High dose insulin for calcium
channel blocker overdose
1
PAN WONG
PGY1 PHARMACY PRACTICE RESIDENT
UWMC ED ROTATION
APRIL 2014
Outline
2
 Background
 Basic Pharmacology Review
 Clinical Presentation
 Mechanism of Toxicity
 Pharmacological management
 High Dose Insulin at UWMC
Background
3
 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
4
 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
5
 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
6
 Blockade of L-type calcium channels:
 Myocardial cells


Smooth muscles


Weaken cardiac contraction & blunt cardiac automaticity 
bradycardia & heart blocks
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
7
 Hypotension
 Bradycardia
 Cardiogenic shock
 Heart block
 Hyperglycemia
 Metabolic acidosis
 CNS: confusion, seizure, coma
Management
8
 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
9
 Calcium
 MoA: augment
extracellular calcium to
overcome blocked
calcium channels to
maximize calcium entry
into cell
Management: Pharmacologic Therapy
10
 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
11
 Inotropes and vasopressors
 MoA: Could increase inotropy, chronotropy, and
vasoconstriction (depending on selected agents)
 Various agents cited in case reports:


Efficacy:


Epinephrine, Norepinephrine, Dopamine, Isoproterenol,
Dobutamine
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.
Management: Pharmacologic Therapy
12
 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.
Management: Pharmacologic Therapy
13
 Glucagon
 MoA: exerts positive
inotropic and chronotropic
effects on the cardiac
myocytes by stimulating
adenylate cyclase through a
separate receptor
Management: Pharmacologic Therapy
14
 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
15
 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
16
 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.
High Dose Insulin at UWMC
17
 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
18
 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
19
 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

Management: Pharmacologic Therapy
20
 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
21
 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
22
PAN WONG
PGY1 PHARMACY PRACTICE RESIDENT
UWMC ED ROTATION
APRIL 2014
References
23
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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.