Neuroleptic Agent Toxicity Treatment & Management

No specific antidotes exist for the adverse effects of neuroleptic medications. Because these effects are so diverse and do not occur in most cases, prophylactic treatment for seizures, dystonia, dysrhythmias, or neuroleptic malignant syndrome (NMS) is not indicated.

Patients with an acute overdose of neuroleptic medication can be transferred if they are stable for a period of 6 hours. Transferring a patient before 6 hours of observation is imprudent because of the risk of developing seizures, hypotension, and dysrhythmias. Patients with NMS are critically ill and generally are not candidates for transfer, unless the initial treating facility is unable to provide adequate medical care. Once the patient appears to be improving and is clinically stable with decreasing creatine kinase levels and normal mentation, transfer may be undertaken safely.

Be aware that patients with an antipsychotic (neuroleptic) overdose are at risk of rapid deterioration with coma, seizures, hypotension, or dysrhythmias. They all require transport to a hospital facility because the severity of overdose cannot be ascertained immediately after ingestion.

Treatment with activated charcoal, 1 g/kg, is indicated as soon as possible. This can be administered in the field if permitted by local protocol and if altered mental status does not create a risk for aspiration.

Establish a large-bore intravenous (IV) line of isotonic sodium chloride solution in anticipation of possible hypotension or the need to administer medications.

Seizure activity usually responds to benzodiazepines in the usual anticonvulsant doses.

Treat ventricular dysrhythmias with standard advanced cardiac life support (ACLS) pharmaceutical agents.

Emergency department care varies depending on the patient's condition and on the care already provided in the field. The standard approach to resuscitation (airway, breathing, circulation, drugs, and environment [ABCDE]) is used as indicated by the patient's condition. Active airway management is indicated for patients who are in shock, status epilepticus, coma, or cardiac arrest.

No specific antidote for any of the neuroleptics exists.

Gastrointestinal (GI) decontamination (gastric lavage), if used within an hour of ingestion, may be useful in decreasing the absorption of neuroleptics. Protect the patient's airway before lavage if an altered level of consciousness is present. Patients sick enough to require intubation for their clinical condition should also be lavaged. Activated charcoal remains the GI decontamination method of choice. Neuroleptics are generally well bound by activated charcoal and should be administered in standard doses as soon as possible postingestion. Multiple-dose activated charcoal is of limited benefit and cannot be used if an ileus is present. Ipecac syrup is never recommended.

Hemoperfusion, hemodialysis, and forced diuresis are not effective.

Seizures are treated in a stepwise fashion, beginning with benzodiazepines (eg, lorazepam, midazolam) and followed by barbiturates (eg, phenobarbital, pentobarbital).

The combination of peripheral alpha-blockade and dehydration may result in severe hypotension during major tranquilizer overdose. Initial treatment involves administration of a volume challenge with isotonic saline. If the patient remains hypotensive after fluid challenge or manifests signs of cardiogenic shock, vasoconstrictor agents may be required. Norepinephrine is the preferred vasoconstrictor in this circumstance because it has direct alpha-agonist effects. Paradoxically, epinephrine or dopamine may lower the blood pressure because alpha-blockade from major tranquilizer exposure causes unopposed beta-agonist peripheral vasodilation.

Placement of a Foley catheter may be necessary in cases of the following:

• Coma
• Shock or severe dehydration (in order to monitor urine output)
• Urinary retention from the anticholinergic effects of the overdose

For patients manifesting neuroleptic malignant syndrome (NMS) with worsening hyperthermia, immediate cooling measures (eg, fans, wet cloths, ice packs in groin and axilla, and rectal acetaminophen) are indicated. Severe hyperthermia should be treated aggressively and rapidly with ice bath immersion.

Bromocriptine and amantadine are central dopaminergic agonists that may be effective in reversing the dopaminergic blockade caused by the neuroleptics. They have been reported as effective in treating NMS but work slowly (eg, over several days). They are given orally or by nasogastric tube, and they should be tapered gradually to avoid precipitation of another episode of NMS.

Oral levodopa, with or without carbidopa, and intravenous levodopa are therapies used more commonly in patients with Parkinson disease who develop NMS on sudden withdrawal of their dopaminergic therapy. Steroid pulse therapy may be useful in NMS for reducing the illness duration and improving symptoms in patients with Parkinson disease.

Dantrolene sodium (1-10 mg/kg) may be considered as adjunctive therapy for patients manifesting severe hyperthermia (rectal temperatures > 105°F [40.6º C]) and significant muscle rigidity. Dantrolene is incompatible with acidic solutions and is mixed with sterile water for injection. It must be given directly by slow IV push or by IV piggyback into a large-bore IV near the catheter with the IV fluid shut off. Great care must be taken to avoid extravasation into the tissues. Dantrolene is given in 1-2 mg/kg doses until a maximum dose of 10 mg/kg or until the rectal temperature breaks.

Dantrolene may be effective in malignant hyperthermia by dissociating the excitation-contraction coupling of skeletal muscles. While the precise mechanism of action and molecular targets are still incompletely known, dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. In 2004, Krause et al stated that studies have identified the ryanodine receptor (the major calcium release channel of the skeletal muscle sarcoplasmic reticulum) as a dantrolene-binding site. ^[18] A direct or indirect inhibition of the ryanodine receptor is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration.

Dantrolene acts primarily peripherally and has no effect on the cardiovascular or respiratory systems in this acute setting.

Some studies have questioned the efficacy of dantrolene, ^[19] but anecdotal reports still advocate for its use. Dantrolene should not be used as monotherapy.

Patients who develop signs of potentially serious toxicity require admission. Patients who remain asymptomatic after a period of observation (6 h recommended) can be discharged home or given psychiatric evaluation. ^[20]

Potentially serious signs of toxicity include persistent hypotension, dysrhythmias or abnormal ECG, seizures, or movement disorders that fail to respond to anticholinergic treatment.

Patients with dysrhythmias, status epilepticus, coma, or those who require pressor agents to maintain blood pressure should be treated in an ICU setting.

Repeated doses of activated charcoal every 6 hours without cathartics may increase clearance of some neuroleptics that undergo enterohepatic circulation. There must be no ileus of the gut for this method of enhanced elimination. Perform standard measures for treating comatose patients (eg, eye care, position changes).

Follow-up with a psychiatrist is recommended for patients with intentional overdose and for those who require medication changes because of adverse effects from neuroleptics. Once the patient is stable and awake, psychiatric evaluation can take place before discharge from hospital.

Notification of the regional poison control center is indicated. In complex or severe cases, consult with the regional poison control center or a medical toxicologist for additional information and patient care recommendations. Once the patient's medical condition has stabilized, psychiatric assessment may be indicated to determine any suicidal intent.

Medications should be labeled and stored safety. Child-resistant closures should be applied to all medications and substances that can cause significant toxicity. 

Most patients with neuroleptic overdose recover without sequelae and do not require ongoing medical treatment.

Patients who have developed neuroleptic malignant syndrome (NMS) pose a difficult problem if they require ongoing antipsychotic medication monitoring and adjustment. Neuroleptics have been successfully reintroduced following episodes of NMS, but this must be done carefully and under the supervision of a psychiatrist. Alternative medications with a lower potency that are less likely to produce NMS may be used.