Calcium Channel Blocker Toxicity
Practice Essentials
Ingestion of excessive calcium channel blocker (CCB) agents is one of the most potentially lethal prescription drug overdoses. Overdoses of immediate-release CCBs are characterized by rapid progression to hypotension, bradydysrhythmia, and cardiac arrest, while overdoses of extended-release formulations can result in delayed onset of dysrhythmias, shock, sudden cardiac collapse, and bowel ischemia. [1] The image below illustrates the chemical structure of the calcium channel blocker diltiazem. Calcium channel blocker; diltiazem.
Signs and symptoms
Signs and symptoms of CCB toxicity may include any of the following:
Dizziness or lightheadedness
Weakness
Syncope
Chest pain
Palpitations
Diaphoresis
Flushing
Peripheral edema
Dyspnea
Confusion
Seizure
Headache
Nausea and vomiting
Physical examination findings may include the following:
Slowed heart rate
Hypotension
Depressed level of consciousness
Diagnosis
Abnormal findings on blood tests in patients with CCB toxicity include the following:
Hyperglycemia
Hypokalemia
Acidosis
On ECG, toxicity from calcium channel blockers may manifest as any of the following:
Bradycardia
First-, second-, or third-degree atrioventricular (AV) block
Any type of bundle-branch block
Nonspecific ST-T wave changes
In patients who present after a suicide attempt, and those with a history of co-ingestion, laboratory tests should also include the following:
Serum aspirin level
Serum acetaminophen level
Basic chemistry panel
Urine toxicology - Results may suggest significant co-ingestants such as opiates
Management
Basic supportive care is the first, and possibly most important, mode of management for CCB toxicity: Stabilize airway, breathing, and circulation (ABCs). Correction of acid-base disturbances and electrolyte abnormalities is also important, to optimize cardiac function.
Generally, the recommended duration of clinical observation for asymptomatic patients with significant exposure to CCBs is as follows [2, 3] :
Immediate-release products: 6 hours
Standard-release products: 6-12 hours
Extended-release or once-a-day preparations: 24-36 hours
In cases of intentional overdose, patients who remain asymptomatic after an adequate observation time may be referred for psychiatric evaluation.
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. [4] Before administration of activated charcoal, protect the patient's airway to prevent vomiting and aspiration.
Consult an American Association of Poison Control Centers–certified regional poison control center in all cases to assist in management, because poisonings can be quite severe and dynamic, and treatment is often complicated and multimodal. For these reasons, when patients are critically ill, besides the initial discussion with the certified specialist in poison information, request to speak with the medical toxicologist on call.
Specific agents used in treatment include the following:
IV volume expansion - Normal saline or Ringer lactate
Calcium
Glucagon
Vasopressors (eg, dopamine, epinephrine, norepinephrine)
High-dose insulin/euglycemia (HIE) therapy
Lipid emulsion therapy
Cardiac pacing may be required.
Calcium
Calcium can be administered IV to patients who present with symptomatic hypotension or heart block, as follows [5, 6, 7] :
Calcium gluconate, 30 mL of 10% solution, infused over 10-15 minutes in adults
Recommended pediatric dose of calcium gluconate is 60 mg/kg, with a maximum dose of 1 g [8]
Calcium chloride (1-4 g) is preferably given via central line, slowly
Glucagon
Reconstitute in D5W, not propylene glycol
Give an initial IV bolus of 5-10 mg; if a positive clinical effect is noted, continue an infusion at 5-10 mg/h
Insulin therapy
High-dose insulin therapy is administered as follows:
Infuse one ampule of D50W
Give an insulin bolus of 1 U/kg, followed by an infusion of 1-10 U/kg/h
Monitor serum potassium and glucose levels every 20-30 minutes
D5W infusions usually suffice to maintain glucose levels
Background
Calcium channel blocker (CCB) toxicity is one of the most lethal prescription drug overdoses; therefore, understanding the emergent management of such cases is essential. Overdoses of immediate-release CCBs are characterized by rapid progression to hypotension, bradydysrhythmia, and cardiac arrest. Overdoses of extended-release formulations can result in delayed onset of dysrhythmias, shock, sudden cardiac collapse, and bowel ischemia. [1]
Among the most widely prescribed drugs in the United States, CCBs are used to treat angina, hypertension, and dysrhythmias and to prevent migraines. They are marketed under many brand names, in a range of doses and formulations. Because they are found in many households and children may sometimes mistake them for candy, unintentional ingestion of CCBs is common. In addition, pediatricians have used these agents to treat children (eg, those with congenital heart malformations) for conditions such as dysrhythmias, hypertension, and chronic heart failure. Thus, dosing errors are also a possible source of toxicity in this age group.
