Pediatric Calcium Channel Blocker Toxicity Treatment & Management

When calling a poison control center, be prepared to give as much information as possible during the initial call. Estimate amount and type of drug ingested, elapsed time since ingestion, and time treatment was started. Many poison control centers make follow-up calls to offer additional management recommendations and learn patient outcomes; the physician can supply additional information at that time.

Patients with calcium channel blocker toxicity should be treated in a well-equipped emergency facility or an intensive care setting. Numerous strategies for treating patients who have ingested calcium channel blockers are available.^[6]

Basic supportive care is the first, and possibly most important, mode of management; address airway, breathing, and circulation (ABCs).

Correction of acid-base disturbances and electrolyte abnormalities is also important, to optimize cardiac function.

The asymptomatic, exploratory ingestion

In the case of an asymptomatic, exploratory ingestion, it is best to confer with your regional poison control center for monitoring guidelines. As described earlier, calcium channel blockers vary widely in their potency and onset and duration of action. Generally, significant exposure to immediate-release products requires clinical observation for 6 hours, while exposure to extended-release products requires 24-hour observation for signs and symptoms of toxicity.

In such circumstances, it is reasonable to administer activated charcoal (see below), given the high potential toxicity of calcium channel blockers.

Antiemetics

Ipecac syrup always is contraindicated in calcium channel blocker toxicity because the patient may rapidly lose consciousness and may develop seizures. The added vagal tone of emesis can also worsen cardiovascular status. For this reason, an antiemetic can be administered to prevent vomiting secondary to the initial calcium channel blocker ingestion.

Diet

Do not allow patients with calcium channel blocker toxicity to eat after the ingestion, because they risk rapid mental status deterioration, including seizures, and may require intubation.

Placement of an endotracheal tube when the patient has an empty stomach decreases the risk of aspiration. For these same reasons, do not administer ipecac syrup.

Activity

Orthostatic hypotension is a particular concern in patients who ingest calcium channel blockers. Limit the activity level of these patients to bed rest at the first clinical signs of calcium channel blocker toxicity.

Transfer

Some patients may present with overwhelming bradycardia and hypotension that is unresponsive to available medical management. Patients with these complications may require cardiopulmonary bypass, extracorporeal membrane oxygenation (ECMO), or an intra-aortic balloon pump to maintain peripheral perfusion until the calcium channel blocker has cleared their system; transferring these patients to a facility offering such services may be reasonable.

Not all community hospitals offer a pediatric intensive care unit (PICU) for inpatient care of the hemodynamically unstable child. This may also be an indication to transfer the patient.

Prevention

Parents should keep all medicine out of reach of children. Use childproof bottles for all medications, especially those that are potentially dangerous to youngsters.

Blood pressure can be augmented with isotonic sodium chloride solution or Ringer lactate solution. Both are efficient volume expanders. Deliver fluid in 20-mL/kg boluses, which may be repeated 1, 2, or even 3 times if the patient remains hypotensive.

If blood pressure normalizes with these fluid challenges, start intravenous (IV) fluid at 1-2 times the normal maintenance rate. If this does not raise the blood pressure to the desired level, positive inotropes (eg, dopamine, norepinephrine, epinephrine) can be added.

In patients with persistent hypotension, administering supplemental oxygen and placing them in the Trendelenburg position can help to perfuse the brain with well-oxygenated blood.

Gut decontamination may be considered because calcium channel blockers slow gastric motility and delay gastric emptying.

Activated charcoal

Activated charcoal has been demonstrated to significantly absorb immediate-release medications within 1 hour of ingestion and extended-release medications as long as 4 hours after ingestion.^[7] If the ingested dose is known, a 10:1 charcoal-to-drug weight ratio can be used to calculate the optimal dose of activated charcoal to completely bind the ingested drug.^[8] Otherwise, a 1-g/kg initial dose is recommended.

The potential benefit of decreased drug absorption must be weighed against the risk of gastric distention with subsequent aspiration. Any conditions predisposing to aspiration (eg altered mental status, nausea, seizures) are relative contraindications to administration of activated charcoal. In patients with severe toxicity, interventions such as antiemetics and intubation with satisfactory sedation should be performed prior to administration of activated charcoal.

Gastric lavage

Gastric lavage may be advisable. Lavage is especially important for patients who may have taken a large dose of medication or for those who have ingested sustained-release preparations.

However, the usefulness of gastric lavage is still debated. Weigh the risk of aspiration against the probability of removing undigested medications remaining in the stomach. An endotracheal tube cuff protects the airway during the lavage, thus placing patients at lower risk of aspiration by intubating them.

