High dose insulin for calcium channel blocker overdose Pan wong PGY1 Pharmacy practice resident UWMC Ed rotation April 2014

Outline Background Basic Pharmacology Review Clinical Presentation Mechanism of Toxicity Pharmacological management High Dose Insulin at UWMC

Background Calcium channel blockers (CCB) overdose is associated with significant morbidity and mortality American Association of Poison Control Centers Exposure Surveillance System Annual Report 2012 Calcium channel blockers: 11,910 cases with 24 deaths Highest mortality rate amongst cardiovascular agents Lyden AE, et al. Clin Toxicol . 2013 Dec;51(10):949-1229

Brief Pharmacology Review Calcium signaling in cardiac myocytes Catecholamines (B-agonists) activates Gs protein Activiates adenylate cyclace (AC)  converts ATP to cAMP cAMP activates protein kinase A (PKA) Causes L-type calcium channel to open leading to calcium influx Causes sarcoplasmic reticulum to release Ca2+  contraction

Calcium Channel Blocker Mechanism of toxicity The life-threatening toxicities are an extension of the therapeutic effects on the cardiovascular system Dihydropyridine Acts predominately on peripheral vasculature Non-dihydropyridine Less selective- both cardiac & peripheral vasculature In overdose, receptor selectivity is lost Distinction between these agents may not be clinically evident Shepherd G, et al. Ann Pharmacother. 2005 May;39(5):923-30.

Calcium Channel Blocker Mechanism of toxicity Blockade of L-type calcium channels: Myocardial cells Weaken cardiac contraction & blunt cardiac automaticity  bradycardia & heart blocks Smooth muscles Relaxation of vascular smooth muscles  hypotension B-islet cells of pancreas Inhibits insulin secretion Reduces myocardial cells ability to use glucose  reduced tissue perfusion  metabolic acidosis Hyperglycemia

Clinical Presentation Hypotension Bradycardia Cardiogenic shock Heart block Hyperglycemia Metabolic acidosis CNS: confusion, seizure, coma

Management Supportive Care Maintain airway Treat hypotension with IV fluid boluses Give atropine for initial treatment (0.5-1mg IV up to 3 doses) Continuous cardiac monitoring Consider GI decontamination Gastric lavage Within 1 -2 hours of ingestion Whole bowel irrigation For consumption of extended release formulations Engebretsen KM, et al. Clin Toxicol. 2011 Apr;49(4):277-83.

Management: Pharmacologic Therapy Calcium MoA: augment extracellular calcium to overcome blocked calcium channels to maximize calcium entry into cell

Management: Pharmacologic Therapy Calcium No optimal dosing has been established Bolus Calcium chloride: 10 to 20 mL of a 10% solution Calcium gluconate: 30 to 60 mL of 10% solution Continuous Infusion Calcium chloride: 0.2 to 0.4 mL/kg per hour of 10% solution Calcium gluconate: 0.6 to 1.2 mL/kg per hour of 10% solution Precautions Close monitoring of serum calcium Use central line for calcium chloride Safest agent is calcium gluconate Efficacy: Mixed clinical experience Kerns, W. Emerg med Clin N Am 25 (2007): 209-331.

Management: Pharmacologic Therapy Inotropes and vasopressors MoA: Could increase inotropy, chronotropy, and vasoconstriction (depending on selected agents) Various agents cited in case reports: Epinephrine, Norepinephrine, Dopamine, Isoproterenol, Dobutamine Efficacy: No selected agent is universally effective Best approach is to choose an agent based on hemodynamics Median rate for EPI was 20 mcg/min and NOREPI 15mcg/min Kerns, W. Emerg med Clin N Am 25 (2007): 209-331.

Management: Pharmacologic Therapy Inotropes and vasopressors Dosing: No set dosing guideline for this indication Titrate to keep MAP >65 Levine et al. 2013 Many received doses much higher doses and did not appear to experience complications Associated with good clinical outcomes Median rate for EPI was 20 mcg/min and NOREPI 15mcg/min Levine M, et al. Ann Emerg Med. 2013 Sep;62(3):252-8.

Management: Pharmacologic Therapy Glucagon MoA: exerts positive inotropic and chronotropic effects on the cardiac myocytes by stimulating adenylate cyclase through a separate receptor

Management: Pharmacologic Therapy Glucagon Dosing Start with 5mg IV bolus (watch for response within 10 mins) Repeat with 10mg IV bolus if no response If response is seen, start IV continuous infusion at 3-5mg/hr and uptitrate Precautions/adverse events: Nausea/vomiting Pre-medicate with ondansteron 4mg IV prior to glucagon Efficacy: Mixed clinical experiences Woodward C, et al. DARU J Pharm Sci 2014 22:36.

