Consider the Following…
A call came in to transport an adult female patient with the provisional diagnosis of a calcium channel blocker (CCB) overdose. Initial reports indicated that the patient had ingested approximately 40+, 140mg tablets of Verapamil nine hours prior to the call. The patient sought care in a critical access emergency room (approximately a 60-minute rotor wing flight time) after experiencing nausea and vomiting. She arrived obtunded, hypotensive (systolic blood pressure in the low 90 mmHg range) and bradycardic (50-60 BPM). The referring hospital felt that the patient required more intensive care than they could offer and might require ECMO cannulation.
Background
Calcium Channel Blockers (CCB) have been widely used for treatment of hypertension since the 1960’s. CCB are divided into types, dihydropyridines (nifedipine, amlodipine, felodipine, nicardipine, nisoldipine, isradipine and lacidipine) and non-dihydropyridines (diltiazem and verapamil). Dihydropyridines are selective drugs that block the L-type calcium channels located on the muscle cells of the vasculature. This reduces systemic vascular resistance by vasodilation. The non-dihydropyridines block L-type calcium channels in myocardium, causing decrease in myocardial contractility and pacemaker rate. Non-dihydropyridines also decrease SVR but are much weaker than dihydropyridines.
Why is this patient toxic?
Calcium channel blocker (CCB) toxicity is highly lethal resulting in cardiovascular collapse and death if not treated aggressively.
Cardiac toxicity results from the excessive negative inotropy (myocardial depression) and negative chronotropy (bradycardia). Additionally, there is a negative effect on the conduction speed through the AV node (dromotropy) causing brady arrhythmias.
Effects of this toxicity on smooth muscle result in diminished afterload and hypotension.
Furthermore, there are direct effects on metabolism resulting in hyperglycemia. Insulin release depends on calcium influx into the Islet beta cells of the pancreas and there is the inherent calcium channel blocker induced insulin resistance. CCB impair the energy substrate (free fatty acids) favored by the myocardial muscle cells causing a shift to carbohydrates due to the compromised uptake of glucose and free fatty acids and inhibition of mitochondrial activity (calcium dependent) required for glucose metabolism.
What is it I am seeing?
The symptoms seen with standard preparations of CCB medications are usually observed within 1-2 hours. Timed release preparations can be delayed up to 12-24 hours after ingestion.
Essentially an extension of CCB therapeutic effects, you can expect to see hypotension (vasodilation) decreased SVR, bradycardia and AV block and overall decreased cardiac contractility (decreased cardiac output) resulting in profound shock often unresponsive to fluids.
Laboratory tests should include electrolytes, BUN, creatinine, and lactate levels. Because of the possibility of co-ingestions, a digoxin level should be obtained. (Along those lines, standard overdose levels such as ethanol, salicylate, acetaminophen should be obtained. (And, although there are no easy lab tests to detect them, one should always consider the possible co-ingestion of a beta blocker in this scenario).
Stabilization and Transport
Upon arrival of the transport team, the patient was intubated and had a subclavian multi-lumen central venous catheter placed. She had received 16 liters of isotonic crystalloid, 350 mEq of Sodium Bicarbonate (seven 50 ml syringes), 4 gm of Calcium Gluconate, and 10+ mg of Midazolam for sedation. Continuous infusions included Norepinephrine at 0.02 mcg/kg/min, Insulin at 1 unit/kg/hr, and a 10% Dextrose solution at 145 ml/hr. The transport team placed a radial arterial line and drew a blood gas revealing a pH of 6.9, PaCO2 33 mmHg, PaO2 83 mmHg, HCO3 7.8 mEq/L, and an oxygen saturation of 88%. POC Glucose revealed a value of 165 mg/dl and the patient’s Ionized Calcium was 0.89 mmol/L with a serum potassium of 2.5 mEq/L. The patient was placed on the transport ventilator with the goal of providing adequate minute ventilation to address the patient’s profound acidosis.
Consultation with the accepting facility staff determined that the plan of care should include continuing blood pressure support with the addition of an Epinephrine infusion, maintain the high dose Insulin therapy, provide additional Sodium Bicarbonate if the pH remained less than 7.0. Additionally, a Calcium Chloride infusion was prepared as well as a preparation of 20% Intralipids. Blood pressure was stabilized on aforementioned therapy and electrolyte replacement was also initiated enroute to the receiving center.
Mainstay Therapy and Rationale
CCB toxicity is mainly managed through supportive care. Consultation with a toxicologist and local / regional poison control may help guide management decisions. The following video short describes management and rationale based on Survival Flight and Michigan Medicine care. While there is no “antidote,” per se, therapy revolves around increasing calcium availability to cardiac muscle and vascular smooth muscle, deactivating lipophilic agents contributing to the hemodynamic issues and providing improved cardiac contractility through direct action and energy supply to affected cells.
“Take Home” Points
- CCB Toxicity is mainly diagnosed through a thorough history and physical exam.
- Management is primarily supportive.
- This management affects vital electrolyte profiles, so serial lab value acquisition and replacement will be required based upon transport times.
- Hemodynamic stability often hinges upon an adequate acid-base balance (i.e., pH). This is done by attempting to improve perfusion and cardiac output, chemical buffer agents and appropriate ventilatory management.
References
Bartlett, D. (2016). β-Blocker and Calcium Channel Blocker Poisoning: High-Dose Insulin/Glucose Therapy. Critical care nurse, 36(2), 45-50.
Cole, J. B., Arens, A. M., Laes, J. R., Klein, L. R., Bangh, S. A., & Olives, T. D. (2018). High dose insulin for beta-blocker and calcium channel-blocker poisoning. The American journal of emergency medicine, 36(10), 1817-1824.
Mesiha, N., Gugnani, M., & Tieku, S. (2018). Lipid emulsion therapy and high dose insulin in management of calcium channel blocker toxicity. In D46. CRITICAL CARE CASE REPORTS: TOXICOLOGY AND POISONINGS (pp. A6919-A6919). American Thoracic Society.
Nickson, C. (2019, April 2). Calcium Channel Blocker Toxicity • LITFL • CCC Toxicology. Retrieved from https://litfl.com/calcium-channel-blocker-toxicity/.
Pickens, A. (2013, October 10). Calcium Channel Blocker (CCB) Toxicity: “EM in 5”. Retrieved October 1, 2019, from https://youtu.be/twKMOXaH2dE.
St-Onge, M., Anseeuw, K., Cantrell, F. L., Gilchrist, I. C., Hantson, P., Bailey, B., … & Kerns, W. (2017). Experts consensus recommendations for the management of calcium channel blocker poisoning in adults. Critical care medicine, 45(3), e306.