›Prefer a propofol infusion 20 to 60 mcg/kg/min IV or dexmedetomidine 0.2 to 1 mcg/kg/h IV with an opioid, adding a benzodiazepine if seizure risk is high
›Do not schedule antipsychotics for sedation because they add QT, extrapyramidal, and antimuscarinic burden
›General supportive monitoring
›Continuous cardiac, oximetry, temperature, and capnography monitoring with hourly neurologic checks
›Pharmacologic venous thromboembolism prophylaxis once bleeding risk is acceptable, given immobility
›Pressure-injury care and eye protection for the obtunded patient
›Bladder scan and catheterize for a retained volume over 300 mL or suprapubic discomfort
›Emergency interventions that are contraindicated or need modification in this poisoning
›Intubation: use a hemodynamically neutral induction agent and rocuronium 1.2 mg/kg IV rather than succinylcholine 1 to 1.5 mg/kg IV when rhabdomyolysis and hyperkalemia are plausible
›Sedation: benzodiazepines and dexmedetomidine are preferred; do not use scheduled antipsychotics such as haloperidol 5 mg IV, which add QT, extrapyramidal, and antimuscarinic burden
›Fluid loading: give 10 to 20 mL/kg boluses but stop for crackles or hypoxia, particularly with clozapine myocarditis or in older adults
›Oxygen and naloxone: keep saturation 94 to 98 percent, or 88 to 92 percent in COPD; a naloxone 0.04 to 0.4 mg IV titrated trial is reasonable when opioid co-ingestion is possible, but a negative response is expected
›Vasopressors: use norepinephrine, phenylephrine, or vasopressin; avoid epinephrine as first line because alpha-1 blockade unmasks beta-2 vasodilation and can worsen hypotension
›Mechanical circulatory support: an intra-aortic balloon pump or venoarterial extracorporeal membrane oxygenation are reasonable bridges in refractory toxic cardiogenic shock because the poison clears
›Anticoagulation: not indicated for the toxidrome; give venous thromboembolism prophylaxis for immobility once bleeding risk allows
›Fibrinolysis and catheterization laboratory activation: do not trigger for the Brugada-like or wide-complex ECG of sodium channel blockade; treat with sodium bicarbonate instead
›Analgesia: minimize opioids, which deepen CNS and respiratory depression and hypotension; prefer acetaminophen 1 g IV or orally every 6 hours, maximum 3 g per day
›Antiemetics: use ondansetron 4 mg IV with a repeat QTc check; avoid metoclopramide 10 mg IV, prochlorperazine 10 mg IV, and droperidol 1.25 mg IV, which add dopamine blockade and QT effect
›Flumazenil 0.2 mg IV: contraindicated because it can precipitate seizures in the proconvulsant or benzodiazepine-dependent patient
›Phenytoin 15 to 20 mg/kg IV: ineffective for toxic seizures and can worsen cardiac sodium channel blockade
Hypotension and vasopressor selection
›Fluid resuscitation
›Isotonic crystalloid 10 to 20 mL/kg IV bolus, reassessed against the lung examination and perfusion
›Stop boluses when crackles, hypoxia, or a plethoric inferior vena cava appear
›First-line vasopressor
›Norepinephrine
›Norepinephrine infusion starting at 0.05 mcg/kg/min IV
›Titrate by 0.05 mcg/kg/min every 5 minutes to a mean arterial pressure of 65 mmHg against an arterial line
›Target a higher mean arterial pressure near 75 mmHg in chronic hypertension, dialysis dependence, or older age, and accept a lower value in pregnancy
›Wean in small decrements once pressure is stable to avoid hypertensive overshoot
›No fixed maximum in refractory vasoplegia; add a second agent rather than using very high single-agent rates
›Alternative and add-on pressors
›Phenylephrine 0.5 mcg/kg/min IV infusion or 50 to 200 mcg IV boluses when tachycardia limits norepinephrine
›Vasopressin 0.03 units/min IV as the preferred add-on because it bypasses adrenergic receptors
›Agents to avoid
›Epinephrine as a first-line pressor, because unopposed beta-2 vasodilation with alpha-1 blockade can deepen hypotension
›Isolated beta agonists such as dobutamine 2 to 20 mcg/kg/min IV unless echocardiography confirms a pump-failure phenotype
›Refractory shock: therapy-is-not-working pathway
›Repeat echocardiography to separate vasoplegia from cardiogenic shock
›Add vasopressin, then consider high-dose insulin euglycemia therapy 1 unit/kg IV bolus then 0.5 to 1 unit/kg/h with glucose and potassium monitoring for a membrane-depressant picture
›Intravenous lipid emulsion at the rescue dose for refractory collapse
