HYPERTHERMIA SYNDROMES-3: DRUG INDUCED HYPERTHERMIA

"The person who takes medicine must recover twice, 
once from the disease, and once from the medicine"
                                                        - William Osler

NEUROLEPTIC MALIGNANT SYNDROME (NMS):

NMS is defined as tetrad of hyperthermia, rigidity, mental status changes and autonomic instability, developing after 24 hours (first 2 weeks) of starting, dose escalating or switching to another, dopamine antagonist medications, including neuroleptics (antipsychotics).

Mental status changes can present as coma, stupor, mutism or agitation. Muscle rigidity is characterized by lead pipe type and hyporeflexia. Superimposed tremors may give impression of cogwheel phenomenon.

There is prominent diaphoresis and sialorrhea.

Usually symptomatology develops over 1 to 3 days, with change in mental status followed by rigidity, then hyperthermia and autonomic dysfunction.

Reported incidence of NMS, among patients taking neuroleptic (antipsychotic) medications, range from 0.02 to 3 percent.

Drugs associated with NMS are antipsychotics (haloperidol, quetiapine, risperidone, fluphenazine, chlorpromazine, olanzapine, clozapine, thioridazine) and antiemetics (metocloperamide, domeperidone, promethazine, prochlorperazine, droperidol).

Of these HALOPERIDOL, QUETIAPINE AND METOCLOPERAMIDE are very commonly used drugs in ICU.

Though drug association with NMS is idiosyncratic, higher dose, rapid dose escalation, switching from one to another agent and parenteral route of administration are risk factors for development of syndrome.

Other risk factors are concomitant use of lithium or other psychotropic drugs and acute medical illness (trauma, surgery, infection).

NMS is also seen after withdrawal and dose reduction of dopamine agonist in patient of parkinsonism.

PATHOPHYSIOLOGY: Dopamine antagonism, in the hypothalamus results in disordered thermoregulation, whereas that in nigrostriatal pathway leads to parkinsonism symptoms like rigidity. Hyperthermia is caused by deranged thermoregulation and increased heat production secondary to muscle rigidity.

Familial predisposition has also been suggested in NMS. Presence of specific allele of dopamine D2 receptor gene is over represented in NMS patients.

Diagnostic criteria involves, hyperthermia and muscle rigidity, associated with use of dopamine antagonist medications, and presence of two of the following- diaphoresis, change in level of consciousness, mutism, tremors, autonomic dysfunction (labile blood pressure) and rhabdomyolysis.

TREATMENT:

Stop all dopamine blockers promptly. In cases where it is the result of withdrawal of dopamine agonist drug (medications for parkinsonsonism), prompt resumption of therapy should be done.

Quick assessment and management of airway, breathing and circulation should not be delayed. Rapid fluid resuscitation with cold isotonic saline is the answer, to optimize intravascular volume, organ perfusion and prevent/ minimize complication associated with rhabdomyolysis.

Electrolytes should be optimized.

Cooling measure like evaporative cooling, ice packs and cooling blankets should be employed.

Benzodiazepine like lorazepam 1-2 mg every 4-6 hourly, may ameliorate symptoms, like agitation, mutism and immobility. Intubated patients should be sedated optimally with midazolam.

Specific treatment involves Dopamine agonist like bromocriptine and amantadine.  

Bromocriptine is started as 2.5 mg every 6 hourly enteral and titrated to maximum dose of 45 mg per day. To prevent recurrence, it should be continued for 10 days after symptoms are controlled, then tapered slowly. Adverse effects of bromocriptine are psychosis, vomiting (and associated aspiration) and hypotension.

Amantadine is an alternative for bromocriptine. It is started as 100 mg enteral and titrated to maximum dose of 200 mg every 12 hourly.

Dantrolene (muscle relaxation without total paresis), may be used in patients with extreme hyperthermia and rigidity. It acts by inhibition of sarcoplasmic calcium release. It is administered as 1-2.5 mg/kg intravenous followed by 1mg/kg every 6 hourly, if hyperthermia and rigidity reduces after first dose. It should be tapered to oral route, and continued for 3 days after resolution of symptoms, to prevent recurrence.

It may be combined with dopamine agonist therapy.

Calcium channel blockers must be avoided, if dantrolene is being considered, as it may precipitate hypotension and worsen cardiac function.

Liver toxicity is the most dreaded adverse effect of dantrolene.

Electroconvulsive therapy (ECT) may be considered in refractory cases. This therapy is based on, its success in severe/ refractory parkinsonism.

Symptoms usually resolve over 1 to 2 weeks of discontinuing offending agent.

Restarting neuroleptics is a little tricky. To minimize chances of recurrence, neuroleptic medication should be started at least 2 weeks after resolution of syndrome. Use of low potency drug, slow titration to upward dose, avoidance of concurrent administration of lithium are other precautions to reduce recurrence.

Reported mortality is 5-20 percent.


NMS and SS must not be confused with other, as definitive treatment is entirely different. Bromocriptine (dopamine agonist) administered for mistaken diagnosis of NMS, may worsen SS. Similarly chlorpromazine (dopamine antagonist) given for erroneous diagnosis of SS, may worsen NMS.