusion of calcium chloride and magnesium chloride. Oral supplements were required for 4 weeks. He had a good myelopoietic response to the rh GMCSF, with a neutrophil peak of 1.8 x 109/L 10 days after treatment ended, and the oral infection quickly resolved. The origin of the metabolic disturbances in this case was probably multifactorial. Although diarrhea was not observed and parenteral nutritional supplementation was prescribed, aminoglycosides and amphotericin B can cause excess tubular
leakage of potassium and magnesium (4, 5). The timing and unusual severity of the hypocalcemia and hypomagnesemia in this case does, however, suggest that rh GM-CSF may have been an exacerbating factor. One possible mechanism is a secondary hyperaldosteronism and increased proximal tubular excretion of calcium and magnesium after rh GM-CSF-induced capillary leakage and hypoalbuminemia. Patients with severe aplastic anemia often require prolonged courses of aminoglycosides and amphotericin B. Frequent serum chemistry measurement is advisable if rh GM-CSF is used concurrently. M. N. Potter, MB M. G. Mott, MB A. Oakhill, MB Bristol Royal Hospital for Sick Children Bristol BS2 8BJ, United Kingdom
References 1. Vadhan-Raj S, Buescher S, Broxmeyer HE, et al. Stimulation of myelopoiesis in patients with aplastic anemia by recombinant human granulocyte-macrophage colony stimulating factor. N Engl J Med. 1988;319:1628-34. 2. Nissen C, Tichelli A, Gratwohl A, et al. Failure of recombinant human granulocyte-macrophage colony stimulating factor therapy in aplastic anemia patients with very severe neutropenia. Blood. 1988; 72:2045-7. 3. Viens P, Thyss A, Gamier G, Ayela P, Lagrange M, Schneider M. GM-CSF treatment and hypokalemia [Letter]. Ann Intern Med. 1989; 111:263. 4. Davies SV, Murray JA. Amphotericin B, aminoglycosides and hypomagnesaemic tetany. Br Med J. 1986;292:1395-6. 5. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med. 1984;77:471-4.
Tumor Necrosis Factor and Hypermetabolism To the Editor: The role of tumor necrosis factor (cachectin) in the pathogenesis of cachexia from cancer and other chronic diseases remains to be fully explored. Tumor necrosis factor (TNF) inhibits lipoprotein lipase in vitro and causes depletion of fat stores and muscle wasting in animal models (1). We suggest that TNF may also be responsible for alterations in resting metabolic rate. We measured the resting metabolic rate and respiratory quotient in the fasting state by indirect calorimetry in two patients receiving a 24-hour infusion of human recombinant TNF-alpha (200 /ig/m2 body surface area daily) as part of a phase I chemotherapy trial. Patient 1, a 66-year-old man, had hepatic cell carcinoma (height, 168 cm; weight, 59 kg). Patient 2, a 66-year-old woman, had head and neck cancer (height, 150 cm; weight, 45 kg). The resting metabolic rate measured before infusion of TNF was 1501 kcal/24 hours (respiratory quotient, 0.73; oral temperature, 37 °C) in Patient 1 and 1136 kcal/24 hours (respiratory quotient, 0.81; oral temperature, 36.8 °C) in Patient 2. The resting metabolic rates during the last hour of the 24-hour infusion were 1790 kcal/24 hours (respiratory quotient, 0.81; oral temperature, 36.8 °C) and 1407 kcal/24 hours (respiratory quotient, 0.75; oral temperature, 37.1 °C), respectively. The 19% and 25% increase in resting metabolic rate in these two patients were unexpected. Increases in resting metabolic rate associated with pharmacologic TNF infusion in humans have been reported; however, these patients were febrile during the TNF infusion, which may have caused the increased resting metabolic rate (2). The increased rate seen in our two patients could have been either a direct effect of TNF or secondary to other processes such as elevations in catecholamine, Cortisol, or glucagon levels; such elevations have been observed in animal models in which shock was induced by TNF (3). Tumor necrosis factor has been implicated as a mediator of cachexia in cancer and other chronic wasting diseases despite difficulties in its detection. In 64% of patients with oat cell carcinoma, TNF has been detected using a very sensitive assay (4). Interestingly, patients with oat cell cancer have also been shown to be hypermetabolic (5). Our observation poses an interesting question as to whether
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TNF, in addition to possibly altering fuel use in cancer patients, can also alter resting metabolic rate. Timothy B. Seat on, MD Nancy Coombe Abraham Mittelman, MD New York Medical College at Westchester County Medical Center Valhalla, NY 10595
References 1. Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987;316:379-85. 2. Starnes HF, Warren RS, Jeevanadam M, et al. Tumor necrosis factor and the acute metabolic response to tissue injury. J Clin Invest. 1988;82:1321-5. 3. Tracey KJ, Lowry SF, Fahey TJ, et al. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gyn Obs. 1987;164:415-22. 4. Balk will F, Burke F, Talbot D, et al. Evidence for tumor necrosis factor/cachectin production in cancer. Lancet. 1987;2:1229-32. 5. Russell DM, Shike M, Marliss EB, et al. Effects of total parenteral nutrition and chemotherapy on the metabolic derangenments in small cell lung cancer. Can Res. 1984:1706-11.
Richard L. Leff, MD John P. Case, MD National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda, MD 20892 Robin McKenzie, MD National Institute of Allergy and Infectious Diseases Bethesda, MD 20892 References 1. Carson CW, Cannon GW, Egger MJ, et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum. 1987;16:186-95. 2. Perruquet JL, Harrington TM, Davis DE. Pneumocystis carinii pneumonia following methotrexate therapy for rheumatoid arthritis [Letter]. Arthritis Rheum. 1983;26:1291-2. 3. Wallis PJ, Ryatt KS, Constable TJ. Pneumocystis carinii pneumonia complicating low dose methotrexate treatment for psoriatic arthropathy. Ann Rheum Dis. 1989;48:247-9. 4. Altz-Smith M, Kendall LG Jr, Stamm AM. Cryptococcosis associated with low dose methotrexate for arthritis. Am J Med. 1984;83:179-81. 5. Keegan JM, Byrd JW. Nocardiosis associated with low dose methotrexate for rheumatoid arthritis [Letter]. J Rheumatol. 1988;15:1585.
