The Gist: Although high dose insulin (HDI/hyperinsulinemia euglycemia) therapy has been embraced as a treatment modality for calcium channel blocker (CCB) toxicity, glucagon remains one of the "textbook" answers as the antidote of choice in the United States. This is likely outdated as many experts think this should be removed or given as only a cursory measure given the other modalities available.
Why do we care?
Problems with glucagon:
Why do we care?
- CCBs are a "one pill can kill" medication in children.
- They're commonly encountered in practice and have devastating consequences. We may not encounter these regularly but when we do, it's vital to be acquainted with the treatment modalities.
- For a case-based review of CCB toxicity, check out this toxicology conundrum and this overview by Kerns (full text) (below is not a complete review of CCB toxicity).
- Also, physicians tend to practice the teachings garnered from school, tests, and texts. If these resources, the foundation of a provider's medical knowledge, lag, then it follows that practice (in some cases) may lag.
Glucagon in CCB toxicity:
- Increases hemodynamic parameters in models (heart rate and blood pressure)
- Mechanism: stimulates adenylate cyclase to increase cAMP which may improve cardiac contractility.
- Initial dose: 2-5 mg IV over 30-60 seconds for an adult and 50 mg/kg in children and can be repeated. If the patient has a postive response, they should be started on a continuous infusion of the initial“response dose” given per hour (1).
- It takes a lot of glucagon, more than many EDs generally have to offset the effects of a calcium channel blocker overdose. A one hour glucagon infusion could exhaust many hospitals glucagon supply.
- Vomiting. This is precisely why glucagon is used, occasionally successfully in patients with a food bolus. In sick patients or those who aren't protecting their airway, this increases the risk of aspiration.
- Cost. According to a consensus paper on antidote stocking in Annals of EM, an eight hour course of glucagon therapy would cost nearly $8,000 (US).
- Efficacy. The paper by Kline et al demonstrates that HDI therapy is far more efficacious than glucagon in the canine model.
- Duke University's Emergency Medicine grand rounds are available on iTunes and Dr. Kerns happens to cover CCB overdose in this lecture (#43). An astounding piece of information is nestled in this talk: Nearly all studies examining glucagon in CCB toxicity were conducted prior to the availability of recombinant glucagon and used Eli Lilly's standard glucagon preparations instead. What are the repercussions of this?
- The standard preparation of glucagon, made from mammalian pancreatic extract, contained insulin (also from pancreatic cells) until recombinant glucagon was available in 1998. Some vials of glucagon, when analyzed by this study group at Carolinas Medical Center, contained 100 units of insulin. This was demonstrated in the study on HIE therapy in verapamil poisoning Kline et al. Thus, benefit seen with glucagon may be partially a result of the insulin in the preparation. I couldn't find any published studies of this.
- EMCrit podcast #27 features the renowned Dr. Leon Gussow of The Poison Review and supports the notion that glucagon probably does nothing for CCB toxicity, whereas the published clinical experience supports HDI.
But does this FOAM appear on the wards? Yes!
I had the fortune to learn from Dr. Kerns at Carolinas Medical Center on a recent toxicology rotation. The voice from the Duke EM podcast above sounded familiar and I had the opportunity to ask him about CCBs in detail. He suggested the following algorithm in the case of known CCB toxicity, with emphasis on moving quickly through some of the earlier steps (as many therapies are likely required and titrating therapies to effect, since each patient may respond differently:
- Activated charcoal if appropriate, especially if a sustained release preparation.
- All CCBs are not equal. Verapamil seems to be the worst, with diltiazem next, and the dihydropyrines behind diltiazem.
- IV fluids -careful with heart failure. Will likely have minimal response, just fill the tank.
- Calcium - Often doesn't work. If one gives enough calcium, may be able to overcome competitive inhibition in some individuals. Push the calcium to 15-20 mg/dL. Effect is short lived (15-20 minutes) so repeat boluses and begin infusion if patient responds.
- Calcium gluconate - peripherally start with at least 3 amps
- Calcium chloride - central administration.
- Glucagon - can give it but move past this step quickly because it has limited utility.
- Vasopressors - use bedside ultrasound to look at cardiac contractility
- Insulin will increase cardiac contractility so if there's already decent contractility, try pressors (norepinephrine) and escalate the dose every 5 minutes. If contractility is depressed, move on to HDI
- High dose insulin (HDI) - Move fairly quickly through above interventions to this point in the sick, hypotensive, bradycardic patients.
- Improves the utiliziation of glucose by the myocardium. In the stressed state, the heart switches from predominantly using free fatty acids to using carbohydrates as a substrate.
- CCBs induce a state of relative insulin resistance and deficiency by preventing insulin release by the pancreas and organ/cellular uptake.
- Recent literature show that this therapy is more efficacious than glucagon and pressors, including this review by Megarbane et al.
- Give a bolus initially to saturate the insulin receptors since it takes ~20-45 minutes for the metabolic response to insulin to really become apparent at a dose of 1-10 units/kg, followed by a infusion at the bolus response rate (per hour) (2).
- Requires q30 minute glucose checks and frequent potassium monitoring (insulin drives potassium intracellularly so levels appear low while body stores are normal) (2)
- Is there a downside? Nickson (of LITFL fame) and Little articulate them well in this article. Essentially, HDI therapy is cumbersome and toxicologic patients are not well-suited for RCTs (due to number of patients and the very individual nature of the circumstances) so data are limited. Also, due to the infrequent nature of these toxicities are all providers knowledgeable about the beneficial role of early HDI?
I also had the privilege of training with South Carolina's toxicologist who added in two additional pearls:
- Lipid emulsion - experiential and published case reports demonstrates improved morbidity and mortality, including a marked decrease in norepinephrine requirements (Ozcan and Weinberg and Cave et al). Here are some talks on lipid emulsion in general.
- ECMO - case reports suggest that ECMO may work in some patients but published data is limited and a bias toward publishing positive results may exist (Koltz et al, De Rita et al)
1. Zaologa GP, Malcolm D, Holladay J, Chernow B. Glucagon Reverses the Hypotension and Bradycardia of Verapamil overdose in rats. Crit Care Med 1985;13:273
2. Kerns, W. Management of b-Adrenergic Blocker and Calcium Channel Antagonist Toxicity. Emerg Med Clin N Am 25 (2007) 309–331