Pediatric patients with calcium channel blocker toxicity should be treated in a well-equipped emergency facility or in an intensive care setting. Numerous strategies for treating patients who have ingested calcium channel blockers are available. Among the most widely prescribed drugs in America, these calcium channel blockers are marketed under many brand names and many doses in many colors. They look appealing to children, resembling candy, and are found in many households; therefore, unintentional ingestion of calcium channel blockers is common. (See Etiology and Epidemiology.)
Calcium channel blockers include ultralong-acting medications and sustained-release forms of existing preparations. As of December 2011, 9 drugs in 3 classes in multiple immediate and sustained-release preparations were available in the United States. These classes are as follows (see Etiology and Treatment):
Diphenylalkylamines (eg, verapamil) - These agents poison the atrioventricular (AV) node and peripheral vasculature equally
Benzothiazines (eg, diltiazem) - These agents are more chronotropic than vasoactive
Dihydropyridines (eg, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine) - These agents primarily affect the peripheral vasculature, while cardiac toxicity may be observed in overdose
These medications have different onsets of action, and many are available in sustained-release forms, which complicates the physician's decision regarding the most appropriate time to release patients with calcium channel blocker ingestion. (See Presentation and Workup.)
The current range of indications for calcium channel blockers is broad. Although most of the disease processes that respond to calcium channel blockers affect adults, pediatricians have used calcium channel blockers to treat children with congenital heart malformations, arrhythmias, hypertension, subarachnoid hemorrhage, and/or congestive heart failure.
Physiology
Calcium channel blockers function by binding to the L-subtype, voltage-sensitive, slow calcium channels in cell membranes. This binding decreases the flow of calcium into the cell, which leads to an inhibition of the phase 0 depolarization in cardiac pacemaker cells and causes the phase 2 plateau of Purkinje cells, cardiac myocytes, and vascular smooth muscle cells. Some calcium channel blockers may also demonstrate weak cross-reactivity with fast sodium channels, partially blocking these voltage-gated ion pores, which are responsible for rapid membrane depolarization. (See the image below.)
View Image
Calcium channel blocker.
Different calcium channel blockers work by slightly different mechanisms. Nifedipine likely "plugs" the slow calcium channel, whereas drugs such as diltiazem and verapamil are use-dependent. That is, they interact with the calcium channel after it has been depolarized to its inactivated recovery state.
Each calcium channel blocker has a certain degree of tissue specificity, but the drugs do have common properties. Calcium channel blockers are all absorbed early in the gastrointestinal (GI) system, are substantially bound by plasma proteins, and are predominantly metabolized by the liver. Therefore, impaired renal function should not alter calcium channel blocker metabolism.
Complications
Complications relating to calcium channel blocker toxicity include the following (see Prognosis, Treatment, and Medication):
Seizure
Coma
Death
Anoxic encephalopathy from prolonged central nervous system (CNS) hypoxia
Ileus
Bowel infarction or perforation from mesenteric hypotension
Noncardiogenic pulmonary edema
Aspiration pneumonia
Patient education
Educate parents who take calcium channel blocker medications about child safety. All homes should have the number of the national poison control center (800-222-1222) posted on or near their telephones for use in an emergency. Calling this number connects the caller to his or her regional poison control center.
As previously mentioned, calcium channel blockers are some of the most widely prescribed drugs in America. They are marketed under many brand names and many doses in many colors. Because they look appealing to children, resembling candy, and are found in many households, unintentional ingestion of these drugs is common.
Verapamil
Verapamil (Calan, Isoptin), a phenylalkylamine, has a higher affinity for calcium slow channels in the cardiac conducting system than in peripheral smooth muscle cells; therefore, it causes a greater negative inotropic effect than do other calcium channel blocker agents. Several sustained-release formulations are available (eg, Calan SR, Isoptin SR, Verelan, Covera HS).
Patients who ingest any of these preparations should be observed longer than those who consume other preparations to guard against a delayed onset of toxicity. Verapamil almost exclusively undergoes hepatic metabolism, yielding a single active metabolite, norverapamil. This compound has 20% of the pharmacologic activity of the parent drug.
Nifedipine
Nifedipine (Procardia, Procardia XL, Adalat, Adalat CC) is a dihydropyridine. Nifedipine has relatively high affinity for the calcium channels in the smooth muscle cells of vascular tissue and causes little to no AV nodal interference. The primary manifestation of nifedipine-related toxicity is hypotension secondary to loss of systemic vascular resistance. This agent has no active metabolites after hepatic metabolism and attains peak drug levels 2-6 hours after ingestion.