If a gastric lavage is performed, use a large-bore orogastric hose. Always consider airway protection with an endotracheal tube if there are concerns that the patient’s mental status presents a risk for aspiration.

Sustained-release tablets, which are large and resistant to breakdown, may not fit through a simple Salem sump nasogastric tube. A small tube diameter decreases the effectiveness of lavage.

Whole-bowel irrigation

If the child has ingested a large number of calcium channel blocker tablets, especially sustained-release tablets, consider whole-bowel irrigation with polyethylene glycol or a cathartic, such as sorbitol, which is included in some activated charcoal products. Under these circumstances, the pills may aggregate to form bezoars and can be continuously absorbed for long periods. Administer polyethylene glycol at a rate of 0.5 L/h for 4-6 hours or until rectal effluent becomes clear.

Note that whole-bowel irrigation is absolutely contraindicated if bowel sounds are absent. This suggests that an ileus, secondary to shock or drug toxicity, has occurred. In these circumstances, large volumes of fluid lead to massive bowel distention, risking bowel perforation.

Coadminister activated charcoal in a 1-g/kg initial dose; this administration can be repeated every 4 hours at half the initial dose. Because gastric emptying may be delayed, administer activated charcoal even if the patient presents well after the ingestion.

In children, care must be used not to administer a significant amount of sorbitol-containing products, because of the potential to induce electrolyte disturbances. Some package inserts recommend not using sorbitol-containing charcoal products in children who weigh less than 32 kg and recommend not using these products as multiple-dose agents.

Many pharmacologic therapies have been proven beneficial in calcium channel blocker toxicity. Intravenously administered calcium theoretically creates a concentration gradient large enough to partially overcome the channel blockade, driving calcium into the cells.

Calcium is usually administered intravenously as calcium gluconate or calcium chloride; either form is acceptable to manage calcium channel blocker overdose if an equal amount of ionized calcium is administered. Administer a calcium bolus if the patient is symptomatic at presentation. A high-dose IV bolus of calcium can be repeated, or a slow calcium infusion (eg 20-50 mg/kg/h) can be implemented if the response to the initial bolus begins to diminish. In cases of severe calcium channel blocker toxicity, serum calcium concentrations have been titrated to 1.5-2 times the upper limit of normal, leading to improved cardiac function.

Positive inotropes

Positive inotropes (eg, dopamine, epinephrine) stimulate myocardial contractility and cause vasoconstriction by activating adrenergic receptors on the cell membrane. These receptors then activate adenylyl cyclase to produce the second messenger, cyclic adenosine monophosphate (cAMP). This intracellular intermediary causes calcium to enter the cell and causes its release from the endoplasmic reticulum. Calcium then effects conformational changes to cellular machinery and initiates smooth and cardiac muscle contractions.

Glucagon

Other agents that raise intracellular cAMP levels indirectly cause an increased cellular response by promoting calcium entry into the cell. Glucagon, a polypeptide hormone, is thought to have a receptor that is separate from adrenergic receptors. Stimulation of this receptor is also believed to increase cAMP production.

Glucagon is supplied as a lyophilized powder and must be reconstituted. The manufacturer includes an ampule of propylene glycol that can be used for single injections. However, if an excessive amount is administered, propylene glycol (the same diluent that comes with phenytoin) causes hypotension and arrhythmias. For this reason, glucagon infusions and repeat doses should be reconstituted in 5% dextrose in water (D5W) to avoid administering large doses of propylene glycol. If a positive clinical effect is noted after an initial IV bolus dose of 5-10 mg, an infusion can be continued at 5-10 mg/h. Note that such high-dose usage of glucagon exhausts a typical hospital pharmacy’s supply within a few hours.

High-dose insulin therapy has become accepted as second-line therapy in calcium channel blocker toxicity refractory to standard vasopressor therapy.^[9] Because calcium channel blocker agents inhibit insulin production or release and decrease the ability of the heart to use free fatty acids, it seems intuitive that exogenous insulin administration would improve the clinical picture in calcium channel blockertoxicity. Animal models and numerous case reports and case series demonstrate that high-dose insulin is beneficial in calcium channel blockertoxicity by increasing inotropy, intracellular glucose transport, and vascular dilatation.

After one ampule of D50W has been given, an insulin bolus of 1 U/kg is given, followed by an infusion of 1-10 U/kg/h. Remarkably, when this therapy is used in calcium channel blocker toxicity, rarely is more supplemental dextrose necessary than a D5W infusion. However, one must always closely monitor serum potassium and glucose levels when using this treatment modality.

Note that 2 opposing hormones, such as insulin and glucagon, both have beneficial effects in treating calcium channel blocker toxicity.