Overuse of Hypotonic Fluids Rheumatoid Arthritis, Methotrexate Therapy, and Pneumocystis Pneumonia To the Editor: Low-dose methotrexate therapy has a 1% to 5% incidence of pneumonitis (1). However, Pneumocystis carinn pneumonia resembling methotrexate-induced pneumonitis has been reported (2, 3) in two patients. In both cases, concomitant low-dose daily corticosteroids may have contributed to immunosuppression. We report a case of P. carinii pneumonia in a patient with rheumatoid arthritis who was treated with low-dose methotrexate without corticosteroids. A 66-year-old man with rheumatoid arthritis presented with progressive cough, fever, and shortness of breath. Methotrexate therapy had been started 6 months earlier, up to 22.5 mg/wk, with marked improvement in his rheumatoid arthritis. A stable dose of tolmetin was the patient's only other medication. He had had coronary artery bypass surgery in 1984. On examination, bilateral basilar crackles were heard. A chest roentgenogram showed diffuse bibasilar and perihilar interstitial infiltrates and right hilar adenopathy with a normal cardiac silhouette. Arterial blood gas on room air had a Po 2 of 60 mm Hg (saturation, 93%). The leukocyte count was 4200/mm3 with a normal differential count. Sputum gram stain and cultures showed no pathogens and multiple blood cultures were negative. A preliminary diagnosis of methotrexate-induced pneumonitis was made, and administration of a single dose of prednisone (60 mg) was followed by rapid defervescence. Bronchoscopy was done the next day, and the wash revealed clusters of P. carinii cysts. Stains and cultures for other organisms were negative. Therapy with high-dose trimethoprim and sulfamethoxazole, followed by pentamidine for a total of 2 weeks resulted in rapid clinical improvement. Over the next 2 years the patient had normal results on tests for T4:T8 ratio, total T4 count, peripheral lymphocyte responsiveness to mitogens, antibody to the human immunodeficiency virus-type 1 (HIV-1) by ELISA and Western blot analysis, polymerase chain reaction for gag sequences, and culture for HIV-1. During this period, the patient's rheumatoid arthritis has remained active and no further significant infections have occurred. Low-dose methotrexate therapy has been implicated as a risk factor for opportunistic infection by cryptococci (4) and in association with concomitant daily corticosteroid therapy for infection by P. carinii (2, 3) and nocardia (5). We would like to add the present case as the first example of P. carinii pneumonia associated with low-dose methotrexate therapy as the sole predisposing factor. The patient we report had peripheral lymphocytes of normal number and function. We suggest, therefore, that opportunistic infections be considered before a definitive diagnosis of methotrexate-induced pneumonitis is made. 716
To the Editor: The recent article by Fraser and Arieff (1) is very well written and provides helpful information concerning the pathophysiology involved in hyponatremia. However, I read this article with dismay and sadness as I thought about the many who died because of the trend to use hypotonic solutions for intravenous fluid therapy. I became aware of this trend about 6 years ago and questioned younger surgeons and anesthesiologists about how it had developed. It appears that university hospital anesthesiologists were aware of a tendency of surgical patients having anesthesia to retain sodium, and hypotonic infusions were thought to be a corrective factor. If so, they were overlooking the capability of stress, anesthesia, narcotics, and surgical procedures to produce SIADH (syndrome of inappropriate antidiuretic hormone) tendencies. Some younger physicians have told me that they were introduced to the idea in their first 2 years of medical school when nonclinicians were teaching correction of theoretical acid-base balance problems using hypotonic solutions. Such "blackboard corrections" obviously did not take into consideration the kidneys, lungs, pituitary gland, and other organs. I am uncertain if the authors handled this subject gingerly because of the medicolegal implications, but it would be a grave oversight if the journal fails to call to the attention of its readers the hazards of this trend, how it can be avoided, and how it should be treated when it does occur. While attending the 1988 Annual Session of the American College of Physicians in New York, my concern prompted me to attend a session by Dr. Patricia Gabow on hyponatremia and hypernatremia. I inquired whether she and others were seeing many patients with hyponatremia. Everyone in the room seemed to have encountered this problem in association with the use of hypotonic fluid infusions. The lecturer described how she herself almost received a similar infusion in the hospital where she had taught house officers not to use hypotonic fluids. In response to my own local inquiry, I found that there are many factors, including use of PC A machines to administer narcotics with an accompanying infusion of hypotonic fluid; the tendency of a busy nurse to respond to the plaintive beep of the infusion device by simply "hanging" fluids similar to the ones the patient had been receiving without considering the duration, sequence, and rate; and the attending physician being unaware of the need to use other than hypotonic fluids, and not reviewing daily the administration, the duration of fluid infusion, the type of fluids being administered, the total received, not ordering SM-7 studies, and not including any of this in the daily progress notes. While I am referring to factors which I believe cause hyponatremia from my observations, I want to stress that I think my hospital and others in this area have been very lucky, and we are alerting staff members to recognize and prevent these
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problems. The reason that this problem was not encountered previously is that the former custom was to alternate infusions and D5 in 0.9% saline with D5 in water, which would average out to be infusions of 0.45% saline. I believe that studies would show that there has been a marked decrease in the infusion of 0.9% saline; when 0.45% saline is alternated with D5 in water, hyponatremia can easily develop. Although most medical techniques and treatments have improved, this instance is one in which progress has been backward.
Michael J. Moore, MD Lewis-Gale Clinic, Inc. Salem, VA 24153
Reference 1. Fraser CL, Arieff AI. Fatal central diabetes mellitus and insipidus resulting from hyponatremia. A new syndrome. Ann Intern Med. 1990;112:113-9. Correction: Title of Book Reviewed in The Literature of Medicine Section The title of a book reviewed in the 15 March 1990 issue (1) should have read: The Story of Iodine Deficiency: An International Challenge in Nutrition. Reference 1. Bertenshaw R, Refetoff S. The Study of Iodine Deficiency: An International Challenge in Nutrition. Ann Intern Med. 1990;112:478.
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Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request.
Kirk V. Shepard, MD Roxane Laboratories, Inc. Columbus, OH 43216-6532 References 1. Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med. 1989;111:947-9. 2. Burnett RJ. Sodium poly sty rene-sorbitol enemas. Ann Intern Med. 1990;112:311-2. 3. Product Information: Sodium Polystyrene Sulfonate Suspension. Roxane Laboratories, Columbus, Ohio, 1988. [Available from Roxane Laboratories, Inc., P.O. Box 16532, Columbus, OH 43216-6532.] 4. Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101:266-72.
