Emergent Management of Calcium Channel Blocker Toxicity 

  • Author: B Zane Horowitz, MD, FACMT; Chief Editor: Asim Tarabar, MD   more...
 
Updated: Feb 1, 2012
 

Overview

Calcium channel blocker (CCB) toxicity is rapidly emerging as one of the most lethal prescription drug ingestions; therefore, understanding the emergent management of such cases is essential.

In 1996, the American Association of Poison Control Centers (AAPCC) reported 8555 exposures to CCBs resulting in 58 fatalities and 225 major outcomes; 2,299 of the 8,555 exposures (27% of reported cases) occurred in children younger than 6 years.[1] In 2008, the AAPCC reported 10,398 exposures to CCBs, resulting in 12 deaths and 63 major outcomes; 1,430 of the 10,398 exposures (13.7% of reported cases) occurred in children younger than 6 years.[1] Unfortunately, the past decade has seen only a minimal decline in the percentage of pediatric exposures to CCBs of all cases called to Poison Centers nationally.[2, 3, 4, 5, 6]

These drugs are used to treat angina, hypertension, arrhythmias, and prevention of migraines. However, overdose by immediate-release (IR) CCB agents is characterized by rapid progression to hypotension, bradyarrhythmias, and cardiac arrest. Overdose by extended-release (ER) formulations can result in delayed onset of arrhythmias, shock, sudden cardiac collapse, and bowel ischemia.[7]

See also Pediatric Calcium Channel Blocker Toxicity.

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CCB Dosages - Hospital Evaluation

The American Association of Poison Control Centers (AAPCC) consensus panel recommends that patients who ingested the following amounts of calcium channel blockers (CCBs) should be evaluated in the hospital (co-ingestants must be taken into account; these amounts assume an isolated unintentional  ingestion of only the calcium blocking medication)[8] :

Table 1. Recommendations for In-hospital Evaluation Based on Drug and Dosage of Calcium Channel Blocker Ingested (Open Table in a new window)

DrugAdult DosagePediatric Dosage
Amlodipine>10 mg>0.3 mg/kg
Bepridil>300 mgAny amount
Diltiazem>120 mg immediate release formulation; >360 mg sustained release formulation>1 mg/kg
Felodipine>10 mg>0.3 mg/kg
Isradipine>20 mg>0.1 mg/kg
Nicardipine>40 mg immediate release; >60 mg sustained release>1.25 mg/kg
Nifedipine>30 mg immediate release; >120 mg sustained releaseAny amount
Nimodipine>60 mgAny amount
Nisoldipine>30 mgAny amount
Verapamil>120 mg immediate release; >480 mg sustained release>2.5 mg/kg
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Treatment Considerations

Calcium channel blocker (CCB) blood levels are generally not available with any reasonable turnaround time. Treatment must be instituted based on symptoms. Blood levels can be used to confirm elevated levels if the diagnosis is in doubt.[9, 10]

Initiate early high-insulin/glucose therapy for the treatment of severe CCB overdose.

Before administration of activated charcoal or glucagon in a patient, protect the patient's airway to prevent vomiting and aspiration.

Aggressively decontaminate the patient after an extended-release (ER) formulation overdose. In addition, extended-release tablets have a delayed onset of up to 12 hours; releasing a patient who has ingested an extended-release tablet too soon places them in jeopardy.

Consult an American Association of Poison Control Centers (AAPCC)–certified regional poison control center, with a specific request to speak directly to their medical toxicologist, in all cases to assist in management, because several options for treatment exist and each case is unique.

Special concerns

Bepridil is a unique CCB with antiarrhythmic activity. It is also proarrhythmic, even at therapeutic doses, and may cause torsade de pointes.

Mibefradil, which was taken off the market in 1998, was associated with profound cardiogenic shock and fatality when switching to another CCB after stopping mibefradil.[11, 12, 13]

Avoid administering calcium gluconate or calcium chloride to a patient with concomitant cardiac glycoside (eg, digoxin) toxicity as this may induce fatal arrhythmias.

