6.5.3) TREATMENT
A) SUPPORT 1) Discontinue offending drug(s); initiate prompt supportive care (eg, hydration, rapid cooling measures), and stabilize respiratory, renal, and cardiac systems. Specific drug therapies (ie, muscle relaxants, dopamine agonists) need to be adjusted as necessary to treat signs and symptoms. Combination therapy may be necessary in refractory cases.
2) Immediately stop ALL medications with known or suspected dopaminergic blocking properties However, if NMS is suspected to be secondary to recent withdrawal of dopaminergic medication, therapy with these agents should be reinstated (Rosebush & Stewart, 1989; Granner & Wooten, 1991; (Fink, 2001)). Supportive treatment includes cooling measures to promote heat dissipation. Other measures require restoration of fluid and electrolyte balance and aggressive pharmacologic treatment ((Fink, 2001)).
3) BENZODIAZEPINES: Benzodiazepines (usually lorazepam) are considered the first-line of therapy in the treatment of NMS. They can be beneficial due to their rapid onset, especially in patients with agitation and restlessness. Therapy is nonspecific but it may have a role in attenuating the sympathetic hyperactivity that is observed with NMS (Juurlink, 2011; Wysokinski, 2012).
4) Many of the therapies described below have not been studied using well-designed methodologies; many have been proposed based on single case reports. Therefore, clear treatment recommendations are not possible. Management of NMS focuses primarily on supportive care (Carbone, 2000).
B) MONITORING OF PATIENT 1) No laboratory studies will confirm the diagnosis of NMS.
2) Monitor mental status and vital signs; continuous monitoring of core temperature is advised.
3) Monitor serum chemistry, renal function, creatinine kinase, CBC, liver enzymes or venous or arterial blood gases, urinalysis and urine output.
C) REHYDRATION THERAPY 1) Assess clinical status to determine magnitude of dehydration. Assuming normal renal function: NS or LR is used initially as a 1- to 2-liter bolus over 30 to 60 minutes in a moderately dehydrated patient. Slow response may require an additional bolus of up to one liter in the subsequent 30 minutes. CVP monitoring may be necessary to follow additional fluid replacement. Swan-Ganz catherization for pulmonary artery pressure monitoring is recommended in elderly patients with cardiac, pulmonary, or renal dysfunction.
D) COOLING THE PATIENT 1) Vigorous treatment with cooling blankets, mist and fan technique, tepid sponging; continuous venovenous hemofiltration for hyperthermia unresponsive to other measures. a) PERITONEAL LAVAGE: Iced saline (2 liters) via peritoneal lavage has been used successfully to treat hyperthermia unresponsive to conventional methods (Horowitz, 1989). b) ICED BATH IMMERSION: In cases of severe hyperpyrexia (greater than 41.1 degrees C), iced bath immersion may be required (Rosebush & Stewart, 1989; Schneider, 1991). c) DURATION: To avoid hypothermia, cooling measures should be discontinued when the patient's temperature reaches 38.5 degrees C; normothermia should be reached in 45 to 60 minutes (Graham et al, 1986). d) CONTINUOUS VENOVENOUS HEMOFILTRATION with cooling of extracorporeal system has been successful in decreasing temperature refractory to other treatments in NMS (Perez-Vela et al, 1996). e) OTHER: Measures such as colonic lavage and dialysis have been reported anecdotally, but have NOT been evaluated critically and are NOT recommended. f) Pharmacologic Agents: 1) ANTIPYRETICS a) Although antipyretics generally do not have a role in the treatment of conditions attributable to imbalance between heat generation and heat dissipation, they may be indicated in NMS (Rosebush & Stewart, 1989; Rosebush & Mazurek, 1991b).
b) Some data suggest that NMS may be a form of the acute phase reaction, many features of which are mediated by prostaglandin E2, which can be inhibited by salicylates and acetaminophen (Rosebush & Mazurek, 1991b).
c) RECOMMENDED DOSE: ADULT: Aspirin or Acetaminophen 650 mg orally every 4 to 6 hours; rectal suppositories may be considered if unable to take orally.