5. Flanigan RC, Reckard CR, Lucas BA. Colonic complications of renal transplantation. J Urol. 1988;139:503-6. Antibiotics for Urinary Tract Infections in Women
Cleansing Enemas after Sodium Polystyrene Sulfonate Enemas To the Editor: An article by Wootton and colleagues (1) in a recent issue concerned a patient who had necrosis of the colon after he was administered a sodium polystyrene sulfonate suspension enema. A subsequent letter to the Editor by Burnett (2) questioned whether cleansing enemas had been administered to the patient before and after the sodium polystyrene sulfonate suspension enema, as is stated in bold type on the product insert, on the product label, and on the carton (3). In a discussion with one of the authors of this case report, I was told that the patient was not given cleansing enemas. Another paper by Lillemoe and colleagues (4), published in 1987, described five patients who had similar complications after sodium polystyrene sulfonate suspension enemas were administered. Subsequent discussions with one of these authors revealed that these patients also were not administered a cleansing enema. The six patients mentioned in these two articles are the only patients reported to us as having had this complication after the administration of sodium polystyrene sulfonate enemas. All six patients had the product administered improperly, and not in accordance with the product insert, product label, and product carton. This complication has never been reported when the product is administered properly according to the insert and label. The authors of the case report (1) attempted to implicate the inclusion of sorbitol in the sodium polystyrene sulfonate suspension enema as the agent causing necrosis of the colon. Because sodium polystyrene sulfonate suspension enemas are usually administered only to very ill patients with hyperkalemia, these case reports do not provide conclusive evidence that sorbitol causes the complications in the colon. There are also other theories, such as the disease itself or other medications, that have been suggested by experts as to why these colonic complications occur (5). The important point is that conclusions reached from research, especially from case reports, on the effects of therapy are inappropriate when the product is administered improperly and not according to the product insert and label.
To the Editor: I read with great interest the fine paper by Johnson and Stamm (1), updating proper diagnosis and treatment of urinary tract infections in women. Their otherwise comprehensive review of a complex subject was slightly marred by the inclusion of nonequivalent doses in some of their comparative tables (Tables 3 and 9). In a footnote, the authors do provide the caveat that in certain patients it may be preferable to use different doses or intervals. Nevertheless, Table 3 seems to indicate (based on the cost per day column) that the choices as given are comparable. This is not the case. As an illustration, a maximal dose of ceftazidime (2 g every 8 hours) is given whereas an agent with a roughly similar half-life and spectrum, aztreonam, is given at half the dose and therefore at seemingly half the cost per day. Similarly, ticarcillinclavulanate usage is for a near maximal dose with a resultant high cost whereas ampicillin-sulbactam and ureidopenicillins are shown for moderate doses and thus appear to be significantly cheaper. The same problem is found in the aminoglycoside grouping and with other betalactams and quinolones. The uninitiated, looking at the cost per day, may draw improper conclusions regarding the optimal cost-effective agent to use. It would be more appropriate to have chosen doses and intervals reflecting clinical usage of the agents for the same type of patient rather that having certain agents listed at a maximal dose (for "sicker" patients) compared with others listed at a minimal dose (for less severely ill patients). Finally, the authors state "in uncomplicated cases a single broad-spectrum intravenous agent can be used initially" and in Table 9 list ampicillin as a possible (albeit not the preferred) choice. Earlier in the article, however, the authors accurately state that increasing frequency of resistance to ampicillin among even community-acquired Escherichia coli strains has greatly diminished the attractiveness of ampicillin as part of an empiric regimen. Therefore, it would have been better to delete ampicillin as a (sole) initial choice for intravenous therapy for acute pyelonephritis. Aaron E. Glatt, MD Nassau County Medical Center East Meadow, NY 11554 Reference 1. Johnson JR, Stamm WE. Urinary tract infections in women: diagnosis and treatment. Ann Intern Med. 1989;111:906-17.
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In response: We thank Dr. Glatt for his warm reception of our paper (1) and appreciate the opportunity to respond to his specific comments. Determining equivalent doses for different antimicrobial agents can be problematic. We agree that it is desirable for doses and intervals shown in tables comparing drug costs to reflect actual clinical usage of the agents. In preparing the tables in our study (1), we considered the regimens used in published clinical trials of these newer agents and the dosing recommendations by authorities in the field (2). Dr. Glatt is concerned that we chose too high a dose for ceftazidime in comparison with the dose chosen for aztreonam, thereby exaggerating the difference in cost between these agents. We concur that the dose we selected for ceftazidime is at the high end although it is not inconsistent with clinical practice. As Dr. Glatt suggests, a fairer cost comparison with aztreonam might be obtained using half the given dose of ceftazidime; however, ceftazidime would still cost more. Although aztreonam doses ranging from 1 to 6 g daily have been used in clinical trials (reference 72 of [1]), most patients in these studies received 1 g every 6 or 8 hours (reference 71 of [1]). The dose of 1 g every 8 hours shown in our table reflects this experience. Dr. Glatt is concerned that we selected a "near maximal" dose for ticarcillin plus clavulanate, but only "moderate" doses for the ureidopenicillins. For ticarcillin plus clavulanate, however, the dose we used (3.1 g every 6 hours) is only half of the maximal dose listed in one source (2) and is entirely consistent with doses studied in several clinical trials (references 48-50 of [1]). For the ureidopenicillins, the dose we used (2 g every 6 hours) is not low in the context of doses used in recent trials (references 48 and 61 of [1]), and is even higher (for mezlocillin) than that recommended for urinary tract infections in one source (2). The doses we showed for the aminoglycosides (4.5 mg/ kg • d; 15 mg/kg • d for amikacin) are standard. We suggested a twice-daily dose of 400 mg for norfloxacin and 250 mg for ciprofloxacin because most of the published clinical experience with these agents in urinary tract infection has been with these doses (3). It should be noted that preparation and administration charges add $10 to $15 to the cost of each dose of antibiotic administered. Thus, actual total daily costs for antibiotic therapy depend not only on the total amount of drug given (as shown in our tables [1]) but on the number of doses administered, with shorter dosing intervals leading to markedly increased costs exclusive of the cost of the agent itself. Additionally, the prices shown in our tables (1) reflect manufacturers' average wholesale prices; actual costs may be lower with competitive bidding. We join with Dr. Glatt in discouraging the use of intravenous ampicillin alone for the initial therapy of acute pyelonephritis. As indicated in a footnote to Table 9(1), any initial regimen for acute pyelonephritis should cover all likely pathogens; it is clear from Table 2(1) that ampicillin fails badly in this respect if not combined with a more broadly active agent. We included ampicillin in Table 9 because ampicillin is currently among the most commonly used agents in the treatment of acute pyelonephritis, especially during pregnancy, and because intravenous ampicillin alone is acceptable once the isolate has been shown to be susceptible to it. James R. Johnson, MD University of Minnesota Minneapolis, MN 55455 Walter E. Stamm, MD University of Washington Harborview Medical Center Seattle, WA 98104
References 1. Johnson JR, Stamm WE. Urinary tract infections in women: diagnosis and treatment. Ann Intern Med. 1989;111:906-17. 2. Sanford JP. Guide to Antimicrobial Therapy. West Bethesda, Maryland: Antimicrobial Therapy, Inc.; 1988:44-59.