›Early referral for venoarterial extracorporeal membrane oxygenation or an intra-aortic balloon pump as a bridge, since the toxin clears over hours to days
›Reconsider clozapine myocarditis and an occult co-ingestant such as a beta-blocker or calcium channel blocker
Wide QRS and sodium channel blockade
›Recognition
›QRS beyond 100 ms, a terminal R wave over 3 mm in lead aVR, or a rightward terminal QRS axis indicate sodium channel blockade
›Most likely with thioridazine and chlorpromazine, and with a massive quetiapine ingestion
›A Brugada-like pattern can appear and is not an indication for fibrinolysis or the catheterization laboratory
›Sodium bicarbonate
›Bolus therapy
›Sodium bicarbonate 1 to 2 mmol/kg IV bolus
›Repeat 1 mmol/kg every 3 to 5 minutes while the QRS remains wide or ventricular ectopy continues
›Switch to smaller boluses and stop escalating once the QRS narrows below 100 ms or arterial pH reaches 7.50 to 7.55
›Do not exceed arterial pH 7.55 or serum sodium 155 mmol/l
›Maintenance infusion
›150 mmol sodium bicarbonate in 1 liter of 5 percent dextrose infused at 1.5 times maintenance
›Recheck potassium every 1 to 2 hours because bicarbonate drives hypokalemia that worsens the QT
›Ventricular dysrhythmia from sodium channel blockade
›Lidocaine 1 to 1.5 mg/kg IV is the antiarrhythmic of choice if bicarbonate and mild hyperventilation fail
›Avoid class Ia, class Ic, and class III antiarrhythmics, which worsen conduction or the QT
›Persistent wide QRS despite maximal bicarbonate
›Hypertonic saline 3 percent 2 mL/kg IV as an adjunct sodium load
›Maximize the pH strategy and correct hypokalemia and hypomagnesemia before escalating further
QT prolongation and torsades de pointes
›Risk assessment
›Measure the QT and heart rate and plot on the QT nomogram; an absolute QTc above 500 ms markedly raises torsades risk
›Baseline congenital long QT, structural heart disease, female sex, bradycardia, and other QT-prolonging drugs raise the risk further
›Electrolyte optimization
›Keep potassium above 4.0 mmol/l and replace toward 4.5 to 5.0 mmol/l after any torsades
›Keep magnesium above 1.0 mmol/l
›Magnesium for torsades
›Magnesium sulfate
›Magnesium sulfate 2 g IV over 15 minutes for torsades de pointes with a pulse
›Repeat 2 g IV once for recurrence
›Follow with an infusion 1 to 2 g/h and monitor deep tendon reflexes for magnesium toxicity
›Reduce the dose and slow the infusion in renal impairment
›Refractory or recurrent torsades
›Raise the heart rate to 90 to 110 per minute with transvenous overdrive pacing to shorten the QT
›Isoproterenol 2 to 10 mcg/min IV titrated to the same rate target while pacing is arranged, avoiding it in ischemia
›Defibrillate unstable or pulseless torsades
›Prevention
›Remove every other QT-prolonging drug from the record
›Continue telemetry until the QTc normalizes
›First-line benzodiazepine
›Lorazepam 4 mg IV, may repeat once after 5 to 10 minutes
›Diazepam 10 mg IV or midazolam 10 mg IM are equivalent alternatives when lorazepam or intravenous access is unavailable
›Support ventilation and blood pressure after dosing
›Second-line
›Levetiracetam 60 mg/kg IV, maximum 4500 mg
›Phenobarbital 15 to 20 mg/kg IV for benzodiazepine-refractory seizures
›Refractory status epilepticus
›Propofol or midazolam infusion with intubation and continuous electroencephalography
›Agents to avoid
›Phenytoin and fosphenytoin are ineffective for toxic seizures and can worsen cardiac sodium channel blockade
›After any seizure
›Check glucose, sodium, and an ECG, and consider non-convulsive status if consciousness does not recover
›Measure creatine kinase and temperature for rhabdomyolysis and hyperthermia
Acute dystonia, akathisia, and parkinsonism
›Acute dystonia including oculogyric crisis, torticollis, and trismus
›Benztropine
›Benztropine 1 to 2 mg IV or IM, may repeat once after 20 to 30 minutes
›Expect relief within 5 to 20 minutes
›Continue an oral anticholinergic such as benztropine 1 to 2 mg twice daily for 2 to 3 days because dystonia recurs while drug levels persist
›Diphenhydramine 25 to 50 mg IV or IM is the alternative, maximum 100 mg for the acute episode
›In children under 3 years use diphenhydramine rather than benztropine
›Laryngeal dystonia
›Treat as an airway emergency with the same intravenous anticholinergic, prepared to support ventilation
›Akathisia
›Propranolol 10 to 20 mg orally three times daily, avoiding it in asthma and in hypotension
›Lorazepam 1 mg orally or IV is an alternative
›Drug-induced parkinsonism
