Cardiovascular BB & CCB Intoxication

1. Cardiovascular BB & CCB Intoxication Zohair Al Aseri MD,FRCPC EM & CCM

2. Introduction • a 64-year-old man in the critical bay who took an overdose of his medications. Zohair Al Aseri MD,FRCPC EM & CCM

3. has a history of hypertension, atrial fibrillation, and depression. • lethargic but arousable • reports he took about 40 tablets of immediate-release metoprolol three hours ago in an attempt to “end it all.” Zohair Al Aseri MD,FRCPC EM & CCM

4. “Is it too late for gastric decontamination? • If he is symptomatic, which therapy will you try first, and what are your options?” Zohair Al Aseri MD,FRCPC EM & CCM

5. a 2-year-old child in the pediatric area who was found playing with grandma’s bottle of verapamil controlled release 15 minutes ago. • The grandmother thinks that at most there are three tablets missing. Zohair Al Aseri MD,FRCPC EM & CCM

6. Child looks great • “Are three tablets a big deal? • Can we just watch the child for a couple of hours? • Do we need an IV and blood work? Zohair Al Aseri MD,FRCPC EM & CCM

7. BETA-ADRENERGIC BLOCKERS Perspective • Overdose of propranolol is the most deadly, followed by acebutolol, oxprenolol, and alprenolol Zohair Al Aseri MD,FRCPC EM & CCM

8. Principles of Disease Pathophysiology • inhibit endogenous catecholamines such as epinephrine at the beta-receptor. Zohair Al Aseri MD,FRCPC EM & CCM

9. Principles of Disease Pathophysiology • Equally important properties, which vary from one beta-blocker to another, include cardioselectivity, membrane-stabilizing effect, lipophilicity, and intrinsic sympathomimetic activity. • Although cardioselectivity is lost in overdose, cardioselective beta-blockers such as atenolol, metoprolol, and esmolol are associated with a lower mortality rate than propranolol, the oldest beta-blocker. Zohair Al Aseri MD,FRCPC EM & CCM

10. Selected Characteristics of Common Beta-Blockers Zohair Al Aseri MD,FRCPC EM & CCM

11. Principles of Disease Pathophysiology • Beta-blockers are rapidly absorbed after oral ingestion, and the peak effect of normal-release preparations occurs in 1 to 4 hours.  • Hepatic metabolism on first pass results in significantly less bioavailability after oral dosing than with IV injection (1 : 40 for propranolol). • Volume of distribution for various beta-blockers generally exceeds 1 L/kg, meaning tissue concentrations exceed those of serum. Zohair Al Aseri MD,FRCPC EM & CCM

12. Principles of Disease Pathophysiology • Therefore, hemodialysis is not efficacious for most beta-blockers. • Protein binding varies from 0% for sotalol to 93% for propranolol. • Elimination half-lives vary from 8 to 9 minutes for esmolol to as long as 24 hours for nadolol and others  Zohair Al Aseri MD,FRCPC EM & CCM

13. Clinical Features • Bradycardia the most common • Hypotension and unconsciousness are the second and third most common signs. • Much of propranolol's toxicity derives from its lipophilic nature and membrane-stabilizing effect that allow it to penetrate the CNS, leading to obtundation, respiratory depression, and seizures. Other beta-blockers do not have these effects. Zohair Al Aseri MD,FRCPC EM & CCM

14. Clinical Features • Seizures probably result from a combination of hypotension, hypoglycemia, hypoxia, and direct CNS toxicity. • Surprisingly, bronchospasm is not problematic in cases of beta-blocker overdose, even with nonselective beta-blockers. Zohair Al Aseri MD,FRCPC EM & CCM

15. MANIFESTATIONS AND COMPLICATIONS OF BETA-BLOCKER OVERDOSEIN ORDER OF DECREASING FREQUENCY Zohair Al Aseri MD,FRCPC EM & CCM

16. Clinical Features • Propranolol's membrane-stabilizing effect impairs SA and AV node function and leads to bradycardia and AV block. • Ventricular conduction is also depressed, leading to QRS widening and occasional ventricular dysrhythmias. • Nadolol and acebutolol also have a significant membrane-stabilizing effect. • These BB, like the TCA, can cause ventricular dysrhythmias such as VT, VF and torsades de pointes as well as the bradydysrhythmias more characteristic of beta-blockers in general. Zohair Al Aseri MD,FRCPC EM & CCM

17. Clinical Features • The intrinsic sympathomimetic activity of some beta-blockers such as pindolol and carteolol has led to some unusual manifestations such as sinus tachycardia instead of bradycardia and ventricular dysrhythmias. • Labetalol is unique in that it also blocks alpha-adrenergic receptors, yielding an additional mechanism for hypotension. • However, labetalol's beta-blockade is three to seven times more potent than its alpha-blockade. Zohair Al Aseri MD,FRCPC EM & CCM

18. Clinical Features • In contrast to digitalis, beta-blocker toxicity has a more rapid onset: life-threatening CNS and cardiovascular effects can occur 30 minutes after oral overdose. • Patients ingesting delayed-release preparations may remain asymptomatic for several hours, affording a valuable therapeutic window. Zohair Al Aseri MD,FRCPC EM & CCM