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3. Naber KG. Use of quinolones in urinary tract infections and prostatitis. Rev Infect Dis. 1989;ll(Suppl 5):S1321-7.
Myocardial Infarction during Cocaine Withdrawal To the Editor: Nademanee and colleagues (1) demonstrated ST segment changes of silent ischemia during Holter monitoring in 8 of 21 chronic cocaine abusers who had stopped taking the drug an average of 8.5 days before testing. These patients had normal exercise treadmill tests and were presumed free of significant coronary atherosclerosis. The authors of this interesting study proposed the dopamine depletion hypothesis to explain the coronary vasoconstriction (spasm) observed in these subjects. We report a case of myocardial infarction during cocaine withdrawal and postulate an alternative hypothesis to explain this phenomenon. A 42-year-old male chronic cocaine (crack) smoker was hospitalized for severe chest pain that occurred with strenuous exercise 3 days after he stopped using cocaine. The patient was alert, diaphoretic, and agitated. His lungs were clear and heart sounds were normal. The electrocardiogram showed ST elevations in III and AVF. The creatine kinase level was 738 U/L with an MB fraction of 7.5%. Cocaine metabolites were absent in the blood but present in the urine. A cardiac angiogram showed normal coronary arteries and inferior-wall hypokinesis. An exercise stress test done before discharge was normal. We believe our case is the first report of a myocardial infarction during cocaine withdrawal. Previously reported cases of cocaine-related myocardial infarction have been attributed to a direct effect of the drug (2). Because of cocaine's short half-life, however, it is likely that many infarctions were not caused by the drug itself. The dopamine depletion hypothesis may explain the psychologic abnormalities and the central system effects induced by cocaine (3). Nevertheless, there is no convincing evidence that presynaptic dopamine receptors play a significant role in adrenergic neurotransmision (4). It is known, however, that chronic cocaine abuse induces catecholamine depletion and paradoxic upregulation of postsynaptic receptors (2). We suspect that, during abstinence, progressive replenishment of catecholamine may occur in the setting of increased adrenergic receptors. This transient imbalance can provide the context for a disproportionate sympathetic response to an adrenergic stimulus such as exercise. The potential for ischemic complications would be determined by the degree of adrenergic stimulation and by the presence of other known risk factors. Cesar Del Aguila, MD Howard Rosman, MD Henry Ford Hospital Detroit, MI 48202-2689
References 1. Nademanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111:876-80. 2. Frishman WH, Karpenos A, Molloy TJ. Cocaine-induced coronary artery disease: recognition and treatment. Med Clin North Am. 1989; 73:475-86. 3. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev. 1985;9:1-9. 4. Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol Rev. 1980;32:337-62.
Visual Symptoms after Atenolol Therapy for Migraine To the Editor: Chronic headache is common in the general population. Ten to twenty percent of chronic headaches are migraine. Beta blockers have been used widely to prevent both common and classic migraine for more than 20 years. In studies documenting the effectiveness of propranolol and other beta blockers, including atenolol, timolol, nadolol, and metoprolol, in preventing migraine, the reported side effects have been drowsiness, fatigue, nightmares, and depression. We report a patient who developed marked visual symptoms consisting of
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scotoma and scintillations in the absence of headache after treatment of her migraine with atenolol. A 37-year-old woman was seen in our headache clinic with a history of migraine from age 17. Her headaches initially occurred two to three times a year but had increased to three to five times a month during the last 5 years. Scotoma and scintillations occurred only once or twice a year. After being evaluated, she was started on atenolol, 50 mg/d. After 3 weeks of treatment, she noted a marked reduction in the frequency and severity of her headaches. At the same time, she noticed visual symptoms consisting of scotoma and scintillations that occurred two to three times a week, lasted for 20 to 30 minutes, and were followed rarely by a headache. Atenolol was withdrawn and she was started on timed-release verapamil, 240 mg/d. Since then, she has not had any visual symptoms or migraine. During further discussion of her visual symptoms and their likely relationship to atenolol therapy, the patient recalled having had similar symptoms during treatment with nadolol several years ago. The mechanism by which beta blockers prevent migraine is not well defined. They are known, however, to decrease cerebral blood flow. During the aura of a migraine attack, cerebral blood flow is reduced. By further reducing the cerebral blood flow during the aura, beta blockers could potentially produce cerebral ischemia or infarction. This hypothesis is supported by case reports of patients with classic and hemiplegic migraine who had strokes while on propranolol therapy (1-3). In a controlled trial (4) of the prophylactic effect of metoprolol on patients with classic migraine, scintillations occurred more often in patients on metoprolol therapy than on placebo. However, patients in this study were reported to have symptoms of aura without a headache. Our patient appears to be unique because she had prominent visual symptoms without the headache, a side effect of therapy not previously reported. Because of the pathophysiology of migraine and reports of occurrence of strokes during treatment with beta blockers, we believe that beta blockers should not be used in patients with complicated migraine and only with caution in classic migraine. Similarly, ergotamines, which have a vasoconstrictive effect on cerebral circulation, should be considered as contraindicated in such patients. Calcium channel blockers may increase the cerebral blood flow and thus may be the agents of choice in such patients (5). Kusum L. Kumar, MD Thomas G. Cooney, MD Oregon Health Sciences University Veterans Affairs Medical Center Portland, OR 97207
Clinical trials of acute stroke should be based on rational, clinically testable hypotheses and therapeutic approaches. For rational hypothesis testing, the pathogenesis of acute cerebral focal ischemia in a given patient may need to be known. The time-consuming nature of such investigations has been shown in well-conducted studies of the very early acute use of fibrinolytic agents after the onset of thrombotic stroke, at highly motivated and efficient centers in three countries. In all cases, computed tomographic (CT) scans and angiographic procedures were required immediately after the patient arrived to identify the symptomatic occlusion. The intervals from symptom onset to treatment averaged 7.6 ± 5.6 h (2) and 4.3 ± 2.9 h (3) in carotid territory stroke, and less than 24 h in one study (4) of vertebrobasilar territory stroke. In one cohort of patients entered into the ongoing t-PA/Acute Stroke Study Group trial (5), the average interval from hospital arrival to completion of CT scan and angiography has been 2.38 ± 0.74 h. The hypotheses to be tested in each case were that acute intervention with thrombolytic agents is feasible and produces reperfusion of documented symptomatic arterial thrombotic occlusions, and that vascular reperfusion by such agents is safe. In this setting early entry alone does not compensate for not knowing the cause of the stroke (that is, whether a thrombus is present). In addition, spontaneous neurologic recovery after focal stroke may occur without intervention as late as 6 hours after the onset of symptoms, often obscuring the relation between unproven "therapies" and outcome. Hence, many questions remain regarding the minimum and maximum intervals necessary for successful stroke intervention and their relation to the therapy being tested. Although early treatment of stroke remains a pursued and laudable goal, a "trauma-style approach" will not be feasible until we develop rational therapeutic strategies based on pathophysiology, and test them in randomized clinical trials. There is little question of the need for rational hypotheses and relevant testable agents and approaches in concert with well-directed, national and community-based patient education. Gregory J. del Zoppo, MD Scripps Clinic and Research Foundation La Jolla, CA Anthony Furlan, MD The Cleveland Clinic Foundation Cleveland, OH Werner Hacke, MD Universitat Heidelberg Heidelberg, Federal Republic of Germany
References 1. Gilbert GJ. An occurrence of complicated migraine during propranolol therapy. Headache. 1982;22:81-3. 2. Bard well A, Trott J A. Stroke in migraine as a consequence of propranolol. Headache. 1987;27:381-3. 3. Prendes JL. Considerations on the use of propranolol in complicated migraine. Headache. 1980;20:93-5. 4. Hedman C, Andersen AR, Andersson PG, et al. Symptoms of classic migraine attacks: modifications brought about by metoprolol. Cephalalgia. 1988;8:279-84. 5. Solomon GD. Comparative efficacy of calcium antagonist drugs in the prophylaxis of migraine. Headache. 1985;25:368-71.