These medications have different onsets of action, and many are available in sustained-release forms, all of which complicates the physician's decision regarding the appropriate duration of monitoring for patients with a history of CCB ingestion. (See Presentation and Workup.)
Patients with CCB toxicity should be treated in a well-equipped emergency facility or in an intensive care setting. Numerous strategies for treating patients who have ingested CCBs are available. (See Treatment.)
Pathophysiology
All existing CCBs function by binding to the L-subtype, voltage-sensitive, slow calcium channels in cell membranes. (Mibefradil, the only T-channel calcium blocker, was withdrawn from the market in 1998 because of multiple drug interactions and risk or death.) [9] The L-type calcium channel blockers decrease the flow of calcium into the cells of the cardiac conduction pathway, which leads to an inhibition of phase 0 in cardiac pacemaker cells and slows the phase 2 plateau in Purkinje cells, cardiac myocytes, and vascular smooth muscle cells. In cardiac muscle and vascular smooth, muscle rapid calcium influx causes myosin and actin binding and contraction. The different classes of CCBs, by inhibiting calcium influx, cause decreased myocardial contractility and peripheral arterial vasodilation.
Calcium channel blockers have the following four cardiovascular effects:
Peripheral arterial vasodilatation
Negative chronotropy (decreased heart rate through sinoatrial node inhibition)
Negative dromotropy (decreased cardiac conduction through atrioventricular node inhibition)
Negative inotropy (decreased cardiac contractility)
Other physiologic responses to CCB overdose include suppression of insulin release from the pancreas and decreased free fatty acid utilization by the myocardium. These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.
A unique CCB, bepridil, also demonstrates weak cross-reactivity with fast sodium channels and potassium rectifier channels, partially blocking these voltage-gated ion channels, which are responsible for rapid membrane depolarization. There is a propensity towards QTc prolongation and a risk for torsade de pointes.
Etiology
The toxic potential of calcium channel blockers (CCBs) varies with the formulation (eg, immediate-release or sustained-release) and the pharmacologic subclass. The CCBs have a certain degree of tissue specificity, but the drugs do have common properties. CCBs are all well absorbed in the gastrointestinal (GI) system, although diltiazem has extensive first-pass metabolism. The CCBs are substantially bound by plasma proteins and are predominantly metabolized by the liver. Therefore, impaired renal function should not alter CCB metabolism.
CCBs are divided into 3 subclasses. These classes and their effects are as follows [10] :
Phenylalkylamines: Affect the atrioventricular (AV) node and peripheral vasculature equally; verapamil is the only available agent in this class
Benzothiazines: More negative chronotropic effects than vasoactive; diltiazem is the only available agent in this class
Dihydropyridines: Primarily affect the peripheral vasculature, although cardiac toxicity may be observed in overdose; agents in this class are amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine
The pharmacokinetics of CCBs are as follows:
Amlodipine (Norvasc): Peak plasma level, 6-9 hours; half-life, 30-50 hours
Bepridil (Vascor): Peak plasma level, 2-3 hours; half-life, 24 hours
Diltiazem immediate release (IR) (Cardizem): Peak plasma level, 2-4 hours; half-life, 3.5-6 hours
Diltiazem sustained-release (SR) (Cardizem SR): Peak plasma level, 6-11 hours; half-life, 5-7 hours
Diltiazem controlled delivery (Cardizem CD): Peak plasma level, 10-14 hours; half-life, 5-8 hours
Diltiazem extended-release (XR or XT) (Dilacor): Peak plasma level, 4-6 hours; half-life, 5-10 hours
Felodipine (Plendil): Peak plasma level, 2.5-5 hours; half-life, 11-16 hours
Isradipine (DynaCirc): Peak plasma level, 0.5-2 hours; half-life, 8 hours
Nicardipine (Cardene): Peak plasma level, 0.5-2 hours; half-life, 2-4 hours
Nifedipine immediate release (IR) (Procardia): Peak plasma level, 0.5 hour; half-life, 2-5 hours
Nifedipine extended-release (XL) (Procardia XL): Peak plasma level, 7-10 hours; half-life, 7 hours
Nimodipine (Nimotop): Peak plasma level, less than 1 hour; half-life, 1-2 hours
Nisoldipine (Sular): Peak plasma level, less than 6-12 hours; half-life, 7-12 hours
Verapamil immediate release (IR) (Calan Isoptin): Peak plasma level, less than 1-2 hours; half-life, 3-7 hours
Verapamil sustained-release (Calan SR, Isoptin SR, Verelan): Peak plasma level, less than 5-11 hours; half-life, 12 hours
Nondihydropyridines
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 dromotropic and inotropic effect than do other CCBs. Several sustained-release formulations are available (eg, Calan SR, Isoptin SR, Verelan, Covera HS).
