8/14/2019 Acute Renal Failure in the Setting of the Neuroleptic Malignant Syndrome

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Nephrol Dial Transplant (1996) 11: 885-886

Case ReportNephrologyDialysisTransplantation

Acute renal failure in the setting of the neuroleptic malignant syndromeZ. Korzets, E. Zeltzer and J. BernheimDept. of Nephrology, Meir Hospital, Kfar Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Key words: acute renal failure; neuroleptic malignantsyndrome; rhabdomyolysis

IntroductionNeuroleptic malignant syndrome (NMS) is a rare butpotentially fatal reaction associated with neurolepticdrugs. It is characterized by hyperthermia, muscularrigidity, changes in mental status and autonomicdysfunction [1]. The diffuse muscle rigidity leads tomyonecrosis with resultant rhabdomyolysis and thepossible production of myoglobinuric renal failure.In this report we present a patient with NMS aftertreatment with haloperidol, who developed acute renalfailure due to rhabdomyolysis. The clinical features ofNMS, their pathophysiology, and the associationbetween the syndrome and rhabdomyolysis-inducedacute renal failure are discussed. As the presence ofrenal failure in NMS confers a worse prognosis [1,2],physician awareness is mandatory for rapid diagnosisof NMS and the early institution of aggressive treat-ment modalities.

Case ReportAn 83-year-old Caucasian female was initially admittedto our hospital because of ascending cholangitis.Relevant past history included the presence of coronaryheart disease with repeated hospitalizations for pul-monary oedema. The patient had also been diagnosedas suffering from an organic brain syndrome.Laboratory data showed a leukocytosis of 11500/ul,serum urea 73 mg/dl, creatinine 1.6mg/dl, aspartateaminotransferase 316 IU/1 (N 7-37), alanine amino-transferase 319 IU/1 (N 0-40), y-glutamyl transferase868 IU/1 (N 7-49), alkaline phosphatase 559 IU/1 (N53-128), and a bilirubin of 4.3 mg/dl (2.5 mg/dldirect). Total protein was 7.7 g/dl with an albuminlevel of 4.3 g/dl, calcium 10 mg/dl, phosphorus3.6 mg/dl and creatinine phosphokinase (CPK) 170Correspondence and offprint requests to: Prof. J. Bernheim, Dept. ofNephrology, Meir Hospital, Kfar Saba, Israel.

IU/1 (N 15-170). Treatment with intravenous fluidsand broad-spectrum antibiotics led to a rapid improve-ment, with resolution of the patient's fever and jaun-dice. However, she became extremely agitated andrestless and was prescribed haloperidol 2 mg daily fromthe third hospital day. In a much calmer andsedate state, she was discharged after 7 days with arecommendation to continue haloperidol at a doseof 1 mg/day.Twelve days later, the patient was readmittedbecause of the onset of extreme pyrexia. Physicalexamination revealed an obese woman in a highlydisoriented and confused state. Body temperature was41.5C, pulse 150 b.p.m., and blood pressure variedwidely between 130/80 and 60/40 mm Hg. Significantgeneralized body rigidity was evident. Laboratoryinvestigations this time showed a haemotocrit of 26%,leukocytes 19 400/(xl with a shift to the left, thrombo-cytes 91000/ul, serum sodium 161 mEq/1, potassium3.5 mEq/1, urea 217 mg/dl, creatinine 6.4 mg/dl, cal-cium 3.8 mg/dl, phosphorus 26 mg/dl, albumin 3 g/dl,and bicarbonate 21 mEq/1. CPK values peaked at15200 IU/1 with a lactate dehydrogenase of 2830 IU/1(range 230-460). Aminotransferases, alkaline phos-photase, and bilirubin were within normal limits. Urineoutpu t was 200 ml/day with urinalysis being unrem ark-able. Urine myoglobin was negative. A chest X-raywas without abnormality. Repeated blood and urinecultures were negative. Cerebrospinal fluid was normal.Aggressive supportive measures (notably without dia-lysis) were initiated in addition to empiric treatmentwith bromocriptine mesylate 5 mg thrice daily. Withinthe next 9 days the patient's condition improved con-siderably. Her fever abated, she became orientated,and blood pressure stabilized at 130/70 mm Hg. Sheentered a polyuric phase with a decline of serumcreatinine to her baseline value of 1.6 mg/dl. In parallel,CPK values decreased to 1119 IU/1, calcium increasedto 7.8 mg/dl, and phosphorus returned to a normal3.1 mg/dl. However, despite this dramatic improve-ment, she suddenly died on the 12th hospital day.DiscussionThe entity known as NMS was first described in 1960by Delay et al. [3] during the early clinical trials of

