Salicylate-associated asystole: Report of two cases

BRIEF CLINICAL

cating severe salicylate poisoning are described. Patient 1. A 45-year-old woman found wandering a downtown street and talking senselessly was triaged to the emergency department’s psychiatric unit, and then referred for medical evaluation of hyperpnea. She had a history of alcoholism, but not of psychiatric disease. The patient was hyperacUniversity Hospital Vrije tive, delusional, and oriented to Universiteit Brussel self only. Temperature was 99.7’F Brussels, Belgium JACQUES~AEMAERT,M.D. and respirations were 26lminute. There were no focal neurologic University Hospital Ghent findings. Pertinent laboratory Ghent, Belgium GUYEBINGER, M.D. studies revealed the following valUniversity Hospital Vrije ues: bicarbonate 13.8 mEq/liter, Universiteit Brussel blood urea nitrogen 28 mg/dl, creBrussels, Belgium atinine 1.8 mg/dl, and glucose 76 mg/dl. Anion gap was 17. Plasma ACKNOWLEDGMENT ammonia level was 24 mmol/liter (normal: 11 to 35 mmol/liter). We thank Mrs. Yolande Hanssens for her skill and intelligence in the preparation of this manuscript. Chest radiography revealed a faint, diffuse, bilateral interstitial infil1. Mengel CE, Shaffer RD: The carcinoid syndrome. In: Holland JF, Freri E, eds. Cancer medicine. Philatrate. Electrocardiography showed delphia: Lea and Febrger, 1973; 1584-1594. sinus tachycardia. Respiratory rate 2. Kirkpatrick DB, Dawson E, Haskell C, et al: Metaincreased to 42/minute; at a fracstatic carcinoid presenting as a spinal tumor. Surg tional inspired oxygen value of 0.4, Neurol 1975; 4: 283-287. 3. Hoefnagel CA, den Hartog Jager FCA, Taal BG, arterial blood gas levels were pH Abeling NGGM, Engelsman EE: The role of I-131.MIBG 7.40, oxygen tension 48 mm Hg, in the diagnosis and therapy of carcinoids. Eur J Nucl and carbon dioxide tension 24 mm Med 1987; 13: 187-191. Hg. Diazepam 8 mg was adminis4. Patchell RA, Posner JB: Neurologic complications of carcinoid. Neurology 1986; 36: 745-749. tered intravenously over 10 min5. Baugh RF, Wolf GT. McClatchey KD, Lloyd RV, Evutes before nasotracheal intubaans DA: Carcinoid (neuroendocrine carcinoma) of the tion and assisted ventilation. One larynx. Ann Otol Rhino1 Laryngol 1987; 96: 315-321. minute later, asystole ensued and 6. Weighill JS, Tankel JW, Mene A: Carcinoid tumour cardiopulmonary resuscitation was of the larynx (a case report and review of the literature). J Laryngol Otol 1986; 100: 1421-1426. initiated, with adjunctive intrave7. Cefis F, Cattaneo M. Marziano P. Ricci C: Primarv nous atropine and epinephrine. Sipolypeptide hormones and mucin-producing maliinus rhythm at 132 beats/minute nant carcinoid of the larynx. Ultrastruct Pathol 1983: 5: 45-53. was rapidly restored, with normal 8. Pages A, Pignodel CH. Ramos J: Carcinoide du larblood pressure. Repeat chest radiynx: etude ultrastructurale et immunofluorescence. ography revealed evolving adult Ann Pathol 1983; 3: 59-64. respiratory distress syndrome. The Submitted November 30, 1988, and accepted in repatient became febrile to 101.8OF vised form January 24, 1989 and required continued ventilatory assistance. Hemodynamic monitoring revealed cardiac outputs ranging from 4.8 to 7.6 liters/minute with normal pulmonary capilSALICYLATE-ASSOCIATED lary wedge pressures. The result of /l;l;;OLE: REPORT OF TWO an admission urine drug screen was reported positive for opiates and salicylates on the third day; salicyAbrupt cardiovascular collapse is a late level obtained on the third hosrecognized complication of salicy- pital day was 19.0 mg/dl. No infeclate poisoning [l-3], but events tious pathogen was identified desurrounding such cases have re- spite extensive investigation. The ceived scant attention in medical patient was extubated on the 29th reports. Animal experiments demi hospital day, and was discharged onstrating potent depressant ef- home in asymptomatic condition fects on cardiac pacemaker funcon the 36th day. tion and impulse conduction sugPatient 2. A 69-year-old man gest a mechanism for was brought to the emergency desalicylate-induced cardiac arrest. partment after sudden onset of Two patients with asystole compliweakness and confusion. One agnosis of tumoral CNS lesions, even in the absence of generalization. Furthermore, our report suggests that 1231-MIBG scintigraphy can be of diagnostic value in the preoperative work-up of these type of space-occupying lesions. DIRKDELEU,M.D. FRANKD~GEETER,M.D. THERESEBUISSERET,M.D. ANITA GOOSSENS,M.D.