Nicardipine and nimodipine
Nicardipine (Cardene, Cardene SR) and nimodipine (Nimotop) are similar to nifedipine, although they demonstrate greater peripheral vascular smooth muscle effects. The selectivity of nimodipine is directed at the cerebral vasculature because of its high lipid solubility and ability to cross the blood-brain barrier. Nimodipine has been approved for use in the treatment of cerebral ischemia after subarachnoid hemorrhage. Nicardipine and nimodipine may have small, negative inotropic effects. These compounds are predominantly metabolized by the liver. They do not exhibit a large first-pass effect, as is observed with other calcium channel blockers.
Diltiazem
Diltiazem (Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Teczem, Tiazac) has properties from the drug categories mentioned above. Although diltiazem demonstrates an affinity for cardiac conductive tissues and vascular smooth muscle cells, its clinical response more closely resembles that of verapamil than of nifedipine. Diltiazem mainly undergoes hepatic metabolism with a large first-pass effect that may differ from patient to patient. Its peak plasma concentration in non–sustained-release preparations is 2-8 hours.
Amlodipine
Amlodipine (Norvasc) has a long half-life of 30-58 hours.[1] Clinical effects of amlodipine are similar to those of nicardipine. Because of its long effect time, amlodipine ingestion increases the risk of morbidity and mortality.
Felodipine
Felodipine (Plendil), another dihydropyridine, is highly protein bound and exhibits a half-life of 11-16 hours. Because of the protein binding, the drug’s elimination is prolonged. Because of its hypotensive effect, felodipine causes a reflex tachycardia.
Isradipine
Isradipine (DynaCirc) is similar to felodipine but with a smaller volume of distribution and half-life of 8 hours.
Nisoldipine
Nisoldipine (Sular) elicits predominantly hemodynamic effects and decreases systemic vascular resistance and blood pressure.
Bepridil
Bepridil (Vascor) is a unique calcium channel blocker with some sodium channel blocking activity. It is used for refractory angina and may prolong the QT interval corrected for heart rate (QTc) through a potassium channel blocking effect. Similar to other drugs with this property, Bepridil can cause torsades de pointes. Bepridil is no longer available in the United States.
Sales of calcium channel blockers have increased over the last decade. Increased availability in the home has led to an increase in the number and severity of calcium channel blocker ingestions by children.
Occurrence in the United States
According to the American Association of Poison Control Centers (AAPCC), of the nearly 3 million exposures logged in 2007, 5,027 of these cases were single or primary exposures to calcium channel blockers.[2] Approximately 1,519 (30%) of the calcium channel blocker exposures occurred in children younger than 6 years, and 274 (5.5%) occurred in children aged 6-19 years.[2]
Race-, sex-, and age-related demographics
Although calcium channel blocker ingestion has no race predilection among young children, racial trends mirror suicide attempt statistics among adolescents.
Among young children, a male predilection for calcium channel blocker toxicity is observed. In adolescence, the sex predilection again mirrors suicide attempt statistics, with more female adolescents ingesting calcium channel blocker agents than male adolescents.
Calcium channel blocker ingestions show a bimodal distribution in the pediatric age range. Infants and toddlers often unintentionally ingest tablets that they mistake for food or candy. Teenagers ingest calcium channel blocker agents as a suicide gesture.
Prognosis in calcium channel blocker toxicity depends on the following:
Amount and formulation of drug ingested
Co-ingestions
Patient's age
Time elapsed before treatment begins
Underlying disease states
Specific treatments
Initial rhythm
Use of a pacemaker and time before it is placed
Morbidity and mortality
In 2009, calcium channel blockers resulted in 16 (0.3%) fatalities and 62 (1.2%) major poisonings among the 5,027 individuals primarily exposed to calcium channel blockers. The single pediatric fatality was a 16-year-old who intentionally ingested verapamil.[2]
Koren reviewed the literature and considered sustained-release calcium channel blockers to be one of the medications considered to be lethal to infants with the ingestion of a single pill.[3] Therefore, whenever a physician or parent suspects that a child has taken a calcium channel blocker, aggressive treatment in a well-equipped hospital setting should be rapidly initiated.
Whenever a patient presents with bradycardia, hypotension, and an altered mental status, gather a short and AMPLE (ie, allergies, medications, past medical history, last meal, and events of the incident) medical history.
