From the moment I called Toxicology regarding a recent life-threatening Verapamil overdose, I realized that the number and variety of potential treatments for this toxicity can be overwhelming in an emergent situation. I was instructed to give “10-20mL of 10% calcium chloride followed by 48.75mEq/hour or 19.5-39mL/hour of 10% calcium chloride if needed.” None of these are order options on my computer screen! Now, in addition to traditional resuscitation, I am trying to place a central line to give calcium chloride while calling my pharmacist (and hoping they can translate that into grams), even though calcium is often of little benefit?
Meanwhile, UpToDate is telling me that if the situation arises, atropine may not work for my patient’s symptomatic bradycardia, that successful capture with transvenous pacing may not improve cardiac output or blood pressure, and that a norepinephrine infusion up to 100mcg/min may be necessary. Likewise, I may have to give insulin in excess of 400 units/hour (Philadelphians like their cheesesteaks which is stressing my weight-based dosing!) Furthermore, other treatment options including lipid emulsion therapy, phosphodiesterase inhibitors, and ECMO are bouncing around in my mind at the rate of my personal supraventricular tachycardia. This is emergency medicine. This is a common overdose. Isn’t there an algorithm I can follow? Do I need to do all of these things? Which are the most important? Which are evidence based?
Fortunately, my patient had a good outcome. But it left me wanting to read everything that I could about this topic. So, let’s discuss the life-threatening complications of calcium channel blockers (CCB) overdoses, common therapies currently in practice for this overdose, and an evidence based approach for the management of these patients.
Mechanism of Action
CCB bind L-type calcium channels preventing the intracellular influx of calcium. These channels are vital to function of cardiac myocytes, vascular smooth muscle, and islet beta cells. CCB have 4 cardiovascular effects: peripheral arterial dilation, negative chronotropy (bradycardia through SA node inhibition), negative inotropy (decreased cardiac contractility), and negative dromotropy (decreased cardiac conduction through AV node inhibition).
Types of CCBs
There are three classes, but let’s simplify that and just talk about the two main flavors. Dihydropyridines like amlodipine, nifedipine, and nicardipine act primarily on the vascular smooth muscle and will cause hypotension and usually reflexive tachycardia in an overdose. The nondihydropyridines consist of two classes – mainly Verapamil and Diltiazem. These medications are more active on the myocardium, and overdose of these medications, particularly Verapamil, will give you profound hypotension, bradycardia, and conduction disturbances. These patients can rapidly deteriorate to cardiogenic shock. However, ion overdoses, receptor selectivity is often lost, therefore, even dihydropyridines can cause cardiotoxicity and subsequent cardiovascular collapse.
Let’s talk resuscitation. When this patient comes into your ED, you’re going to start with your standard resuscitation and run through your tried and true alphabet – ABC, IV, O2, monitor, EKG, and consider GI decontamination if patient presents within 1-2 hours and is asymptomatic (may consider lengthening this time window or using repeat doses of activated charcoal if patient ingested sustained release formulation) . In severe overdoses, place a central line early because you will need to be giving calcium, pressors, and you will want to be able to give multiple meds at once.
There are a few standard therapies for bradycardia and hypotension that don’t tend to be useful in these patients…. it’s like bringing a knife to a gun fight…something North Philly has taught us all! Atropine for example, is unlikely to improve bradycardia in severe overdoses because these patients often have infranodal blocks . Similarly, pacing may not improve your cardiac output because the patient still has decreased inotropy .
Calcium and Glucagon
So, what does work? Let’s start off with a couple of adjunct therapies because they can be useful early on. Glucagon may be more effective than atropine in these patients in treating bradycardia because it increases cAMP directly and does not act on the SA node (these patients often have SA nodal blockade and infrandodal blockade which limits the effectiveness of atropine) However, the effect is short lived, so continue to be aggressive in initiating your other therapies. Giving high doses of calcium can theoretically flood the system and eventually overcome the blockade. And there are case reports of patients being maintained solely on high dose calcium drips [2-5]. However, the dosing can be complex and these patients need to be monitored closely for potential complications of hypercalcemia.
