Recurrent Ventricular Tachycardia Due to Pentamidine-Induced Cardiotoxicity

although 25 percent of cases are asymptomatic. CT scan can accurately diagnose diaphragmatic defects and differentiate a Bochdalek hernia from a diaphragmatic eventration. 5 Complete absence of a hemidiaphragm is a rare entity even in neonates. In a retrospective study of 143 cases of diaphragmatic hernia, only one case of complete diaphragmatic absence was found." In reporting on 42 cases of congenital diaphragmatic hernias, Jackson encountered three infants with diaphragmatic agenesis; all had a fatal outcome." Neville and Clowles' also reported two infants with complete absence of the hemidiaphrgam. In one case, a large right-sided defect was successfully corrected by using a hepatic lobe, but the second patient with an absent left hemidiaphragm did not survive the operation. The oldest reported patient with agenesis of a hemidiaphragm and successful outcome after surgical correction was a six-yearold girl. 8 Passarge and colleagues" raised the possibility of a genetic predisposition for this disorder after describing diaphragm agenesis in two siblings. All reported cases of diaphragmatic agenesis have been characterized by the presence of small diaphragmatic remnants making the term "absence of diaphragm" more accurate than "agenesis of the diaphragm. "3,8,10,11 Our patient extends the clinical spectrum of diaphragmatic hernia to include the totally asymptomatic adult, and to our knowledge, is the first of its kind reported. The therapeutic approach of this entity differs from that of a partial defect found in an otherwise asymptomatic adult. In the latter, immediate operation is unanimously recommended to avoid bowel mcarceration.tv' In our case, however, surgical correction has no role; the free movements of intestinal contents and the small likelihood of adhesions makes strangulation of intestines quite unlikely This particular anatomy may complicate the diagnosis of intraabdominal processes such as appendicitis. While undoubtedly rare, knowledge of the potential for complete diaphragmatic absence should aid the clinician in recognition of the entity in patients with an unusual lower lobe "infiltrate." REFERENCES

1 Kirkland]A. Congenital posterolateral diaphragmatic hernia in the adult Br J Surg 1959; 4:16-22 Abbott AC, Goodhand TK. Herniation through 2 MacDougall congenital diaphragmatic defect in adults. Canad J Surg 1963; 6:301-16 3 David TJ, Illingworth CA. Diaphragmatic hernia in the southwest of England. J Med Genet 1976; 13:253-62 4 Langman J. Medical embryology 4th ed. Baltimore: Williams and Wilkins, 1981; 282-317 5 Gale ME. Bochdalek hernia: Prevalence and CT characteristics. Radiology 1985; 156:449-52 6 Jackson TM. Congenital diaphragmatic hernia. Arch Surg 1967; 95:102-10 7 Neville WE, Clowles GHA Jr. Congenital absence of hemidiaphragm and use of a lobe of liver in its surgical correction. Arch Surg 1954; 69:282-90 8 Hatzitheophilou C, Conlan AA, Nicolaou N. Agenesis of the diaphragm. A case report S Afr Med J 1982; 62:999-1001 9 Passarge E, Halsey H, German J. Unilateral agenesis of the diaphragm. Humangenetic 1968; 5:226-30 10 Toran N, Emery JL. Congenital bilateral absence of diaphragm. Thorax 1981; 36:157-58 11 Eichelberger MR, Kettrick RG, Hoelzer OJ, Swedlow DB, Schnaufer L. Agenesis of the left diaphragm: Surgical repair and physiologic consequences. J Ped Surg 1980; 15:395-97

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Recurrent Ventricular Tachycardia Due to Pentamidine-Induced Cardiotoxicity* Mark R. Bibler; M.D.;t Te-Chuan Chou, M.D.;+ Robert J Toltzis, M.D.;§ and Patricia A Wade, M.D.II

