Successful Treatment of Six Patients with Neuroleptic Malignant Syndrome Associated with Myoglobulinemic Acute Renal Failure

Abstract

Neuroleptic malignant syndrome is a rare but potentially lethal, rare reaction to neuroleptics which is characterized by altered levels of consciousness, extrapyramidal effects, autonomic instability, hyperthermia, and elevated serum creatine phosphokinase levels. The most serious complication of neuroleptic malignant syndrome is acute renal failure.

We investigated six cases of neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure due to rhabdomyolysis and effect of hemodialysis or hemodiafiltration.

The patients were five males and one female with a mean age of 43.5 yr. All of the patients, who developed acute renal failure induced from rhabdomyolysis, had previously received butyrophenone (haloperidol), phenothiazine, benzamide, iminomide, benzisoxazole, antidepressants, and hypnotics (benzodiazepine and barbiturate) for the treatment of schizophrenia. The clinical manifestations of neuroleptic malignant syndrome were characterized by altered consciousness, muscle rigidity and weakness, fever, and excessive perspiration. The peak laboratory data were blood urea nitrogen 102 ± 26 (mean ± SD) mg/dL, serum creatinine 9.1 ± 2.1 mg/dL, serum creatine phosphokinase 229,720 ± 289,940 IU/L, and all of them developed oliguric acute renal failure. Dantrolene sodium administration was given to five cases and hemodialysis or hemodiafiltration was performed in all of them. The serum creatinine level after hemodialysis or hemodiafiltration was 1.4 ± 1.0 mg/dL. All patients were successfully cured of acute renal failure by hemodialysis or hemodiafiltration.

As a result, myoglobulinemic acute renal failure associated with neuroleptic malignant syndrome was successfully treated by hemodialysis or hemodiafiltration.

Keywords:

• acute renal failure
• dantrolene sodium
• hemodialysis
• hemodiafiltration
• neuroleptic malignant syndrome
• rhabdomyolysis

INTRODUCTION

Neuroleptic malignant syndrome (NMS) was induced by the combination treatment of neuroleptics including butyrophenone (haloperidol, chlorpromazine, levomepromazine) and phenothiazine, and an overdose of neuroleptics. In particular, the proposed risk factors for NMS include the introduction, an abrupt increase, or high-dose administration of neuroleptics, intramuscular administration, and use of depot medication forms.[[1–4]]

NMS is relatively rare, occurring at an estimated exposure incidence of 0.5–1.4%,[[5–9]] but it is potentially fatal and is characterized by an altered consciousness, muscle rigidity, fever, and autonomic nervous system dysfunction. The most common and serious complications of NMS are cardiac arrhythmias, cardiovascular collapse, respiratory disturbance, disseminated intravascular coagulation,[[2],[10]] electrolyte disturbances,[[11]] and acute renal failure (ARF) induced by rhabdomyolysis,[[1],[10]] which occurs in 16% of such cases.[[5]]

ARF associated with NMS was successfully treated with hemodialysis or hemodiafiltration.[[12]] Hemodialysis effectively cures myoglobulinemic ARF with NMS,[[13]] and direct hemoperfusion removes the metabolites of neuroleptics.[[14]]

Six patients suffering from schizophrenia who developed myoglobulinemic ARF induced by rhabdomyolysis, were successfully treated by either hemodialysis or hemodiafiltration.

MATERIAL AND METHODS

Patients

Between 1986 and 2004, we treated six cases with ARF due to NMS, at the Division of Nephrology, Department of Internal Medicine, National Kyushu Medical Center; the Division of Nephrology, St. Mary’ s Hospital; and the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

Methods

As shown in Table 1, there were five male and one female patients with a mean age of 43.5 yr, ranging from 22 to 59 yr of age. Six patients suffered from schizophrenia and had developed NMS associated with ARF induced by rhabdomyolysis, haloperidol, and other neuroleptics. Although not listed in Table 1, none of the patients had abnormal urinalysis findings or a history of renal dysfunction. No patients had a history of heavy drinking or smoking. They had no family history of NMS, but two had family histories of schizophrenia, their history of schizophrenia from ranged from 2 months to 31 yr.

Table 1 Six patients with neuroleptic malignant syndrome associated with acute renal failure who had been treated by psychotropic drugs

			Neuroleptic					Antidep-ressant	Hypnotic
Case	Age (years)	Sex	Butyrophenone (Haloperidol)	Pheno-thiazine	Beza-mide	Imino-mide	Benzi-soxazol		Benzo-diazepam	Barbi-turate
1	48	M			○	○		○
2	22	M	•	○					○	○
3	59	M		○				○	○	○
4	45	F					○
5	53	M		○					○	○
6	34	M					○		○
1–6	43.5 ± 13.5		1 case	3 cases	1 case	1 case	2 cases	2 cases	4 cases	3 cases

○: orally, •: intravenously. Data are expressed as the mean ± SD.

