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Psychiatric Intoxication 9 th September Emergency Department CME Jing Dong Emergency Registrar

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Overview Case based Major classes SNRI SSRI TCA Atypical Antipsychotics

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Case 1.1 26 y.o. female Paranoid schizophrenia; multiple attempts of suicide Alleged ingestion >10 g of white tablets GCS 8/15 at 2.5 h postingestion Intubation ICU Signs and symptoms Sinus tachycardia (130-140) Blood pressure 135/70 Pupils 3mm and sluggish Within 16 h, GCS 15/15 Tachycardia lasted for 40 h postingestion. Medically cleared and transferred to psychiatric inpatient unit T.J. Harmon, J.G. Benitez et al. J. Analytical Toxicol L 36:599-602 (1998)

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Case 1.2 34-year-old woman with chronic schizophrenia Ingested 36 g of extending release form of white tablets Initially lethargy only Rapid deterioration and collapsed unconscious at 2 hours: Deep coma GCS 9/15. Intubated ICU for ventilatory support and close monitoring Restored spontaneous breathing at 36 hours Two days later, discharged without complications. Capuano A, Ruggiero S et al. Drug Chem Toxicol. 2011;34(4):475-7

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Case 1.3 A 59-year-old woman with schizophrenia 2 hours after intentionally ingesting 20 g On arrival, GCS 14/15, HR125, 82/51mmHg. ECG sinus tachycardia only 1L 0.9% saline BP 90/60 mmHg An hour later, GCS11/15 Tracheal intubation (Midazolam fentanyl and suxamethonium). Morphine and midazolam infusion. After intubation, BP 70/40mmHg Hypotension not responding to 3L normal saline Central venous access & an adrenaline infusion at 5 g/min, then 20 5 g/min, SBP 53 Called toxicologist, withdrew adrenaline, noradrenaline infusion at15 g/min. SBP rose to 120 mmHg ICU, noradrenaline withdrawn at 6h, then extubated. Hawkins DJ, Unwin P. Crit Care Resusc. 2008. Dec;10(4):320-2.

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Quetiapine Atypical antipsychotic Serotonin-Dopamine Antagonists Antagonism of Dopamine type 2 (D2) & Serotonin type 2 (5-HT2) Peripheral -adrenergic ( 1) & Histamine (H1) receptors Known receptor pharmacology Absence of extrapyramidal effects (D2) Prominence of orthostatic hypotension and tachycardia ( 1) Sedation (H1)

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Clinical features Onset: 2-4 h Duration: 24-72h Dose dependent 120bpm) >3g CNS depression, coma, hypotension (coma lasts 18-48h) Seizure is uncommon (

Disposition Observe 4H with serial ECG Children >100mg (Warn EPS up to 3d) Adult 3g Or clinical features of intoxication

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Case 1.4 1.6 16 y.o. female, schizophrenia. Hypersalivation, sedation, agitation, SBP 90, HR 130, pupils 2mm and reactive. 21 y.o. male, BPAD. Agitation, constricted pupils and a GCS fluctuating between 6 to 11. ECG showed sinus tachycardia, ST depression and tall T-waves. 6 y.o. Girl Accidentally taken 2g of mothers pill. Dystonia, mild tahycardia, lethargic. ECG prolonged QTc

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Clozapine D1&D2, 5HT and 1antagonist Potent antagonist at muscarinic (M1), histamine (H1) and GABA receptors Receptor pharmacology Anticholinergic effects: Hypersalivation, agitation, urinary retention, mydirasis or miosis Sedation (H1) Tachycardia and hypotension ( 1) Seizures (GABA) 5-10% EPS more common in children (D1) Observe for 6H and serial ECG EPS in children up to 7d

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Case 1.4 1.6 16 y.o. female, schizophrenia. Hypersalivation, sedation, agitation, SBP 90, HR 130, pupils 2mm and reactive. 21 y.o. male, BPAD. Agitation, constricted pupils and a GCS fluctuating between 6 to 11. ECG showed sinus tachycardia, ST depression and tall T-waves. 6 y.o. Girl Accidentally taken 2g of mothers pill. Dystonia, mild tahycardia, lethargic. ECG prolonged QTc