Treatment of Acute Stroke To the Editor: We read with admiration the recent editorial of Barsan and colleagues (1) regarding their experience with "trauma-style" approaches to early treatment for acute ischemic stroke. Clearly, entry of patients within 90 minutes of symptom onset requires an efficient and labor-intensive accrual system, currently available in few communities. Although we agree that "early treatment should be a priority in future treatment trials of acute ischemic stroke," several significant and practical limitations revealed by recent acute stroke trials should not be overlooked.
References 1. Barsan WG, Brott TG, Olinger CP, Marler JR. Early treatment for acute ischemic stroke. Ann Intern Med. 1989;111:449-51. 2. del Zoppo GJ, Ferbert A, Otis S, et al. Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study. Stroke. 1988; 19:307-13. 3. Mori E, Tabuchi M, Yoshida T, Yamadori A. Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke. 1988;19:802-12. 4. Hacke W, Zeumer H, Ferbert A, Bruckmann H, del Zoppo GJ. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988;19:1216-22. 5. An open multicenter study of the safety and efficacy of various doses of rt-PA in patients with acute stroke: preliminary results The t-PA/Acute Stroke Study Group. [Abstract]. Stroke. 1988;19:134.
Lovastatin, Pravastatin, and Serum Lipoprotein(a) To the Editor: Genetically determined high concentrations of lipoprotein(a) [Lp(a)] have been strongly associated with premature cardiovascular disease (1), myocardial infarction (2), and cerebrovascular disease (3) in men. Until now, none of the classic hypolipidemic drugs has clearly been shown to influence this risk factor (4). There are controversial findings regarding the new class of HMG-CoA (3-hydroxy-3-methylglu-
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taryl coenzyme A) reductase inhibitors. Berg and Leren (5) reported unchanged serum Lp(a) concentrations in 30 patients with familial hypercholesterolemia treated with lovastatin, whereas Jurgens and colleagues (6) found an increased Lp(a) level during treatment with lovastatin in 8 patients. We therefore studied the effect of two HMG-CoA reductase inhibitors (lovastatin and pravastatin) on the serum levels of Lp(a) in 35 patients with severe hypercholesterolemia. During a 16-week period, 17 patients (10 women, 7 men) were treated consecutively with 20 mg, 40 mg, and 80 mg of lovastatin daily, whereas 18 patients (6 women, 12 men) were given 20 mg and 40 mg of pravastatin daily for 16 weeks. The lovastatin group did not differ significantly from the pravastatin group in mean age (50 compared with 51 years); body-mass index (25.6 compared with 24.5 kg/m2); total serum cholesterol before treatment (373 ± 14 compared with 373 ± 17 mg/dL); low-density lipoprotein (300 ± 13 compared with 307 ± 17 mg/dL); high-density lipoprotein (45 ± 3 mg/dL in both groups); triglycerides (152 ± 19 compared with 136 ± 14 mg/ dL); and Lp(a) (17.6 ± 3.1 compared with 23.7 ± 4.3 mg/dL). (The Lp[a] level was determined using a radioimmunometric assay [Pharmacia, Uppsala, Sweden].) Additionally, another group of 8 patients (3 women, 5 men) who were being treated with cholestyramine, 16 g daily, was followed for 16 weeks (initial Lp[a] level, 11.9 ± 2.9 mg/dL). Lovastatin and pravastatin (in terms of milligrams of drug given daily) showed marked and similar effects on the reduction of total cholesterol, low-density lipoprotein, and apolipoprotein B. However, pretreatment Lp(a) values did not differ significantly from those observed during therapy (week 16, 16.9 ± 3.5 mg/dL [-4%] in the lovastatin group; 25.3 ± 5.0 mg/dL [-1-7%] in the pravastatin group). Studying only the patients with higher Lp(a) values (exceeding 30 mg/dL) we observed no significant change in Lp(a) values with therapy, especially no increase. As shown previously (4), cholestyramine alone also had no effect on serum Lp(a) in the group of 8 patients (week 16, 12.8 ± 4.0 mg/dL; +8%). After 16 weeks on HMG-CoA reductase inhibitor therapy, cholestyramine, 8 g/d, was added to the regimen for these patients. Six of the patients receiving combined therapy with lovastatin and cholestyramine and 13 of the patients receiving pravastatin and cholestyramine were followed for over 1 year. Even after this long treatment period, neither of the two HMGCoA reductase inhibitors was able to influence the Lp(a) level (lovastatin plus cholestyramine, 17.7 ± 9.5 compared with 17.4 ± 9.2 mg/dL; pravastatin plus cholestyramine, 21.8 ± 6.4 compared with 20.4 ± 6.4 mg/dL). We conclude that HMGCoA reductase inhibitors do not exert any unfavorable effect on Lp(a) serum levels. Bernd G. Jacob, MD Werner O. Richter, MD Peter Schwandt, MD University of Munich 8000 Munich 70 Federal Republic of Germany
References 1. Dahlen GH, Guyton JR, Attar M, Farmer J A, Kautz JA, Gotto AM Jr. Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation. 1986;74:758-65. 2. Rhoads GG, Dahlen GH, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA. 1986; 256:2540-4. 3. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M. Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction. Atherosclerosis. 1986;59:199-204. 4. Kostner G, Klein G, Krempler F. Can serum Lp(a) concentrations be lowered by drugs and/or diet? In: Carlson LA, Olsson AG, eds. Treatment of Hyperlipoproteinemia. New York: Raven Press; 1984: 151-6. 5. Berg K, Leren TP. Unchanged serum lipoprotein(a) concentrations with lovastatin [Letter]. Lancet. 1989;2:812. 6. Jurgens G, Ashy A, Zenker G. Raised serum lipoprotein during treatment with lovastatin [Letter]. Lancet. 1989;1:911-2.