The clinical manifestations of NMS were observed as a consciousness disturbance that was evaluated based on the Japan Coma Scale (JCS) (3–3–9 system; 300 ∼ 1), JCS III: 300 ∼ 100, deep coma, coma, semicoma, JCS II: 30 ∼ 10, stupor, lethargy, hypersomnia, somnolence, drowsiness, JCS I: 3 ∼ 1, delirium, confusion, senselessness.

The laboratory data were based on standard hospital procedures, and the following standard laboratory tests were performed: urinalysis, measurements of blood urea nitrogen (BUN), serum creatinine, serum creatine phosphokinase (CPK), and the serum and urinary myoglobin concentrations.

Dantrium^® (dantrolene sodium) was administered to five patients upon admission, and all were treated with hemodialysis or hemodiafiltration (BK 2.1F, polymethylmethacrylate, TORAY Co., Tokyo).

RESULTS

We investigated six similar cases suffering from NMS associated with myoglobulinemic ARF due to neuroleptics without any prior history of renal disease.

The causes of NMS in these six cases were due to high doses of haloperidol (one case), a high dose of other neuroleptic (one case), a withdrawal of other neuroleptics (two cases), H₂ blocker (one case), and unknown (one case). As shown in Table 1, all six patients with NMS associated with ARF had been administered psychotropic drugs. There were five men and one woman with a mean age of 43.5 ± 13.5 (mean ± SD) yr. One of the six patients was administered butyrophenone (haloperidol) (intravenously), phenothiazines in three patient, benzamide in one patient, iminomide in one patient, and benzisoxazoles in two patients, antidepressants in two patients, benzodiazepams in four patients, and barbiturates had been given to three patients. Only one of six patients had haloperidol.

Table 2 lists the major clinical symptoms of NMS at admission. The clinical manifestations of NMS were assessed by observed consciousness disturbance; JCS-1 in two cases, JCS-10 in two cases, and JCS-200 in two cases. The extrapyramidal symptoms are characterized by muscle rigidity, muscle weakness, muscle cramps, and tremors. The autonomic nervous system dysfunctions are characterized by fever (hyperthermia), excessive perspiration, and hypertension.

Table 2 The major clinical symptoms at admission in patients with neuroleptic malignant syndrome

Case	Altered consciousness (JCS)	Extrapyramidal symptoms	Autonomic nervous system dysfunctions
1	10	Muscle rigidity	Fever, excessive perspiration, hypertension
2	1	Muscle weakness	Fever, excessive perspiration
3	200	Muscle rigidity	Fever, excessive perspiration
4	1	Muscle rigidity	Fever, excessive perspiration, hypertension
5	200	Muscle rigidity	Fever, excessive perspiration
6	10	Muscle weakness, cramp, tremor	Fever, excessive perspiration

JCS: Japan Coma Scale (3–3–9 system); III: 300 ∼ 100, deep coma, coma, semicoma; II: 30 ∼ 10, stupor, lethargy, hypersomnia, somnolence, drowsiness; and I: 3 ∼ 1, delirium, confusion, senselessness.

The urine color in all of these patients was dark, brownish but a slight amount of RBC was also found in the sediments. Severe myoglobulinemia had dramatically increased in all cases, and myoglobulinuria was also observed. As shown in Table 3 regarding the peak laboratory data in six patients with NMS associated with ARF, four cases were anuric and two cases oliguric. The BUN levels were 102 ± 26 (70 ∼ 129) mg/dL, serum creatinine levels 9.1 ± 2.1 (6.4 ∼ 12.2) mg/dL, serum CPK levels 229,720 ± 289,940 (27,676 ∼ 808,800) IU/L, serum myoglobin levels 5,306 ± 2,954 (1,835 ∼ 8,627) ng/mL and urinary myoglobin levels 21,590 ± 45,606 (177,689 ∼ 280,000, n = 3) ng/mL. The laboratory examination results showed a marked elevation of BUN, serum creatinine, CPK, myoglobin, and urine myoglobin. These data indicated the existence of ARF induced by rhabdomyolysis.

Table 3 Peak laboratory data in six patients with neuroleptic malignant syndrome associated with acute renal failure

Case	Urine volume	BUN (mg/dL)	Creatinine (mg/dL)	CPK (IU/L)	Serum myoglobin(ng/mL)	Urinary myoglobin (ng/mL)
1	Anuria	124	12.2	27,676	8,627	177,689
2	Anuria	129	8.2	120,590	2,400	ND
3	Anuria	123	7.8	81,680	2,900	ND
4	Anuria	70	8.9	209,551	7,775	ND
5	Oliguria	82	6.4	130,024	8,300	280,000
6	Oliguria	84	10.9	808,800	1,835	190,000
1–6		102 ± 26	9.1 ± 2.1	229,720 ± 289,940	5,306 ± 2,954	21,590 ± 45,606

Data are expressed as the mean ± SD. ND: not done.

The therapies used and the outcome in six patients of NMS with ARF are listed in Table 4. Dantrium^® (dantrolene sodium) administration was given to five patients, when all of them were successfully treated with hemodialysis (4–10 times), and hemodialysis (three times) and hemodiafiltration (five times) in case 6. The BUN levels decreased to 16 ± 11 mg/dL after hemodialysis and hemodiafiltration. The serum creatinine levels also decreased to 1.4 ± 1.0 mg/dL after hemodialysis or hemodiafiltration. All of the patients associated with ARF induced by rhabdomyolysis were successfully treated with either hemodialysis or hemodiafiltration.