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Olanzapine D2,5HT2,H1, 1, M1antagonist Dose dependent 300mg: Coma (last 18-48h), hypotension Sedation, ataxia, miosis, hypotension and tachy are common Non-specific ST-T wave changes (15%) Disposition Children >0.5mg/kg: 4 h observation Discharge when clinically well Intubated for agitation or delirium ICU for up to 48h

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Case 1.4 1.6 16 y.o. female, schizophrenia. Hypersalivation, sedation, agitation, SBP 90, HR 130, pupils 2mm and reactive. 21 y.o. male, BPAD. Agitation, constricted pupils and a GCS fluctuating between 6 to 11. ECG showed sinus tachycardia, ST depression and tall T-waves. 6 y.o. Girl Accidentally taken 2g of mothers pill. Dystonia, mild tahycardia, lethargic. ECG prolonged QTc

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Risperidone Much lower affinity for H1 and M1 Lethargy, confusion, mild sedation and tachycardia are common QT prolongation may occur If coma, seizures, significant abnormal vital signs consider alternative diagnosis Children >1mg required observation EPS up to 3d

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Case 2 36-year-old woman Depression Presented with shakiness, numbness in the arms, and palpitations at 32 hours after ingesting 50 (20-mg) tablets. BP84/44 mmHg, HR102150 bpm, RR 17, T 37.3 First ECG

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ECG 1

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ECG 2 20 minutes after later.. Transient hypotension and loss of consciousness.

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ECG 3

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Case 2 Treated with magnesium, lidocaine & IV KCl Temporary transvenous pacemaker Transferred to CCU Paced at a heart rate of 110 bpm for 24 hours, nil further arrhythmias QT prolongation resolved at 24 hours after presentation

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ECG 4

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Selective Serotonin Reuptake Inhibitors (SSRI) Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline Many remain asymptomatic Nausea Mild serotonin syndrome (anxiety, tremor, tachy/brady, mydriasis) in

SSRI - Investigations Citalopram >600mg: serial ECG up to 8h post-ingestion Citalopram >1000mg: serial ECG up to 13H post-ingstion Ongoing monitor until normalised QTc

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SSRI - Management Supportive Seizure & agitation: benzodiazepine Serotonin syndrome (T, benzo) Increasing anxiety, sweating, tremor, tachy and mydriasis prophylactic benzodiazapine Ongoing cardiac monitoring Decontamination Alert, cooperative >600mg citalopram 50g activated charcoal within 4h post- ingestion

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Case 3 A Fatal Case 40 y.o. Male Depression and TIIDM 45mins post ingesting 90 (150mg tablets, XR) total 19g Nausea only HR 136, BP 133/90, RR 16, T36.3 50g activated charcoal, WBI with PEG 2h tonic-clonic seizures. Lasted 3mins (2mg IV lorazepam) Second seizure at 4.5h (2mg IV lorazepam) Admitted to ICU Clear progression of prolonged QRS and QTc VF at 9h and then deceased Bosse GM, Spiller HA, Collins AM. J Med Toxicol. 2008 Mar;4(1):18-20.

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Case 3

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Serotonin Noradrenaline Reuptake Inhibitors (SNRI) Venlafaxine, Desvenlafaxine SNRI & Sodium channel blocking Life-threatening emergency Seizures, Cardiovascular toxicity Dose-dependant 4.5g: Seizures 100%, Hypotension, QRS & QT prolongation >7g: Hypotension and cardiac arrhythmia

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SNRI Delayed onset: up to 6-12 hours Anxiety, mydriasis, sweating, tremor, clonus, tachycardia and HTN are common Generalised seizures, short duration Serotonin syndrome (esp co-ingestion) Rhabdomyolysis in some

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SNRI Serial ECG, CK Early intubation and ventilation for ingestion >7g Seizures: Benzodiazepine Broad complex tachycardia: intubation, hyperventilation and NaCO3 Hyperthermia Activated charcoal within 2H of >4.5g ingestion if alert and cooperative >7g ingestion and seizure after intubation

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SNRI ALL IV access and observe for 16H >4.5g, cardiac monitoring and serial ECG Severe venlafaxine intoxication or serotonin syndrome ICU Pearls Early prophylactic benzodiazepine Anticipate and prepare for delayed onset of symptoms and seizures Activated charcoal or WBI

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SSRI vs SNRI SNRI more toxic: pro-convulsant activity & cardiac sodium channel blocking Risk assessment: Older (mean age 37.4 vs 28.8 years, p0.001) Higher suicidal intent (p0.017). High dose: Median venlafaxine dose taken was 35 defined daily doses (DDDs) vs19.4 DDDs in SSRI. Positive risk benefit profile for depression and GAD, esp second line to SSRIs.

