You are in: eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Critical Care Neuroleptic Malignant SyndromeArticle Last Updated: Aug 14, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Mary C Mancini, MD, PhD, Director of Cardiothoracic Transplantation, Professor, Department of Surgery, Louisiana State University Health Sciences Center Mary C Mancini is a member of the following medical societies: American Heart Association, American Medical Association, American Thoracic Society, Association for Academic Surgery, Association for Surgical Education, International College of Surgeons, International Society for Heart and Lung Transplantation, New York Academy of Sciences, Phi Beta Kappa, and Southern Thoracic Surgical Association Coauthor(s): Girish G Deshpande, MD, MBBS, FAAP, Assistant Professor, Department of Pediatrics, Division of Critical Care Medicine, Children's Hospital of Illinois at OSF St Francis Medical Center Editors: G Patricia Cantwell, MD, Associate Clinical Professor, Department of Pediatrics, University of Miami; Director of Pediatric Critical Care Medicine, Miller School of Medicine, Jackson Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry J Evans, MD, Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center; Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Associate Professor, Department of Clinical Pediatrics, State University of New York at Stony Brook; Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center Author and Editor Disclosure Synonyms and related keywords: neuroleptic malignant syndrome, NMS, neuroleptics, antidopaminergic activity, serotonin INTRODUCTIONSection 2 of 10
  BackgroundNeuroleptic malignant syndrome (NMS), first described in 1963 by Delay et al in the French psychiatric literature, is a rare but potentially lethal complication of treatment with potent neuroleptics. Neuroleptic drugs (ie, antipsychotic drugs, antischizophrenic drugs) are primarily used to treat schizophrenia and other psychotic states. Traditional drugs have action through inhibition of dopaminergic receptors, while the newer agents work by causing blockade of serotonin receptors. NMS often occurs as treatment begins, when physicians progressively increase doses of neuroleptics. No clear relationship has been established between neuroleptic dosage and risk of developing NMS. A drug's potential for inducing NMS seems to parallel its antidopaminergic activity. PathophysiologyNMS pathophysiology is largely speculative. Neuroleptic drugs block dopaminergic receptors, creating a functional dopamine-deficiency state. Dopaminergic receptor blockade in the substantia nigra causes muscle rigidity and alters thermoregulation in the hypothalamus. Increased heat production from muscle rigidity causes fever, impaired heat dissipation (by reducing cutaneous vasodilatation or by sweating), and possibly a higher core temperature set point in the hypothalamus. MM isoenzyme of creatine kinase increases. Muscle biopsy demonstrates morphologic and histoenzymologic abnormalities in muscle fibers. FrequencyInternationalIncidence varies because of differing diagnostic criteria, patient characteristics, and available information. Reported incidence of NMS in neuroleptic-treated patients ranges from 0.1-5.5%. NMS onset ranges from 1-44 days following administration of neuroleptic drug; mean onset is 10 days. Lazarus et al reported NMS occurring in 67% of patients within 1 week and 96% of patients within 30 days following administration of neuroleptics. Mortality/MorbidityOnce reported to be 20-30%, the mortality rate is now estimated at 5-11.6%. Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism). Renal failure is associated with a 50% mortality rate. No consistent long-term physical, neurological, cognitive, or laboratory sequelae have been attributed to NMS alone, although sequelae may result from such secondary complications as prolonged hypoxia or ischemic encephalopathy. Researchers have noted sporadic cases of prolonged rigidity and long-term neuropsychological deficits. SexThe male-to-female ratio is 2:1. AgeNMS occurs in people of all age groups, with a reported mean age of 40 years. CLINICALSection 3 of 10
History
Physical
Causes
DIFFERENTIALSSection 4 of 10
Bacteremia Head Trauma Hyperthyroidism Meningitis, Aseptic Meningitis, Bacterial Multiple Endocrine Neoplasia Pheochromocytoma Schizophrenia and Other Psychoses Substance Abuse: Cocaine Systemic Lupus Erythematosus Tetanus Thyroid Storm Toxicity, Monoamine Oxidase Inhibitor Toxicity, Selective Serotonin Reuptake Inhibitor
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| Drug Name | Dantrolene sodium (Dantrium) |
|---|---|
| Description | Interferes with release of calcium from sarcoplasmic reticulum, thus directly inhibiting muscle contraction. Also prevents or reduces increase in myoplasmic calcium ion concentration that activates acute catabolic process associated with malignant hyperthermia. Available as sodium salt in 25-, 50-, and 100-mg caps and in 20-mg powder for injection. |
| Adult Dose | Spasticity: 25 mg/d PO initially, gradually increase to tid/qid; then increase dose by 25 mg q4-7d; not to exceed 100 mg 2-4 times/d or 400 mg/d Hyperthermia: Preoperative prophylaxis: 4-8 mg/kg/d PO divided qid administered 1-2 d before surgery for patients at risk; to prevent recurrence, administer last dose 3-4 h before scheduled surgery; alternatively, 2.5 mg/kg IV 1.25 h before surgery and infused over 1 h; additional doses may be needed during surgery, especially if prolonged Crisis: 1 mg/kg IV, may repeat prn; not to exceed a cumulative dose of 10 mg/kg; if physiologic and metabolic abnormalities reappear, repeat regimen Postcrisis follow-up: 4-8 mg/kg/d PO divided qid for 1-3 d; administer IV when PO therapy is not practical; individualize dosage beginning with 1 mg/kg IV or more as clinical situation dictates |
| Pediatric Dose | Spasticity: 0.5 mg/kg PO bid initially, increase frequency to tid/qid at 4- to 7-d intervals; then increase dose by 0.5 mg/kg; not to exceed 3 mg/kg 2-4 times/d up to 400 mg/d Hyperthermia: Administer as in adults |
| Contraindications | Documented hypersensitivity; active hepatic disease (eg, hepatitis, cirrhosis) |
| Interactions | Use with verapamil may result in hyperkalemia and myocardial depression; concomitant use of estrogen increases risk of hepatotoxicity; CNS depression is exaggerated when used with CNS depressants; incompatible when mixed with dextrose, saline, or bacteriostatic water solutions |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution with impaired cardiac or pulmonary function or history of previous liver disease; may cause hepatotoxicity (more common in females or patients >35 y), onset of overt hepatitis typically 3-12 mo after treatment initiation; monitor baseline and periodic liver function; adverse reactions include hepatitis, drowsiness, seizures, dizziness, lightheadedness, confusion, headaches, pleural effusion with pericarditis, tachycardia, hematuria, diarrhea, nausea, vomiting, GI bleeding, severe constipation, dysphagia, rash, photosensitization, acnelike rash, pruritus, urticaria, and abnormal hair growth; avoid alcohol and unnecessary exposure to sunlight; causes drowsiness; may impair ability to perform hazardous functions requiring mental alertness or physical coordination; protect IV from light; use reconstituted injection within 6 h; precipitant forms when IV placed in glass containers |
For a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. D2 receptor blockade might cause NMS by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents (eg, phenothiazines).