›Usually needs no acute pharmacotherapy; withhold the antipsychotic and arrange psychiatric follow-up
›Symptoms resolve over days to weeks as the drug clears
Anticholinergic toxicity and physostigmine
›Supportive management is usually sufficient
›Active cooling for hyperthermia, benzodiazepines for agitation, and catheterization for urinary retention
›Bowel rest and electrolyte correction for ileus
›Physostigmine has a narrow indication
›Physostigmine 0.5 to 1 mg IV over 5 minutes, may repeat to a total of 2 mg, for pure antimuscarinic delirium without any cardiac conduction delay
›Have atropine 0.5 mg IV available, roughly half the physostigmine dose, for cholinergic excess
›Continuous cardiac monitoring during and for at least 1 hour after administration
›Do not repeat beyond the 2 mg total in the acute setting without toxicology advice
›Contraindicated with QRS prolongation, reactive airway disease, bradyarrhythmia, seizures, or suspected tricyclic co-ingestion
›Do not use it as a diagnostic trial in mixed antipsychotic overdose
Hyperthermia, neuroleptic malignant syndrome, and agitation
›Undifferentiated hyperthermia
›Begin active external cooling for a core temperature above 38.5 degrees C and target below 38 degrees C
›For life-threatening hyperthermia above 40 degrees C with rigidity, intubate, paralyze with rocuronium, and cool aggressively
›Antipyretics do not work for toxic or neuroleptic-malignant hyperthermia because the hypothalamic set point is not raised
›Neuroleptic malignant syndrome
›Stop all dopamine antagonists and provide aggressive cooling, isotonic intravenous fluids, and electrolyte correction
›Lorazepam 1 to 2 mg IV every 4 to 6 hours for rigidity and agitation, first-line for mild disease
›Dantrolene 1 to 2.5 mg/kg IV, repeated every 6 hours to a maximum of 10 mg/kg per day, for severe rigidity and hyperthermia
›Hold for hepatic injury and monitor liver enzymes during therapy
›Bromocriptine 2.5 mg orally or by tube every 8 hours, titrated up to 5 mg every 6 hours
›Can worsen psychosis and cause hypotension and vomiting
›Monitor for rhabdomyolysis, acute kidney injury, aspiration, venous thromboembolism, and disseminated intravascular coagulation
›Agitation
›Benzodiazepines are first line: lorazepam 1 to 2 mg IV or midazolam 2.5 to 5 mg IV, repeated and titrated
›Dexmedetomidine infusion 0.2 to 1 mcg/kg/h IV for persistent agitation without a secured airway
›Avoid additional antipsychotics including haloperidol 5 mg IV and droperidol 1.25 mg IV for agitation control
Agent-specific management
›Quetiapine
›Dose-related CNS depression and intubation risk, sinus tachycardia, hypotension, QT prolongation, and anticholinergic delirium
›Sustained-release tablets warrant whole bowel irrigation and 12 to 24 hours of cardiac monitoring
›Causes a false-positive tricyclic antidepressant urine immunoassay
›Olanzapine
›Fluctuating consciousness with alternating agitation and somnolence, miosis, prominent antimuscarinic features, and a prolonged course
›Can precipitate acute hyperglycemia and diabetic ketoacidosis
›Clozapine
›Sedation, hypersalivation, seizures, tachycardia, hypotension, delirium, and ileus
›Check the absolute neutrophil count for agranulocytosis and troponin with C-reactive protein for myocarditis in the first 6 weeks of therapy
›Toxicity can occur at normal doses after an infection or smoking cessation raises drug levels
›Risperidone and paliperidone
›Extrapyramidal symptoms, orthostatic hypotension, QT prolongation, and less sedation
›Paliperidone osmotic-release tablets prolong the time course and warrant whole bowel irrigation
›Aripiprazole, brexpiprazole, and cariprazine
›Partial dopamine D2 agonists with generally lower acute toxicity, but very long half-lives and active metabolites cause delayed and prolonged somnolence
›Ziprasidone, lurasidone, and asenapine
›QT prolongation is the theoretical concern with ziprasidone, but reported overdoses are usually benign with sedation only
›Thioridazine and chlorpromazine
›Highest cardiotoxicity with QRS widening, QT prolongation, torsades, refractory hypotension, and seizures
›Manage the QRS with sodium bicarbonate as above and monitor for at least 24 hours
›Haloperidol and droperidol
›Fewer sedative and anticholinergic effects; the principal risk is dose-related QT prolongation and torsades, greatest with intravenous use
›Droperidol carries a regulatory boxed warning for QT prolongation and torsades