Verapamil almost exclusively undergoes hepatic metabolism, yielding a single active metabolite, norverapamil. This compound has 20% of the pharmacologic activity of the parent drug.
Diltiazem
Diltiazem (Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Teczem, Tiazac) demonstrates an affinity for cardiac conductive tissues and vascular smooth muscle cells, but 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.
Dihydropyridines
Nifedipine
Nifedipine (Procardia, Procardia XL, Adalat, Adalat CC) is a dihydropyridine. Nifedipine has a relatively high affinity for the calcium channels in the smooth muscle cells of vascular tissue and causes little to no AV nodal interference. At therapeutic doses a slight rebound tachycardia may occur. 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.
Nicardipine and nimodipine
Nicardipine (Cardene, Cardene SR) and nimodipine (Nimotop) are similar to nifedipine, although they demonstrate greater peripheral vascular smooth muscle effects. They may have small, negative inotropic effects. Nicardipine and nimodipine are predominantly metabolized by the liver. They do not exhibit a large first-pass effect, as is observed with other CCBs. Nimodipine has selectivity for the cerebral vasculature because of its high lipid solubility and ability to cross the blood-brain barrier; it has been approved for use in the treatment of cerebral ischemia after subarachnoid hemorrhage. Nicardipine is also available as an IV formulation for the control of hypertension.
Amlodipine
Amlodipine (Norvasc) has a long half-life of 30-50 hours. [11] The clinical effects of amlodipine are similar to those of nicardipine. Amlodipine’s long duration of action increases the risk of morbidity and mortality from an overdose.
Felodipine
Felodipine is highly protein-bound and exhibits a half-life of 11-16 hours. Because of protein binding, the drug’s elimination is prolonged. Due to its hypotensive effect, felodipine may cause a reflex tachycardia.
Isradipine
Isradipine (DynaCirc) is similar to felodipine. However, it has a smaller volume of distribution and a half-life of 8 hours. It has some inhibition at the sinoatrial node and therefore has less reflex tachycardia than other dihydropyridines.
Nisoldipine
Nisoldipine (Sular), a dihydropyridine, is highly metabolized, which results in only 1 active metabolite that has about 10% the activity of the parent compound. Nisoldipine elicits predominantly peripheral hemodynamic effects. It decreases systemic vascular resistance and blood pressure. It has a relatively high affinity for the calcium channels in the smooth muscle cells of vascular tissue and causes little to no AV nodal interference.
Clevidipine
Clevidipine (Cleviprex) is a dihydropyridine L-type CCB administered intravenously. It is rapidly distributed and metabolized and therefore has a very short half-life (terminal half-life of approximately 15 min). L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. Clevidipine reduces mean arterial blood pressure by decreasing systemic vascular resistance. It does not reduce cardiac filling pressure (preload), confirming a lack of effects on the venous capacitance vessels.
Epidemiology
United States statistics
In 2019, the American Association of Poison Control Centers (AAPCC) reported 6020 single exposures to calcium channel blockers (CCBs), resulting in 31 deaths and 111 major outcomes; 1198 exposures occurred in children younger than 6 years. [12] The past decade has seen only a minimal decline in the percentage of pediatric exposures to CCBs of all cases called to Poison Control centers nationally. [13, 14, 15, 16, 17]
Race-, sex-, and age-related differences in incidence
Although CCB ingestion has no race predilection among young children, racial trends mirror suicide attempt statistics among adolescents. In young children, a male predilection for CCB toxicity is observed. In adolescents, the sex predilection again mirrors suicide attempt statistics, with more females than males ingesting calcium channel blocker agents.
CCB 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 CCBs as a suicide gesture.
Prognosis
Prognosis in calcium channel blocker (CCB) toxicity depends on the following:
Amount and formulation of drug ingested
Co-ingestions
Patient's age
Underlying disease states
Specific treatments
Initial cardiac rhythm
Time elapsed before treatment begins
Specific treatments
Use of a pacemaker and time before it is placed
In 2019, the American Association of Poison Control Centers (AAPCC) reported that calcium channel blockers (CCBs) were the sixth leading cause of fatality. [12]
Complications
Complications relating to CCB toxicity include the following:
Dysrhythmias
Seizure
Coma
Anoxic encephalopathy from prolonged central nervous system (CNS) hypoxia
Ileus
Bowel infarction or perforation from mesenteric hypotension
Noncardiogenic pulmonary edema
Aspiration pneumonia
Death
CCBs, especially sustained-release formulations, can be lethal in toddlers; a few rare ingestions of a single pill have been documented to cause death. [16, 18, 19] Therefore, whenever a physician or parent suspects that a child has taken a CCB, aggressive treatment in a well-equipped hospital setting should be rapidly initiated.