2) VASODILATORS a) NITROPRUSSIDE/INDICATIONS: May be beneficial in patients with significant or refractory peripheral vasoconstriction contributing to hyperthermia; may decrease temperature via increase in heat loss through the skin (Schneider, 1991; Blue et al, 1986).
b) RECOMMENDATION: ADULT: Begin intravenous infusion at 0.1 mcg/kg/min and titrate to desired effect; up to 10 mcg/kg/min may be required (American Heart Association, 2005). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 mcg/kg/min (Kleinman et al, 2010).
c) PRECAUTIONS: Contraindicated in patients taking sildenafil (Viagra(R)) and in the treatment of compensatory hypertension (ie, arteriovenous shunt, coarctation of aorta); caution in liver and renal disease and Leber's optic atrophy and in patients susceptible to developing methemoglobinemia.
E) DRUG THERAPY 1) DOPAMINE AGONISTS a) BROMOCRIPTINE 1) INDICATIONS a) Specific therapy is directed at reversing dopamine blockade with a centrally-acting dopamine agonist, eg, bromocriptine. but can particularly be useful in patients with primary thermoregulatory abnormalities (Schneider, 1991; Dhib-Jalbut et al, 1983) (Zubenko & Harrison, 1983). It can be given alone or in combination with dantrolene (Brady et al, 1999). b) Available only in oral form; must be given early, before patient loses gag reflex, which limits usefulness to less severe cases or to use concomitantly with dantrolene (Schneider, 1991). 1) Some studies report no beneficial effects and suggest that bromocriptine might actually worsen the course of NMS (Rosebush & Stewart, 1989; Rosebush et al, 1991a).
c) RECOMMENDATION 1) Doses of 2.5 to 10 mg orally {or via nasogastric tube} 3 to 4 times per day (Juurlink, 2011); if response is inadequate, increase dose by 2.5 mg every 24 hours until a response or until reaching a maximum dose of 45 mg/day (Berman, 2011).
2) It is usually maintained for at least 10 days to treat NMS for patient's exposed to oral neuroleptics and 2 to 3 weeks for depot neuroleptics. Early discontinuation may result in relapse (Berman, 2011).
d) PRECAUTIONS 1) It directly opposes the dopamine effects of antipsychotic medications, but may be associated with worsening a patient's underlying psychiatric illness (Perry & Wilborn, 2012; Juurlink, 2011).
2) Contraindicated in uncontrolled hypertension or toxemia of pregnancy; caution in patients with hypotension, dementia, or a history of myocardial infarction.
b) OTHER DOPAMINERGIC AGENTS 1) SUMMARY: Other dopaminergic agents that have been used include amantadine, levodopa and apomorphine (Berman, 2011). 2) AMANTADINE a) INDICATIONS 1) Specific therapy is directed at reversing dopamine blockade with a centrally-acting dopamine agonist (eg, amantadine). Particularly useful in patients with primary thermoregulatory abnormalities (Velamoor, 1998). Amantadine has been anecdotally associated with success as a dopamine agonists (Juurlink, 2011; Berman, 2011).
b) RECOMMENDATION (ADULT) 1) DOSE: ADULT: 100 mg orally or by nasogastric tube every 8 hours. Continue for up to 7 days, until patient's condition improves clinically or until creatine kinase levels return to normal. Then, withdraw slowly over additional 3 days. Early discontinuation may result in relapse (Velamoor, 1998).
c) PRECAUTIONS 1) Seizure risk increased in patients with active seizure disorder (use lower dose); reduce dose of other anticholinergics; use cautiously with CNS stimulants; increased amantadine plasma concentrations with concomitant hydrochlorothiazide/triamterene therapy.
