eMedicine Specialties > Emergency Medicine > Toxicology
Neuroleptic Malignant Syndrome: Treatment & Medication
Updated: Aug 18, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Prehospital Care
- Any patient being evaluated by prehospital personnel requires assessment of the airway, breathing, and circulation (ABCs).
- Any patient with altered mental status should receive thiamine, dextrose (or rapid glucose determination), and naloxone.
- Prehospital personnel must assess the patient's safety and, if necessary, restrain the patient. Restraint use in agitated, hyperthermic patients can increase the risk of significant morbidity and mortality in various disease states (eg, NMS, cocaine intoxication, amphetamine abuse). Chemical restraints (eg, benzodiazepines), if available, may be preferable in such situations.
- Prehospital personnel should try to get an accurate medication list. If that is impossible, bring all the medication bottles found with the patient. Simultaneous administration of 2 dopamine-blocking agents can sometimes precipitate NMS.
Emergency Department Care
Successful treatment requires prompt recognition, withdrawal of neuroleptic agent, exclusion of other medical conditions, aggressive supportive care, and administration of certain pharmacotherapies.
- A careful history should be taken before starting a new neuroleptic medication.
- NMS may recur when medications are restarted.
- Monitor a patient carefully while administering neuroleptic medication to prevent excessive agitation and dehydration because these conditions may predispose a patient to NMS.
- Benzodiazepines and physical restraints may be useful.
- Stop all neuroleptics.
- Correct volume depletion and hypotension with intravenous fluids.
- Methods to reduce the temperature include the following:
- Cooling blankets
- Antipyretics
- Cooled intravenous fluids
- Ice packs
- Evaporative cooling
- Various pharmacotherapies to reduce rigidity (see below)
- When rhabdomyolysis occurs, maintain vigorous hydration and alkalinize the urine with intravenous NaHCO3 to prevent renal failure.
- Electroconvulsive therapy (ECT) has been used to treat NMS. It can help with the alteration of temperature, level of consciousness, and diaphoresis. It may also be useful in treating the underlying psychiatric disease in patients who are unable to take neuroleptics. ECT with anesthesia has generally been safe with no increased incidence of malignant hyperthermia from succinylcholine administration.5,6
Consultations
- Consultation with a neurologist may be needed if the diagnosis is in question.
- Consultation with a psychiatrist can be helpful to manage the underlying psychiatric disease once the neuroleptics have been withdrawn.
- Consultation with a nephrologist is needed if the patient develops rhabdomyolysis and renal failure.
Medication
Pharmacotherapy recommendations are from noncontrolled prospective and retrospective studies and case reports; no controlled studies exist. The mortality rate has declined from approximately 20% to less than 10%. The decrease may be due to improved supportive care modalities. Whether the addition of dantrolene to dopamine agonists will improve the prognosis is unclear. A recent review of case reports indicates that combining dantrolene with other pharmacotherapy prolongs the recovery period. Using dantrolene as monotherapy seemed to be associated with increased mortality. Dopaminergic medications can be especially useful if the NMS was caused by withdrawal of anti-Parkinson medication.7,8,9
Dopamine agonists
Dopamine agonists reverse the dopamine D2-receptor blockade produced by neuroleptics. In retrospective studies, agonists appear to decrease mortality and shorten the course of NMS.
Bromocriptine (Parlodel)
Semisynthetic, ergot alkaloid derivative. Strong, dopamine D2-receptor agonist. Partial dopamine, D1-receptor agonist.
May relieve akinesia, rigidity, and tremor associated with Parkinson disease. Stimulates dopamine receptors in the corpus striatum.
Approximately 28% is absorbed from the GI tract and metabolized in the liver. Approximate elimination half-life is 50 h with 85% excreted in feces and 3-6% eliminated in urine.
Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess dosage titration q2wk. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.
Adult
7.5-30 mg/d PO divided tid (2.5-10 mg/dose); not to exceed 100 mg/d
Pediatric
<15 years: Not recommended
>15 years: Not established
Toxicity may increase with ergot alkaloids, erythromycin, isometheptene, phenylpropanolamine (recalled from US market), and ethanol; amitriptyline, butyrophenones, zotepine, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects
Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal or hepatic disease, breastfeeding women, cardiovascular disease, and concomitant antihypertensive therapy
Amantadine (Symmetrel)
May act to release dopamine from dopaminergic terminals and other central sites.