Clinical Presentation
History
All accidental ingestions of a calcium channel blocker (CCB) by pediatric and adult patients in the amounts listed below must be managed in a hospital for cardiac monitoring; confirmed witnessed accidental ingestions of less than the amounts listed below may be managed at home through a poison control center.
Pediatric referral amounts for accidental extra dosing are as follows:
Amlodipine: >0.3 mg/kg
Bepridil: Any amount
Diltiazem: >1 mg/kg
Felodipine: >0.3 mg/kg
Isradipine: >0.1 mg/kg
Nicardipine: ≥ 1.25 mg/kg
Nifedipine: Any amount
Nimodipine: Any amount
Nisoldipine: Any amount
Verapamil: >2.5 mg/kg
Adult referral amounts for accidental extra dosing are as follows:
Amlodipine: >10 mg
Bepridil: >300 mg
Diltiazem immediate release: >120 mg
Diltiazem sustained release: >360 mg swallowed or >120 mg if chewed or unknown
Diltiazem extended release: >540 mg
Felodipine: >10 mg
Isradipine: >20 mg
Nicardipine immediate release: >40 mg
Nicardipine sustained release: >60 mg swallowed or >40 mg if chewed or unknown
Nifedipine immediate release: >30 mg
Nifedipine sustained release: >120 mg swallowed or >30 mg if chewed or unknown
Nimodipine: >60 mg
Nisoldipine: >30 mg
Verapamil immediate release: >120 mg
Verapamil sustained release: >480 mg swallowed or >120 mg if chewed or unknown
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. With young children, ask for a complete list of medications for all household members.
With accidental pediatric ingestions, 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 ingested drug is a single-agent product or a combination. New combination pharmaceutical products may have both a calcium channel blocker and a second antihypertensive such as an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.
Ascertain whether the ingested drug is a sustained-release preparation. 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 drug has 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 are potentially lethal, both have known medical treatment modalities, and a specific antidote is available for acetaminophen toxicity.
When calcium channel blocker ingestion is suspected, specifically question the patient or family about symptoms that may indicate cardiac or pulmonary manifestations of calcium channel blocker toxicity. Signs and symptoms may include any of the following:
Chest pain
Palpitations
Diaphoresis
Flushing
Weakness
Peripheral edema
Dyspnea
Drowsiness
Confusion
Seizure
Dizziness
Syncope
Headache
Nausea
Vomiting
Physical Examination The cardiac, vascular, and neurologic examinations deserve particular attention because calcium channel blocker (CCB) toxicity manifests most physical findings in these systems. According to one study, elapsed time to onset of symptoms ranged from 3 hours (seen with normal preparations) to 14 hours (in the setting of sustained-release medications). [14] These onset times should be considered when discharging patients home who may or may not have ingested calcium channel blockers. Measurement of vital signs may reveal a slowed heart rate if the sinoatrial (SA) node blockade occurs, or an increased heart rate if the patient is experiencing reflex tachycardia secondary to peripheral vasodilation and hypotension. Hypotension may last over 24 hours with some sustained-release, long-acting preparations. When examining the head, eyes, ears, nose, and throat, evaluate the patient's pupil size and reactivity to light. Specifically, look for focal neurologic deficits. A detailed 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 and 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.
Differential Diagnoses
Diagnostic Considerations
The conditions listed below should be considered in the differential diagnosis of calcium channel blocker (CCB) toxicity.
The following are the main common toxicity-causing agents:
Ingestion of beta-blocking agents
Acute or chronic digoxin toxicity
Ingestion of clonidine or other central alpha-2 agonists
Ingestion of any plants containing digoxin-like compounds or other cardiotoxins (eg, grayanotoxin, oleander, foxglove)
Opioid toxicity
Ingestion of any sedative-hypnotics, including benzodiazepines, barbiturates, and nonbarbiturate sedative-hypnotics
Other medical conditions to be considered may include the following:
Head trauma with Cushing reflex
Pontine hemorrhage
Septicemia
Septic shock
Spinal shock
Hypothyroidism
Allergic reaction
Trauma resulting in tamponade and tension pneumothorax
Respiratory arrest (infants)
Bacterial pericarditis
Viral pericarditis
Differential Diagnoses
Workup
Approach Considerations
Tests to order in patients with suspected calcium channel blocker toxicity include glucose, potassium, bicarbonate, lactate, and calcium levels and an electrocardiogram (ECG). Measurement of arterial blood gases should be considered in patients with significant toxicity, to determine the acid-base status and respiratory function. Lactate levels should be considered in all hypotensive patients.
