NEUROLEPTICS INTOXICATION

NEUROLEPTICS INTOXICATION

Background: The term neuroleptic refers to the effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents comprise a group of the following 7 classes of drugs:

• Phenothiazines, further divided into the aliphatics, piperidines, and piperazines
• Thioxanthenes (eg, droperidol)
• Butyrophenones (eg, haloperidol)
• Dibenzoxazepines (eg, loxapine)
• Dihydroindolone (eg, molindone)
• Diphenylbutylpiperidine (eg, pimozide)
• Benzisoxazole (eg, risperidone)

The adverse effects of neuroleptics are not confined to psychiatric patients. Neuroleptics also are used as sedatives, for their antiemetic properties, to control hiccups, to treat migraine headaches, as antidotes for drug-induced psychosis, and in conjunction with opioid analgesia. Any of the acute adverse effects of neuroleptics may occur in these settings.

Pathophysiology: The major tranquilizers have complex central nervous system (CNS) actions that are incompletely defined. Their therapeutic action is thought to be primarily owing to antagonism of central dopaminergic (D-2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, alpha1-adrenergic, and H1-histaminergic receptors.

Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug. Generally, all neuroleptic medications are capable of causing the following symptoms:

• Hypotension: Phenothiazines are potent alpha-adrenergic blockers that result in significant orthostatic hypotension, even in therapeutic doses for some patients. In overdose, hypotension may be severe.
• Anticholinergic effects: Neuroleptic agent toxicity can result in tachycardia, hyperthermia, urinary retention, ileus, mydriasis, toxic psychosis, and hot dry flushed skin.
• Extrapyramidal symptoms: Alteration in the normal balance between central acetylcholine and dopamine transmission can produce dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia, and other movement disorders. Chronic use of major tranquilizers is associated with buccolingual dysplasia (tardive dyskinesia [TD]), parkinsonism, and akathisia.
• Neuroleptic malignant syndrome: All of the major tranquilizers have been implicated in the development of neuroleptic malignant syndrome (NMS), a life-threatening derangement that affects multiple organ systems and results in significant mortality.
• Seizures: Most major tranquilizers lower the seizure threshold and can result in seizures at high doses and in susceptible individuals. With loxapine, seizures may be recurrent.
• Hypothermia: Certain major tranquilizers prevent shivering, limiting the body's ability to generate heat.
• Cardiac effects: Prolongation of the QT interval and QRS can result in arrhythmias.
• Respiratory depression: Hypoxia and aspiration of gastric contents can occur

Physical: Numerous physical findings are potentially associated with overdose of major tranquilizers, although some patients may remain relatively asymptomatic.

• Anticholinergic syndrome: Toxic psychosis, agitation, confusion, mydriasis, urinary retention, ileus, hot flushed dry skin, and tachycardia may occur.

• Movement disorders

• Increased muscle tone, extrapyramidal symptoms, akathisia, restless legs, parkinsonism, or dystonia may occur.

• After chronic use of these medications (>24 mo), certain patients develop irreversible TD that consists of characteristic involuntary movements of the face, lips, and tongue.

• A disorder associated with intravenous use of prochlorperazine (Compazine) has been noted. Patients with this disorder become intensely anxious and restless and occasionally elope from the ED. These patients describe this acute dysphoric reaction as being very uncomfortable and creating the urge to crawl out of their skin. Whether this is an intense form of akathisia or a new movement disorder is unclear.

• Neuroleptic malignant syndrome

• Patients with NMS have impressive physical findings that may evolve over several days.

• Initial findings usually involve increased muscle tone, worsening extrapyramidal symptoms, and altered mental status.

• Diffuse lead-pipe muscle rigidity is invariably present at some point during the condition. Chronic muscle contraction leads to rhabdomyolysis and, consequently, myoglobinuric renal failure. CK levels often are dramatically elevated (50-100% of cases). Muscle rigidity may be observed without NMS.

• Hyperthermia manifesting as core temperature elevation from 101-108F or higher is common. At the high range of temperature, acidosis results and essential enzymatic functions cease, resulting in multiple organ failure and possibly death. Hyperthermia may be observed in many patients who take neuroleptic medications without full-blown NMS.

• Patients with NMS are generally confused and disoriented and may become catatonic or comatose.

• Miscellaneous abnormalities include metabolic acidosis, pulmonary edema, acute respiratory distress syndrome (ARDS), acute myocardial infarction, renal failure, pulmonary embolus, and disseminated intravascular coagulation (DIC).

