ECG manifestations of drug overdose

Vera Ruchti1st of May 2014

Sir Charles Gairdner Hospital Emergency Department

Approach to ECG in Toxicology• rate and rhythm

• PR interval, heart block

• Determine QRS duration in lead II

•Check for right axis deviation of the terminal QRS

•Determine QT interval

•evidence of increased cardiac ectopy or automaticity

•evidence of myocardial ischaemia.

Normal ECG Parameters

• Rate 60-100/minute• PR: < 200 ms, > 120 ms (3-5 small squares)• QRS duration: < 100 ms (2.5 small squares)• QTc interval: < 450 ms• QTc = QT/ RR1/2

Rate

• Sinustachycardia– Anticholinergic:

blockade of M2 muscarinic receptors

– Sympathicomimetica– Serotonin syndrome

• Sinusbradycardia– Calciumchannel

blockade– Beta-adrenergic

blockade– Sodium channel blockers– Cholinergic syndrome

PR interval heart block

• From beginning of p-wave till beginning of QRS complex

• PR prolongation is an early sign of Beta- or Ca-channel blockade

• Significes AV nodal conduction delay

• Drugs: – Beta blockers, Digoxin, Calcium Channel blockers

Beta blocker overdose

Sodium channel blockade

ECG manifestations of Na channel blockade

• Bradycardia (ominous sign in TCA toxicity)

• QRS duration > 100 ms measured in lead II– > 100 ms: seizure– > 160 ms: ventricular dysrhythmia

• Right axis deviation of the terminal QRS

– Terminal R wave > 3 mm in aVR

– R/S ratio > 0.7 in aVR

Drugs that cause fast sodium channel blockade

• Trycyclic antidepressants– Amitriptyline– Desipramine– Dothiepine– Imipramine– nortriptyline

• Class 1A antidysrhythmic agents– Procainamide– Quinidine– disopyramide

• Class 1c antidysrhythmic – Flecainide– encainide

• Local anaesthetics– Bupivacaine– Cocaine– ropivacaine

• Pheothiazines• Amantadine• Carbamazepine• Chloroquine• Diltiazem• Dephenhydramine• Hydroxychloroquine• Propoxyphene• Propranolol• quinine

Sodium channel blockade

Prolonged QT interval• Incidence: unknown• UK survey: 3 % of total noncardiac

prescription drugs have an official warning of QT-prolongation

How to measure QT-interval• Men: > 440 ms• Women: > 460 ms

• From start of QRS-complex to end of t-wave• Lead II• Correction for heart rate:– Bazett’s square root formula:– QTc = QT/ RR1/2

– Fridericia’s cube root formula:– QTc = QT/RR1/3

Pathophysiology of drugs induced QT prolongation

• Prolongation of action potential: prolongation of repolarisation.

• Two proposed mechanisms:

– Blockade of Ikr (rapid delayed rectifier channels)

– Abnormal protein trafficking required for the Ikr to the cell membrane

Why does QT prolongation cause TdP?

• Prolonged repolarisation may result in early after depolarisation

• M-cells (midventricular myocardcells) show a more pronounced AP prolongation in response to Ikr blockade.

• This causes a dispersion of repolisation (heterogenous recovery of excitability)

• Re-entry, may provoke TdP

• No linear relationship between drug dose and QT-prolongation

• No relationship between the degree of QT-prolongation and the likelihood of development of TdP

• So maybe it is better to measure QT interval dispersion: maximum-minimum QT-interval, as it is an indirect measure of spatial heterogeneity of repolarisation

All drugs are equal, but some drugs are more equal than others

• Example of amiodarone and sotalol– Same potent effect on QT prolongation

– Amiodarone: • No higher risk with higher dose• incidence of QT prolongation is 0-0.7%, all in patients with

other co-existing risk factors

– Sotalol• 0.3 % incidence 80 mg• 3.8 % incidence > 680 mg• >3.8 mg in patients with risk factors.

