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Neuroleptic Malignant Syndrome
The features of NMS, serotonin syndrome (SS), and other toxidromes overlap substantially.Table 2 illustrates shared and unique features of NMS and SS. The DSM-IV criteria for NMS include severe muscle rigidity, elevated temperature, and other related findings (e.g., diaphoresis, incontinence, decreased level of consciousness, mutism, elevated or labile blood pressure, elevated creatine phosphokinase) developing in association with the use of neuroleptic (i.e., antipsychotic) medication.Box 2 lists common antipsychotic medications, as well as other dopamine-blocking drugs (e.g., antinausea medications) that can contribute to NMS. Other adverse drug reactions associated with hyperthermia that should be considered in the differential diagnosis of NMS and SS include adrenergic or anticholinergic toxicity, or uncoupling of oxidative phosphorylation—none of which should be associated with rigidity; malignant hyperthermia (postanesthesia); and baclofen withdrawal (with muscle spasm).
NMS may be increasingly relevant to ICU physicians, given the frequent administration of antipsychotics to critically ill patients for agitated delirium. Importantly, several NMS risk factors are common in ICU patients: agitation and use of typical antipsychotics (e.g., haloperidol), often in parenteral form, in higher doses (e.g., 20 mg of haloperidol daily), and in patients who are neuroleptic-naïve.
Treatment
The correct diagnosis is vital. In particular, the dopamine agonist bromocriptine, given for presumed NMS, can cause or worsen SS. Also, antipsychotics for hyperactive delirium or presumed SS can worsen/prolong NMS. No medications are approved by the Food and Drug Administration for the treatment of NMS; recommendations for treatment have been drawn from case series. Note that consultation with local poison control centers can be helpful in the management of both NMS and SS (listed at http://www.aapcc.org/dnn/default.aspx).
Discontinue All Dopamine Blockers. It is important to note that antipsychotics are not the only drugs that block dopamine neurotransmission. As shown in Box 2, metoclopramide, prochlorperazine, and promethazine are also dopamine blockers.
Provide Supportive Care. Supportive care is the mainstay of treatment for NMS. This includes vigorous hydration, attention to electrolyte abnormalities, external cooling for extreme hyperthermia, and managing complications (cardiorespiratory and renal failure, aspiration, and coagulopathies).
Consider Benzodiazepines for Milder Cases. Benzodiazepines (e.g., lorazepam 1–2 mg intravenously every 4–6 hrs) may ameliorate symptoms in milder cases of NMS, particularly catatonic symptoms like mutism and immobility.
Consider Dopaminergic Agents. Bromocriptine (starting at 2.5 mg bid-tid, up to 45 mg/day), amantadine (200–400 mg/day in divided doses), and other enterally administered dopaminergic agents may reverse parkinsonian symptoms (e.g., rigidity), speed recovery, and reduce mortality. Note that bromocriptine can precipitate psychosis, hypotension, and vomiting, in which case alternative medications should be considered. Bromocriptine should be continued for 10 days after resolution of NMS, as patients can have a recurrence if it is discontinued prematurely.
Consider Dantrolene. The skeletal muscle relaxant dantrolene appears to reduce symptoms, speed recovery, and reduce mortality in patients with NMS who have extreme hyperthermia and rigidity. Note that benzodiazepines or dopamine agonists can be administered with dantrolene, but not calcium channel blockers given the risk of cardiovascular collapse. Patients can be administered 1.0–2.5 mg/kg intravenously, then 1 mg/kg every 6 hrs if hyperthermia and/or rigidity reduces after the first dose. Side effects can include respiratory and hepatic impairment. If the patient has a good response, dantrolene can be tapered and switched to an oral preparation after the first few days. Dantrolene should be continued for 10 days after resolution of NMS, as patients can have a recurrence if it is withdrawn prematurely.
Consider Electroconvulsive Therapy. Electroconvulsive therapy should be considered if supportive care and pharmacotherapy are ineffective after 2 days. Electroconvulsive therapy has been effective in pharmacotherapy-resistant cases.
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