Abnormal findings may include hyperglycemia, hypokalemia, and a decreased serum bicarbonate level secondary to lactic acidosis. The calcium level is used as a baseline before administering intravenous calcium; however, patients with severe poisoning may require calcium therapy before the value becomes available.
Foley catheter placement may be indicated to monitor urine output in severely poisoned patients.
In patients who present to the emergency department (ED) after a suicide attempt, as well as those with a history of co-ingestion, laboratory tests should also include the following:
Serum aspirin level
Serum acetaminophen level
Urine toxicology - Results may suggest significant co-ingestants such as opiates
Cardiac biomarkers, such as troponin I, may help differentiate drug-induced bradycardia from ischemic causes
Glucose levels
Calcium channel blocker (CCB) overdose can result in hyperglycemia from impaired insulin release. Hyperglycemia can help distinguish CCB toxicity from beta-blocker toxicity, which produces a very similar clinical picture but often lowers 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 and 129 mg/dL, respectively. The median peak serum glucose concentrations for those 2 groups were 364 mg/dL and 145 mg/dL, respectively. [20]
Electrocardiography
An 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 any of the following:
Bradycardia
Tachycardia, reflex secondary to vasodilation
First-, second-, or third-degree atrioventricular (AV) block
Any type of bundle-branch block
Nonspecific ST-T wave changes
The ECG can also be used to evaluate for signs of digitalis toxicity and tricyclic antidepressant (TCA) toxicity. Blockade of cardiac myocyte fast sodium channels by TCAs results in a widened QRS complex and a positive deflection in the augmented voltage unipolar right arm lead (aVR) in the terminal 40 microseconds of the complex, noted as an positive R wave in aVR greater than 3 mm. Sodium channel blockade can rapidly progress to malignant dysrhythmias if left untreated.
Imaging Studies A chest radiograph may be helpful to determine heart size and the presence or absence of congestive heart failure. In patients with congestive heart failure, aggressive fluid boluses to treat hypotension may exacerbate heart failure or cause acute pulmonary edema. Cardiac echocardiography may be needed to help distinguish causes of refractory hypotension from vasodilation versus cardiac pump failure. If bowel obstruction is suspected, abdominal radiography is recommended. Color-flow vascular ultrasonography of the intra-abdominal arterial supply may confirm bowel infarction.
Prehospital Management
Establish that the patient has adequate ABCs, obtain intravenous (IV) access, provide oxygen, and monitor closely. Rapid transport before the patient with calcium channel blocker (CCB) toxicity deteriorates is crucial.
Atropine may be tried if hemodynamically significant bradycardia occurs; however, infranodal heart block is usually resistant to atropine in CCB toxicity.
Empiric use of glucagon (adults: 5-15 mg IV) may be warranted for patients with an unknown overdose who present with bradycardia or hypotension.
Treat hypotension with fluid boluses of normal saline if no evidence of decompensated congestive heart (CHF) exists. Administer IV calcium gluconate (up to 4 g) or IV calcium chloride (1 g) and/or glucagon (5-10 mg) if hypotension persists. [24] If profound hypotension fails to respond to fluid resuscitation and/or if a long transport time is likely, administer a 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. Patients with CCB overdose have survived neurologically intact after 1 hour of CPR. Consideration should be given for a bolus dose of intralipid emulsion.
Administer activated charcoal (AC) if the patient's airway is protected.
Emergency Department Management
Basic overdose management includes airway protection, gastric lavage, and activated charcoal. Patients who are hemodynamically stable who have taken extra doses of their own medication can be monitored 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. Large and intentional overdoses should always be managed in an ICU.
Only asymptomatic patients should be watched in an observation unit. If manifestations of cardiac depression occur, transfer the patient to an ICU setting with the capacity for advanced cardiac life support (ACLS), including tracheal intubation and cardiac pacing.
Aggressive cardiovascular support is necessary for managing 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 case reports, glucagon has been used with good results in some cases. However, vasopressors are frequently necessary for adequate resuscitation and should be started early if hypotension occurs. [25] Dopamine may be used for isolated bradycardia, but hypotensive patients should preferentially have direct vasopressors such as norepinephrine.
