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. Clin Toxicol Dec;51(10):

4. 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

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 May;39(5):

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. Clin Toxicol Apr;49(4):

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. Emerg med Clin N Am 25 (2007):

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
Median rate for EPI was 20 mcg/min and NOREPI 15mcg/min
Kerns, W. Emerg med Clin N Am 25 (2007):

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
Median rate for EPI was 20 mcg/min and NOREPI 15mcg/min
Levine M, et al. Ann Emerg Med Sep;62(3):252-8.

13. Management: Pharmacologic Therapy
Glucagon
MoA: exerts positive inotropic and chronotropic effects on the cardiac myocytes by stimulating adenylate cyclase 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 Sci :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
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.

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
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 May;39(5):

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

20. 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 Apr;46(4):

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 Apr;46(4):
Engebretsen KM, et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol Apr;49(4):
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
Kerns, W. Management beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg med Clin N Am 25 (2007):
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 Sep;62(3):252-8.
Mowry JB, et al Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol Dec;51(10):
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
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 May;39(5):
Woodward C, et al. High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity. DARU J Pharm Sci :36.