H igh dose insulin for calcium channel blocker overdose

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

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

3. 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. ClinToxicol. 2013 Dec;51(10):949-1229

4. Brief Pharmacology Review Calcium signaling in cardiac myocytes • Catecholamines(B-agonists) activates Gs protein • Activiatesadenylatecyclace(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

5. 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.

6. 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

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

8. 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. ClinToxicol. 2011 Apr;49(4):277-83.

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

10. 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. Emergmed Clin N Am 25 (2007): 209-331.

11. 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 Kerns, W. Emergmed Clin N Am 25 (2007): 209-331.

12. 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 Levine M, et al. Ann Emerg Med. 2013 Sep;62(3):252-8.

13. Management: Pharmacologic Therapy • Glucagon • MoA: exerts positive inotropic and chronotropic effects on the cardiac myocytes by stimulating adenylatecyclase through a separate receptor

14. 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 Sci2014 22:36.

15. 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 • CCBinhibits 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.

16. 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 Shepherd G, et al. Ann Pharmacother. 2005 May;39(5):923-30.

17. 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

18. 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)

19. 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 • Replete PRN

20. Management: Pharmacologic Therapy • Lipid Emulsion (lipid Rescue) • MoAyet 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 myocytefunction • 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.

21. 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

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

23. 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. ClinToxicol. 2011 Apr;49(4):277-83. EnglundJ.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. MowryJB, et al. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. ClinToxicol. 2013 Dec;51(10):949-1229. LydenAE, et al. Beta-Blocker Overdose Treated with Extended Duration High Dose Insulin Therapy. J PharmacolClinToxicol2(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 Sci2014 22:36.