Hyperinsulinemia euglycemia treatment (1 unit/kg bolus of regular insulin with 0.5 g/kg dextrose push followed by 0.5–1 unit/kg/hr of regular insulin with concomitant dextrose drip) may improve circulatory shock in CCB overdose patients. Early institution of this therapy may be useful, as the onset of benefit is delayed. Both glucose and potassium levels should be frequently monitored in patients receiving this treatment and potassium should be replaced if the level falls below 3 mmol/L [21, 26]
Indications for Inpatient Evaluation Inpatient evaluation is indicated for patients who have ingested calcium blockers above a certain amount. [24] See Table 1, below. Co-ingestants must be taken into account; these amounts assume isolated unintentional ingestion of only the calcium-blocking medication
Gastrointestinal Decontamination
Gastrointestinal (GI) decontamination may be considered because calcium channel blockers (CCBs) slow gastric motility and delay gastric emptying. Options include activated charcoal, gastric lavage, and whole-bowel lavage.
Activated charcoal
Activated charcoal has been demonstrated to significantly adsorb immediate-release medications within 1 hour of ingestion and extended-release medications as long as 4 hours after ingestion. [4] 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. [27] 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 contraindications to administration of activated charcoal. In patients with severe toxicity, interventions such as antiemetics and intubation with satisfactory sedation should be performed before administration of activated charcoal via a nasogastric tube.
Gastric lavage
Gastric 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. Placement of an endotracheal tube before performing the lavage protects the airway and reduces the risk of aspiration.
If gastric lavage is performed, use a large-bore orogastric hose. Sustained-release tablets, which are large and resistant to breakdown, may not fit through a simple Salem sump nasogastric tube.
Whole-bowel irrigation
If a patient has ingested a large number of CCB tablets, especially sustained-release tablets, the pills may aggregate to form bezoars and the drug can be continuously absorbed for long periods. In this situation, the clinician may consider whole-bowel irrigation with polyethylene glycol (PEG). In adults, administer PEG at a rate of 1-2 L/h for 4-6 hours or until rectal effluent becomes clear.
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 intestinal fluid lead to massive bowel distention, risking bowel perforation.
Coadminister activated charcoal in a 1 g/kg initial dose; activated charcoal administration can be repeated every 4 hours at half the initial dose. Because gastric emptying may be delayed, activated charcoal may be considered even if the patient presents several hours after the ingestion.
In children, care must be used never to administer sorbitol-containing products, because of the potential to induce electrolyte disturbances. In the rare instance of large ingestion in a preschool-age child, whole-bowel irrigation with PEG solution (Go-Lightly) may be used.
Treatment of Hypotension
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 in children or 1-L boluses in adults. These may be repeated once, twice, or even three times if the patient remains hypotensive. Bedside ultrasound assessment of inferior vena cava size may guide adequate volume replacement. If blood pressure normalizes with fluid challenges, infuse IV fluid at 1-2 times the normal maintenance rate.
However, vasopressors are frequently necessary for adequate resuscitation and should be started early if hypotension occurs. [25]
Calcium Therapy
Calcium can be administered intravenously to patients who present with symptomatic hypotension or heart block. [5, 6, 7] High-dose calcium theoretically creates a concentration gradient large enough to partially overcome the channel blockade, driving calcium into the cells. Calcium is usually administered as calcium gluconate or calcium chloride. Calcium chloride is sclerosing to veins so should be avoided in children, and it should be used in adults only in a larger, free-flowing IV line. Calcium chloride has 4 times the calcium content as calcium gluconate.
Calcium gluconate, 30 mL of 10% solution, can be administered IV over 10-15 minutes in adults. The recommended pediatric dose of calcium gluconate is 60 mg/kg, with a maximum dose of 1 g. [8] Calcium chloride (1-4 g) is preferably given via central line, slowly. The bolus can be repeated, or a slow calcium infusion (eg 20-50 mg/kg/h) can be implemented.
Calcium gluconate boluses may be repeated every 15-20 minutes, if the response to the initial bolus begins to diminish, for a total of 3 doses. After the third bolus, the ionized calcium level should be checked. 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.
Glucagon Therapy
Glucagon promotes calcium entry into cells via stimulation of a receptor that is considered to be separate from adrenergic receptors. Note that the actions of glucagon oppose those of insulin, yet both have beneficial effects in treating CCB toxicity.
Glucagon is supplied as a lyophilized powder and must be reconstituted. Some manufacturers include an ampule of propylene glycol that can be used for single injections. However, the administration of large amounts of propylene glycol (the same diluent that is used for phenytoin) causes hypotension and dysrhythmias.
For this reason, glucagon infusions and repeat doses should be reconstituted in D5W to avoid giving large amounts 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.