A standard approach is to start with 2 grams (20mL) IV calcium chloride with repeat boluses given up to 3 times. Remember, calcium chloride must be given through a central line. If the patient does not yet have a central line, an alternative is to give 60mL IV of calcium gluconate, and repeat up to 3 times. Pediatric dosing is 0.2mL/kg claim chloride and 06.-1.0 mL/kg or calcium gluconate.
Team Catecholamine vs Team HIE
There are two schools of thought in the toxicology world regarding the mainstay of CCB toxicity treatment. There is Team Catecholamine and Team Hyperinsulinemia Euglycemia (HIE). Let’s examine both treatment modalities.
Pressors and Inotropes
Catecholamines, your vasopressor and inotropes, can be the foundation of your treatment in a severe CCB toxicity. With CCB overdose, the problem is some combination of hypotension and bradycardia, so why not use medications that target these specific problems. However, we need to understand that these patients may require significantly high dosing than we are usually comfortable with. For example, there are case reports citing norepinephrine doses up to 100mcg/min, and epinephrine up to 150mcg/min . However, these are the extremes and most patients will require something closer to a standard dose or moderately above that. Just be prepared, to go high on your dosing if needed. If possible, use bedside ultrasound to guide your decision in medication choice in terms of the need for more inotropy or more pressor activity. If you can’t do this, then get a stat cardiology consult. The potential downsides of using this therapy is that the patient may develop ischemic complications from the vasoconstriction. However, one of the largest case series published evaluating CCB toxicity management found “despite high doses of vasopressors, ischemic complications were the exception and were usually present before the use of vasopressors” . Lastly, if the calcium blockade is severe enough, catecholamines alone may not be able to overcome the hypotension and bradycardia
The other main therapy for CCB overdose is HIE therapy. This involves an optional bolus of 1U/kg followed by an infusion of 1-10U/kg/hr and maintaining euglycemia with a dextrose infusion. The MOA is not fully understood, but we do know that in high doses, insulin act as an inotrope. Calcium-dependent inotropic effect is, at least in part, mediated by phosphatidylinositol 3-kinase (PI3K) . There are many animal studies and case series in which HIE successfully managed CCB overdose with or without the use of pressors [8-9]. It is important to monitor serum glucose closely in these patients as they are at risk of hypoglycemia and hypokalemia. (But remember, CCB toxicity often causes hyperglycemia which may play a protective role against hypoglycemia in these patients receiving HIE therapy.) The major benefit to HIE therapy, is there is no vasoconstriction or risk of subsequent ischemic injury.
Now what about places like Philadelphia where I work and where people love their cheese steaks. This can drive your weight-based dosing up well in excess of 500units/hr. So, make sure to concentrate the insulin, to avoid fluid overloading your patient. Lastly, it is important to start HIE early for two reasons. One because it can take 30-60 minutes to start taking effect. And two, the evidence that we do have suggests that HIE is most effective when started early.
Lipid Emulsion Therapy
What about Lipid emulsion therapy? The theory behind IV lipid emulsion therapy is that it creates a lipid sink which draws the drug out of the tissue and then sequesters it in the lipid compartment within the plasma. While this therapy has potential, it is not actually that well understood, and it is not a first or second line treatment, so it’s reasonable to do some cognitive offloading and remove this from your ED management of CCB toxicity. However, many toxicologists will advocate for giving it in refractory cases and (peri) arrest situation as a last-ditch effort.