Although pentamidine isethionate is effective in the treatment of Pneumocy8tiB carinii pneumonia, it frequently causes serious adverse reactions. We report a case of reversible pentamidine-induced cardiotoxicity, characterized electrocardiographically by prolongation of the QT interval, T-wave inversion, and electrical a1temans of the U-wave. In addition, the patient had repeated episodes of ventricular tachycardia that culminated in torsades de pointes. Our case re-emphasizes the need for close patient monitoring during pentamidine therapy. Chest 1988; 94:1303-06

P

entamidine isethionate is a protozoacidal agent effective in the treatment of Pneumocystis carinii pneumonia.':" U nfortunately half of all patients receiving prolonged pentamidine therapy experience a major adverse drug reaction. 4·6 In this report, we describe a patient with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis pneumonia who developed reversible pentamidine-induced cardiotoxicity manifested by recurrent malignant ventricular tachycardia and unusual electrocardiographic abnormalities. CASE REPORT A previously well 37-year-old homosexual man with known

antibody to human immunodeficiency virus was admitted to the hospital for treatment of Pneumocystis pneumonia. He had no history or physical findings suggestive of heart disease. The ECG on admission (Fig 1) showed sinus tachycardia and borderline prolongation of the QT interval (QT 0.28 s, QTc 0.41 s: lead Vs) without other abnormalities. Initial therapy with trimethoprimsulfamethoxazole failed, and on hospital day 11, pentamidine isethionate was begun (4 rag/kg/day by intravenous infusion over two hours). Two days later, he underwent endotracheal intubation and positive pressure ventilation. On hospital day 17, he had a spontaneous tension pneumothorax which resolved with tube thoraeostomy On hospital day 22, he developed transient catheterassociated Staphylococcus aureus bacteremia which cleared promptly; he was given ticarcillin-clavulanic acid through hospital day 29, then vancomycin through hospital day 36. He also had idiopathic secretory diarrhea for which total parenteral hyperalimentation was instituted on hospital day 25. The patient tolerated his initial pentamidine therapy well. However, two hours following the completion of his eighth dose on hospital day 18, he had a 3O-secondepisode of ventricular tachycardia for which a lidocaine infusion was given. Serum electrolytes and glucose levels were normal. The 12-lead ECG after reversion to sinus rhythm (Fig 2) revealed further prolongation of the QTinterval

(QT 0.33 s, QTc 0.44 s: lead Vs) and T-wave inversion in the anterior precordial leads. Myocardial infarction was excluded by normal

*From the Department of Internal Medicine, University ofCincinnati College of Medicine, Cincinnati. t Assistant Professor of Clinical Medicine. tProfessor of Medicine. §Associate Professor of Clinical Medicine. IISenior Resident in Medicine. Reprint requests: Dr. Bibler, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Mail Location 535, Cincinnati

45267-0535

CHEST I 94 I 6 I DECEMBER. 1988

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FIGURE 1. Baseline 12-lead ECG prior to pentamidine administration.

FIGURE 2. Twelve-lead ECG after the eighth pentamidine dose. The tracing shows further prolongation of the QT interval and inverted T-waves in the anterior precordial leads. values for serum cardiac isoenzymes. A pulmonary artery catheter, inserted and removed five days previously, had demonstrated a pulmonary capillary wedge pressure of 10 mm Hg and cardiae outputs ranging from 7.2 to 11.4 Umin. He had no further ectopy, and the lidocaine infusion was discontinued after 48 hours. At the completion of his 19th pentamidine dose on hospital day 29, the patient again developed frequent bursts of sustained ventricular tachycardia that could not be controlled with lidocaine, and a procainamide infusion was begun. Ventricular tachycardia recurred the next day two hours following pentamidine administration, and a bretyllium infusion was substituted for procainamide. Seven hours later, polymorphic ventricular tachycardia developed with morphology characteristic of torsades de pointes (Fig 3~ After repeated electrical cardioversion, the arrhythmia was controlled finally by an isoproterenol infusion. Calcium chloride and magnesium sulfate also were given empirically, but serum levels ofcalcium, magnesium, and potassium obtained prior to their administration were determined subsequently to be normal. The serum procainamide level was 1.9 ILglml, and that of n-acetyl procainamide was less than 2.0 ILglml. A 12-lead ECG revealed persistent prolongation of the QT interval, marked T-wave inversion in leads I, aVL, and VI-V" and V-wave altemans (Fig 4~ An M-mode and two-dimensional echocardiogram was entirely normal. Pentamidine was discontinued, and isoproterenol was weaned off without further