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The Myelodysplastic Syndrome and Bronchiolitis Obliterans To the Editor: We have identified bronchiolitis obliterans with organizing pneumonia as a cause of refractory hypoxemia, infiltrates, and relentless fever in a patient with the myelodysplastic syndrome. A 58-year-old white man with a 40-pack-year smoking history presented with a 6-week history of fever, productive cough, dyspnea, and a weight loss of 4 kg. He also had pancytopenia. The total leukocyte count was 2700/mm3; the hemoglobin, 10.0 g/dL; and the platelet count, 73 x 103/ mm3. A bone marrow biopsy specimen showed refractory anemia with excess blasts-a myelodysplastic syndrome. Physical examination showed the following: blood pressure, 125/65 mm Hg; pulse, 95/min; respiratory rate, 21/min; and temperature, 38.3 °C. There were bibasilar rales with egophony in both midlung fields. The initial chest roentgenogram showed bilateral infiltrates. The room air arterial blood gas analysis showed the following: Pao^, 62 mm Hg; Pacc^, 35 mm Hg; and pH, 7.43. Despite several courses of broad-spectrum antibiotics and amphotericin over 3 weeks, daily fever (38.3 °C to 39.4 °C) continued, and hypoxemia worsened (Pac^, 72 mm Hg with 50% Fio2). A repeat chest roentgenogram showed some clearing of the left lung infiltrate, but a progressive alveolar consolidation appeared on the right side. All surveillance cultures and special stains from both bronchoalveolar lavage and transbronchial biopsy specimens were negative for pathogens. A biopsy specimen obtained during the thoracotomy showed peribronchial and interstitial lymphoplasmacytic inflammation, poorly formed histiocytic granulomas with intrabronchiolar necrosis, distal focal collections of alveolar neutrophils, and edema in a patchy distribution consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia. All antibiotics were withdrawn, and prednisone was started at 1.5 mg/kg body weight daily. All symptoms and hypoxemia resolved within 4 days. Although bronchiolitis obliterans with organizing pneumonia was first described in 1901, the first large clinical study and classification of this disease occurred only recently (1). It presents as a cough and flu-like illness that lasts 4 to 10 weeks in most cases. The cough is severe in 75% of the patients, whereas dyspnea dominates the symptom complex in about 50% of the cases. Lung examination shows crackles in 70%, and wheezing occurs only in a few patients (10% to 20%). The disease affects men and women equally (1). The roentgenographic patterns vary; progressive focal or peripheral lesions can result in amorphous opacification with air bronchograms, patchy ground-glass densities, or diffuse nodular infiltrates. Honeycombing is not a feature of the disease (2). Pulmonary function tests show restriction of lung volumes and decreased diffusing capacity. Bronchiolitis obliterans with organizing pneumonia is different from bronchiolitis obliterans with irreversible obstruction seen in transplant patients. It is often confused with idiopathic pulmonary fibrosis, but the pathologic findings, as in the case of our patient, are distinctive (3). The diagnosis of bronchiolitis obliterans with organizing pneumonia cannot be considered if the pathologic findings include eosinophilic pneumonia, features of allergic alveolitis, aspiration, the bronchial sequelae of long-term smoking, or the post-obstructive effects associated with endobronchial tumors (1). Our patient had a total neutrophil count of less than 1200/ mm3 throughout the course of his illness. Considerable debate occurred regarding the cause of his illness and the mechanism of immunologic response in this immunosuppressed host. The granulomatous changes persuaded some to continue antifungal therapy. It was only with the initiation of prednisone therapy that his progressive hypoxemia and disabling febrile course were reversed. The recognition of bronchiolitis obliterans with organizing pneumonia in all settings, including the immunocompromised host, is most critical because of the complete clinical and physiologic recovery seen in 65% of patients treated with prednisone. Recovery should begin within a few days. Although relapses occur with 3-month treatment, most patients respond to extended therapy (3 to 12 months).
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Michael F. Tenholder, MD V e t e r a n s Affairs Medical C e n t e r A u g u s t a , G A 30910 Gregory L. Becker, MD Manuel I. Cervoni, MD W a l t e r R e e d A r m y Medical C e n t e r W a s h i n g t o n , D C 20307-5001
References 1. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med. 1985; 312:152-8. 2. Bartter T, Irwin RS, Nash G, Balikian JP, Hollingsworth HH. Idiopathic bronchiolitis obliterans organizing pneumonia with peripheral infiltrates on chest roentgenogram. Arch Intern Med. 1989;149:273-9. 3. Guerry-Force ML, Muller NL, Wright JL, et al. A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis. 1987; 135:705-12.