Table 4 Therapy and outcome in six patients with neuroleptic malignant syndrome associated with acute renal failure

			BUN (mg/dL)/Serum Creatinine(mg/dL)
Case	Dantrolene Sodium Administration	Blood Purification Therapy	Before	After
1	None	HD 10 times	124/12.2	18/1.3
2	Intravenously	HD 4 times	129/8.2	8/0.9
3	Intravenously	HD 8 times	123/7.8	38/3.4
4	Intravenously	HD 10 times	70/8.9	15/1.2
5	Intravenously	HD 8 times	82/6.4	8/0.7
6	Intravenously, orally	HD 3 times, HDF 5 times	84/10.9	10/0.9

HD: hemodialysis; HDF: hemodiafiltration.

DISCUSSION

We clinically investigated six similar cases with myoglobulinemic ARF induced by rhabdomyolysis due to NMS without any prior history of renal disease. All six patients with NMS associated with myoglobulinemic ARF were successfully treated with hemodialysis or hemodiafiltration.

According to Levenson[[1]] (diagnostic criteria for NMS), the major manifestations are fever, rigidity, and an elevated serum CPK level, and the minor manifestations are tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, and leukocytosis. The presence of all three major, or two major and four minor, manifestations indicates a high probability of the presence of NMS. The presence of such manifestations indicates a high probability that all six patients demonstrated NMS in this study.

The major competing theories to explain NMS are central dopamine blockade versus a direct toxic (hypermetabolic) effect on the skeletal muscle.[[1]] NMS may develop an unusual symptom complex that consists of extrapyramidal symptoms, disturbances of consciousness, diaphoresis, fever, and increased serum CPK following the discontinuation of large doses of combined anti-Parkinsonian drugs in a patient with Parkinson’ s disease.[[15]] The patient's symptoms disappeared after the administration of dopamine agonist.[[15]] A direct-acting dopamine agonist, bromocriptine, is a potentially effective drug for the treatment of this syndrome,[[13]] and it has been shown to be successful.[[5]]

Muscle contraction was the most common manifestation after haloperidol in the NMS patients, and the possibility of direct muscular involvement in NMS has been reported.[[16]] The direct toxin to the striated muscles has been observed to be sensitive to the causative drug (haloperidol) to start contractions in the NMS patients.[[16]] Dantrium^® (dantrolene sodium), a lipid-soluble hydantoin derivative acting as a skeletal muscle relaxant, is the treatment of choice for this syndrome,[[13]] and it has been shown to be consistently effective for the treatment of NMS.[[5]] Dantrium^® (dantrolene sodium) was used in our cases except for case 1 who was treated with frequent and long-term hemodialysis.

Mortality from NMS has been reported to range from 4 to 30% since 1980.[[5],[17–20]] The complications, particularly rhabdomyolysis, myoglobinemia, and renal failure should be monitored for systematically.[[5]] Because there is a strong relationship between the serum CPK level and the severity of NMS, ARF may develop when NMS is severe, and patients have high serum CPK levels and the high serum and urine myoglobin levels. As a result, one of the most common serious complications of NMS is ARF due to rhabdomyolysis,[[1],[17]] which occurs in 16% of all cases.[[5]] Furthermore, 11 of 52 cases (21%) with NMS-related ARF died during hospitalization.[[21]] However, six patients, who developed NMS associated with ARF due to rhabdomyolysis while receiving neuroleptic therapy for schizophrenia, were successfully treated with hemodialysis or hemodiafiltration.

Myoglobin is a heme protein, a small molecule with a molecular weight of 17,800 kDa, and it is slightly smaller than the B-J protein. The serum myoglobin levels are not attenuated by hemodialysis in ARF with rhabdomyolysis. However, a highly permeable membrane filter (protein leakage hemodiafiltration dialyzer) can decrease the serum myoglobin levels, and hemodiafiltration is the first choice of treatment in ARF with rhabdomyolysis due to increased serum myoglobin levels.[[12]] Case 6 was successfully treated with a highly permeable membrane filter (hemodiafiltration) in ARF with rhabdomyolysis due to an increased serum myoglobin level. Further studies are required to clarify whether hemodiafiltration should be the treatment of choice in ARF patients with rhabdomyolysis.

CONCLUSIONS

Carbone[[21]] emphasized that supportive treatment with hydration, cooling, intensive ICU monitoring of ECG and vital signs, and aspiration are important in NMS. In this study, six similar cases with myoglobulinemic ARF were induced by rhabdomyolysis due to NMS without any prior history of renal disease. As a result, an early identification and correct diagnosis, along with the appropriate treatment for ARF in patients with NMS are essential for obtaining a good prognosis.[[22]] In particular, six cases in NMS were successfully cured of ARF by either hemodialysis or hemodiafiltration.

ACKNOWLEDGMENTS

We thank Mr. B. Quinn for carefully reading and editing the manuscript.