Fatal hepatic failure and encephalopathy associated with amiodarone therapy

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Our study was designed to determine the pharmaeokinetic profile and safe dosage of morphine in neonates. Additional work is needed to delineate analgesic response to morphine in these patients. Because of the potentially greater sensitiyity of the neonate to morphine, and the higher concentrations measured in plasma, it appears that the postoperative morphine infusion dose should not exceed 15 u g / k g / h r . Although an infusion of 20 # g / k g / h r was not associated with complications, there was a large variability in plasma concentrations of morphine with this dose, the highest being in the range associated with seizures in two of the infants. Until more data and experience in this population are available, a lower infusion rate appears prudent. We thank Dr. Marc Greenwald for reviewing the manuscript.

REFERENCES 1. Chureh.JJ. Continuous narcotic infusions for relief of postoperative pain. Br Med J 1980;280:12. 2. Lynn AM, Opheim KE, Tyler DC. Morphine infusion after pediatric cardiac surgery. Crit Care Med 1984;12:863. 3. Datstr~m B, Bolme P, Feychting H, Noack G, Paalzow L. Morphine kinetics in children. Clin Pharmacol Ther 1979;26:354. 4. Orr JA, Keenan DJM, Dundee JW. Improved pain relief

Morphine infusion in neonates

5.

6.

7.

8. 9.

10.

II. 12. 13.

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after thoracotomy: use of cryoprobe and morphine infusion. Br Med J 1981;283:945. Vandenberghe H. Macleod SM. Chinyanga H. Soldin SJ. Analysis of morphine in serum by high performance liquid chromatography with amperometric detection. Ther Drug Monit 1982:4:307. Stanski DR. Greenblatt DJ. Lappas DG. Koch Wesser J, Lowenstein E. Kinetics of high-dose intravenous morphine in cardiac surgery pauents. Clin Pharmacol Ther 1976:19:752. Morselli PL. Franco-Morsetli R. Bossi L. Clinical pharmacokinetics in newborns and infants In: Gibaldi M. Prescott L, eds. Handbook of clinical pharmacokinetics. ADIS Health Sci. Press Section II. 1983:98-141 Gibaldi M. Prescott L. eds. Handbook of clinical pharmacokinetics. ADIS Health Sci. Press Section Ill 1983:182-200. Way WL. Cost[ey EC. Leong Way E. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965:6:454. Johannesson T. Becker BA. Morphine analgesia in rats at various ages. Acta Pharmacol Toxico] (Copenh) 1973;33:429. Goodman LS, Gilman A. The pharmacological basis of therapeutics. New York: Macmillan, 1980:501. Bray J. Postoperative analgesia provided by morphine infusion in children.. Anaesthesia 1983;38:1075. Dahlstr6m B, Paalzow L: Quantitative determination of morphine in bio[ogical samples by gas liquid chromatography and electron capture detection. J Pharm Pharmacol 1975;27:172.

Clinical and laboratory observations Fatal hepatic failure and encephalopathy associated with amiodarone therapy Pabio Yagepsky, M.D., Elyahu Gazala, M.D., Shaul Sofer, M.D., Esther Maor, M.D., and Jacob Abarbane|, M.D. Beer-Sheba, Israel

From the Pediatric Intensive Care Unit and the Departments of Pathology and Neurology, Soroka Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev. Submitted for publication April 10, 1985; accepted June 19, 1985. Reprint requests." Shaul So['er, M.D., Pediatric Intensive Care Unit, Soroka Medical Center, P.O. Box 151, Beer-Sheba 84-101, Israel.

