Author: Annemarie Daecher, MD, Emergency Medicine Resident PGY1
Fellow: Alexis Cates, DO, Medical Toxicology Fellow PGY6
Faculty: David Goldberger, MD, Medical Toxicology / Emergency Medicine Attending
You are an intern working in a busy level 1 trauma center in Philadelphia when medics brings in a 67 year old female whose daughter called 911 after she found her mom at home “not acting right.” Her daughter is at bedside and reports that when she got to her mother’s house about an hour ago, her mother was extremely drowsy and stated that she “just wanted to nap” which was very unlike her. In addition, she could not stand back up without feeling as if she would pass out. Upon arrival, your patient is alert and oriented to self but not to place or time. Her vitals are: HR 45, BP 82/65, RR 14, SpO2 98% on room air, Temp 37C. An electrocardiogram (ECG) shows sinus bradycardia without any QRS widening or QT prolongation.
Her physical exam is significant for bilateral lower lung lobe crackles and is otherwise unremarkable. She is able to tell you that she has a history of hypertension, hyperlipidemia, and gastro-esophageal reflux disease (GERD) and was just started on a new blood pressure medication by her doctor yesterday. She cannot remember the name of it. Luckily, her daughter brought all of her prescriptions with her and you discover that she takes metoprolol, diltiazem, atorvastatin, and famotidine. She is able to tell you that the diltiazem 100mg twice daily is a new medication. You notice that the prescription was just filled this morning but that there are 4 pills missing instead of the 1 that you would expect.
Learning Point 1: Calcium Channel Blockers Pharmacology and Toxicity
Calcium channel blockers (CCBs) were first introduced commercially in the United States in the 1970s. They are used for multiple medical conditions including stable angina, hypertension, migraines, subarachnoid hemorrhage and dysrhythmias. They are available as immediate release or extended release formulations and their potential for toxicity is often underappreciated. According to 2007 Poison Control Center data, 10,084 exposures with 435 cases of major toxicity and 17 deaths were reported in the United States (4). Although 16% of all cardiovascular drug exposures are due to CCBs, they account for 38% of the deaths within that group.
All CCBs exert their effects via antagonistic actions on the L-type calcium channel. Each group of CCBs binds to a different alpha submit on the channel and thus have different affinities for the calcium channel. The nondihydropyridines, diltiazem and verapamil, promote their inhibitory effects directly on the sinoatrial and atrioventricular nodes, whereas the dihydropyridines such as nifedipine, amlodipine, and nicardipine have little myocardial inhibitory effect and are more potent vasodilators. For this reason, verapamil and diltiazem are most often used to decrease the myocardial oxygen demand and to abolish supraventricular tachycardias whereas the dihydropyridines are more often used to treat diseases with increased peripheral vascular tone such as hypertension, Raynauds, prinzmetal angina, and post-subarachnoid hemorrhage vasospasm.
To understand how CCBs work, let’s review what happens on a cellular level. Calcium enters the cardiac myocyte through L-type calcium channels following its concentration gradient. As it enters the cell, calcium activates channels on the sarcoplasmic reticulum which releases calcium stores into the cytoplasm of the myocyte. The calcium within the cytoplasm then binds to troponin C and causes a conformational change that allows actin and myosin to bind, leading to contraction of the myocyte (Figure 1). The alpha1c subunit is the pore forming part of the calcium channel and is the portion where all CCBs bind to inhibit calcium entry into the myocyte. Inhibition of these channels by CCBs results in decreased force of contraction as the myocardium is dependent on calcium to function normally.
Clinical features of toxicity:
- Hypotension is the most common abnormal vital sign
- Often more significant with dihydropyridines
- Bradycardia is more often associated with verapamil and diltiazem (nondihydropyridines) poisoning but can be seen in dihydropyridine poisoning
- A reflex tachycardia due to hypotension may occur
- Early signs include fatigue and lightheadedness but can progress to syncope, altered mental status, coma, and death
- Hyperglycemia due to inhibition of insulin release from the beta islet cells of the pancreas which is L-type calcium channel mediated
- Acute pulmonary injury thought to be due to increased precapillary vasodilation causing an increase in hydrostatic pressure and transudates in pulmonary capillaries, ultimately leading to interstitial edema
- Standard release formulations – initial symptoms typically within 2-3 hours after ingestion; Extended release formulations – initial symptoms typically within 6-8 hours after ingestion
- Delayed effects are possible with prolonged absorption, large ingestion, & extended release formulations.