Administer glucagon (5-10 mg IV bolus up to 15 mg, followed by an infusion) after fluid resuscitation is performed for persistent hypotension. Since glucagon dilates the lower esophageal sphincter, vomiting and aspiration may occur; therefore, this treatment should only occur in an awake patient who can protect his or her own airway if vomiting occurs. Pretreatment with an antiemetic and large-bore bedside suction should be used. If an initial bolus of 5 mg of glucagon has no effect on blood pressure, it is reasonable to double the dose. The recommended infusion rate for adults is 5-10 mg/h. The recommended pediatric dose is 50 mcg/kg IV over 5 minutes, followed by an infusion at 0.07 mg/kg/h. [28, 29, 30, 31, 32, 33, 34, 35]
Vasopressor Therapy
If volume expansion does not raise the blood pressure to the desired level, vasopressors (eg, norepinephrine, epinephrine) can stimulate myocardial contractility and cause vasoconstriction, thus supporting blood pressure and cardiac output. In the hypotensive and bradycardic patient, administer dopamine initially at medium-to-high doses early to support the heart rate. Failure to respond to the maximal dose of dopamine should prompt the addition of norepinephrine.
Various combinations of dopamine, norepinephrine, epinephrine, phenylephrine, vasopressin, and metaraminol have all been used in cases of hypotension and shock. [1, 2, 33, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45] Inamrinone, a phosphodiesterase inhibitor with inotropic activity, may be of additional benefit in profound cardiac contractile failure. [34, 42, 46] Bedside cardiac echocardiography may help distinguish cardiogenic shock form vasodilatory shock.
Insulin Therapy
High-dose insulin has become accepted as therapy in calcium channel blocker (CCB) toxicity refractory to standard vasopressor therapy. [47] Hyperglycemia may occur in CCB toxicity, as calcium channel blockade inhibits insulin release. [20, 48, 48] Although no human trial has been completed, animal models and numerous case reports and case series demonstrate that high-dose insulin increases inotropy, increases intracellular glucose transport, and improves vascular dilation in CCB toxicity. [41, 49, 6, 50, 51, 52, 53, 54, 55, 56, 57, 58]
High-dose insulin therapy is administered as follows: infuse one ampule of 50% dextrose in water (D50W), then give an insulin bolus of 1 U/kg, followed by an infusion of regular insulin at 1-10 U/kg/h. Remarkably, patients with CCB toxicity who receive this therapy rarely require more supplemental dextrose than a D5W infusion. However, their serum potassium and glucose levels should be monitored every 20-30 minutes.
High-dose insulin therapy has a delayed onset of action. Consequently, it should be started soon after the patient presents with refractory hypotension.
High-dose insulin euglycemia (HIE) guidelines
Indications
Hypodynamic shock due to calcium channel antagonist (CCB) or beta-blocker (BB) toxicity:
HIE is most effective when there is evidence of depressed myocardial activity
HIE can be considered for use alongside other pharmacological measures for CCB toxicity (intravenous fluid, calcium, glucagon, dopamine, or norepinephrine)
Setting
Only in a critical care area of the hospital (ED or ICU) owing to unstable hemodynamics associated with CCB toxicity, frequent requirements for central IV access/monitoring, and frequent glucose monitoring
Initiation
Initial insulin bolus to saturate insulin receptors and assure adequate glucose availability:
1 unit/kg regular human insulin IV
1 amp (25 g) D50 IV: May hold if blood glucose >400 mg/dL (22.24 mmol/L)
Continuous infusion:
Insulin infusion: A rapid insulin infusion bag can be created by adding 500 U regular human insulin to 500 mL normal saline (1 U/mL). Ideally, a concentrated insulin infusion bag (10 U/ml) should be used to decrease fluid overload, since very large quantities of insulin may be needed. Start infusion at 0.5 U/kg/h with an infusion pump to avoid iatrogenic insulin overdose. Reassess cardiac function and blood pressure every 15-30 minutes. Increase infusion to 1-2 units/kg/h if there is no improvement after 30 minutes.
Dextrose infusion: 0.5 mg/kg/h dextrose IV as D5 (5 g of dextrose per 100 mL), D10 (10 g of dextrose per 100 mL), or D25 (25 g of dextrose per 100 mL). Titrate to maintain blood glucose of 100-200 mg/dL. Initial dextrose infusion requirement may vary depending on the patient's initial blood glucose level and the presence of underlying diabetes; higher concentrations of dextrose (ie, D25 and D50) must be administered via a central IV line, due to local issue irritant effects of concentrated dextrose solutions.