If the patient ingested medications, ascertain type, dose, and number or amount. Determine the number of tablets that are missing from the bottle of medicine ingested by the patient. If the number of pills in the bottle at the time of the ingestion is unknown, determine the number of pills that the bottle initially contained (ie, the maximum number of pills the child could have taken).
Ascertain whether the ingestion is a sustained-release preparation. Ask the patient's family members what medications they are taking, because these are most likely the substances that the patient ingested.
Finally, try to determine the time between the ingestion and presentation to the emergency department (ED), because this interval provides an indication of how long the pharmaceuticals have had to be absorbed in the patient's digestive system.
If a suicide attempt is suspected, try to determine whether other medications or alcohol could have been co-ingested. Acetaminophen or aspirin ingestion is especially important to determine because both have known medical treatment modalities.
When calcium channel blocker ingestion is suspected, specifically question the patient or family about cardiac or pulmonary manifestations of calcium channel blocker toxicity.
Other questions to answer include the following:
Did the patient exhibit chest pain, diaphoresis, flushing, palpitations, weakness, peripheral edema, dyspnea, or cough
Does the patient exhibit any signs of CNS involvement
Does the patient have a history of drowsiness, confusion, seizure, dizziness, headache, tremor, nausea, vomiting, or syncope
Pay particular attention to the cardiac, vascular, and neurologic examinations because calcium channel blocker toxicity manifests most physical findings in these systems. According to one study, maximal elapsed time to onset of symptoms ranged from 3 hours (seen with normal preparations) to 14 hours (in the setting of sustained-release medications).[4] These onset times should be considered when discharging patients home who may or may not have ingested calcium channel blockers.
Begin the physical examination of the patient who has ingested an unknown amount of a calcium channel blocker by checking vital signs. The heart rate may be decreased if the sinoatrial (SA) node is poisoned or may be increased if the patient is experiencing reflex tachycardia secondary to peripheral vasodilation and hypotension. Hypotension may last up to 24 hours with some sustained-release, long-acting medications.
When examining the head, eyes, ears, nose, and throat, ensure that the patient's pupils are equal, round, reactive to light, and not pinpoint. Specifically look for signs of focal neurologic deficits.
A detailed, 6-part neurologic examination should be performed, and the findings should be documented. With the exception of nimodipine, calcium channel blockers have poor CNS penetration. Therefore, drowsiness, seizures, or altered mental status in the absence of hemodynamic collapse should alert the physician to the possibility of co-ingestions.
Examine the abdomen, paying particularly close attention to the right upper quadrant. With calcium channel blocker toxicity, venous congestion can lead to hepatic engorgement and stretching of the hepatic capsule, causing hepatic tenderness and hepatomegaly. Hepatojugular reflux may also be observed. Listen for bowel sounds because calcium channel blockers may cause enteric dysmotility. Bowel perforation secondary to calcium channel blocker ingestions has been reported. Peritoneal signs of rebound and guarding are ominous findings.
Hyperglycemia may result from impaired insulin release in addition to insulin resistance. Although beta-antagonist toxicity may resemble calcium channel blocker toxicity in most aspects of the physical examination, the serum glucose level may help to identify which cardiovascular toxin was ingested, because beta antagonists often lower the glucose level.
Levine et al retrospectively analyzed 40 nondihydropyridine overdoses and found that the severity of toxicity correlated directly with the degree of hyperglycemia. For patients requiring temporary pacemaker placement or vasopressor support compared with those who did not, median initial serum glucose concentrations were 188 mg/dL (interquartile range, 143.5-270.5 mg/dL) and 129 mg/dL (98.5-156.6 mg/dL), respectively. The median peak serum glucose concentrations for those 2 groups were 364 mg/dL (267.5-408.5 mg/dL) and 145 mg/dL (107.5-160.5 mg/dL).[5]
Look for hyperglycemia, hypokalemia, and a decreased serum bicarbonate level secondary to acidosis in patients with suspected calcium channel blocker toxicity. Obtain a baseline calcium level before intravenously administering calcium, unless the patient requires immediate detoxification due to severe poisoning. Other tests that can be performed include the following:
Arterial blood gas - Consider this test in severely affected patients; in patients with significant toxicity, arterial blood gases can be used to assess the acid-base status and respiratory function
Aspirin level - Determine the aspirin level of all patients who present to the ED after a suicide attempt
Acetaminophen level - Determine the acetaminophen level of all patients who present to the ED after a suicide attempt
Urine toxicology - Positive screening testing may suggest significant co-ingestants such as opiates
Determining the serum drug level of the ingested medication quickly enough to assist clinical decision-making is rarely feasible unless you have immediate access to a research laboratory.