AMIODARONE, a benzofuran derivative used originally

for angina, has been found to be effective in the treatment of supraventricular tachyarrhythmias, including those associated with Wolff-Parkinson-white syndrome. TM The drug apparently has less cardiotoxicity than m o s t other antiarrhytmic agents, ~ but noncardiac adverse effects have been reported and include pulmonary fibrosis, hypothy-

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The Journal of ~ediatrics December 1985

Fig. 1. Liver biopsy specimen showing diffuse "ballooning" degeneration of hepatocytes. (Hematoxyli n and eosin; x250.)

r0idism, hyperthyroidism, corneal microdeposits, neurologic disturbances, 5 and hepatotoxicity. 6 W e describe a fatal Reye-like Syndrome in a child given amiodarone for Wolff-Parkinson-White syndrome. CASE REPORT This 8-year-old girl was admitted to the Pediatric Intensive Care Unit in coma with circulatory and respiratory failure. She had been in good health until 2 days before admission, when she began to vomit andbecame progressively lethargic. Thepatient had had repeated attacks of supraventricular tachycardia since infancy, and electrocardiograms repeatedly showed evidence of underlying Wolff-Parkinson-White syndrome. She had been given propranolol for 7 years until 2 months before admission, when recurrent episodes of tachycardia occurred up to three times a week. Propranolol was replaced by amiodarone 200 mg/day (9 mg/kg/day), with a satisfactory clinical response. One day before admission the patient had a brief episode of tachycardia with palpitation, followed by vomiting and restlessness; amiodarone therapy was continued and no other drug was administered . On admission to a pediatric Ward she was drowsy but responded to verbal communication and was able to answer simple questions. Her temperature was 36.7 ~ C, pulse rate 90/min and regular, and blood pressure 100/70 mm Hg. Physical examination yielded normal findingsi her abdomen was soft, and the liver was not palpable. Laboratory tests showed hemoglobin 12.8 gm/dl, white blood count 9600/mm ~, blood urea 44 mg/dl, sodium 134 mEq/l, potassium 4.9 mEq/l, calcium 9.8 mg/dl, and glucose 52 mg/dl i Electrocardiogram and chest radiograph were normal. Cerebrospinal fluid microscopy and chemistry valves were normal. CSF and blood cultures were sterile. Therapy was started with Ringer solution, and because of the history of palpitation on the previous day the amiodarone dose was increased to 300 rag/day (14

mg/kg/day), On the second day the patient's condition deteriorated rapidly. She lapsed into coma and became hypotonic and hyporeflexic; the pupils were dilated and unresponsive to light. Shortly thereafter she developed hypotension and had an episode of respiratory arrest with bradycardia. The trachea Was intubated, and mechanical ventilation started. On admission tO the Pediatric Intensive Care Unit she was in a deep coma, with fixed dilated pupils. Heart rate was 120 beats/miri. Systolic blood pressure was 30 mm Hg, with central Venous pressure 10 cm H20. Mechanical ventilation was continued, and continious intravenous influsion of dopamine administered. Blood tests showed glucose 60 mg/dl, prothrombin time 27% partial thr0mboplastin time 45 seconds (control 26 seconds), SGOT 8270 1U/ml (normal <40 IU/ml), SGPT 5610 IU/ml (normal <40 IU/ml), total bilirubin 1.5 mg/dl, and ammonium 825 #g/dl (normal ~I00 ~g/dl). Repeated blood examinations showed severe metabolic acidosis. The blood urea level rose to 81 mg/dl, and creatinine was 1:5 mg/dl. Results of seroiog.ic studies for hepatitis A and B, cytomegalovirus, and herpes symplex virus were negative. Despite restriction o f fluid intake, intravenous administration of mannitol and bicarbonate, and oral administration of lactulose, the patient died 2 days later. Needle biopsy of the liver and kidney was performed shortly after death; permission for a complete autopsy was not granted. Pathologic findings. The hepatic architecture Was mildly distorted by diffuse ballooning degeneration of hepatocytes accompanied by a few rosette formations (Fig: 1). Kupffer cells appeared prominent. Mononuclear cell infiltrates, consisting mainly of lymphocytes and large mononuclear cells, were noted in the portal spaces (Fig. 2); the latter were confined to the portal areas and did not infiltrate the hepatic lobules. There were no significant fatty changes nor any appreciable necrosis of liver Cells. No inclusions nor Mallory bodies were noted. Examination of the kidney biopsy specimen did not reveal any significant abnormalities.