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Prehospital Management

Establish the patient's airway, breathing, and circulation (ABCs), obtain intravenous (IV) access, provide oxygen, and monitor closely.

Rapid transport before the patient with calcium channel blocker (CCB) toxicity deteriorates is crucial. Empiric use of glucagon (adults: 5-15 mg IV) may be warranted for patients with an unknown overdose presenting with bradycardia or hypotension.

Consider using calcium only if a witness confirms a CCB overdose; calcium may induce fatal arrhythmias in digoxin overdose, which can present with similar findings.

Atropine may be tried if hemodynamically significant bradycardia occurs; however, heart block is usually resistant to atropine in CCB toxicity. Mid-dose dopamine (5-10 mcg/kg/min) may improve heart rate and contractility.

Treat hypotension with fluid boluses of normal saline if no evidence of decompensated congestive heart failure (CHF) exists. Administer IV calcium gluconate (up to 4 g) or IV calcium chloride (1g) and/or glucagon (5-10 mg) if hypotension persists.[8] If profound hypotension fails to respond to fluid resuscitation and/or if a long transport time is likely, administer a dopamine or norepinephrine drip, if permitted by local prehospital care protocols.

If the patient deteriorates to cardiac arrest from a CCB overdose, perform prolonged cardiopulmonary resuscitation (CPR) in the field, because patients have survived neurologically intact after 1 hour of CPR.

Avoid ipecac syrup.[8] Administer activated charcoal (AC) if the patient's airway is protected.

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Emergency Department Management

Aggressive cardiovascular support is necessary for managing the massive calcium channel blocker (CCB) overdose. Although calcium (gluconate or chloride) in high doses (4-6 g) may overcome some of the adverse effects of CCBs, it rarely restores normal cardiovascular status. According to many case reports, glucagon and inamrinone (formerly amrinone) have been used with good results. However, vasopressors are frequently necessary for adequate resuscitation and should be started early if hypotension occurs. Additional basic overdose management includes airway protection, gastric lavage, and activated charcoal.

Gastric decontamination

Gastric lavage may be useful in early presentations (< 1-2 h postingestion), especially in cases of extended- or delayed-release tablet ingestion.[14]

Activated charcoal (AC) (50-100 g orally [PO]) should be administered after gastric lavage.

Completely asymptomatic patients may be treated with activated charcoal and close observation.

Whole-bowel irrigation with polyethylene glycol solution (eg, GoLYTELY, NuLytely, Colyte) may be useful in extended-release preparations. However, be sure that ileus, bowel obstruction, and bowel ischemia have not occurred; case reports of bowel ischemia and infarction have appeared with CCB overdose.[15, 16, 17, 18, 19, 20]

Medications

Glucagon, calcium chloride and calcium gluconate, vasopressors, inamrinone, and insulin and glucose are discussed below.

Hypotension

Administer glucagon (5-10 mg intravenous [IV] bolus up to 15 mg), followed by an infusion after fluid resuscitation is performed for persistent hypotension. If an initial bolus of 5 mg has no effect on blood pressure, it is reasonable to double the dose. The recommended infusion rate for adults is 3-5 mg/h. The recommended pediatric dose is 50 mcg/kg IV over 5 minutes, followed by an infusion at 0.07 mg/kg/h.[21, 22, 23, 24, 25, 26, 27, 28]

Calcium chloride (1-4 g IV; preferably via central line, slowly) can be administered for hypotension or heart block.[19, 29, 30]

Thirty milliliters (30 mL) of 10% calcium gluconate can be administered IV over 10-15 minutes in adults. Boluses may be repeated every 15-20 minutes for a total of 3 doses. After the third bolus, the ionized calcium level should be checked. The recommended pediatric dose of calcium gluconate is 60 mg/kg, with a maximum dose of 1 g.[31, 32]