Foley catheter placement
This may be indicated to monitor urine output in severely poisoned patients.
Imaging studies
An abdominal flat plate may be obtained if a co-ingestion with a radio-opaque tablet is also suspected.
Electrocardiography (ECG) is neither sensitive nor specific for calcium channel blocker toxicity. Even so, ECG should be performed in all patients who present to the ED who may have ingested any cardiac medication. Toxicity from calcium channel blockers may manifest as bradycardia; tachycardia; first-, second-, or third-degree AV block; any type of bundle-branch block; and/or nonspecific ST-T wave changes.
Electrocardiography should also be evaluated for signs of tricyclic antidepressant (TCA) overdose. This results in a positive deflection in the augmented voltage unipolar right arm lead (aVR) in the terminal 40 microseconds of the complex. TCA toxicity can rapidly progress to malignant arrhythmia if left untreated.
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 (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.
Initial management for a symptomatic calcium channel blocker overdose includes cardiovascular support with IV fluids and positive inotropy. (In addition, always use basic GI decontamination in overdose situations.) Calcium administration can partially overcome channel blockade and, in all but the most severe cases, should improve the clinical condition. By increasing intracellular cAMP concentrations, glucagon also reportedly improves blood pressure and heart blockade.
High-dose insulin has been recently established as an effective therapy for calcium channel blocker overdose. Lipid emulsion therapy may be beneficial and should be considered in the patient in extremis, refractory to all other treatment modalities. Newer agents, such as levosimendan, are also showing promise in the treatment of this occasionally fatal ingestion.
These agents theoretically increase calcium's concentration gradient, overcoming the channel blockade and driving calcium into the cells. Calcium is given to reverse hypotension and improve cardiac conduction defects.
Clinical Context:
Norepinephrine stimulates beta1- and alpha-adrenergic receptors, which, in turn, increase cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases. Mix 4 mg in 500 mL D5W to yield 8 mcg/mL.
Clinical Context:
Epinephrine has alpha-agonist effects, which include causing increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. The drug's beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects. Mix 1 mg in 250 mL D5W to yield 4 mcg/mL.
Clinical Context:
Dopamine activates dopamine receptors first, then beta1 receptors, and then alpha1 receptors. A low dose of 0.5-3 mcg/kg/min activates dopamine receptors and causes splanchnic vasodilation. An intermediate dose of 3-7.5 mcg/kg/min activates beta1 receptors, increasing cardiac inotropy and chronotropy. High doses of 7.5 mcg/kg/min or greater activate alpha1 receptors, causing vasoconstriction.
Doses of greater than 20 mcg/kg/min are unlikely to produce additional effects; therefore, the addition of a second agent (eg, norepinephrine) is probably indicated at that time. Mix 400 mg of dopamine in 250 mL D5W to yield 1600 mcg/mL.
These agents augment blood pressure by stimulating dopamine, alpha-adrenergic receptors, and beta-adrenergic receptors. This extracellular effect is transduced across the cell membrane and activates adenylyl cyclase in the cell to form cAMP. The activation induces calcium inflow from the endoplasmic reticulum and the extracellular space, which initiates muscle cell contraction. Sympathomimetics lead to vasoconstriction and increased cardiac inotropy, chronotropy, and dromotropy.
Clinical Context:
Glucagon binds to a specific cell surface receptor found on cardiac myocytes and stimulates adenyl cyclase via G proteins. This results in the release of intracellular cAMP, thereby increasing phosphorylation of L-type calcium channels and calcium influx into cells.
One study showed that glucagon performed its action on cardiac function best in a normocalcemic environment. Mix glucagon with 0.9% sodium chloride (NaCl) to yield 1 mg/mL (1 U = 1 mg); do not use the diluent (propylene glycol) supplied with the single-dose ampule.
Glucagon uses a different receptor than that used by sympathomimetics to stimulate intracellular cAMP production, increasing cardiac conduction and contractility. Glucagon has positive inotropic and chronotropic effects, which may be useful for treating bradycardia caused by calcium channel blockers.