April 1989

OBSERVATIONS

month before, he had been hospitalized for a right parieto-occipital thrombotic infarct and discharged, ambulating with a cane, three days prior to his new problem. He was afebrile but diaphoretic, and deeply obtunded. Gaze was intermittently left-directed, and left-sided deep tendon reflexes were slightly diminished. Laboratory studies revealed the following values: bicarbonate 11.5 mEq/liter, blood urea nitrogen 14 mg/dl, creatinine 1.0 mgldl, and glucose 167 mgldl. Anion gap was 32. Arterial blood gas values obtained with the patient breathing oxygen by nasal cannulae were pH 7.44, oxygen tension 136 mm Hg, and carbon dioxide tension 22 mm Hg. Chest radiography showed cardiomegaly. Electrocardiography revealed left ventricular hypertrophy. Computed tomography of the head revealed no new event. Although no abnormal movements were noted, intravenous diazepam 10 mg was administered over 10 minutes by a neurology consultant as treatment for possible status epilepticus. When respirations decreased, orotracheal intubation with assisted ventilation was accomplished uneventfully. Within one minute, asystole was noted on a cardiac monitor. Despite vigorous advanced life support measures, no further cardiac electrical activity was observed. Salicylate level was reported to be 110 mgldl, and oil of wintergreen was found in the stomach at postmortem examination. In summary, two patients with severe salicylate intoxication experienced asystole shortly after intravenous diazepam administration. In the second case, underlying heart disease may have contributed to the event, but the first patient exhibited no evidence of intrinsic cardiac disease. This patient, with a salicylate level of 19 mgldl on the third hospital day, may have had a level greater than 100 mg/dl at the time of admission [41. At least two previous reports link aspirin or methylsalicylate intoxication with cardiac rhythm interruption ranging from brief uncomplicated periods of sinus arrest to intractable lethal asystole [5,6]. Animal experiments affirm salicylate’s potential for inhibition of cardiac impulse propagation and conduction. A dose-dependent decrease in discharge frequency was

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observed in rabbit sinoatrial cells exposed to salicylate concentrations of 0.3 to 0.5 mm01 (1 mm01 = 18 mg/dl) [7]. Isolated animal atria1 preparations were depressed or rendered inexcitable by salicylate (0.5 to 6.24 mmol) [7-91 and decreased pacemaker depolarization was observed in sheep Purkinje fibers exposed to salicylate (10 mmol) [lo]. Aspirin in therapeutic doses increased the refractory period of the left ventricle of intact cats to stimulation by a pacing electrode 1111. How salicylate induces cardiodepression is unclear. Most workers have emphasized effects on membrane potentials and ion flux [7,10]. Brasch’s [9,12] experiments suggest, however, that salicylate exerts its effects upon cardiac conduction by uncoupling of oxidative phosphorylation. Secondary membrane effects are not excluded by this hypothesis, but membrane-active compounds lacking uncoupling activity had no effect in his studies. Plasma concentration of free salicylate in humans is strongly affected by protein binding. At therapeutic levels (20 mg/dl), 90 percent is bound, but as total plasma salicylate increases, the proteinbound fraction decreases [13]. Since only 40 percent is bound at 100 mg/dl, free salicylate is approximately 60 mg/dl or 3.3 mmol [13]. In most of the aforementioned in vitro experiments, the salicylate concentrations are therefore within or close to the scale observed in human poisonings. Little change occurs in protein binding over the pH range observed in salicylate overdoses [14,15]. In both of the described cases, asystole occurred shortly after diazepam had induced a degree of respiratory depression, which in itself could not account for cardiac arrest. This is not unexpected: since salicylates are organic acids, a decrease in pH resulting from moderation of respiratory alkalosis increases the non-ionized, membrane-penetrating fraction. Hill [16] calculated that a decrease in pH from 7.40 to 7.20 could double the concentration of non-ionized salicylate. Our experience emphasizes the necessity of avoiding interventions that may compromise respiratory alkalosis or worsen metabolic aci-