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Hypocalcemia, and Hypomagnesemia To the Editor: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is currently being studied as a possible therapy for severe aplastic anemia, although the myelopoietic response to such therapy is usually only transient (1) and is often disappointing in patients with very severe neutropenia (2). Adverse metabolic effects associated with this treatment are rare, but hypokalemia in the setting of GM-CSF therapy has recently been described (3). We report a case of acute hypocalcemia and hypomagnesemia causing tetany in a patient with severe aplastic anemia who was treated with human recombinant mammalian glycosylate (rh) GM-CSF (Sandoz-Schering Plouth, Basel, Switzerland). A 4-year-old boy with idiopathic severe aplastic anemia (hemoglobin, 63 g/L; leukocyte count, 2.6 x 109/L, with all lymphocytes; and platelet count, 11 x 109/L at presentation) was initially treated with rabbit antilymphocyte globulin (Merieux, Lyons, France). He required blood and platelet transfusion support and broad-spectrum antibiotics including cefuroxime, tobramycin, and metronidazole for a persistent oral infection with Vincent organisms (a fusobacterium and a spirochete). Amphotericin B to 1 mg/kg body weight on alternate days was added because of a persisting pyrexia, and oral prednisolone, 1 mg/kg body weight daily, was required for a serum sickness reaction to the antilymphocyte globulin, which manifested as a florid rash and arthralgias. The oral infection did not improve and because of anticipated delay in response to the antilymphocyte globulin, a supply of rh GM-CSF was provided by Sandoz (Basel, Switzerland) for compassionate use. The patient has no siblings and a search for a matched, unrelated donor for possible allogeneic bone marrow transplantation is currently being conducted. Pretreatment assessments of serum creatinine, urea, potassium, calcium, magnesium, and albumin were normal. The rh GM-CSF was given by continuous intravenous infusion via a central line at a dose of 8 fxg/kg body weight daily for 14 days. Adverse effects included further arthralgias, edema of the legs and scrotum, and, on the final day of treatment, acute bilateral tetany of the hands. At this time, the serum albumin level was 27 g/L (normal, 33 to 35 g/L); corrected calcium, 0.99 mmol/L (normal, 2.25 to 2.70 mmol/L); and magnesium, 0.18 mmol/L (normal, 0.7 to 1.0 mmol/L). The serum potassium was also low (2.8 mmol/L [normal, 3.5 to 5.0 mmol/L]), but urea, creatinine, and phosphate remained normal. Urinalysis showed an inappropriately high renal magnesium and calcium loss. The patient responded to intravenous infusion of calcium chloride and magnesium chloride. Oral supplements were required for 4 weeks. He had a good myelopoietic response to the rh GMCSF, with a neutrophil peak of 1.8 x 109/L 10 days after treatment ended, and the oral infection quickly resolved. The origin of the metabolic disturbances in this case was probably multifactorial. Although diarrhea was not observed and parenteral nutritional supplementation was prescribed, aminoglycosides and amphotericin B can cause excess tubular
leakage of potassium and magnesium (4, 5). The timing and unusual severity of the hypocalcemia and hypomagnesemia in this case does, however, suggest that rh GM-CSF may have been an exacerbating factor. One possible mechanism is a secondary hyperaldosteronism and increased proximal tubular excretion of calcium and magnesium after rh GM-CSF-induced capillary leakage and hypoalbuminemia. Patients with severe aplastic anemia often require prolonged courses of aminoglycosides and amphotericin B. Frequent serum chemistry measurement is advisable if rh GM-CSF is used concurrently. M. N. Potter, MB M. G. Mott, MB A. Oakhill, MB Bristol Royal Hospital for Sick Children Bristol BS2 8BJ, United Kingdom
References 1. Vadhan-Raj S, Buescher S, Broxmeyer HE, et al. Stimulation of myelopoiesis in patients with aplastic anemia by recombinant human granulocyte-macrophage colony stimulating factor. N Engl J Med. 1988;319:1628-34. 2. Nissen C, Tichelli A, Gratwohl A, et al. Failure of recombinant human granulocyte-macrophage colony stimulating factor therapy in aplastic anemia patients with very severe neutropenia. Blood. 1988; 72:2045-7. 3. Viens P, Thyss A, Gamier G, Ayela P, Lagrange M, Schneider M. GM-CSF treatment and hypokalemia [Letter]. Ann Intern Med. 1989; 111:263. 4. Davies SV, Murray JA. Amphotericin B, aminoglycosides and hypomagnesaemic tetany. Br Med J. 1986;292:1395-6. 5. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med. 1984;77:471-4.
Tumor Necrosis Factor and Hypermetabolism To the Editor: The role of tumor necrosis factor (cachectin) in the pathogenesis of cachexia from cancer and other chronic diseases remains to be fully explored. Tumor necrosis factor (TNF) inhibits lipoprotein lipase in vitro and causes depletion of fat stores and muscle wasting in animal models (1). We suggest that TNF may also be responsible for alterations in resting metabolic rate. We measured the resting metabolic rate and respiratory quotient in the fasting state by indirect calorimetry in two patients receiving a 24-hour infusion of human recombinant TNF-alpha (200 /ig/m2 body surface area daily) as part of a phase I chemotherapy trial. Patient 1, a 66-year-old man, had hepatic cell carcinoma (height, 168 cm; weight, 59 kg). Patient 2, a 66-year-old woman, had head and neck cancer (height, 150 cm; weight, 45 kg). The resting metabolic rate measured before infusion of TNF was 1501 kcal/24 hours (respiratory quotient, 0.73; oral temperature, 37 °C) in Patient 1 and 1136 kcal/24 hours (respiratory quotient, 0.81; oral temperature, 36.8 °C) in Patient 2. The resting metabolic rates during the last hour of the 24-hour infusion were 1790 kcal/24 hours (respiratory quotient, 0.81; oral temperature, 36.8 °C) and 1407 kcal/24 hours (respiratory quotient, 0.75; oral temperature, 37.1 °C), respectively. The 19% and 25% increase in resting metabolic rate in these two patients were unexpected. Increases in resting metabolic rate associated with pharmacologic TNF infusion in humans have been reported; however, these patients were febrile during the TNF infusion, which may have caused the increased resting metabolic rate (2). The increased rate seen in our two patients could have been either a direct effect of TNF or secondary to other processes such as elevations in catecholamine, Cortisol, or glucagon levels; such elevations have been observed in animal models in which shock was induced by TNF (3). Tumor necrosis factor has been implicated as a mediator of cachexia in cancer and other chronic wasting diseases despite difficulties in its detection. In 64% of patients with oat cell carcinoma, TNF has been detected using a very sensitive assay (4). Interestingly, patients with oat cell cancer have also been shown to be hypermetabolic (5). Our observation poses an interesting question as to whether
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TNF, in addition to possibly altering fuel use in cancer patients, can also alter resting metabolic rate. Timothy B. Seat on, MD Nancy Coombe Abraham Mittelman, MD New York Medical College at Westchester County Medical Center Valhalla, NY 10595
References 1. Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987;316:379-85. 2. Starnes HF, Warren RS, Jeevanadam M, et al. Tumor necrosis factor and the acute metabolic response to tissue injury. J Clin Invest. 1988;82:1321-5. 3. Tracey KJ, Lowry SF, Fahey TJ, et al. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gyn Obs. 1987;164:415-22. 4. Balk will F, Burke F, Talbot D, et al. Evidence for tumor necrosis factor/cachectin production in cancer. Lancet. 1987;2:1229-32. 5. Russell DM, Shike M, Marliss EB, et al. Effects of total parenteral nutrition and chemotherapy on the metabolic derangenments in small cell lung cancer. Can Res. 1984:1706-11.