Although the therapeutic efficiency of high-dose insulin has been effective in animal models, no human trial has been completed. One must always closely monitor serum potassium and glucose levels when administering high doses of insulin.

Lipid emulsion therapy (eg, Intralipid), now established as the definitive antidote for bupivacaine toxicity, is being studied for other overdoses. Its therapeutic effect is most commonly ascribed to the “lipid sink” theory, such that the lipid emulsion bolus sequesters lipophilic drugs from their target site, mitigating toxicity. Lipid emulsion therapy has been studied in a few animal models of verapamil toxicity, demonstrating increased survival.^{[10, 11]} A few case reports have found either clinical improvement^{[12, 13]} or significant drug sequestration.^[14] Because this drug is quite lipophilic, it is theoretically amenable to lipid emulsion therapy.^[15]

Clearly, although these studies have not definitely established the utility of lipid emulsion antidotal therapy in calcium channel blocker overdose, with no known adverse effects, it can be considered as a therapy of last resort. Currently, the American College of Medical Toxicologists states that “in circumstances where there is serious hemodynamic, or other, instability from a xenobiotic with a high degree of lipid solubility, lipid resuscitation therapy is viewed as a reasonable consideration for therapy, even if the patient is not in cardiac arrest.”^[16] A 20% lipid emulsion is administered initially as a 1.5-mL/kg bolus over 2-3 minutes, followed by an infusion of 0.25 mL/kg/min. The bolus may be repeated in patients who have recrudescent toxicity or cardiac arrest.

4-Aminopyridine or its more potent cousin 3,4-diaminopyridine increases calcium entry into the cell. Their exact mechanism is not fully understood, but they may indirectly promote calcium entry by blocking voltage-sensitive potassium channels. Although these medications have reversed verapamil toxicity in feline, canine, and rabbit experiments, their value and safety in human calcium channel blocker toxicity has not been established.

Levosimendan (Simdax, Abbott Pharmaceuticals) is an investigational drug in the United States that acts intracellularly to sensitize myocytes to calcium by binding to cardiac troponin C but that does not increase intracellular calcium.^[17] Therefore, it theoretically should help increase cardiac output while not altering the metabolic demands of the cell. It is thought to accomplish this by stabilizing the kinetics of actin-myosin cross-bridges. It also opens K+ channels, which leads to vasodilation, decreasing afterload to aid cardiac output in depressed myocardial states.

As with medical care for calcium channel blocker overdose, many surgical modalities can be used. A transvenous pacemaker may be placed if the transthoracic cutaneous pacer fails to capture in the face of symptomatic bradycardia. Pacing may decrease the need for pressors in a patient who may not tolerate a positive cardiac inotrope because of cardiac ischemia, although this likely is not a concern for pediatric patients. Cardiac pacing is typically required for 12-48 hours.

Consider temporary placement of an intra-aortic balloon pump for hypotension that is refractory to all other medical and surgical treatments.

Cardiopulmonary bypass can be a last resort to support the blood pressure long enough for the body to clear the ingested toxin.

Extracorporeal membrane oxygenation (ECMO) has also been attempted in patients who have hypotension refractory to all pharmacologic therapies. One case reported by Durward described a massive diltiazem ingestion (12 g Cardura CD) that resulted in prolonged cardiac standstill.^[18] However, after 48 hours of ECMO and 15 days in the critical care unit, the patient made a very good recovery and was discharged home "fit and well,” showing “no evidence of neurologic dysfunction."

Hemodialysis or charcoal hemoperfusion may provide a method of drug removal in cases of severe toxicity when the patient's condition appears to be worsening or if the ingestion is known to be large. Although calcium channel blockers are highly protein bound, some physicians believe that hemodialysis or charcoal hemoperfusion may be used as a last resort in severely toxic patients who have no other hope. These treatment modalities are debatable.

Many different specialists can help the physician to care for a patient who has ingested a calcium channel blocker.

A hemodynamically unstable child who has ingested a calcium channel blocker requires prolonged care in a PICU; arrange for consultation with this service soon after starting treatment in the ED. If the hospital does not have a PICU, transfer to a more specialized hospital should be considered sooner rather than later when severe toxicity has already developed.

Request consultation with a pediatric cardiologist to place a transvenous pacemaker if capture cannot be accomplished with transthoracic cutaneous pacing pads.

Even if the ED personnel do not need care advice for the patient with calcium channel blocker overdose, notify the hospital's regional poison control center to document the overdose characteristics and help create an accurate database for epidemiologic studies. In general, working in partnership with regional poison control centers on all ingestions is a good practice.

After any patient who has attempted suicide is medically stable, request a psychiatric consultation.