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Fig. 2. Mononuclear cell infiltrate in portal space. (Hematoxylin and eosin; X125.)

DISCUSSION After several years of successful treatment of supraventricular tachyarrhythmias in adults, amiodarone has been used in the pediatric age group. 3,4 Because of its prolonged effect and high therapeutic index, amiodarone has been considered a "nearly ideal antiarrhythmic agent". 7 However, increasing evidence of its extra cardiac toxicity has accumulated during the last decade, predominantly in adults? The relative lack of adverse reactions in children has been attributed to a faster metabolism than in adults, resulting in less tissue accumulation of the drug? Recently, however, undesirable side effects in children similar to those reported in adults have been described?,8 Hepatic dysfunction in patients given amiodarone was reported in 1969 by Plomteux et al. 9 Elevation of liver enzymes and potentiation of the anticoagulant effect of warfarin were described; however, these changes were considered transient? ~ In 1982 Waxman et al. s reported three cases of amiodarone-induced hepatic damage; fatty infiltration with minimal inflammatory reaction was observed in liver biopsy specimens. In a fourth case, changes "compatible with a probable recent viral hepatitis" were found. Subsequently, Fogoros et al. 11 reported severe nonspecific hepatitis in a patient given amiodarone, and in two recent reports fatty infiltration of the liver, focal necrosis, inflammatory infiltrates, and collagen proliferation mimicking alcoholic hepatitis or cirrhosis have been describedr '~2 Although in most cases the patients were asymptomatic or had only mild clinical disease, in one patient jaundice and prolonged ascites persisted for several months after the discontinuation of amiodarone therapy?

The clinical findings in our patient, who appeared to have a Reye-like syndrome including vomiting, encephalopathy, and severe hepatic failure without jaundice, are highly suggestive of a toxic cause, most probably related to amiodarone therapy. There was no history of exposure to any other drugs or poisons. Furthermore, Reye syndrome was ruled out by liver histology, which failed to disclose the typical fatty changes. Thus we conclude that the hepatic failure and encephalopathy in our patient were induced by amiodarone. The child received a dose of 9 mg/kg/day for 2 months, which is considerably higher than the dose that we and others usually give to children (10 to 15 mg/kg loading dose, followed by 5 mg/kg/day). 4 Although amiodarone is an effective antiarrhythmic agent, use of this drug is not without complications. We recommend periodic monitoring of liver function in patients receiving amiodarone, and discontinuation of the drug if any evidence of hepatic dysfunction becomes apparent. Alternative therapy for tachyarrhythmias and Wolff-Parkinson-White syndrome is available; pending further experience with its use, amiodarone should not be considered for therapy of arrhythmias in children unless other measures have failed. REFERENCES 1. Rosenbaum MB, ChiMe PA, Halpern MS, et al. Clinical efficacy of amiodarone as an arrhythmic agent. Am J Cardiol 1976;38:934-944. 2. Wellens HJ J, Lie KI, Bar FW, et al. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 1976;38:189-194. 3. Coumell P, Fidelle J. Amiodarone in the treatment of cardiac

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arrhythmias in children: one hundred thirty-five cases. Am Heart J 1980;100:1063-1069. Shahar E, Barzilay Z, Frand M, Feigl A. Amiodarone in control of sustained tachyarrhythmias in children with WolffParkinson-White syndrome. Pediatrics 1983;72:813-816. Waxman HL, Groh WB, Marchinski FE, et al. Amiodarone for control of sustained ventricular tachyarrhythmia: clinical and electrophysiologic effects in 51 patients. Am J Cardiol 1982;50:1066-1074. Simon JB, Manley PN, Brien JF, et al. Amiodarone hepatotoxicity simulating alcoholic liver disease. N. Engl J Med 1984;311:167-172. Dreifus LS, Ogawa S. Quality of the ideal antiarrhythmic drug. Am J Cardiol 1977;39:466-468.