Cardiac output

Vasopressor support to maintain blood pressure and cardiac output is critical. In the hypotensive patient, administer dopamine initially at medium to high doses early for cardiac contractility for heart rate support. Failure to respond to the maximal dose of dopamine should prompt the addition of norepinephrine for blood pressure support. Various combinations of dopamine, norepinephrine, epinephrine, phenylephrine, vasopressin, and metaraminol have all been used in cases of hypotension and shock.[7, 26, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46]

Inamrinone, a phosphodiesterase inhibitor with inotropic activity, may be of additional benefit in profound cardiac contractile failure.[27, 40, 47]

Hypoglycemia and cardiac output

Hyperglycemia may occur as calcium channel blockade inhibits insulin release.[48, 49, 50, 51] In multiple case reports, high-dose insulin infusion (0.1-1 U/kg/h) with dextrose infusion (usually D10W-D25W) to maintain normal serum glucose levels have been successful for stabilizing cardiac output.[14, 39, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64] When using this technique, frequent monitoring of glucose and potassium every 20-30 minutes is necessary. Due to delayed onset of action, high-dose insulin/glucose therapy should be started earlier in the course of disease.

Potential therapies

Anecdotal efficacy of cardiopulmonary bypass exists,[65, 66] plasma exchange,[67] and continuous renal replacement techniques with hemodiafiltration[68] have each been used in cases of severe poisoning resistant to aggressive medical treatments, such as patients failing glucagon and norepinephrine infusions.[65, 66, 67, 68] Hemoperfusion has had little efficacy.[69]

A patient developing acute respiratory distress syndrome (ARDS) was successfully treated with partial liquid ventilation; however, this procedure is no longer available.[70]

Methylene blue, a novel experimental treatment in shock, has been used in one case of amlodipine overdose.[71]

Use of Intralipid infusion to trap the lipid soluble CCBs in the plasma and prevent it from penetrating cardiac tissue has been used in some limited case reports.[72, 73, 74]

Data are emerging for use of fat emulsion as an antidote for cardiac toxicity of drugs with high lipid solubility.[75] Levosimendan, a unique inotropic agent that enhances contractility by improving available cytosolic calcium has been used in 2 cases.[76]

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Continued ED Management vs Admission

If the patient is hemodynamically stable, observation may occur in observation units if available to the emergency department (ED). Adequate intensive care unit (ICU) capabilities must be present in the observation unit, because these patients may require intubation, pacemaker placement, or vasopressor support.

Only asymptomatic ingestions should be watched in an observation unit, and if cardiodepressive symptoms occur, transfer the patient to an ICU setting capable of advanced cardiac life support (ACLS), including intubation and pacing.

Admit all ingestions to ICU monitoring for 6-12 hours in cases of standard-release preparation overdose and for 24-36 hours in cases of extended-release or once-a-day preparation overdose.[77, 44, 78]

After an adequate observation time, the asymptomatic patient may be referred for psychiatric evaluation.

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Contributor Information and Disclosures
Author

B Zane Horowitz, MD, FACMT  Professor, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System

B Zane Horowitz, MD, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Specialty Editor Board

David C Lee, MD  Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD  Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

John G Benitez, MD, MPH  Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD  Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

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Table 1. Recommendations for In-hospital Evaluation Based on Drug and Dosage of Calcium Channel Blocker Ingested
DrugAdult DosagePediatric Dosage
Amlodipine>10 mg>0.3 mg/kg
Bepridil>300 mgAny amount
Diltiazem>120 mg immediate release formulation; >360 mg sustained release formulation>1 mg/kg
Felodipine>10 mg>0.3 mg/kg
Isradipine>20 mg>0.1 mg/kg
Nicardipine>40 mg immediate release; >60 mg sustained release>1.25 mg/kg
Nifedipine>30 mg immediate release; >120 mg sustained releaseAny amount
Nimodipine>60 mgAny amount
Nisoldipine>30 mgAny amount
Verapamil>120 mg immediate release; >480 mg sustained release>2.5 mg/kg
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