ventricular ectopy. An ECG obtained eight days later showed resolution of the T- and V-waveabnormalities and a decrease in the QT interval back to the pretreatment baseline (QT 0.28 50 QTc 0.41 s; lead V,). The patient was extubated on hospital day 37. The next day he

had a generalized seizure. The serum glucose value was normal. A

computerized tomographic brain scan showed only diffuse edema . Lumbar puncture was normal. Determinations of serum Toxoplasma antibody and cerebrospinal fluid cryptococcal antigen were negative. The patient died the following day. Postmortem examination was remarkable for striking generalized edema of all the internal organs. The lungs showed persistent Pneumocystis pneumonia. The brain exhibited cerebral edema with focal areas of nonspecific necrosis and hemorrhage in the occipital lobes. The heart weighed 490 g and showed biventricular dilatation. No valvular or pericardia1 abnormalities were found. The right ventricular and left ventricular myocardial thickness measured 0.3 and 1.4 em, respectively; there was no evidence of myocardial infarction. Multiple microscopic sections from the left ventricle revealed diffuse intercellular edema, as well as occasional enlarged myoeytes, some of which contained double nuclei, suggestive of early hypertrophic changes. No acute degenerative or inflammatory lesions were noted .

FIGURE 3. Rhythm strip showing torsades de pointes followingthe 20th pentamidine dose.

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RecurrentVentricularTachycardia (Bibler at 81)

FIGURE 4. Twelve-lead ECG after the 20th pentamidine dose. The tracing shows persistent prolongation of the QT interval, more marked anteriorT-wave inversion, and Il-wave alternans most pronounced in the limbleads.

DISCUSSION

The efficacy and toxicity of pentamidine for Pneumocystis pneumonia have been well documented in a variety of patient populations-t and have been reviewed recently.l,3 Major adverse reactions, including cytopenias, azotemia, hepatitis, and hypoglycemia, necessitate discontinuation of therapy in half of all patients given the drug. Pentamidine administration also precipitates immediate adverse reactions in 9.6 percent of patients.8 These reactions include hypotension, tachycardia, cutaneous Hushing, nausea, and vomiting and have been postulated to result from an autonomic vasodilatory effect or drug-induced histamine release rather than from direct cardiac toxicity> Nevertheless, deaths directly attributable to pentamidine administration have been rare and poorly documented. I .• Most deaths appear to have resulted from intractable seizures which may have been a consequence of unrecognized hypoglycemia.' .• We believe that the patient described above had welldocumented pentamidine-induced cardiotoxicity, characterized electrocardiographically by progressive prolongation of the QT interval, T-wave inversion, and V-wave alternans. In addition, he had repeated episodes of increasingly more refractory ventricular tachycardia, each temporally related to pentamidine infusion. The patient had no history of antecedent intrinsic heart disease . Indeed, results from invasive hemodynamic and echocardiographic studies perfunned during his hospitalization were normal, and postmortem examination of the heart revealed no significant pathologic findings other than nonspecific intercellular edema similar to that seen in the other internal organs. None of the clinical or histopathologic features of his case were typical of the congestive cardiomyopathy and myocarditis recently described in AIDS patients. '•·1l Finally, his electrocardiographic abnormalities and arrhythmias resolved upon discontinuation of pentamidine. Our patient had the first of many episodes of ventricular tachycardia after the eighth dose of pentamidine. Despite administration of various antiarrhythmic agents, torsades de pointes developed, and repeated electrical cardioversion and isoproterenol infusion were required for its control.