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dosis in patients with suspected ar known salicylate intoxication [14,16,17]. Asystole as well as neurologic toxicity may represent the fatal culmination of severe salicylate intoxication. Practitioners should be mindful of the potentially catastrophic effect of sedative drugs and approach with caution their use in patients with severe salicylate overdoses. ‘WILLIAM A. BERK, M.D. JUDITH C. ANDERSEN,M.D. Detroit Receiuing Hospital Wayne State University Detroit, Michigan 1. Anderson RJ, Potts DE, Gabow PA, Rumack BH, Schrier RW: Unrecognized adult salicylate intoxication. Ann Intern Med 1976; 85: 745-748. 2. Benowitz NL. Rosenberg J. Becker CE: Cardiooulmonary catastrophes in drug-overdosed patients. Med Clin North Am 1979; 63: 267-296. 3. Beveridge GW, Forshall W. Munro JF. Owen JA, Weston IGTAcute salicylate poisoning in adults. Lancet 1964; I: 1406-1409. 4. Done AK: Salicylate intoxication. Significance of measurements in blood in cases of acute ingestion. Pediatrics 1960; 26: 800-807. 5. Mukerji V, Alpert MA, Flaker GC, Beach CL, Weber RD: Cardiac conduction abnormalities and atrial arrhythmias associated with salicylate toxicity. Pharmacotherapy 1986; 6: 41-43. 6. Ojiambo HP: Methylsalicylate poisoning in man. East Afr Med J 1971; 48: 735-740. 7. Neto FR: Electrophysiological effects of the salicylates on isolated atrial muscle of the rabbit. Br J Pharmacol 1982; 77: 285-292. 8. Shibata S. Hollander PB: Effects of amobarbital and sodium salicylate on the membrane potentials and mechanical activity of cardiac muscle. Eur J Pharmacol 1968; 3: 360-363. 9. Brasch H: Lack of direct antiarrhythmic electrophysiological effects of salicylate on isolated guineapig myocardium. Naunyn Schmiedebergs Arch Pharmacol 1983; 323: 343-349. 10. Cohen I, Noble D, Ohba M, Ojeda C: Action of salicylate ions on the electrical properties of sheep cardiac Purkinje fibres. J Physiol (London) 1979; 297: 163-185. 11. Kwiatkowska-Patzer B, Herbaczynska-Cedro K: Low dose of acetylsalicylic acid prolongs refractory period in normal cat myocardium. Arzneimittelforschung 1981; 31: 959-961. 12. Brasch H: Negative inotrooic effects of Na-salicvlate and three c&geners on the guinea-pig Langenorff heart. Arch Int Pharmacodyn Ther 1983; 262: 242-249. 13. Wosilait WD: Theoretical analysis of the binding of salicylate by human serum albumin: the relationship between free and bound drun and theraoeutic levels. Eur J Pharmacol 1976; 9: 285-290. 14. Hill JB: Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatrics 1971; 47: 658-665. 15. Moran CJ, Walker WHC: The binding of salicylate to human serum. Biochem Pharmacoll968: 7: 153156. 16. Hill JB: Salicylate intoxication. N Engl J Med 1973; 288: 1110-1113. 17. Goldberg MA, Barlow CF. Roth LJ: The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system. J Pharmacol Exp Ther 1961; 131: 308-318. L

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9. 1988, and accepted in revised form January 25, 1989

NAIL DISCOLORATION AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Bluish discoloration of the nails in patients with acquired immunodeficiency syndrome (AIDS) has been attributed to use of zidovudine (formerly called azidothymidine NW) [1,21.0 n separate occasions, we encountered two previously untreated patients, both with newly diagnosed human immunodeficiency virus (HIV) infection, who had mild bluish pigmentation of fingernails and toenails. Two young, black homosexual men were referred by their personal physicians to the Infectious Diseases Clinic because of HIV seropositivity. Significant past medical history included seborrheic dermatitis of scalp and facial seborrhea treated with hydrocortisone ointment, Both patients denied any history of sexually transmitted diseases. Neither patient was taking or had recently taken any medications. On physical examination, the only remarkable findings in both patients were facial seborrhea, non-tender, generalized lymphadenopathy, and mild bluish pigmentation of fingernails and toenails. The discoloration was noted over the entire nail plate, most marked over the proximal ends of the thumbs and big toes. No tranverse or longitudinal ridging, no loss or diminution of lunulae, and no onycholysis were noted. Both patients had a normal hematocrit and normal white blood cell and platelet counts, but markedly depressed T4 lymphocyte cell count with a reversal of T4:T8 ratios. Neither patient was in any respiratory difficulty, and analysis of arterial blood gas levels was therefore not performed. Upon further questioning, both revealed that they had noted a gradual change in their nail hue over the previous few months. These two cases illustrate that blue discoloration of nails can occur in HIV-infected patients without prior exposure to any chemotherapeutic drugs. Panwalker [2] reported similar clinical findings in an AIDS patient who had received trimethoprim/sulfamethoxazole and oral nystatin but not zidovudine. Another form of nail discoloration, namely yellow nail syndrome, has been described in four AIDS patients [3]. These four pa-