The Journal of Pedit~trics December 1985

8. Hesslein PS. Amiodarone therapy in children: a cautionary comment. Pediatrics 1983;72:817-818. 9. Plomteux G, Heusghem C, Ernould H, et al. Long-term hepatic tolerance of amiodarone in the clinic. Eur J Pharmacol 1969;8:369-376. 10. Harris L, McKenna WJ, Rowland E,. et al. Side effects of long-term amiodarone therapy. Circulation 1983;67:45-51. 11. Fogoros RN, Anderson KP, Winkle RA, et al. Amiodarone efficacy and toxicity in 96 patients with recurrent, drug refractory arrhythmias. Circulation 1983;68:88-94. 12. Poucell S, Ireton J, Valencia Mayoral P, et al. Amiodarone associated phospholipidosis and fibrosis of the liver: light, immunohistochemical and electron microscopic studies. Gastroenterology 1984;86:926-936.

Accidental chlorpromazine ingestion as a cause of neuroleptic malignant syndrome in children Susan K. Klein, M.D., Morris W. Levinsohn, M.D., and Jeffrey L. Blumer, M.D., Ph.D. Cleveland, Ohio

THE NEUROLEPTIC MALIGNANT SYNDROME is a rare complication of neuroleptic drug therapy characterized by fever, movement disorder, autonomic disturbances, and altered mental status. ~ In adults, the development of N M S is related neither to dose nor to duration of t h e r a p y ? W e present two examples in children of N M S that followed accidental chlorprornazine ingestion. CASE REPORTS Patient 1. A 289 Hispanic girl weighing 12.6 kg was transferred to Rainbow Babies and Childrens Hospital from another emergency room. The maternal grandmother reported that the child had been playing in a bag of pills that afternoon; 3 hours later, she was unarousable. Vital signs in the emergency room were blood pressure 120/P mm Hg, pulse rate 100 beats per minute, temperature 36.4 ~ C, respirations 20 per minute. The child was stuporous but responded to painful stimulation, and her initial physical examination was otherwise unremarkable. The tablets were identified as chlorpromazine, and a urinary toxicolo-

From the Divisions of Pediatric Pharmacology and Critical Care and Child Neurology, Rainbow Babies and Childrens Hospital, and the Departments of Pediatrics and Pharmacology, Case Western Reserve University. Submitted for publication March 29, 1985; accepted June 12, 1985. Reprint requests: Jeffrey L. Blumer, Ph.D., M.D., Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, 2101 Adelbert Rd., Cleveland. OH 44106.

gy screen confirmed the presence of phenothiazine metabolites. Blood chlorpromazine level was 0.06 mg/dl. On admission to the Pediatric Intensive Care Unit, her arterial blood gas values in 40% oxygen were pH 7.51, Po2 333 mm Hg, Pr 27 mm Hg, HCO3 21 mm Hg. The CBC and platelet count were normal. Blood, CSF, and urine cultures were negative. A nasogastric infusion of activated charcoal in 70% sorbitol (0.5 gm/kg/hr) and an intravenous infusion of 5% dextrose and 0.22% sodium chloride with 20 mEq K C I / L at 50 ml/hr were begun. Approximately 20 hours after the ingestion, the patient was noted to have a decrease in skin turgor and oliguria; urine output CBC CK CSF EEG NMS

Complete blood count Creatine kinase Cerebrospinal fluid Electroencephalogram Neuroleptic malignant syndrome

was <0.01 ml/kg/hr. Renal function was normal. Her heart rate rose to 212 beats per minute and her core temperature to 41.9 ~ C. Physical examination showed rotatory nystagmus and increased agitation progressing to coma. She was given diphenhydramine, 1 mg/kg intravenously, without response. The intravenous fluids were increased to 100 ml/hr. Laboratory evaluation revealed a pH 7.07, which was treated with an infusion of 3 mEq/kg sodium bicarbonate; a serum sodium concentration of 173 mEq/L while receiving 3.4 mEq/kg/day sodium; blood sugar 726 mg/dl while receiving <1 mg/kg/min glucose intravenously; and serum CK activity 810 U/L, compared with 78 U / L on admission.