| Drug Name | Bromocriptine (Parlodel) |
|---|---|
| Description | Is an ergot alkaloid with dopamine receptor agonist action. |
| Adult Dose | 10 mg PO tid initially; if no improvement in 24 h, may increase dose; not to exceed 20 mg PO qid |
| Pediatric Dose | Limited data exist; 1.25 mg PO q12h initially, may gradually increase dose prn; not to exceed 20 mg/d |
| Contraindications | Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders |
| Interactions | Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | May worsen condition of patient with psychiatric illness, peptic ulcer disease, or preexisting peripheral vascular disease; may result in cardiac decompensation in patients with history of myocardial infarction; adverse reactions include orthostatic hypotension, hallucinations, confusion, delirium, nausea, and vomiting |
| Drug Name | Amantadine (Symmetrel) |
|---|---|
| Description | Has been tried in NMS because it increases synaptic dopamine activity. As an antiviral, actions include inhibition of influenza A virus uncoating, prevention of virus penetration into host, and inhibition of M2 protein in the assembly of progeny virions. Exhibits antiparkinsonian activity by blocking reuptake of dopamine into presynaptic neurons and by causing direct stimulation of postsynaptic receptors. |
| Adult Dose | Limited data exist; several case reports describe using 100 mg PO bid |
| Pediatric Dose | Not established; 5 mg/kg/d PO qd or divided bid has been used for influenza A prophylaxis; not to exceed 150 mg/d (age 1-9 y) or 200 mg/d (age >10 y) |
| Contraindications | Documented hypersensitivity |
| Interactions | Drugs with anticholinergic or CNS stimulant activity increase amantadine toxicity; the concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution with liver disease, epilepsy, history of recurrent eczematoid dermatitis, or uncontrolled psychosis; may increase seizure activity or EEG disturbances with preexisting seizure disorders; decrease dosage with renal impairment and with active seizure disorders; adverse reactions include orthostatic hypotension, edema, dizziness, confusion, insomnia, difficulty in concentration, restlessness, hallucinations, seizures, livido reticularis, nausea, vomiting, xerostomia, and urinary retention; avoid alcohol; may cause drowsiness; may impair ability to perform activities requiring mental alertness or coordination; do not abruptly discontinue therapy because may precipitate a parkinsonian crisis |
| Drug Name | Levodopa and carbidopa (Sinemet) |
|---|---|
| Description | Levodopa is a metabolic precursor of dopamine. Few reports of its use in combination with carbidopa (vide infra) in NMS exist because of its dopaminergic action. Crosses the blood-brain barrier and is converted to dopamine by enzyme action, thus restoring dopamine levels in the extrapyramidal centers such as substantia nigra. Carbidopa, a dopamine decarboxylase inhibitor, does not cross the blood-brain barrier. Diminishes the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing levodopa's availability in the CNS and enhancing its effectiveness. A variety of dosage ratios are available (ie, 1:10 carbidopa to levodopa, 1:4 carbidopa to levodopa). Also available as IR and SR dosage forms. |
| Adult Dose | 25 (carbidopa)/250 (levodopa) mg PO tid/qid Alternatively, 500-1000 (based on levodopa component) mg/d PO divided q6-12h; increase by 100-750 mg/d q3-7d until response; not to exceed 8000 mg/d |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions |
| Interactions | Antacids increase bioavailability of levodopa; benzodiazepines, hydantoins, methionine, papaverine, and pyridoxine decrease levodopa effectiveness; iron salts and anticholinergics decrease GI absorption of levodopa; MAOIs may increase hypertensive reaction; may decrease metoclopramide effects; methyldopa may have additive hypotensive effects |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution with severe cardiovascular or pulmonary disease, asthma, occlusive cerebrovascular disease, renal or hepatic or endocrine disease, affective disorders, major psychoses, cardiac arrhythmias, and chronic wide-angle glaucoma |
Neuroleptic Malignant Syndrome excerpt
Article Last Updated: Aug 14, 2006