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Case 4 31 y.o. female Found unresponsive by husband, took an unknown medication for headache. HR 136, SBP 82, RR 21, T 36.3, 7mm pupils sluggish, GCS 8/15 (1/2/5) First ECG

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ECG 1

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Case 1 Management?

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ECG 2 post bicarbonate

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Tricyclic antidepressants (TCA) Amitriptyline, nortryptyline, clomipramine, tripramine, imipramine, dothiepin, doxepin Morbidity and Mortality A BAD DRUG Noradrenaline & serotonin reuptake inhibitors GABAa blockers Blockade of inactivated fast sodium channels Blockade of M1, H1, peripheral A1 Reversible inhibition of K channels Direct myocardial depression

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TCA Risk assessment >10mg/kg = life threatening Dose-dependant risk 10mg/kgComa, Hypotension, seizures, arrhythmia (onset 2-4h) >30mg/kgSevere cardiotoxicity and coma (last>24h)

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TCA - Clinical Features CNS Coma/sedation (H1) Seizures (GABAa) CVS Sinus tachycardia Hypotension (A1 and impaired contractility) Broad-complex tachycardia/bradycardia (Na channel) QT prolongation (K channel) Anticholinergic Effects (M1) Leading causing of death: arrhythmia & hypotension

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ECG Prolongation of PR and QRS Large terminal R wave in aVR Increased R/S ratio in aVR >0.7 QT prolongation QRS widening proportional to Na blockade QRS >100ms seizures QRS >160mg VT

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Management Close monitoring >6H Ventricular arrhythmia Sodium Bicarbonate 2mmol/kg Q1-2mins Then infusion in D5 Hypotension Crystalloid, NaCO3 A or NA infusion Seizures Benzodiazepines Intubated hyperventilation aiming pH7.50-7.55 Activated Charcoal: only if >10mg/kg and intubated

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TCA The Pearls Sodium bicarbonate (The Antidote) Serum alkanization Sodium loading counteracting the sodium channel blockade Endpoints: QRS 7.50, resolution of hypotension Rapid intubation Hyperventilation

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ECG 3 Our Patient: ICU Continuous NaCO3 infusion Extubated on Day 2 Serial ECG on Day 3

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References 1. T.J. Harmon, J.G. Benitez, E.P. Krenzelok, and E Cortes-Belen.Loss of consciousness from acute quetiapine overdosage. J. Analytical Toxicol 36:599-602 (1998) 2. Capuano A, Ruggiero S, Vestini F, Ianniello B, Rafaniello C, Rossi F, Mucci A. Survival from coma induced by an intentional 36-g overdose of extended-release quetiapine. Drug Chem Toxicol. 2011 Oct;34(4):475-7. 3. Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline infusions in massive quetiapine overdose. Crit Care Resusc. 2008. Dec;10(4):320-2. 4. Tarabar AF, Hoffman RS, Nelson L. Citalopram overdose: late presentation of torsades de pointes (TdP) with cardiac arrest. J Med Toxicol. 2008 Jun;4(2):101-5. 5. Bosse GM, Spiller HA, Collins AM. A fatal case of venlafaxine overdose. J Med Toxicol. 2008 Mar;4(1):18-20. 6. Chan AN, Gunja N, Ryan CJ. A comparison of venlafaxine and SSRIs in deliberate self-poisoning. J Med Toxicol. 2010 Jun;6(2):116-21. 7. Chuang R, Bernard A. A 31-year-old woman found unresponsive with tachycardia. Hosp Physician 2009 May-Jun;45(4):29-32 8. Lindsay Murray et al (2010). Toxicology Handbook.