When you ask the patient why there are 4 of the diltiazem pills missing from the bottle as she only picked up the prescription this morning, she states that she misunderstood her doctor and thought she had to take the doses that she missed yesterday because she did not have the medication at that time. She ingested the pills approximately 2 hours prior to arrival. There was no suicidal intention. At this point, you start intravenous fluid resuscitation and decide to consult toxicology to discuss the role of gastrointestinal (GI) decontamination in this case. Her lab work is significant for a blood glucose of 340 mg/dL and a creatinine elevation to 1.2 mg/dL (baseline < 1 mg/dL). The remainder of the lab work is unremarkable.
Learning Point 2: Calcium Channel Blocker Poisoning Management
The initial examination should include adequate oxygenation and airway protection, with usual resuscitative measures. Obtaining intravenous access and placing the patient on a cardiac monitor is paramount. An ECG should be completed immediately on presentation and then assessed every few hours or sooner if a dysrhythmia is noted, especially if they are symptomatic.
When appropriate and no contraindications are met, GI decontamination is critical in these cases to mitigate the potential for significant cardiotoxicity which can be severe and difficult to reverse. Consideration should be given to the following in appropriate circumstances:
- One dose of 1g/kg of activated charcoal orally may be beneficial
- Ensure no contraindications (altered mental status, active vomiting, inability to follow commands, cannot control their own airway, etc).
- This can occur several hours following an ingestion if absorption is believed to still be ongoing in the GI tract.
- Whole bowel irrigation (WBI) may be beneficial
- Consider WBI in particular for: significant symptoms, extended release products, nondihydropyridine poisonings.
- Requires intense use of resources and bedside nursing
- Placement of a nasogastric tube for administration may be warranted
- 1 liter per hour of isotonic fluid per gastric tube in the adult population
Pharmacotherapy should focus on improvement and maintenance of cardiac output and vascular tone. Evidence-based medicine is somewhat limited; however, the current literature cites a number of therapeutic interventions that can potentially improve the hemodynamics of CCB-poisoned patients. Consideration of each, listed below, as it pertains to the individual patient should be given based on signs and symptoms.
- In dog models, atropine was found to increase heart rate and cardiac output in verapamil poisoning; however, clinically, atropine has little effect in severe calcium channel blocker toxicity.
- Can still be a consideration in patients with bradycardia
- Recommended dose: 0.5 – 1.0 mg IV every 2 to 3 minutes (maximum dose 3mg)
- The exact mechanism is unclear but intravenous calcium boluses increase the extracellular concentration of calcium, subsequently increasing the concentration gradient of calcium between the extracellular and intracellular compartments.
- Results in increase in inotropy and improved contractility, contributing to improvement in blood pressure
- Potential effects may be short-lived
- Calcium chloride
- Recommended dose: 10-20 mL of a 10% solution over 10 minutes, if no effect is noted this dose can be repeated up to four times every 20 minutes
- Best administered via central venous access due to potential tissue injury if extravasation occurs
- Calcium gluconate
- Recommended dose: 30-60 mL of a 10% solution over 10 minutes
- Recall that calcium gluconate contains only ⅓ of the elemental calcium as calcium chloride
- Best administered via peripheral or central venous access
- Calcium chloride
- Very effective
- Activation of either the beta-1 receptors in the heart to increase contractility or the alpha-1 receptors on the peripheral vascular smooth muscle to increase tone
- Beta agonists activate adenylate cyclase to produce cAMP which then activates protein kinase A which phosphorylates the alpha subunit of calcium channels responsible for calcium influx into the cell.