• Virtually all neuroleptics produce some degree of extrapyramidal (EP) dysfunction because of inhibition of dopaminergic transmission in the basal ganglia. Several forms of extrapyramidal symptoms (EPS) are associated with neuroleptic toxicity.

• Acute dystonia
• Ingestion of a single therapeutic dose of a neuroleptic can result in involuntary muscle contraction of the face, neck, tongue, extraocular muscles, and, less commonly, of the limbs, larynx, or pharynx. The onset of symptoms is usually delayed several hours.
• Certain neuroleptics (eg, haloperidol, fluphenazine) are more potent inhibitors of dopamine in the basal ganglia and, consequently, cause more prominent EP symptoms.
• Patients present with torticollis, tongue protrusion or deviation, oculogyric crisis, opisthotonus, trismus, and gait disorders. The condition is more common in children (often after administration of neuroleptic antiemetics) and is self-limited. Response to anticholinergic medications is usually dramatic, although the condition may recur over the next several days.

• Parkinsonism
• Resulting from prolonged inhibition of basal ganglia D2 transmission, certain patients who take neuroleptics develop typical features of parkinsonism, including tremor, shuffling gait, and muscle rigidity.
• The condition is more common in elderly patients, those with preexisting parkinsonism, and in females. It responds to anticholinergic medication.

• Akathisia: Motor restlessness and the urge to move are dose-related and occur in up to 20% of cases.

• Tardive dyskinesia
• TD is a manifestation of chronic neuroleptic toxicity that is often permanent. It is characterized by involuntary repetitive movement of the lips and tongue (buccolingual dysplasia), limbs (choreoathetosis), and eyes (rapid blinking movements).
• Older women are most susceptible to TD; however, it may occur at any age after 24 months of therapy.

• All neuroleptics lower the seizure threshold to some degree, although certain ones (eg, chlorpromazine, clozapine, loxapine) have greater convulsant effects than others (eg, haloperidol, fluphenazine). The epileptogenic effect is dose-dependent, and the most common type of convulsion observed is a generalized tonic-clonic seizure.

• Adverse effects associated with chronic neuroleptic use include galactorrhea, priapism, cholestatic jaundice, skin photosensitivity, lens discoloration, and agranulocytosis.

DIFFERENTIALS

DIFFERENTIAL DIAGNOSIS

Delirium Tremens
Heat Exhaustion and Heatstroke
Neuroleptic Malignant Syndrome
Rhabdomyolysis
Status Epilepticus
Torsade de Pointes
Toxicity, Anticholinergic
Toxicity, Antidepressant
Toxicity, Antihistamine
Toxicity, Cocaine
Toxicity, Lithium
Toxicity, Methamphetamine
Toxicity, Salicylate
Withdrawal Syndromes

Lab Studies:

• Perform laboratory tests depending on the nature of the presentation; patients with simple dystonia may require no tests, and patients with neuroleptic malignant syndrome may require multiple tests.

• Qualitative assays are available in most hospitals and are useful in identifying unknown ingestions. However, serum drug levels for major tranquilizers do not correlate well with the clinical severity of the overdose and are not useful.

• Because patients with major tranquilizer ingestion are often prescribed other medications, such as tricyclic antidepressants, benzodiazepines, or lithium, appropriate toxicology screening for these substances and for drugs of abuse is indicated. Serum toxicologic panels must always include a serum acetaminophen level.

• Routine electrolytes, blood urea nitrogen, creatinine, glucose, and bicarbonate are useful in determining hydration status, renal function, acid base status, and in excluding hypoglycemia as the cause for the alteration in sensorium.

• Pulse oximetry or arterial blood gas (ABG) sampling is indicated for patients in coma or with depressed gag reflex and diminished respiratory drive.

• Patients with neuroleptic malignant syndrome are critically ill and frequently sustain end-organ damage to the brain, liver, heart, lungs, and kidneys. Consequently, appropriate laboratory tests to monitor such damage are indicated.

• Creatinine kinase level

• Continuous muscle contraction often produces muscle breakdown that is reflected by an increase in potassium, uric acid, and creatine kinase-MM.

• Massive elevation of CK levels into the 100,000 range may occur and portends a significant risk of renal injury. Elevation of total CK higher than 3 times normal levels occurs in 50-100% of cases.

• Urinalysis

• Muscle breakdown products (eg, myoglobin) precipitate in the kidney, and tubular dysfunction may occur. Dehydration promotes this precipitation.

• Urine specific gravity and hourly output can guide rehydration efforts. Myoglobin assays can be performed to confirm the diagnosis but are usually not required.

