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High dose insulin for calcium channel blocker overdose

PAN WONGPGY1 PHARMACY PRACTICE RESIDENT

UWMC ED ROTATIONAPRIL 2014

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Outline

BackgroundBasic Pharmacology ReviewClinical Presentation Mechanism of Toxicity Pharmacological management High Dose Insulin at UWMC

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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 deathsHighest mortality rate amongst

cardiovascular agents

Lyden AE, et al. Clin Toxicol . 2013 Dec;51(10):949-1229

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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

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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.

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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

Calcium Channel Blocker Mechanism of toxicity

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Clinical Presentation

Hypotension Bradycardia Cardiogenic shock Heart block HyperglycemiaMetabolic acidosis CNS: confusion, seizure, coma

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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.

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Management: Pharmacologic Therapy

Calcium MoA: augment

extracellular calcium to overcome blocked calcium channels to maximize calcium entry into cell

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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.

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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. Emerg med Clin N Am 25 (2007): 209-331.

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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.

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Management: Pharmacologic Therapy

Glucagon MoA: exerts positive

inotropic and chronotropic effects on the cardiac myocytes by stimulating adenylate cyclase through a separate receptor

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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

Management: Pharmacologic Therapy

Woodward C, et al. DARU J Pharm Sci 2014 22:36.

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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

Management: Pharmacologic Therapy

Rizvi I, et al. BMJ Case Reports 2012;10.

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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

Management: Pharmacologic Therapy

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

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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

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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)

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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

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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.

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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

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High dose insulin for calcium channel blocker overdose

PAN WONGPGY1 PHARMACY PRACTICE RESIDENT

UWMC ED ROTATIONAPRIL 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.

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