Procainamide, given inappropriately in the setting of underlying QT prolongation, may have contributed to the genesis of torsades de pointes even though the arrhythmia developed seven hours after infusion of the drug was tenninated at a time when its serum level was subtherapeutic. On the other hand, the antecedent ventricular tachyarrhythmias were more clearly related to pentamidine administration, and ventricular ectopy did not recur after pentamidine was discontinued. The association of QT prolongation and ventricular tachycardia or torsades de pointes is well known." Our patient had borderline prolongation of the corrected QT interval" on his pretreatment ECG. However, in the absence of other factors associated with altered ventricular repolarization, 'U8 the subsequent incremental QT prolongation and T-wave inversion most likely resulted from pentamidine administration. Serum electrolyte levels were normal, and the patient was receiving no other drug known to cause ventricular repolarization abnonnalities. Although patients with increased intracranial pressure frequently have pronounced ST-segment and T-wave changes, in our case the ECG had returned to baseline by the time neurologic abnormalities became evident. Electrical alternans of the V-wave is an interesting but rare phenomenon.P:" As with QT prolongation, this abnormality can be seen in patients with organic heart disease or following head trauma , but it occurs most frequently in association with electrolyte disturbances such as hypokalemia, hyponatremia, hypomagnesemia, and hypochloremia, usually in combination . Since none of these factors could be identified in our case, it is probable that Ll-wave alternans also was related to pentamidine administration. Previous investigators have reported an increased risk ventricular tachycardia or ventricular fibrillation in patients with V-wave alternans." Wharton and colleaguesv have recently described two additional patients who developed malignant ventricular arrhythmias during prolonged pentamidine administration. As in our case, recurrent episodes of torsades de pointes occurred in each patient in association with QT interval CHEST I 94 I 6 I DECEMBER. 1988

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prolongation and T-wave inversion. These electrocardiographic abnormalities resolved slowly over several days to weeks after pentamidine was discontinued. Pentamidine cardiotoxicity has been documented in one other study Jha l 1 noted tachycardia, hypotension, and reversible ST-segment depression and T-wave inversion in 23 percent of 82 patients given pentamidine for antimonyresistant kala-azar, although the number of patients who actually developed electrocardiographic abnormalities is unclear. There were no deaths during treatment, but two patients died suddenly two and six weeks after completion of therapy Of note, all patients recently had received 18 g of sodium stibogluconate, a drug with known myocardial toxicity reflected electrocardiographically by T-wave inversion and prolongation of the QT mterval.v Therefore, cardiotoxicity attributed to pentamidine in this study alternatively may have represented latent or synergistic antimony toxicity! Our case re-emphasizes the need for close patient observation during pentamidine therapy including frequent electrocardiographic monitoring and careful attention to serum electrolyte levels. Concurrent administration of other drugs that may prolong the QT interval should be avoided. In particular, lidocaine, bretyllium, or isoproterenol appear to be the drugs of choice for the management of malignant ventricular tachyarrhythmias in patients receiving pentamidine since class lA antiarrhythmic agents further increase the risk of torsades de pointes. ACKNOWLEDGMENT: The authors thank Dr. Peter Walzer and Dr. Robert Adolph for their critical review of the manuscript and Suzanne Rase for expert secretarial assistance. REFERENCES

2

3 4 5

6

7

8 9

10

Krogstad DJ, Walzer PD. Informational material for physicians: pentamidine isethionate (lomidine). Atlanta: Center for Disease Control, 1971 Sands M, Kron MA, Brown RB. Pentamidine: a review Rev Infect Dis 1985; 7:625-34 Pearson RD, Hewlett EL. Pentamidine for the treatment of Pneumocqstis carinii pneumonia and other protozoal diseases. Ann Intern Med 1985; 103:782-86 Western KA, Perera DR, Schultz MG. Pentamidine isethionate in the treatment of Pneumocyms carinii pneumonia. Ann Intern Med 1970; 73:695-702 Walzer PD, Perl Krogstad DJ, Rawson PG, Schultz MG. Pneumocqstis carinii pneumonia in the United States: epidemiologic, diagnostic, and clinical features. Ann Intern Med 1974; 80:83-93 Wharton JM, Coleman DL, Wofsy CB, et al. 1iimethoprimsulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 1986; 105:37-44 Hughes WI: Feldman S, Chaudhary SC, Ossi MJ, Cox F, Sanyal SK. Comparison of pentamidine isethionate and trimethoprimsulfamethoxazole in the treatment of Pneumocyms carinii pneumonia. J Pediatr 1978; 92:285-91 Barrett-Connor E. Chemoprophylaxis of amebiasis and African trypanosomiasis. Ann Intern Moo 1972; 77:797-805 Waskin H, Sattler FR. Pentamidine-associated dysglycemia [abstract no. 697]. In: Program and abstracts of the 26th interscience conference on antimicrobial agents and chemothera~ Washington DC: American Society for Microbiolo~ 1986 Cohen IS, Anderson D~ Vinnani R, et ale Congestive cardiomyopathy in association with the acquired immunodeficiency