• Liver function tests: Severe sustained hyperthermia can result in hepatic necrosis, which is reflected in significant elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and glutamic-pyruvic transaminase (GPT) liver enzymes.

• Coagulation profile

• Patients with NMS are prone to develop a consumptive coagulopathy or disseminated intravascular coagulation (DIC).
• Establish baseline levels of prothrombin time (PT), activated partial thromboplastin time (aPTT), platelets, and fibrinogen.

• Various infections and septic shock may resemble NMS. Obtain blood, urine, and sputum cultures and perform a lumbar puncture to obtain cerebrospinal fluid (CSF) for examination and culture.

• Consider thyroid function tests (TFTs) because thyrotoxicosis can present with many features similar to NMS.

Imaging Studies:

• No specific radiographs are routinely required; however, if appropriate, the patient's individual condition may require the following radiographs:

• Chest x-rays are important in patients requiring intubation and in those with any respiratory distress. Comatose patients are at risk for aspiration and chest x-rays are routinely obtained for this reason.

• Kidney-ureter-bladder (KUB) x-rays may be helpful because phenothiazines are radio-opaque and are often observed on a plain film of the abdomen. This may be of some use if the ingestion is unknown and may help quantify the number of pills taken if the study is performed soon after ingestion.
• CT scans of the head without contrast are indicated in some cases. Although not all patients with major tranquilizer ingestion require a CT scan of the head, it may be useful in comatose patients, those with seizures or status epilepticus, and in patients with focal neurologic deficits.

Other Tests:

• A 12-lead electrocardiogram (ECG) and cardiac monitoring are indicated to look for potentially serious lengthening of the QT interval, AV block, or dysrhythmias. Symptoms generally present within 6 hours of ingestion; thus, monitoring patients for at least 6 hours is wise.

Prehospital Care: Be aware that patients with major tranquilizer 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.

• Prehospital 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.

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

• Seizure activity usually responds to diazepam in the usual anticonvulsant doses.

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

Emergency Department Care: ED care varies, depending on the patient's condition and on the care already provided in the field.

• No specific antidote for any of the major tranquilizers exists.
• The standard approach to resuscitation (airway, breathing, circulation, drugs, and environment [ABCDE]) is employed as indicated by the patient's condition. Active airway management is indicated for patients who are in shock, status epilepticus, coma, or cardiac arrest.
• Placement of a Foley catheter may be necessary in comatose patients or those with shock or severe dehydration to monitor urine output and to obtain urine specimens in patients who may have urinary retention from the anticholinergic effects of the overdose.
• Gastric lavage and/or activated charcoal

• If employed within 2 hours of ingestion, gastric lavage may be useful in decreasing the absorption of major tranquilizers.
• Because the anticholinergic properties of the drugs involved decrease intestinal motility, gastric emptying may be delayed. Consequently, lavage often is employed up to 4 hours postingestion, as opposed to its usual 2-hour time limit.

• Protect the patient's airway before lavage if an altered level of consciousness is present.
• The lavage tube is also a convenient route for administering activated charcoal.
• Activated charcoal with a saline cathartic remains the GI decontamination method of choice. Major tranquilizers 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 step-wise fashion, beginning with benzodiazepines (eg, diazepam, lorazepam) and followed by barbiturates (eg, phenobarbital, pentobarbital) or general anesthesia if necessary.
• 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 sodium chloride solution. If the patient remains hypotensive after fluid challenge or manifests signs of cardiogenic shock, pressor agents may be required.

• Norepinephrine is the preferred pressor agent in this circumstance because it has pure alpha-agonist effects.
• Paradoxically, epinephrine or dopamine may lower the blood pressure because alpha-blockade from major tranquilizer causes unopposed beta-agonist peripheral vasodilation.

• For patients manifesting NMS with worsening hyperthermia, immediate cooling measures, such as fans, wet cloths, ice packs in groin and axilla, and rectal acetaminophen, are indicated.
• Dantrolene sodium (1-10 mg/kg) is recommended for patients manifesting severe hyperthermia (rectal temperatures >105F).

• 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 intravenous piggyback into a large-bore IV near the needle with the IV fluid shut off. Great care must be taken to avoid extravasation into the tissues.
• Dantrolene is given by 1-2 mg/kg doses until a maximum dose of 10 mg/kg or until the rectal temperature breaks.
• Dantrolene is effective in malignant hyperthermia and acts 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.

• 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 is also useful in NMS for reducing the illness duration and improving symptoms in patients with Parkinson disease.

Consultations:

• A psychiatric assessment is indicated once the patient's medical condition has stabilized to determine any suicidal intent.