19. Diagnostic Strategies • Diagnosis and management depend on the clinical picture • Hypoglycemia is common in children Zohair Al Aseri MD,FRCPC EM & CCM

20. Diagnostic Strategies • Known access of the patient to a beta-blocker and consistent clinical features such as obtundation, seizures, bradydysrhythmias, and occasionally tachydysrhythmias should lead the clinician to consider beta-blocker intoxication. Zohair Al Aseri MD,FRCPC EM & CCM

21. Management • IV fluids • Oxygen • Monitoring of card for rhythm and respirations. • Activated charcoal is unproven treatment. • Multiple-dose charcoal without supporting evidence for an improvement in outcome. Zohair Al Aseri MD,FRCPC EM & CCM

22. Management • Evidence for improved outcome is also lacking but whole-bowel irrigation has been advocated for sustained-release preparations with a polyethylene glycol solution (OCL, GoLytely, CoLyte), administered orally or via nasogastric tube at 1 to 2 L/hour in adults or 20 mL/kg initially in children. Zohair Al Aseri MD,FRCPC EM & CCM

23. Management • Onset of toxicity is so uniformly early that absence of symptoms 4 hours after ingestion implies a low risk for subsequent morbidity unless a delayed-release preparation is involved. Zohair Al Aseri MD,FRCPC EM & CCM

24. Management Hypotension, Bradycardia, and Atrioventricular Block • Catecholamines with chronotropic and dromotropic as well as inotropic and vasopressor effects should be chosen. Zohair Al Aseri MD,FRCPC EM & CCM

25. Management • It is rare for one catecholamine to be equally effective against all four toxic effects, so combinations of drugs are often used in severe cases. Zohair Al Aseri MD,FRCPC EM & CCM

26. Management The first step in the treatment of beta-blocker overdose is • Atropine • Glucagon • Crystalloid fluids. Zohair Al Aseri MD,FRCPC EM & CCM

27. Management • A dose of atropine may quickly wear off or be ineffective, so infusion of more potent drugs or cardiac pacing is usually necessary. • Atropine (0.5 mg for adults, 0.02 mg/kg for children, minimum 0.10 mg) should be given before vagal stimuli such as tracheal or gastric intubation. Zohair Al Aseri MD,FRCPC EM & CCM

28. Management Glucagon • Does not depend on beta-receptors for its action, has both inotropic and chronotropic effects. • it helps to counteract the hypoglycemia induced by beta-blocker overdose. • is given as a 5- to 10-mg IV bolus Zohair Al Aseri MD,FRCPC EM & CCM

29. Management Glucagon • Because of its short (20-minute) half-life, an infusion of 2 to 5 mg/hr (or for children, 0.05–0.1 mg/kg bolus, then 0.05–0.1 mg/kg/hr) should be started immediately after the bolus. • With cumulative large doses, glucagon should be diluted in 5% glucose in water for constant infusion. Zohair Al Aseri MD,FRCPC EM & CCM

30. Management Glucagon • Side effects include nausea and vomiting in most patients, mild hyperglycemia, hypokalemia, and allergic reactions. • The response to glucagon alone is often inadequate. Zohair Al Aseri MD,FRCPC EM & CCM

31. Management sodium bicarbonate • Sodium channel blockade, manifested by QRS widening, occasionally occurs with beta-blocker intoxication and may respond to infusion of sodium bicarbonate. Zohair Al Aseri MD,FRCPC EM & CCM

32. Management • In hypotensive patients, 20 to 40 mL/kg of normal saline or Ringer's lactate solution can be infused and repeated. • If hypotension or bradycardia persists, other cardioactive drugs are indicated. • dopamine, or epinephrine. Zohair Al Aseri MD,FRCPC EM & CCM

33. Management • Other catecholamines include norepinephrine, dobutamine, and phenylephrine. • Often, norepinephrine or dopamine is added to beta-agonists such as isoproterenol that lack vasopressor activity. Zohair Al Aseri MD,FRCPC EM & CCM

34. Management • Because patients are resistant to these drugs, the initial dose should be high and the infusion rates should be rapidly titrated to effect. • A common mistake with cases of beta-blocker overdose is to timidly titrate catecholamine infusions within previously familiar ranges. In the setting of massive beta-blockade, much higher doses are usually needed and the drug is titrated to effect. Zohair Al Aseri MD,FRCPC EM & CCM

35. Treatment Stellpflug SJ, Harris CR, Engebretsen KM, et al. Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. ClinToxicol 2010;48: 227-229.42 High-Dose Insulin Euglycemia (HDIE) Therapy • There are no randomized controlled human trials. • There are multiple case reports of the hemodynamic improvement after institution of HDIE. Zohair Al Aseri MD,FRCPC EM & CCM

