Acute Renal Failure In The Setting Of The Neuroleptic Malignant Syndrome

Nephrol Dial Transplant (1996) 11: 885-886

Nephrology Dialysis Transplantation

Case Report

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

Key words: acute renal failure; neuroleptic malignant syndrome; rhabdomyolysis

Introduction Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal reaction associated with neuroleptic drugs. It is characterized by hyperthermia, muscular rigidity, changes in mental status and autonomic dysfunction [1]. The diffuse muscle rigidity leads to myonecrosis with resultant rhabdomyolysis and the possible production of myoglobinuric renal failure. In this report we present a patient with NMS after treatment with haloperidol, who developed acute renal failure due to rhabdomyolysis. The clinical features of NMS, their pathophysiology, and the association between the syndrome and rhabdomyolysis-induced acute renal failure are discussed. As the presence of renal failure in NMS confers a worse prognosis [1,2], physician awareness is mandatory for rapid diagnosis of NMS and the early institution of aggressive treatment modalities. Case Report An 83-year-old Caucasian female was initially admitted to our hospital because of ascending cholangitis. Relevant past history included the presence of coronary heart disease with repeated hospitalizations for pulmonary oedema. The patient had also been diagnosed as suffering from an organic brain syndrome. Laboratory data showed a leukocytosis of 11500/ul, serum urea 73 mg/dl, creatinine 1.6mg/dl, aspartate aminotransferase 316 IU/1 (N 7-37), alanine aminotransferase 319 IU/1 (N 0-40), y-glutamyl transferase 868 IU/1 (N 7-49), alkaline phosphatase 559 IU/1 (N 53-128), and a bilirubin of 4.3 mg/dl (2.5 mg/dl direct). Total protein was 7.7 g/dl with an albumin level of 4.3 g/dl, calcium 10 mg/dl, phosphorus 3.6 mg/dl and creatinine phosphokinase (CPK) 170

IU/1 (N 15-170). Treatment with intravenous fluids and broad-spectrum antibiotics led to a rapid improvement, with resolution of the patient's fever and jaundice. However, she became extremely agitated and restless and was prescribed haloperidol 2 mg daily from the third hospital day. In a much calmer and sedate state, she was discharged after 7 days with a recommendation to continue haloperidol at a dose of 1 mg/day. Twelve days later, the patient was readmitted because of the onset of extreme pyrexia. Physical examination revealed an obese woman in a highly disoriented and confused state. Body temperature was 41.5°C, pulse 150 b.p.m., and blood pressure varied widely between 130/80 and 60/40 mmHg. Significant generalized body rigidity was evident. Laboratory investigations this time showed a haemotocrit of 26%, leukocytes 19 400/(xl with a shift to the left, thrombocytes 91000/ul, serum sodium 161 mEq/1, potassium 3.5 mEq/1, urea 217 mg/dl, creatinine 6.4 mg/dl, calcium 3.8 mg/dl, phosphorus 26 mg/dl, albumin 3 g/dl, and bicarbonate 21 mEq/1. CPK values peaked at 15200 IU/1 with a lactate dehydrogenase of 2830 IU/1 (range 230-460). Aminotransferases, alkaline phosphotase, and bilirubin were within normal limits. Urine output was 200 ml/day with urinalysis being unremarkable. Urine myoglobin was negative. A chest X-ray was without abnormality. Repeated blood and urine cultures were negative. Cerebrospinal fluid was normal. Aggressive supportive measures (notably without dialysis) were initiated in addition to empiric treatment with bromocriptine mesylate 5 mg thrice daily. Within the next 9 days the patient's condition improved considerably. Her fever abated, she became orientated, and blood pressure stabilized at 130/70 mmHg. She entered a polyuric phase with a decline of serum creatinine to her baseline value of 1.6 mg/dl. In parallel, CPK values decreased to 1119 IU/1, calcium increased to 7.8 mg/dl, and phosphorus returned to a normal 3.1 mg/dl. However, despite this dramatic improvement, she suddenly died on the 12th hospital day. Discussion

Correspondence and offprint requests to: Prof. J. Bernheim, Dept. ofThe entity known as NMS was first described in 1960 Nephrology, Meir Hospital, Kfar Saba, Israel. by Delay et al. [3] during the early clinical trials of © 1996 European Dialysis and Transplant Association-European Renal Association