Management: Pharmacologic Therapy High Dose Insulin (HDI) CCB toxicity and insulin Healthy myocardial tissue depends on free fatty acid for metabolic needs Note this is different from skeletal tissues CCB overdose forces these cells to use glucose as fuel CCB inhibits secretion of insulin Cells unable to uptake glucose efficiently MOA: Promotes cellular uptake of glucose to provide fuel and energy Positive inotropic effects Rizvi I, et al. BMJ Case Reports 2012;10.

Management: Pharmacologic Therapy High Dose Insulin (HDI) Efficacy: No clinical trials comparing use of HDI to other treatments in humans Majority of case reports use HDI after inadequate response to other treatments Appears beneficial in serious intoxication with hypotension Many case reports demonstrated benefits with HDI therapy Precautions/Adverse Effects Hypoglycemia Hypokalemia Given how it has been practiced in case reports/series, it is generally accepted as a later line therapy. But there definitely groups/practices that are pushing for HDI to be first line. Shepherd G, et al. Ann Pharmacother. 2005 May;39(5):923-30.

High Dose Insulin at UWMC UWMC Guidelines Consider HDI for hypotension and/or symptomatic bradycardia, shock secondary to calcium channel blocker overdose Consultation with WA Poison Control Center AND on-call toxicologist is required Parameters must be met prior to initiating HDI Glucose >250mg/dL Potassium > 3.3 mEq/L Goal of therapy Improve hemodynamics Increase perfusion Maintain SBP >100, MAP >65 and HR >60

High Dose Insulin at UWMC Medications Regular Insulin Bolus: 1 unit/kg IV x 1 IV Infusion: start with 0.5 – 1 unit/kg /hour Dextrose If blood glucose < 250mg/dL before starting HDI infusion 50ml of Dextrose 50% IV bolus Recheck blood sugar in 15 minutes If blood glucose > 250mg/dL Start HDI Consider dextrose 10% to maintain glucose >150mg/dL while on HDI (should have this available)

High Dose Insulin at UWMC Monitoring POCT Blood Glucose Q 15 mins x 4 after initiating or increasing HDI infusion rate If stable after 60 mins, decrease checks to q 30 minutes Potassium Q 1 hour x 4 hours Then switch to q 2 hour checks Maintain K+ > 3.3 Replete PRN Other electrolytes Magnesium, calcium and phosphate q 4 hours

Management: Pharmacologic Therapy Lipid Emulsion (lipid Rescue) MoA yet to be fully understood Lipid soaks up lipid soluble toxins from reaching site of action Provide fatty acid substrate for cardiac energy supply and improve myocyte function Dosing not well-established 20% fat emulsion Bolus: 1.5 mL/kg Infusion: 0.25 mL/kg/min x 60 minutes Doepker B, et al. J Emerg Med. 2014 Apr;46(4):486-90.

Conclusion Calcium channel blockers (CCB) overdose are associated with significant morbidity and mortality Various antidotes reported Calcium Glucagon Vasopressors and Inotropes High Dose Insulin Lipid Emulsion Evidence come mainly from animal studies, case reports, and case series High dose insulin is promising Published experience shows good benefit as a rescue agents in patients unresponsive to other regimens

High dose insulin for calcium channel blocker overdose Pan wong PGY1 Pharmacy practice resident UWMC Ed rotation April 2014

References Doepker B, Healy W, Cortez E, Adkins EJ. High-dose insulin and intravenous lipid emulsion therapy for cardiogenic shock induced by intentional calcium-channel blocker and Beta-blocker overdose: a case series. J Emerg Med. 2014 Apr;46(4):486-90. Engebretsen KM, et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol. 2011 Apr;49(4):277-83. Englund J.L., Kerns W.P., II (2011). Chapter 188. β-Blockers. In Tintinalli J.E., Stapczynski J, Ma O, Cline D.M., Cydulka R.K., Meckler G.D., T (Eds), Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. Retrieved April 29, 2014 from http://accessmedicine.mhmedical.com.offcampus.lib.washington.edu/content.aspx?bookid=348&Sectionid=40381669. Kerns, W. Management beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg med Clin N Am 25 (2007): 209-331. Levine M, et al. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. Ann Emerg Med. 2013 Sep;62(3):252-8. Mowry JB, et al. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol . 2013 Dec;51(10):949-1229. Lyden AE, et al. Beta-Blocker Overdose Treated with Extended Duration High Dose Insulin Therapy. J Pharmacol Clin Toxicol 2(1):1015 Minns A.B., Tomaszewski C (2011). Chapter 189. Calcium Channel Blockers. In Tintinalli J.E., Stapczynski J, Ma O, Cline D.M., Cydulka R.K., Meckler G.D., T (Eds), Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. Retrieved April 28, 2014 from http://accessmedicine.mhmedical.com.offcampus.lib.washington.edu/content.aspx?bookid=348&Sectionid=40381670 Rizvi I, et al. Life -threatening calcium channel blocker overdose and its management. BMJ Case Reports 2012;10. Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother. 2005 May;39(5):923-30. Woodward C, et al. High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity. DARU J Pharm Sci 2014 22:36.