36. Treatment Kerns W. Antidotes in Depth: Insulin- Euglycemia Therapy. In: Nelson LS, et al eds. Goldfrank’sToxicologic Emergencies9th ed. New York: McGraw Hill; 2010: 893-5 High-Dose Insulin Euglycemia (HDIE) Therapy • It can take up to 60 minutes to see improvement. • It is given along with a dextrose infusion of 0.5 g/kg/hr. • It is important to follow glucose and potassium levels closely during HDIE and avoid hypoglycemia and hypokalemia. Zohair Al Aseri MD,FRCPC EM & CCM

37. Management Insulin • High-dose (0.5–1 unit/kg/hr) insulin infusion for hemodynamically significant toxicity is often given before traditional pressors. • Beta-blocker toxicity shifts myocardial energy preferences from free fatty acids to carbohydrates, and insulin increases myocardial carbohydrate uptake. • Recent canine and porcine models showed the benefit of insulin infusion up to 10 units/kg/hr. Zohair Al Aseri MD,FRCPC EM & CCM

38. Management Insulin • Glucose, usually in 5 to 10% solutions, is infused to maintain a serum glucose of approximately 100 mg/dL. • The combination of glucose and high-dose insulin augments myocardial contraction independent of beta-receptors. • Glucose and potassium should be monitored frequently during infusion and supplemented as needed to maintain euglycemia and eukalemia. Zohair Al Aseri MD,FRCPC EM & CCM

39. Management • Refractory cases of bradycardia may respond to an external or transvenous pacemaker. Zohair Al Aseri MD,FRCPC EM & CCM

40. Management Calcium • Because deleterious effects on calcium transport may contribute to beta-blocker toxicity, IV calcium salts have been suggested for treating hypotension. • calcium should be given cautiously and less aggressively than for cases of calcium channel blocker overdose. • Constant infusions are safer than boluses. • Give 1 to 2 g over 5 to 10 minutes, monitoring closely for effect. Zohair Al Aseri MD,FRCPC EM & CCM

41. Management Ventricular Dysrhythmias • Although uncharacteristic, ventricular tachydysrhythmias do occur sometimes. • Cardioversion and defibrillation are indicated for ventricular tachycardia and ventricular fibrillation, respectively, following American Heart Association guidelines. • Pulsatile ventricular tachycardia or frequent ventricular ectopy can most safely be treated with lidocaine. Zohair Al Aseri MD,FRCPC EM & CCM

42. Management Ventricular Dysrhythmias • Other antidysrhythmic drugs, especially of classes IA and IC, should be avoided because they may potentiate AV block or be prodysrhythmic because of an additive membrane stabilizing effect. Zohair Al Aseri MD,FRCPC EM & CCM

43. Management Ventricular Dysrhythmias • Sotalol, unlike other beta-blockers, has class III as well as class II effects; that is, it prolongs the QT interval and can cause torsades de pointes and other ventricular dysrhythmias. • Overdrive pacing with isoproterenol or a pacemaker and magnesium sulfate are specific therapies for torsades de pointes. Zohair Al Aseri MD,FRCPC EM & CCM

44. Management Extracorporeal Elimination and Circulatory Assistance • Hemodialysis or hemoperfusion may be beneficial for atenolol, nadolol, sotalol, and timolol, the beta-blockers with lower Vd, lower protein binding, and greater hydrophilicity. Zohair Al Aseri MD,FRCPC EM & CCM

45. Management Extracorporeal Elimination and Circulatory Assistance • can be lifesaving in cases of refractory hypotension.  • To be successful, such heroic measures must be taken before prolonged hypotension leads to multiorgan ischemic injury. Zohair Al Aseri MD,FRCPC EM & CCM

46. Management Extracorporeal Elimination and Circulatory Assistance • Because most patients recover with just supportive care, these expensive and invasive interventions should be reserved for drugs and circumstances, such as propranolol, verapamil, and mixed cardiotoxic overdoses, that are associated with higher rates of mortality. Zohair Al Aseri MD,FRCPC EM & CCM

47. TREATMENT OF BETA-BLOCKER POISONING Zohair Al Aseri MD,FRCPC EM & CCM

48. Intravenous Fat Emulsion Rescue Therapy. • At this time, given the potential benefit and despite no human randomized controlled trials performed to date, IFE may be considered for patients who are failing other modalities or during cardiac arrest. Zohair Al Aseri MD,FRCPC EM & CCM

49. Intravenous Fat Emulsion Rescue Therapy. Driscoll DF. Lipid injectable emulsions: Pharmacopeial and safety issues. Pharm Res 2006;23:1959-69 • Reported adverse effects include acute reactions such as an anaphylactoid reaction, and subacute reactions or the “fat overload syndrome” (i.e., coagulopathy, jaundice, lipid accumulation in the liver). Zohair Al Aseri MD,FRCPC EM & CCM

50. Intravenous Fat Emulsion Rescue Therapy. Weinberg GL. Treatment of Local Anesthetic Systemic Toxicity (LAST). RegAnesth Pain Med 2010;35:188-93 • Based on previous use of intralipid for local anesthetic toxicity, the accepted dosing for IFE is a 20% lipid emulsion given as a 1.5 mL/ kg bolus, followed by an infusion of 0.25 mL/kg/min for 30 minutes (not to exceed 8 mL/kg total initial dose). Zohair Al Aseri MD,FRCPC EM & CCM