1996 European Dialysis and Transplant Association-European Renal Association

8/14/2019 Acute Renal Failure in the Setting of the Neuroleptic Malignant Syndrome

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886haloperidol. Since then it has attracted widespreadattention, particularly amongst neurologists and psy-chiatrists, resulting in a plethora of published literature.NMS constitutes an idiosyncratic drug reaction toneuroleptic agents, occurring in about 0.2% of patientssubjected to this class of compounds [1]. Diagnosticcriteria have recently been denned [4]. They includeneuroleptic treatment within 7 days of onset and theexclusion of oth er drug-induced, systemic, or neuropsy-chiatric illnesses. Major signs required for diagnosisare hyperthermia and muscular rigidity. Of the minorsigns, changes in mental status, tachycardia, bloodpressure oscillations, tachypnoea, diaphoresis, tremor,incontinence, elevated CPK levels, leukocytosis, andmetabolic acidosis; five are required.All neuroleptics implicated in NMS are inherent D2dopamine receptor antagonists. Notably, haloperidol,the drug administered to our patient, is the mostcommon offending agent, being involved in nearly 50%of reported cases. Patients withdrawn from therapywith dopamine agonists for Parkinson's disease havebeen shown to develop NMS-like states [1,5].Neuroleptic drugs effectively produce a blockade ofdopamine receptors in the hypothalamus, corpusstriatum, and throughout the spine. The pathogeneticmechanism responsible for NMS is therefore thoughtto be an acute depletion of dopamine in the centralnervous system. This provides the rationale of treatingNMS with bromocriptine, as was done in our patient.Treatment with this drug, a direct dopamine receptoragonist, was reported to significantly shorten the timeto recovery compared to supportive therapy alone[6,7]. Dysregulation of central dopaminergic pathwaysresults in the extreme elevation of body temperature(hypothalamic centre of thermoregulation), vasomotorinstability, sympathetic overactivity, and continualmuscular contraction.This latter effect is probably responsible for therhabdomyolysis seen in NMS. Associated risk factorsare hyperthermia and immobilization. Rhabdo-myolysis-induced acute renal failure (myoglobinuricrenal failure) was first described during the London'blitz' in World War II [8]. The entity, appropriatelytermed the 'crush' syndrome, was further publicizedfollowing natural catastrophes (earthquakes) or terror-ist activities (collapsed bu ildings). However, today , thecommonest cause of rhabdomyolysis is non-traumatic,namely drugs. Of these, narcotics such as heroin andcocaine occupy an important niche [9-11]. The patho-physiology of the acute renal failure associated withrhabdomyolysis is multifactorial. It involves intratubu-lar obstructions by precipitated myoglobin casts, back-leak of filtrate, vasoconstriction, and disseminatedintravascular coagulation [10,12].There are several predisposing factors to the develop-

Z. Korzets et al.ment of NMS. These include the presence of a highlyagitated state, an organic brain syndrome and dehydra-tion [1,13,14]. Our patient demonstrated all of thesefeatures. The findings on physical examination:extreme pyrexia, tachycardia, labile blood pressure,altered consciousness, and extensive muscle rigidity,fulfil the diagnostic criteria for NMS specified above.In addition, rapid improvement on the institution ofbromocriptine coupled with aggressive supportivemeasures, substantiates the diagnosis. Despite this, shedied suddenly, probably as a result of either infarction,arrythmia or pulmonary embolus. This chain of eventsis in keeping with that reported in the literature [1,7].The overall mortality in NMS ranges from 11.6 to25% (1,15). Of note, the concomitant presence ofrhabdomyolysis and acute renal failure increases themortality risk to nearly 50% [1,2,15], a fact borne outby our patient's course. It is mandatory, therefore,that the physician be aware of the possibility of NMSin predisposed patients and that he initiate steps aimedat preventing the onset of acute renal failure, immedi-ately upon diagnosis. Only thus, will this prohibitivemortality be perhaps reduced.References

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11. Roth DR, Alarcon JF, Fernandez J et al. Acute rhabdomyolysisassociated with cocaine intoxication. N Engl J Med 1988;319: 67312. Koffler A, Friedler RH, Massry SG. Acute renal failure due tonon traumatic rhabdomyolysis. Ann Intern Med 1976; 85: 23- 2813. Shalev A, Munitz H. The neuroleptic malignant syndrome: agentand host interaction. Ada Psychiatr Scand 1986; 73: 337-3 4714. Keck PE, Pope HG , Cohen BH et al. Risk factors for neurolepticmalignant syndrome. Arch Gen Psychiatry 1989: 46: 9 14-91815. Shalev A, Hermesh H, Munitz H. Mortality from neurolepticmalignant syndrome. J Clin Psychiatry 1989; 50: 18-25

Received for publication: 7.12.95Accepted: 13.12.95