2) MUSCLE RELAXANTS a) DANTROLENE 1) INITIAL DOSE: Dantrolene, a muscle relaxant that works by inhibiting calcium release from the sarcoplasmic reticulum, may be effective in shortening the duration of illness. Dantrolene can be started at an initial dose of 1 to 2.5 mg/kg followed by 1 mg/kg every 6 hours up to a maximum dose of 10 mg/kg/day (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Berman, 2011). It appears to be most beneficial in patients with pronounced muscular rigidity. Oral dantrolene can be used in less severe cases or to taper the dose following initial IV therapy after several days. The oral dose can range from 50 to 200 mg/day. NOTE: Dantrolene can be hepatotoxic at levels above 10 mg/kg/day. The drug is usually discontinued once symptoms begin to resolve due to the risk of hepatotoxicity (Berman, 2011). 2) Patients with disturbance of consciousness may require longer duration of treatment (Tsutsumi et al, 1998). 3) INDICATIONS a) Specific therapy is directed at reducing muscle rigidity with a peripherally-acting muscle relaxant, eg, dantrolene. Most useful in cases in which severe muscle rigidity/contraction is predominant feature, particularly if patient loses ability to swallow (Berman, 2011; Coons et al, 1982; Goekopp & Carbatt, 1982; May et al, 1983; Goulon et al, 1983; Caroff & Mann, 1993).
b) Review of NMS in the pediatric literature indicated dantrolene might not be effective in children; mortality was 9%, with 20% serious sequelae; duration of NMS ranged from 1 to 119 days (Silva et al, 1999).
4) PRECAUTIONS a) Caution with history of hepatic, cardiac, or pulmonary dysfunction (obstructive pulmonary disease); discontinue or decrease dose with severe weakness or diarrhea.
5) EFFICACY a) Variable; it can be ineffective as a sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with dopamine agonist (ie, bromocriptine) (Perry & Wilborn, 2012; Granato et al, 1983; Blue et al, 1986; May et al, 1983).
b) Dantrolene and bromocriptine are the 2 most widely used agents used in the treatment of NMS (Perry & Wilborn, 2012). Some studies report NO beneficial effects or inadequate supportive evidence for its use (Juurlink, 2011) and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989) (Rosebush et al, 1991a).
3) OTHER a) It has been suggested that anticholinergic and antihistaminic agents should be considered as first line therapy in patients with a fever of less than 38.5 degrees C. Other agents include benztropine (2 to 8 mg/day IV), trihexyphenidyl hydrochloride (2 to 10 mg/day, orally) and diphenhydramine (50 to 250 mg/day) (Brady et al, 1999).
4) CALCIUM ANTAGONISTS a) NIFEDIPINE 1) Nifedipine has been effective in rapidly eradicating most NMS signs, including hypertension, fever, tachycardia, urinary incontinence, rigidity, and stupor (Hermesh et al, 1988a). 2) Mechanisms through which nifedipine reverses NMS are unknown (Hermesh et al, 1988a): a) May possess anti-NMS potential; may act by displacing offending neuroleptic agents from dopamine D2-receptors in the hypothalamus or striatum.
b) Neuronal or muscular calcium channels may be involved in pathophysiology of NMS; may block excessive calcium flow across muscle plasma membranes and diminish excessive contraction.
c) Further studies of the use of nifedipine in NMS are warranted.
5) ANTICONVULSANTS a) CARBAMAZEPINE 1) One case of NMS associated with a phenothiazine and another associated with a combination of a phenothiazine and butyrophenone both responded to administration of carbamazepine. Mechanism for the treatment of NMS with carbamazepine remains unclear (Thomas et al, 1998).
F) FEELING AGITATED 1) Benzodiazepines are indicated for immediate relaxation, for sedation of violent patients, or when there is a question in differential diagnosis of NMS versus lethal catatonia. NMS may respond to other treatments, but lethal catatonia may improve only with benzodiazepine therapy. Avoid physical restraints, which can increase agitation and core temperature. a) Intravenous DIAZEPAM (Adults: 5 to 10 mg every 5 to 10 minutes as needed; Child: 0.1 to 0.2 mg/kg every 5 to 10 minutes as needed) may be helpful. Monitor for respiratory depression and need for endotracheal intubation.
b) LORAZEPAM has also been suggested in patients with a body temperature of less than 102 degrees F and minimal to moderate behavioral signs: Start with 3 to 4 mg/day, increasing to 12 to 16 mg/day within a few days.