Risk factors for QT prolongation/ TdP

• female gender

• Advanced age (> 60 yrs)

• Genetic predisposition– Congenital long QT syndrome– Family history of sudden death– Previous history of drug induced QT-prolongation

• Structural heart disease/ LV dysfunction

• Hypokalemia/severe hypomagnesaemia– Hyper/hypothyroidism, diabetes

• Absolute or relative bradycardia ( recent conversion from AF)

• Starvation/obesity/ metabolic disorders

• Use of sympathicomimetics

• High drug concentrations:– Rapid iv-administration– High dosages– overdose

QT interval nomogram

Medications that can cause TdP• Antiarrhythmics• Calcium channel blockers• Antimicrobials, including antimalarials,

antifungals• Antidepressants• Antispsychotics• Antiemetics• Antihistamines• immunosuppressants

• Antiarrhythmic drugs • Type 1A (TdP reported in all) • Quinidine (TdP reported) • Procainamide (TdP reported) • Disopyramide (TdP reported) • Ajmaline (TdP reported) • Type 1C (increase QT by prolonging QRS interval) • Encainide • Flecainide • Type 3 (TdP reported in all) • Amiodarone • Sotalol • d-Sotalol • Bretylium • Ibutilide • Dofetilide • Amakalant • Semantilide

• Calcium channel blockers

• Psychiatric drugs Thioridazine (TdP reported) • Chlorpromazine (TdP reported) • Haloperidol (TdP reported) • Droperidol (TdP reported) • Amitriptyline • Nortriptyline • Imipramine (TdP reported) • Desipramine (TdP reported) • Clomipramine • Maprotiline (TdP reported) • Doxepin (TdP reported) • Lithium (TdP reported) • Chloral hydrate • Sertindole (TdP reported, withdrawn in the UK) • Pimozide (TdP reported) • Ziprasidone

• Antihistamines Terfenadine (TdP reported, withdrawn in the USA)

• Astemizole (TdP reported) • Diphenhydramine (TdP reported) • Hydroxyzine • Ebastine • Loratadine • Mizolastine

• Antimicrobial and antimalarial drugs • Erythromycin (TdP reported) • Clarithromycin (TdP reported) • Ketoconazole • Pentamidine (TdP reported) • Quinine • Chloroquine (TdP reported) • Halofantrine (TdP reported) • Amantadine (TdP reported) • Sparfloxacin • Grepafloxacin (TdP reported, withdrawn in the UK and USA) • Pentavalent antimonial meglumine

• Serotonin agonists/antagonists • Ketanserin (TdP reported) • Cisapride (TdP reported, withdrawn in the UK and USA)

• Immunosuppressant Tacrolimus (TdP reported)

• Antidiuretic hormone Vasopressin (TdP reported)

• Other agents Adenosine • Organophosphates • Probucol (TdP reported) • Papaverine (TdP reported) • Cocaine

QT prolongation

Increased cardiac ectopics, increased automaticity

• Ectopics: – Digoxin, alcohol, cocaine, caffeine, TCA’s– Autonomic stimulation

• Increased automaticity– Accelerated juncional rhythm• Rate 60-120/min• Retrograde p-waves: inverted in inferior leads, upright

in aVR and V1• QRS less than 120 ms

– Digoxin toxicity

Accelerated Junctional rhythm

Na/K ATPase pump blockade• Increased automaticity • Decreased AV conduction

• Dysrhythmia: supraventricular tachycardia with slow ventricular response

• Frequent PVCs (the most common abnormality), including ventricular bigeminy and trigeminy

• Sinus bradycardia or slow AF

• Any type of AV block (1st degree, 2nd degree & 3rd degree)

• Regularised AF = AF with complete heart block and a junctional or ventricular escape rhythm

• Ventricular tachycardia, including polymorphic and bidirectional VT

Digoxin toxicity

Cardiac ischemia

• Tachycardia/ hypotension in pre excisting coronary artery disease

• Cocaine.• (remember that cocaine can do all: ischemia,

Na channel blockade and QT prolongation)

• Questions?

My question

• How does Magnesium treat Torsade?

literature• Medscape: Keeping the Rhythm: hERG and

Beyond in Cardiovascular Safety Pharmacology• Life in the fast lane• Toxicology handbook• Yee Guan Yap & A. John Camm. “Drug induced

QT prolongation and Torsade de pointes. Heart; Nov:2003:89 (11) 1363-1372

• C. Holstege, D Eldridge, A Rowede. “ECG manifestations: the poisoned patient”. Emerg. Med. Clin. N. Ame 24(2006) 159-177