- Protein kinase A also enhances release of calcium from troponin after contraction.
- This increase in intracellular calcium causes an increase in chronotropy, inotropy and dromotropy.
- On vascular smooth muscle in the periphery, alpha-1 agonists activate calcium channels associated with the alpha-1 receptor directly, causing calcium to increase in the cell leading to vasoconstriction.
- Choosing an agent depends on whether the patients’ hypotension is most likely due to myocardial depression or decreased vascular tone.
- Epinephrine infusion is most effective especially if the prominent feature is bradycardia
- Norepinephrine infusion is most effective especially if the prominent feature is vasodilation
- High Dose Insulin – Euglycemic Therapy
- Used in severe calcium channel blocker poisoning with features of hypotension and bradycardia
- Several possible mechanisms
- Lack of insulin release from the pancreas results in hyperglycemia
- Myocardium becomes insulin resistant, resulting in impared glucose utilization by myocardial cells leading to diminished contractility
- Therefore, exogenous insulin will result in inotropic effects by assisting myocardial uptake of carbohydrates, improving the local microcirculation and systemic perfusion by producing local vasodilation, and some believe the Na+/Ca2+ antiporter is impaired leading to increased intracellular calcium.
- Recommended dosing: 1 unit/kg/hour infusion, no bolus necessary
- Maintain serum glucose 100-200 mg/dL, if able
- Dextrose-containing infusions may be utilized when needed (concentrate the solution when able to monitor fluid input)
- Monitor glucose every 30 minutes to one hour to attempt to maintain euglycemia to slight hyperglycemia
- Onset of effect of insulin infusion may be delayed 15-45 minutes, so consider adding vasopressor first
- Ideally, vasopressors may be weaned off while insulin infusion continues
- Titrations of up to 10 units/kg/hour have been described
- Maintain serum glucose 100-200 mg/dL, if able
- Glucagon has significant inotropic and chronotropic effects
- Glucagon activates adenylate cyclase and inhibits phosphodiesterase, which allows for increase in cAMP intracellularly and ultimately an influx of intracellular calcium
- Less of a role in CCB poisoning (no advantage over beta agonist therapy) and limited evidence in humans, but still can be considered
- Recommended dosing: 3-5mg IV initially over 1 to 2 minutes then if no improvement in 5 minutes, re-dose with 4-10mg.
- Can consider infusion of glucagon at the dose at which it was effective or up to 10 mg/hour
- Lipid Emulsion Therapy
- Thought to bind lipid soluble xenobiotics and lower the free serum concentrations of these compounds
- The quality of studies supporting intravenous lipid emulsion therapy for CCB poisoning are very low, and as such there are no dosage guidelines.
- Consider administration in the moribound patient in consultation with your local poison control center or on-call toxicologist
- Extracorporeal removal
- There is no data supporting extracorporeal removal as its use is limited due to the significant hemodynamic effects of CCB poisoning.
After speaking with toxicology, you decide to treat your patient with activated charcoal to decrease any continued absorption. You then decide to give 1mg of atropine for a total of two doses which increases your patient’s heart rate from the high 40s to the high 50s. Her blood pressure was unresponsive to the initial fluid bolus so you decide to start her on a norepinephrine drip at 20 mcg/min, give IV calcium gluconate, and start her on an insulin infusion at 1 unit/kg/hour while monitoring her glucose levels. Her cardiac output improved and there was no further escalation of care required. She is then admitted to the ICU for further management.
…. A few days later you check in on your patient and see that she was successfully discharged 2 days after admission as her vasopressors and insulin infusion were weaned. She had no further lab abnormalities from end organ ischemia and her creatinine corrected with improvement of her hemodynamic status. She was sent home with strict instructions on how to take her diltiazem!
- Nelson, L., Goldfrank, L. R, et al. (2011). Goldfrank’s Toxicologic Emergencies (9th ed.). New York: McGraw-Hill Medical. 884-890.
- Stanfield, Cindy L. (2011). Principles of Human Physiology (5th ed.). Pearson Education.