Adult
100-300 mg PO bid
Pediatric
<1 year: Not established
1-9 years: 4.4-8.8 mg/kg/d PO; not to exceed 150 mg/d PO qd or divided bid
9-12 years: 100 mg PO bid
>12 years: Administer as in adults
Drugs with anticholinergic or CNS stimulant activity increase toxicity; concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, seizures, and those receiving CNS stimulant drugs; do not discontinue this medication abruptly
Levodopa and carbidopa (Sinemet)
Large neutral amino acid absorbed in proximal small intestine by saturable carrier-mediated transport system. Absorption is decreased by meals, which include other large neutral amino acids. Only patients with meaningful motor fluctuations need consider a low protein or protein redistributed diet. Greater consistency of absorption achieved when levodopa taken >1 h after meals. Nausea often is reduced if levodopa is taken immediately following meals. Some patients with nausea benefit from additional carbidopa in doses up to 200 mg/d. Half-life of levodopa/carbidopa is approximately 2 h.
Provide at least 70-100 mg/d carbidopa. When more carbidopa required, substitute 25/100 tab for each 10/100 tab. When more levodopa required, substitute 25/250 tab for the 25/100 or 10/100 tab.
Sustained-release formulation of levodopa/carbidopa is more slowly absorbed and provides more sustained levodopa levels than the immediate-release dosage form. Effective as immediate-release formulation when levodopa is required initially and may be more convenient when fewer intakes are desired.
Most patients have been adequately treated with 2-8 tab/d (divided doses) at intervals of 4-8 h while awake. Higher doses (>12 tab/d) and intervals <4 h have been used but are not usually recommended. If <4 h interval used or if divided doses are not equal, give smaller doses at end of day. Allow at least a 3-d interval between dosage adjustments. May administer as whole or half tab, which should not be crushed or chewed.
Adult
25/250 mg PO tid/qid
Pediatric
Not established; 10/100 mg/d PO suggested if patient aged 6-10 y; increase by 1 tab qod prn; not to exceed 60/600 mg/d
Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects; toxicity increases with antacids and MAOIs
Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Certain adverse CNS effects (eg, dyskinesias) may occur at lower dosages and earlier in therapy with SR form; caution in MI, arrhythmias, asthma, and peptic ulcer disease; high-protein diets should be distributed throughout the day to avoid fluctuations in levodopa absorption; short-term adverse effects include nausea, hypotension, and hallucinations; long-term adverse effects include motor fluctuations and dyskinesia (chorea)
Skeletal muscle relaxant
These agents stimulate muscle relaxation by modulating skeletal muscle contractions at site beyond myoneural junction and acting directly on muscle itself.
Dantrolene (Dantrium)
Inhibits ionized calcium release from sarcoplasmic reticulum and results in direct muscle relaxation. Used to treat NMS-associated muscular rigidity and hyperthermia.
Based on retrospective studies, the addition of dantrolene to bromocriptine does not appear to offer additional advantage. Dantrolene therapy alone appears to shorten the duration of illness, but use is controversial. Reduction of fever and rigidity is not immediate but occurs over a mean of 1.7 d. When rapid rigidity reduction is necessary, alternative means (eg, neuromuscular paralysis) may be preferable. A recent review of case reports indicates that adding dantrolene to other medication prolongs the course of NMS. Therapy with dantrolene alone had increased mortality. The only benefit to dantrolene was in patients who prior to NMS had been on a neuroleptic monotherapy.
Most patients respond to 400 mg/d or less.
Adult
1-3 mg/kg IV initial, followed by 10 mg/kg/d PO/IV in divided doses
Pediatric
0.5 mg/kg PO/IV bid initial, increase to 0.5 mg/kg bid/qid, then by increments of 0.5 mg/kg to 3 mg/kg bid/qid prn; not to exceed 100 mg qid
Toxicity may increase with the coadministration of clofibrate and warfarin; coadministration with estrogen may increase hepatotoxicity in women >35 y; coadministration with verapamil may lead to hyperkalemia
Documented hypersensitivity; active hepatic disease (hepatitis and cirrhosis)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause hepatotoxicity (use only for recommended indications); caution in impaired pulmonary function and severe cardiac insufficiency; may cause photosensitivity with exposure to sunlight; unlabeled use for NMS; G-6-PD deficiency
More on Neuroleptic Malignant Syndrome |
| Overview: Neuroleptic Malignant Syndrome |
| Differential Diagnoses & Workup: Neuroleptic Malignant Syndrome |
 Treatment & Medication: Neuroleptic Malignant Syndrome |
| Follow-up: Neuroleptic Malignant Syndrome |
| References |
| « Previous Page | Next Page » |
References
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. Jun 2007;164(6):870-6. [Medline].
Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. Feb 1999;156(2):169-80. [Medline].
Jauss M, Krack P, Franz M, Klett R, Bauer R, Gallhofer B, et al. Imaging of dopamine receptors with [123I]iodobenzamide single-photon emission-computed tomography in neuroleptic malignant syndrome. Mov Disord. Nov 1996;11(6):726-8. [Medline].
Picard LS, Lindsay S, Strawn JR, Kaneria RM, Patel NC, Keck PE Jr. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. Apr 2008;28(4):530-5. [Medline].
Ozer F, Meral H, Aydin B, Hanoglu L, Aydemir T, Oral T. Electroconvulsive therapy in drug-induced psychiatric states and neuroleptic malignant syndrome. J ECT. Jun 2005;21(2):125-7. [Medline].
Hermesh H, Aizenberg D, Weizman A. A successful electroconvulsive treatment of neuroleptic malignant syndrome. Acta Psychiatr Scand. Mar 1987;75(3):237-9. [Medline].
Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry. Nov 1991;159:709-12. [Medline].
Sakkas P, Davis JM, Janicak PG, Wang ZY. Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull. 1991;27(3):381-4. [Medline].
Schneider SM. Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med. Jul 1991;9(4):360-2. [Medline].
Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth. Jul 2000;85(1):129-35. [Medline].
Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin. May 2004;22(2):389-411. [Medline].
Buckley PF, Hutchinson M. Neuroleptic malignant syndrome. J Neurol Neurosurg Psychiatry. Mar 1995;58(3):271-3. [Medline].
Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am. May 2000;18(2):317-25, x. [Medline].
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull. 1988;24(1):25-9. [Medline].
Caroff SN, Mann SC, Lazarus A. Neuroleptic malignant syndrome. Arch Gen Psychiatry. Sep 1987;44(9):838-40. [Medline].
Colosimo C, Merello M, Albanese A. Clinical usefulness of apomorphine in movement disorders. Clin Neuropharmacol. Jun 1994;17(3):243-59. [Medline].
Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. Mar 1993;77(2):477-92. [Medline].
Lazarus A, Mann SC, Caroff SN. The Neuroleptic Malignant Syndrome and Related Conditions. Washington, DC: American Psychiatric Press; 1989.
Nierenberg D, Disch M, Manheimer E, Patterson J, Ross J, Silvestri G, et al. Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol Ther. Nov 1991;50(5 Pt 1):580-6. [Medline].
Reulbach U, Dütsch C, Biermann T, Sperling W, Thuerauf N, Kornhuber J, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11(1):R4. [Medline].
Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry. Aug 1997;154(8):1156-8. [Medline].
Shiloh R, Valevski A, Bodinger L, Misgav S, Aizenberg D, Dorfman-Etrog P, et al. Precautionary measures reduce risk of definite neuroleptic malignant syndrome in newly typical neuroleptic-treated schizophrenia inpatients. Int Clin Psychopharmacol. May 2003;18(3):147-9. [Medline].
Further Reading
Keywords
neuroleptic malignant syndrome, neuroleptic medication, NMS, idiosyncratic reaction, muscular rigidity, autonomic dysfunction, haloperidol, fluphenazine, antipsychotic agents, prochlorperazine, promethazine, clozapine, risperidone, metoclopramide, amoxapine, lithium, dopamine D2-receptor antagonist, withdrawal of anti-Parkinson medication
respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, diffuse intravascular coagulation, DIC, rhabdomyolysis, pneumonia, renal failure, seizures, hyperthermia, profuse diaphoresis, sialorrhea, metabolic acidosis, dopamine receptor blockade, impaired temperature regulation
