Nephrol Dial Transplant (1996) 11: 885-886
Nephrology
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 treat-
ment 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 pul-
monary 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 amino-
transferase 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
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.
© 1996 European Dialysis and Transplant Association-European Renal Association
Dialysis
Transplantation
IU/1 (N 15-170). Treatment with intravenous fluids
and broad-spectrum antibiotics led to a rapid improve-
ment, with resolution of the patient's fever and jaun-
dice. 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, thrombo-
cytes 91000/ul, serum sodium 161 mEq/1, potassium
3.5 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 at
15200 IU/1 with a lactate dehydrogenase of 2830 IU/1
(range 230-460). Aminotransferases, alkaline phos-
photase, and bilirubin were within normal limits. Urine
output was 200 ml/day with urinalysis being unremark-
able. 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 dia-
lysis) were initiated in addition to empiric treatment
with bromocriptine mesylate 5 mg thrice daily. Within
the next 9 days the patient's condition improved con-
siderably. 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 improve-
ment, she suddenly died on the 12th hospital day.
Discussion
by Delay et al. [3] during the early clinical trials of
886
haloperidol. Since then it has attracted widespread
attention, particularly amongst neurologists and psy-
chiatrists, 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 neuropsy-
chiatric 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. Rhabdo-
myolysis-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 terror-
ist 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 patho-
physiology of the acute renal failure associated with
rhabdomyolysis is multifactorial. It involves intratubu-
lar obstructions by precipitated myoglobin casts, back-
leak 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 dehydra-
tion [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, immedi-
ately upon diagnosis. Only thus, will this prohibitive
mortality be perhaps reduced.
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Received for publication: 7.12.95
Accepted: 13.12.95