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syndrome. N Engl J Med 1986; 315:628-30 11 Reilly JM, Cunnion RE, Anderson D~ Virmani R, O'Leary Tj, Parrillo JE. Patients with the acquired immunodeficiency syndrome and histopathological myocarditis frequently manifest major clinical cardiac abnormalities [abstract]. J Am Coli Cardiol 1987; 9:154 12 Fontaine G, Frank R, Grosgogeat Y Torsades de Pointes: definition and management Mod Conc Cardiovasc Dis 1982; 51:103-08 13 Lepeschkin E. Duration of electrocardiographic deflections and intervals: man: Part II. In: Altman PL, Dittmer OS, eds. Respiration and circulation. Bethesda, MD: Federation of American Societies for Experimental Biology 1971:277-78 14 Moss AJ, Schwartz PJ. Delayed repolarization (QT or QTU prolongation) and malignant ventricular arrhythmias. ModCone Cardiovasc Dis 1982; 51:85-90 15 Surawicz B, Knoebel SB. Long QT: Good, bad or indifferent? J Am Coli Cardiol 1984; 4:398-413 16 Bashour 1: Rios JC, Gorman PA. U wave alternans and increased ventricular Irritability Chest 1973; 64:377-79 17 Shimoni A, Flatau E, Schiller D, Barzilary E, Kahn D. Electrical altemans of giant U waves with multiple electrolyte deficits. Am J Cardioll984; 54:920-21 18 Lee U, Sutton FJ. Concomitant pulsus and U-wave alternans after head trauma. Am J CardioI1985; 55:851-52 19 Chou TC. Electrocardiography in clinical practice, 2nd ed. Orlando: Grune and Stratton, 1986:265-72 20 Wharton JM, Demopulos PA, Goldschlager N. Torsades de Pointes during administration of pentamidine isethionate. Am J Med 1987; 83:571-76 21 jha TK. Evaluation of diamidine compound (pentamidine isethionate) in the treatment of resistant cases ofkala-azar occurring in North Bihar, India. Trans R Soc Trap Med Hyg 1983; 77:16770 22 Pearson RD, de Queiroz Sousa A. Leishmania species (kalaazar, cutaneous and mucocutaneous leishmaniasis). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 2nd ed. New York: John Wiley and Sons, 1985:1522-31

Echocardiography in Determining Nonresectability of Carcinoma of the Lung· A Brief Report Martin L. Howard, M.D.; Darryl S. Weiman, M.D.;

and Everett L. Dargan. M.D.

Numerous techniques are currently employed to determine resectability of lung cancer to spare patients an unnecessary thoracotomy. Echocardiography may be used to demonstrate invasion of hilar lesions into the heart. We report a case in which echocardiography demonstrated nonresectability of a lung cancer which was con6nned via a Chamberlain procedure. (Chest 1988; 94:1306-07)

is the only curative therapy for carcinoma of the Surgery lung. Unfortunately, percent of patients presenting 50

*From the Department of Surgery, University of South Carolina School of Medicine, Columbia. Reprint requests: Dr. miman, 2 Richland Medicallbrk, Suite 402, Columbia, South Carolina 29203

Echocardiographyin Detennining Nonresectabilityof Lung CA (Howard, Weiman, Dargan)