Atropine, an anticholinergic medication, works by blocking muscarinic acetylcholine receptors. Use of this drug theoretically lets the sympathetic characteristics of the autonomic nervous system prevail over the parasympathetic system. This action includes vasoconstriction and increased cardiac inotropy and chronotropy.
Clinical Context:
Calcium channel blockers inhibit the production of islet cells and the secretion of insulin and block free fatty acid uptake by the heart muscle. High-dose insulin may augment myocyte uptake of glucose during times of stress induced by calcium channel blocker overdose. Insulin's action provides additional metabolic support to improve cardiac contractility.
Case reports of patients treated with high-dose insulin are beginning to support the use of this drug in calcium channel blocker toxicity. Insulin increases cardiac output and may increase survival as long as plasma glucose levels are monitored and supplemented with exogenous dextrose. To date, no prospective human trials have been published supporting this practice.
Clinical Context:
Activated charcoal is used in emergency treatment for poisoning caused by drugs and chemicals. A network of pores adsorbs 100-1000mg of drug per gram. Activated charcoal does not dissolve in water. Administer it as soon as possible after poison ingestion. Repeated doses may help to lower systemic levels of ingested compounds, especially sustained-release preparations. Activated charcoal is usually administered with sorbitol in alternating doses.
Clinical Context:
Lipid emulsion therapy is used in the emergency treatment of severe toxicity from highly lipid-soluble drugs. It is the antidote of choice for bupivacaine cardiotoxicity and is currently being investigated across other poisonings. Its primary mode of action is as a "lipid sink," sequestering lipid-soluble drugs from their target sites. Some research suggests that it provides a direct inotropic effect by activating myocyte calcium channels. No adverse effects from this modality have been reported. Although still under active investigation, lipid emulsion therapy should be considered in calcium channel blocker poisonings in patients in extremis who are refractory to all other therapies.
Activated charcoal adsorbs ingested medication remaining in the GI system and creates a concentration gradient to "pull back" medication circulating in the blood stream. Cathartics increase GI transit time. Lipid emulsion therapy sequesters highly lipid-soluble drugs from target sites.
Clinical Context:
Polyethylene glycol is a bowel irrigation solution with electrolyte and osmotic effects that has cathartic actions in the GI tract. It increases bowel transit time and interrupts enterohepatic circulation, yet it causes minimal net water and electrolyte shifts.
Clinical Context:
Fampridine is a potassium channel blocking agent that is under investigation in the United States for various neurologic and neuromuscular disorders. It increases acetylcholine release at the neuromuscular junction and CNS. However, fampridine has not been proven in human studies to increase survival after calcium channel blocker ingestion. It probably should not be used in calcium channel blocker toxicity until it has been more thoroughly researched.
Clinical Context:
This potassium channel blocking agent is under investigation in the United States for variety of neurologic and neuromuscular disorders. It increases acetylcholine release at the neuromuscular junction and CNS. The medication is used as an orphan drug for Lambert-Eaton myasthenic syndrome but has not been proven in human studies to increase survival after calcium channel blocker ingestion. It is 6 times more potent than 4-aminopyridine but probably should not be used in calcium channel blocker toxicity until it has been more thoroughly researched.
Clinical Context:
It is used to expand intravascular volume. It is isotonic and has volume-restorative properties. Fluid resuscitation should be started with the pharmacologic treatments above.
Augmenting the intravascular volume may help to move the patient to a more favorable Starling curve, in addition to filling dilated peripheral vascular structures.
Clinical Context:
Levosimendan is investigational in the United States. It elicits inotropic, vasodilating, and calcium-sensitizing effects. The drug is an intracellular agent that sensitizes myocytes to calcium by binding to cardiac troponin C, without increasing intracellular calcium. It is thought to stabilize the kinetics of actin-myosin cross-bridges without increasing myocardial adenosine triphosphate (ATP) consumption. Levosimendan also opens K+ channels, which leads to vasodilation and thereby decreases afterload to aid cardiac output in depressed myocardial states. Levosimendan is available as a 2.5mg/mL solution for IV infusion (dilute with D5W prior to infusion).
Derrick Lung, MD, MPH, Fellow, Medical Toxicology, University of California, San Francisco, School of Medicine; Clinical Instructor, Division of Emergency Medicine, Stanford University Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Mark A Silverberg, MD, MMB, FACEP, Assistant Professor, Associate Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Disclosure: Nothing to disclose.
Additional Contributors
Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Disclosure: Merck Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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