What is the management of calcium channel blocker (CCB) overdose?

From the Guidelines

The management of calcium channel blocker (CCB) overdose should prioritize the administration of high-dose insulin therapy, alongside IV calcium and vasopressors like norepinephrine, as first-line treatments to address hypotension, bradycardia, and cardiogenic shock. For asymptomatic patients, observation and consideration of decontamination following a potentially toxic CCB ingestion is recommended 1. In cases of CCB-induced shock, vasopressor therapy, most commonly norepinephrine, has demonstrated excellent survival rates with low rates of ischemic complications 1. High-dose insulin administration improves inotropy in patients with severe cardiogenic shock from CCB poisoning, with favorable outcomes and lower rates of vasoconstrictive complications than vasopressor-only therapy 1.

Key considerations in the management of CCB overdose include:

• Administering IV calcium (calcium chloride 1g or calcium gluconate 3g) to overcome channel blockade 1
• Initiating vasopressors like norepinephrine (starting at 0.1-0.5 mcg/kg/min) or epinephrine for persistent hypotension 1
• Using high-dose insulin therapy, starting with a 1 unit/kg bolus followed by 0.5-1 unit/kg/hour infusion, alongside glucose monitoring and supplementation 1
• Considering glucagon (5-10mg IV bolus, then 1-5mg/hour infusion) to increase cardiac contractility, although response rates are variable 1
• Using venoarterial extracorporeal membrane oxygenation (VA-ECMO) for patients with refractory cardiogenic shock after CCB overdose, with reported survival rates as high as 77% 1

It is essential to note that the use of lipid emulsion therapy (ILE) has not been found to be beneficial in CCB poisoning 1, and its use should be reconsidered in favor of other treatments. Methylene blue may be effective in treating refractory vasodilatory shock, but responses are mixed, and effects may be transient 1. Atropine is commonly used for bradycardia but may not always be effective 1. Electrical pacing may be reasonable for patients with hemodynamically significant bradydysrhythmias, but it is not always effective 1.

From the FDA Drug Label

The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg. The toxic dose in man is not known Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases. There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered: Bradycardia: Administer atropine (0.60 to 1. 0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously. High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing. Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics. Hypotension: Vasopressors (e.g., dopamine or norepinephrine).

Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially verapamil hydrochloride extended-release), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation Verapamil is known to decrease gastrointestinal transit time. In overdose, tablets of verapamil hydrochloride extended-release have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 g/hour for more than 24 hr) of calcium chloride. Verapamil cannot be removed by hemodialysis Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation.

The management of calcium channel blocker (CCB) overdose includes:

• Supportive care: monitoring, gastrointestinal decontamination, and treatment of symptoms
• Bradycardia: administration of atropine (0.60 to 1.0 mg) or isoproterenol
• High-Degree AV Block: treatment with atropine or cardiac pacing
• Cardiac Failure: administration of inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics
• Hypotension: treatment with vasopressors (e.g., dopamine or norepinephrine)
• Calcium administration: intravenous calcium chloride or calcium gluconate may be effective in reversing the pharmacological effects of CCB overdose, but its effectiveness is inconsistent 2 3
• Monitoring: patients should be monitored for signs of hypercalcemia and other complications Key considerations in the management of CCB overdose include:
• The toxic dose in humans is not known
• Blood levels after a standard dose can vary over tenfold, limiting the usefulness of blood levels in overdose cases
• Most reports of overdose described some supportive medical measure and/or drug treatment
• Treatment should be individualized based on the severity of the clinical situation and the judgment and experience of the treating physician 2 3

From the Research

Management of Calcium Channel Blocker Overdose

The management of calcium channel blocker (CCB) overdose involves various treatment approaches, including:

• Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products 4
• Administration of calcium salts, which may be given in bolus doses or as a continuous infusion 4, 5
• High-dose insulin euglycemia therapy (HIET), which has been used effectively to increase cardiac inotropy and survival 6, 4, 7, 5
• Glucagon administration, which has been tried and has been successful in some cases 6, 4
• Vasopressors, which may be used to support blood pressure 4, 5
• Phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump, or extracorporeal bypass, which may be indicated if antidotal therapy is not effective 4
• Levosimendan, a calcium sensitizer, which has been used in severe CCB poisoning 8

Supportive Care

Supportive care is crucial in the management of CCB overdose, including:

• Large volumes of IV fluids 7
• Cardiac monitoring 4, 5
• Electrocardiogram and a period of observation for asymptomatic patients 4
• Observation in a monitored setting for 12 hours for patients ingesting a nonsustained-release product, and for no less than 24 hours for those ingesting a sustained-release preparation 4

Patient Evaluation and Assessment

Initial patient evaluation and assessment are crucial to identify the severity of CCB toxicity and design the best management strategy 7