Richard L. Leff, MD John P. Case, MD National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda, MD 20892 Robin McKenzie, MD National Institute of Allergy and Infectious Diseases Bethesda, MD 20892 References 1. Carson CW, Cannon GW, Egger MJ, et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum. 1987;16:186-95. 2. Perruquet JL, Harrington TM, Davis DE. Pneumocystis carinii pneumonia following methotrexate therapy for rheumatoid arthritis [Letter]. Arthritis Rheum. 1983;26:1291-2. 3. Wallis PJ, Ryatt KS, Constable TJ. Pneumocystis carinii pneumonia complicating low dose methotrexate treatment for psoriatic arthropathy. Ann Rheum Dis. 1989;48:247-9. 4. Altz-Smith M, Kendall LG Jr, Stamm AM. Cryptococcosis associated with low dose methotrexate for arthritis. Am J Med. 1984;83:179-81. 5. Keegan JM, Byrd JW. Nocardiosis associated with low dose methotrexate for rheumatoid arthritis [Letter]. J Rheumatol. 1988;15:1585.
Overuse of Hypotonic Fluids Rheumatoid Arthritis, Methotrexate Therapy, and Pneumocystis Pneumonia To the Editor: Low-dose methotrexate therapy has a 1% to 5% incidence of pneumonitis (1). However, Pneumocystis carinn pneumonia resembling methotrexate-induced pneumonitis has been reported (2, 3) in two patients. In both cases, concomitant low-dose daily corticosteroids may have contributed to immunosuppression. We report a case of P. carinii pneumonia in a patient with rheumatoid arthritis who was treated with low-dose methotrexate without corticosteroids. A 66-year-old man with rheumatoid arthritis presented with progressive cough, fever, and shortness of breath. Methotrexate therapy had been started 6 months earlier, up to 22.5 mg/wk, with marked improvement in his rheumatoid arthritis. A stable dose of tolmetin was the patient's only other medication. He had had coronary artery bypass surgery in 1984. On examination, bilateral basilar crackles were heard. A chest roentgenogram showed diffuse bibasilar and perihilar interstitial infiltrates and right hilar adenopathy with a normal cardiac silhouette. Arterial blood gas on room air had a Po 2 of 60 mm Hg (saturation, 93%). The leukocyte count was 4200/mm3 with a normal differential count. Sputum gram stain and cultures showed no pathogens and multiple blood cultures were negative. A preliminary diagnosis of methotrexate-induced pneumonitis was made, and administration of a single dose of prednisone (60 mg) was followed by rapid defervescence. Bronchoscopy was done the next day, and the wash revealed clusters of P. carinii cysts. Stains and cultures for other organisms were negative. Therapy with high-dose trimethoprim and sulfamethoxazole, followed by pentamidine for a total of 2 weeks resulted in rapid clinical improvement. Over the next 2 years the patient had normal results on tests for T4:T8 ratio, total T4 count, peripheral lymphocyte responsiveness to mitogens, antibody to the human immunodeficiency virus-type 1 (HIV-1) by ELISA and Western blot analysis, polymerase chain reaction for gag sequences, and culture for HIV-1. During this period, the patient's rheumatoid arthritis has remained active and no further significant infections have occurred. Low-dose methotrexate therapy has been implicated as a risk factor for opportunistic infection by cryptococci (4) and in association with concomitant daily corticosteroid therapy for infection by P. carinii (2, 3) and nocardia (5). We would like to add the present case as the first example of P. carinii pneumonia associated with low-dose methotrexate therapy as the sole predisposing factor. The patient we report had peripheral lymphocytes of normal number and function. We suggest, therefore, that opportunistic infections be considered before a definitive diagnosis of methotrexate-induced pneumonitis is made. 716
To the Editor: The recent article by Fraser and Arieff (1) is very well written and provides helpful information concerning the pathophysiology involved in hyponatremia. However, I read this article with dismay and sadness as I thought about the many who died because of the trend to use hypotonic solutions for intravenous fluid therapy. I became aware of this trend about 6 years ago and questioned younger surgeons and anesthesiologists about how it had developed. It appears that university hospital anesthesiologists were aware of a tendency of surgical patients having anesthesia to retain sodium, and hypotonic infusions were thought to be a corrective factor. If so, they were overlooking the capability of stress, anesthesia, narcotics, and surgical procedures to produce SIADH (syndrome of inappropriate antidiuretic hormone) tendencies. Some younger physicians have told me that they were introduced to the idea in their first 2 years of medical school when nonclinicians were teaching correction of theoretical acid-base balance problems using hypotonic solutions. Such "blackboard corrections" obviously did not take into consideration the kidneys, lungs, pituitary gland, and other organs. I am uncertain if the authors handled this subject gingerly because of the medicolegal implications, but it would be a grave oversight if the journal fails to call to the attention of its readers the hazards of this trend, how it can be avoided, and how it should be treated when it does occur. While attending the 1988 Annual Session of the American College of Physicians in New York, my concern prompted me to attend a session by Dr. Patricia Gabow on hyponatremia and hypernatremia. I inquired whether she and others were seeing many patients with hyponatremia. Everyone in the room seemed to have encountered this problem in association with the use of hypotonic fluid infusions. The lecturer described how she herself almost received a similar infusion in the hospital where she had taught house officers not to use hypotonic fluids. In response to my own local inquiry, I found that there are many factors, including use of PC A machines to administer narcotics with an accompanying infusion of hypotonic fluid; the tendency of a busy nurse to respond to the plaintive beep of the infusion device by simply "hanging" fluids similar to the ones the patient had been receiving without considering the duration, sequence, and rate; and the attending physician being unaware of the need to use other than hypotonic fluids, and not reviewing daily the administration, the duration of fluid infusion, the type of fluids being administered, the total received, not ordering SM-7 studies, and not including any of this in the daily progress notes. While I am referring to factors which I believe cause hyponatremia from my observations, I want to stress that I think my hospital and others in this area have been very lucky, and we are alerting staff members to recognize and prevent these
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problems. The reason that this problem was not encountered previously is that the former custom was to alternate infusions and D5 in 0.9% saline with D5 in water, which would average out to be infusions of 0.45% saline. I believe that studies would show that there has been a marked decrease in the infusion of 0.9% saline; when 0.45% saline is alternated with D5 in water, hyponatremia can easily develop. Although most medical techniques and treatments have improved, this instance is one in which progress has been backward.
Michael J. Moore, MD Lewis-Gale Clinic, Inc. Salem, VA 24153
Reference 1. Fraser CL, Arieff AI. Fatal central diabetes mellitus and insipidus resulting from hyponatremia. A new syndrome. Ann Intern Med. 1990;112:113-9. Correction: Title of Book Reviewed in The Literature of Medicine Section The title of a book reviewed in the 15 March 1990 issue (1) should have read: The Story of Iodine Deficiency: An International Challenge in Nutrition. Reference 1. Bertenshaw R, Refetoff S. The Study of Iodine Deficiency: An International Challenge in Nutrition. Ann Intern Med. 1990;112:478.
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