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haloperidol. Since then it has attracted widespread attention, particularly amongst neurologists and psychiatrists, resulting in a plethora of published literature. NMS constitutes an idiosyncratic drug reaction to neuroleptic agents, occurring in about 0.2% of patients subjected to this class of compounds [1]. Diagnostic criteria have recently been denned [4]. They include neuroleptic treatment within 7 days of onset and the exclusion of other drug-induced, systemic, or neuropsychiatric illnesses. Major signs required for diagnosis are hyperthermia and muscular rigidity. Of the minor signs, changes in mental status, tachycardia, blood pressure oscillations, tachypnoea, diaphoresis, tremor, incontinence, elevated CPK levels, leukocytosis, and metabolic acidosis; five are required. All neuroleptics implicated in NMS are inherent D2 dopamine receptor antagonists. Notably, haloperidol, the drug administered to our patient, is the most common offending agent, being involved in nearly 50% of reported cases. Patients withdrawn from therapy with dopamine agonists for Parkinson's disease have been shown to develop NMS-like states [1,5]. Neuroleptic drugs effectively produce a blockade of dopamine receptors in the hypothalamus, corpus striatum, and throughout the spine. The pathogenetic mechanism responsible for NMS is therefore thought to be an acute depletion of dopamine in the central nervous system. This provides the rationale of treating NMS with bromocriptine, as was done in our patient. Treatment with this drug, a direct dopamine receptor agonist, was reported to significantly shorten the time to recovery compared to supportive therapy alone [6,7]. Dysregulation of central dopaminergic pathways results in the extreme elevation of body temperature (hypothalamic centre of thermoregulation), vasomotor instability, sympathetic overactivity, and continual muscular contraction. This latter effect is probably responsible for the rhabdomyolysis seen in NMS. Associated risk factors are hyperthermia and immobilization. Rhabdomyolysis-induced acute renal failure (myoglobinuric renal failure) was first described during the London 'blitz' in World War II [8]. The entity, appropriately termed the 'crush' syndrome, was further publicized following natural catastrophes (earthquakes) or terrorist activities (collapsed buildings). However, today, the commonest cause of rhabdomyolysis is non-traumatic, namely drugs. Of these, narcotics such as heroin and cocaine occupy an important niche [9-11]. The pathophysiology of the acute renal failure associated with rhabdomyolysis is multifactorial. It involves intratubular obstructions by precipitated myoglobin casts, backleak of filtrate, vasoconstriction, and disseminated intravascular coagulation [10,12]. There are several predisposing factors to the develop-

Z. Korzets et al.

ment of NMS. These include the presence of a highly agitated state, an organic brain syndrome and dehydration [1,13,14]. Our patient demonstrated all of these features. 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 of bromocriptine coupled with aggressive supportive measures, substantiates the diagnosis. Despite this, she died suddenly, probably as a result of either infarction, arrythmia or pulmonary embolus. This chain of events is in keeping with that reported in the literature [1,7]. The overall mortality in NMS ranges from 11.6 to 25% (1,15). Of note, the concomitant presence of rhabdomyolysis and acute renal failure increases the mortality risk to nearly 50% [1,2,15], a fact borne out by our patient's course. It is mandatory, therefore, that the physician be aware of the possibility of NMS in predisposed patients and that he initiate steps aimed at preventing the onset of acute renal failure, immediately upon diagnosis. Only thus, will this prohibitive mortality be perhaps reduced. References 1. Caroff SN, Hann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77(1): 185-202 2. Becker BN, Ismal N. The neuroleptic malignant syndrome and acute renal failure. J Am Soc Nephrol 1994; 4: 1406-1412 3. Delay J, Pichot P, Lemperiere T, Ellisalde B, Peijne F. Un neuroleptique majeur non phenothiazinine et non reserpinique, Phaloperidol dans le traitement des psychoses. Ann Med Psychol 1960; 118: 145-152 4. Caroff SN, Mann SC, Lazarus A et al. Neuroleptic malignant syndrome: Diagnostic issues. Psychiatr Ann 1991; 21: 130-147 5. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathophysiologic role for the dopamine receptor blockade? Neurology 1981; 1331: 132-137 6. Sakkas P, Davis LH, Hua J et al. Pharmacotherapy of neuroleptic malignant syndrome. Psychiatr Ann 1991; 21: 157-164 7. Rosenberg HR, Green H. Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989; 149: 1927-1931 8. Bywaters EGL, Beall D. Crush injuries with impairment of renal function. Br Med J 1941; 1: 427-432 9. Cuny SC, Chang D, Connor D. Drug- and toxin-induced rhabdomyolysis. Ann Emerg Med 1989; 10: 1068-1084 10. Grossman RA, Hamilton RN, Horse BR et al. Non-traumatic rhabdomyolysis and acute renal failure. N Engl J Med 1974; 291: 807-811 11. Roth DR, Alarcon JF, Fernandez J et al. Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988; 319: 673 12. Koffler A, Friedler RH, Massry SG. Acute renal failure due to non traumatic rhabdomyolysis. Ann Intern Med 1976; 85: 23-28 13. Shalev A, Munitz H. The neuroleptic malignant syndrome: agent and host interaction. Ada Psychiatr Scand 1986; 73: 337-347 14. Keck PE, Pope HG, Cohen BH et al. Risk factors for neuroleptic malignant syndrome. Arch Gen Psychiatry 1989: 46: 914-918 15. Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry 1989; 50: 18-25 Received for publication: 7.12.95 Accepted: 13.12.95