Monitoring:
Bedside echocardiogram (ultrasound) for myocardial function: Ideally prior to HIE therapy, if possible; 30 minutes after initiation of HIE, if possible; 30 minutes after every dose increase, if possible
Continuous automated blood pressure monitoring
Foley catheter
Serial physical examinations, especially neurological status
Blood glucose finger-stick monitoring: Every 15-30 minutes until consistently 100-200 mg/dL for 4 hours, then every hour
Serum potassium : Every 1 hour
Lactic acid levels prior to Insulin then 1 hour after infusion
Therapeutic goals:
Normal myocardial ejection fraction (50%)
Blood pressure consistently higher than 90 mm Hg systolic
Improved mental status
Urine output 1-2 mL/kg/h
Decreased use of concomitant vasoactive drugs
Caveats
HIE:
It generally takes approximately 30 minutes to see effects from HIE.
No ceiling dose of insulin has been established; the usual titration range is 0.5-2 units/kg/h.
While cases have shown improved heart rate and conversion from heart block to sinus rhythm in temporal relationship to HIE administration, the main beneficial effect is on myocardial function (ie, ejection fraction and cardiac output), with subsequent improvement in blood pressure and perfusion.
Mean duration of insulin therapy is 31 hours (range, 1-96 h).
Glucose:
Most patients with CCB toxicity present with hyperglycemia and their initial glucose requirements to maintain euglycemia are minimal (due to insulin resistance); however, as organ perfusion improves, the offending drug is metabolized, and insulin resistance abates, dextrose requirements increase.
The mean maximum dextrose requirement is 24 g/h (range, 0.5-75 g/h).
Mean duration of dextrose infusion is 46 hours (range, 12-100 h)
Exogenous dextrose is often required even after insulin infusion is stopped
Intubated patients are at greatest risk of undetected hypoglycemia since they cannot demonstrate typical signs of hypoglycemia, and bedside fingerstick glucose should be checked every 15-30 minutes
Potassium:
Falling serum potassium levels during HIE represent a shift of potassium from the extracellular to intracellular compartments, not a loss; however, replacement to potassium concentration greater than 2.8-3 mEq/L should occur
Investigational Therapies
Treatments that have been used in refractory cases of calcium channel blocker (CCB) toxicity include the following:
Methylene blue
Experimental use of methylene blue in distributive shock has prompted its consideration in calcium channel blocker overdose with cardiogenic shock. Case reports describe successful use in CCB overdose refractory to other therapies, at a starting dose of 1–2 mg/kg IV. [59, 60]
Lipid emulsion therapy
Lipid emulsion therapy (eg, Intralipid) has been studied in a few animal models of verapamil toxicity, demonstrating increased survival. [63, 66] Case reports have found either clinical improvement [61, 67] or significant drug sequestration. [68]
The therapeutic effect of lipid emulsion therapy is most commonly ascribed to the "lipid sink" theory, which posits that the lipid emulsion bolus sequesters lipophilic drugs from their target site, mitigating toxicity. Verapamil is quite lipophilic and thus is theoretically amenable to lipid emulsion therapy. [69] One case report demonstrated significant drug sequestration in a verapamil overdose, but uncertain clinical benefit. [68]
Lipid emulsion therapy can be considered as an antidotal therapy of last resort in calcium channel blocker overdose. 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." [70]
For lipid emulsion therapy, 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.
Lipid emulsion therapy guidelines
Lipid emulsion 20% should be given IV in the following dose regimen:
Lipid emulsion 20%: 1.5 mL/kg over 1 minute
Follow immediately with an infusion at a rate of 0.25 mL/kg/min
Continue chest compressions if patient is receiving cardiopulmonary resuscitation (CPR) (lipid must circulate)
Repeat bolus every 3-5 minutes, up to 3 mL/kg total dose, until circulation is restored
Continue infusion until hemodynamic stability is restored; increase the rate to 0.5 mL/kg/min if blood pressure declines
Maximum total dose of 8 mL/kg is recommended
4-Aminopyridine and 3.4 diaminopyridine
4-Aminopyridine and 3,4-diaminopyridine increase 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. It cannot be recommended at this time for CCB toxicity.
Levosimendan
Levosimendan (Simdax) 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. [71] 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. It cannot be recommended at this time for CCB toxicity.
Procedures
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 treatments. Cardiopulmonary bypass can be a last resort to support the blood pressure long enough for the body to clear the ingested toxin. [72, 73]
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. [74] 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."
Plasma exchange [75] and continuous renal replacement techniques with hemodiafiltration [76] have each been used in cases of severe poisoning resistant to aggressive medical treatments, such as patients failing glucagon and norepinephrine infusions. [72, 73, 75, 76] These cannot be recommended at this time for CCB toxicity.
Although CCBs 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. In a case report of overdose with sustained-release diltiazem, however, charcoal hemoperfusion showed little efficacy. [77]
Diet and Activity
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.
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 ICU for inpatient care of the hemodynamically unstable child. This is an indication to transfer pediatric patients.