Phosphodiesterase inhibitors like milrinone inhibit the breakdown of cAMP which causes smooth muscle to contract and acts as an inotrope. These medications are used in end stage heart failure, so the role for them is understandable, but alone, they are not powerful enough to overcome the effects of CCB overdose. At most, they may be considered to augment other inotropes as needed. Further, phosphodiesterase inhibitors can take 6-8 to take effect and are not going to be a stand-alone therapy, so again, it’s reasonable to remove them from your ED management
Back-up Plan for the Back-up Plan
If all else fails, then you need a mechanical rescue. ECMO can be used as a rescue therapy in cardiovascular collapse after CCB overdoses and can help support the patient until all the drug is metabolized out of their system. Figure out early on what you need to do to implement this therapy if needed. Arrange for transfer early on if needed, involve your ICU admitting service early on and, know what service to call to initiate ECMO in the ED if needed. At our hospital, it is CT surgery. Who is it at your institution? If ECMO is not an option, you may consider placing an intra-aortic balloon pump. Again, with the intent of supporting the patient until the drug is metabolized out of their body.
At the end of the day, there aren’t any randomized control trials looking at pressors, HIE, or any other therapy for that matter. And there are a number of experimental therapies currently being evaluated. So, the best treatment for this overdose has yet to be definitively established.
But based on the evidence currently available, a reasonable approach to CCB overdose is to use pressors and inotropes with or without HIE as the foundation of your therapy in managing your hemodynamically unstable patient. HIE therapy can be quite effective, but you need to start it early. Important adjuncts to remember are glucagon (can reverse bradycardia, but effect is short lived) and calcium. If all else fails, ECMO can be a rescue therapy, so figure out ahead of time what you need to do to mobilize that service for your patient. When possible, do some cognitive offloading and don’t waste your time or energy on therapies that are not useful in the ED.
Author: Nicole Munz – Chief Resident. @nmunzy
- EMCrit – Calcium Channel Blocker Overdose – EMCrirt Podcast 27 (2010)
- Life in the Fast lane – Calcium Channel Blocker Toxicity (2015)
- TPR – Is lipid emulsion therapy effective in calcium-channel-blocker and beta-blocker overdose? (2015)
- TPR – There is no real evidence on treating calcium channel blocker overdose (2014)
- TPR – Are vasopressors effective therapy in calcium channel blocker overdose? (2013)
- TPR – Pressors or high-dose insulin for calcium channel blocker overdose? (2013)
- TPR – Calcium channel blocker toxicity, acidosis, and GI decontamination (2010)
1. Hoffman R, Howland M. et al. Goldfrank’s Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill; 2015
2. Howarth DM, Dawson AH, et al. Calcium channel blocking drug overdose: An Australian series. Hum Exp Toxicol 1994;(13):161–166. PMID: 7909677
3. Ramoska EA, Spiller HA, et al. A One-Year Evaluation of Calcium Channel Blocker Overdoses: Toxicity and treatment. Ann Emerg Med 1993;(22):196–200. PMID: 8427431
4. Henry M, Kay MM, et al. Shock Associated with Calcium-Channel and Beta Blockers: Reversal with Intravenous Calcium Chloride. Am J Emerg Med 1985;(3):334–336. PMID: 860911
5. Strubelt O, Diederich KW. Experimental Investigations on the Antidotal Treatment of Nifedipine Overdosage. J Toxicol Clin Toxicol 1986;(24):135–149. PMID: 3712523
6. 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;62(3):252-8. PMID: 23642908
7. Lewinski von D, Bruns S, et al. Insulin Causes [Ca2+]i-Dependent and [Ca2+]i-Independent Positive Inotropic Effects in Failing Human Myocardium. Circulation 2005; 111: 2588–95. PMID: 15883206
8. Shepherd G, Klein-Schwartz W. High-Dose Insulin Therapy for Calcium Channel Blocker Overdose. Ann Pharmacother 2005;39(5):923-30. PMID: 15811898
9. Engebretsen KM, et al. High-Dose Insulin Therapy in Beta-Blocker and Calcium Channel-Blocker Poisoning. Clin Toxicol (Phila). 2011;49(4):277-83. PMID 21563902