G) DRUG-INDUCED DYSTONIA 1) ADULT a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
2) CHILDREN a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
H) RHABDOMYOLYSIS 1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
I) ELECTROCONVULSIVE THERAPY 1) SUMMARY: Electroconvulsive therapy (ECT) can be effective even in cases of failed drug therapy. It is considered a second-line therapy (Wysokinski, 2012; Juurlink, 2011).
2) MECHANISM: Although its mechanism is not completely understood, NMS has been successfully treated in a limited number of cases with electroconvulsive therapy. If an NMS patient receives ECT, it is recommended that the individual be paralyzed with a nondepolarizing agent, since a depolarizing agent is contraindicated owing to its tendency to increase serum potassium levels (Carbone, 2000).
3) INDICATIONS FOR THERAPY: If pharmacologic treatment has not been successful and the patient continues to have fever, autonomic and behavioral signs or if the severity of the condition is seen as malignant (fever greater than 102 degrees F, severe hypertension and tachycardia, delirium, or stupor), ECT may be considered ((Fink, 2001)). ECT has also been suggested in severe cases of NMS in which patients are at high risk to develop complications including dysphoria with psychosis and catatonia (muscle rigidity) (Perry & Wilborn, 2012).
4) DURATION OF THERAPY: Although the number of ECT sessions is variable, patients with NMS have experienced significant clinical improvement after 3 to 5 sessions of electroconvulsive therapy (ECT); some authors have reported improvements after 8 sessions given over 6 weeks. In most cases, the response to ECT is usually faster than drug therapy and can be more effective in patients with severe symptoms (Wysokinski, 2012).
5) RISK OF THERAPY: The primary risk of therapy includes cardiovascular (initial bradycardia followed by tachycardia), malignant hyperthermia secondary to anaesthesia and hyperkalemia. Due to the potential for increased cardiac work, ischemic injury and dysrhythmias may develop (Verdura Vizcaino et al, 2011).
6) CASE REPORT: A 81-year-old woman, with a history of depression, was admitted with severe depression and psychotic symptoms. Her initial symptoms included irritability, severe anxiety, ideations of being poisoned, and restlessness. Haloperidol was started to treat symptoms (reaching a maximum dose of 4 mg/day) along with restarting her antidepressant medications. By day 4, she had developed signs and symptoms (ie, fever, sweating, rigidity, increased creatinine) consistent with NMS. Her psychopharmacologic medications were stopped and supportive care was initiated. Approximately 2 weeks later, the patient was clinically improved and risperidone was started to treat her depressive mood. Ten days later, the patient had a recurrence of NMS and all medications were discontinued. Following several significant clinical complications (eg, acute coronary syndrome, bilateral pneumonia, splenic infarction and bacteremia), the patient was treated successfully with 8 sessions of electroconvulsive therapy (ECT) (Gonzalez-Blanco et al, 2013).
7) CASE REPORT/REFRACTORY SYMPTOMS: A 44 year-old man, with a long history of paranoid schizophrenia receiving oral clozapine (500 mg/day) and haloperidol (10 mg/day), was admitted with increasing psychomotor agitation, delusions, auditory hallucinations and verbal aggression. Both medications were increased prior to admission. On day 3, the patient became febrile with increasing muscle rigidity and muscle tremor. A neuroinfection was initially suspected, but a rising CPK level (7192 Units/L; peaked at 8241 Units/L) was consistent with NMS. His antipsychotics were discontinued. Due to his deteriorating respiratory status, the patient required intubation and mechanical ventilation. Pharmacologic therapy included amantadine, lorazepam (10 mg/day), bromocriptine 15 mg/day and diazepam as needed. Other therapies included mannitol, furosemide fraxiparine, and metoprolol. Electroconvulsive therapy (ECT) was started on day 6, due to a lack of clinical improvement (ie, increased muscle rigidity in all extremities, multiple contractures in the upper and lower extremities). The patient required a total of 19 ECT sessions with significant clinical improvement following the ninth session. No adverse events developed related to the therapy. However, persistent psychotic symptoms required the restart of clozapine; slowly titrated to a dose of 400 mg/day. The patient's clinical course was slow to improve but he was discharged on day 114 with permanent hypoesthesia and paresis of the left hand fingers. One year later he had no symptoms of NMS (Wysokinski, 2012).
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