Efficacy of Prolonged Large-Dose Dantrolene for Severe Neuroleptic Malignant Syndrome

Abstract

Neuroleptic malignant syndrome (NMS) is associated with major tranquilizer and antipsychotic administration and is characterized by hyperthermia, disorders of consciousness, and muscle rigidity [1-3]. The use of dantrolene may be an effective pharmacologic intervention to reduce muscle rigidity in NMS and in malignant hyperthermia (MH), but a reliable regimen of administration has not been established. We describe a patient with severe NMS who was successfully treated by continuous infusion of dantrolene at a large dose of 6 mg [center dot] kg-1 [center dot] d-1 in combination with hemodialysis and continuous hemodiafiltration (CHDF). We also measured plasma dantrolene concentrations in this patient. Case Report The patient, a 39-yr-old man, was 176 cm tall and weighed 100 kg. He developed schizophrenia at the age of 23 yr. Remissions and relapses were recurrent. The patient received 4 mg of haloperidol and 2 mg of trihexyphenidyl hydrochloride orally three times a day (total daily doses of 12 mg and 6 mg, respectively) at another hospital. Approximately 19 days after the start of medication, he developed a fever of >or=to40[degree sign]C and clouding of consciousness. NMS was suspected, and 40-80 mg of dantrolene was administered IV daily for 5 days. With no improvement, acute renal failure developed due to rhabdomyolysis, which required the admission of the patient to our intensive care unit (ICU). At admission, the patient was stuporous, with muscle rigidity and tremor in the extremities. His rectal temperature was 39.4[degree sign]C, blood pressure was 70/30 mm Hg, heart rate was 130 bpm, and respiratory rate was 40 breaths/min. Blood chemistry analysis showed platelet counts of 41,000/mm3, blood urea nitrogen of 89 mg/dL, and creatinine of 8.5 mg/dL. With O2 delivered at 12 L/min via a face mask, the pHa was 7.36, PaCO2 was 22 mmHg, PaO2 was 124 mmHg, and base excess was -11.9 mEq/L. Serum myoglobin and creatine phosphokinase levels were both increased-129,000 ng/mL (normal <77 ng/mL) and 162,300 IU/L (normal 12-170 IU/L), respectively (Figure 1). The patient was diagnosed as having severe NMS complicated by disseminated intravascular coagulation and acute renal failure. Dantrolene 200 mg was administered IV over 10 min. One hour later, his temperature was reduced to 38.4[degree sign]C. Muscle rigidity and tremor were also relieved. Continuous IV infusion of dantrolene was started at a dose of 400 mg/d in combination with oral bromocriptine 15 mg/d. When high fever, muscle rigidity, or tremor recurred, dantrolene was given as a 60- to 100-mg bolus IV injection. This protocol resulted in a total daily dose of dantrolene of 600 mg (6 mg/kg) for the first 3 days. Thereafter, the dose was gradually reduced. Muscle rigidity or tremor was rarely observed after 7 days. Dantrolene administration was changed to the oral route after 14 days, and medication was terminated after 28 days. For the treatment of acute renal failure, CHDF was performed together with hemodialysis (3 h daily) using a triacetate-membrane dialyzer (FB-210 U[trade mark sign]; Nipro Co., Ltd., Osaka, Japan) for the removal of myoglobin. Weaning from CHDF and hemodialysis was achieved 23 and 36 days after admission, respectively. The patient recovered and left the ICU 45 days after admission.Figure 1: Serum creatine phosphokinase (CPK) and myoglobin levels with time course of administration of dantrolene.Plasma dantrolene concentration was measured by using high-performance liquid chromatography 3, 13, and 25 days after admission. Values were 4.4 [micro sign]g/mL (dantrolene 600 mg/d), 0.88 [micro sign]g/mL (200 mg/d) and 0.25 [micro sign]g/mL (orally 150 mg/d), respectively. The concentrations did not change after hemodialysis (4.37, 0.81, and 0.25 [micro sign]g/mL on each corresponding day). Discussion Flewellen et al. [4] observed that suppression of muscle tone in healthy volunteers was maximal at a dantrolene dose of 2.4 mg/kg corresponding to a plasma dantrolene concentration of approximately 3.6 [micro sign]g/mL. When dantrolene was administered IV to adult patients with MH at a dose of 2.4 mg/kg, a maximal plasma concentration of 5.36 [micro sign]g/mL occurred within five minutes.1 This plasma concentration was maintained at >or=to3.0 [micro sign]g/mL for the next six hours. The elimination half-life of dantrolene is 12 +/- 7 hours, and administration every 5-6 hours is thought to be appropriate.1 For the treatment of MH, the drug is administered in the range of 1-10 mg/kg [5]. (1) Flewellen EH, Nelson TE. Intravenous dantrolene pharmacokinetics in malignant hyperthermia suspect patients [abstract]. Anesthesiology 1985;63:A300. Unfortunately, administration of dantrolene has not been established for the treatment of NMS. Levenson [1] recommended that the drug be administered at a dose of 0.8-2 mg/kg every six hours but provided no evidence to support this recommendation. We performed continuous IV infusion of dantrolene at a large dose because no response had been obtained with a daily IV dose of 40-80 mg over five days, and because temporary relief in muscle rigidity and tremor was observed at the dose of 200 mg soon after admission to the ICU. We also took into consideration that a substantial amount of dantrolene might be removed by CHDF. No investigation has examined plasma dantrolene concentrations in patients with NMS. In the present study, the plasma dantrolene concentration was 4.4 [micro sign]g/mL during continuous infusion at 6 mg [center dot] kg-1 [center dot] d-1. Although it is not clear how much dantrolene is lost by CHDF, the plasma dantrolene level was maintained at 3.6 [micro sign]g/mL in this study. Subsequent plasma dantrolene concentrations, however, were very low, and questions were raised as to whether the drug had produced beneficial effects on NMS during that period. Earlier withdrawal might have been appropriate. In this study, hemodialysis was performed with a triacetate-membrane dialyzer because the rhabdomyolysis was so severe. Although its molecular weight is as low as 399, dantrolene seemed not to be dialyzable. This may be explained by high lipid solubility and high protein binding (97%), but the details are unknown. In conclusion, continuous IV infusion of dantrolene at a large dose was effective in a patient with severe NMS concomitant with acute renal failure. Plasma dantrolene concentrations do not seem to be altered by CHDF.