Calcium Channel Blocker Toxicity

Drugs / By

16 Interesting Facts of Calcium Channel Blocker Toxicity 

  1. Calcium channel blocker toxicity may cause vasodilation, decreased inotropy (ie, contractility), decreased dromotropy (ie, conduction), and/or decreased chronotropy (ie, heart rate); overdose is characterized by hypotension, bradycardia, and potentially death 
  2. Toxicity may occur after intentional or accidental overdose; calcium channel blockers are associated with highest risk of fatality in poisoning among all classes of cardiovascular agents
  3. Toxic ingestion with dihydropyridine agents (eg, nifedipine, amlodipine) usually results in hypotension and reflex tachycardia
  4. Toxic ingestion with nondihydropyridine agents (eg, verapamil, diltiazem) results in hypotension and bradycardia
  5. Suspect and diagnose calcium channel blocker toxicity clinically using history and physical examination
  6. Obtain serum glucose level; ECG with continuous cardiac monitoring; electrolyte levels with calcium, magnesium, and phosphorus; and renal function testing in every patient with confirmed or suspected symptomatic calcium channel blocker toxicity
  7. Hyperglycemia is a common finding in overdose; ECG findings can be normal or may reveal a variety of rhythm and conduction abnormalities
  8. Consult medical toxicologist and/or regional poison control center in all cases of exposure for monitoring and management recommendations
  9. Treatment is largely supportive; initial measures include IV fluid bolus for poor perfusion and atropine trial for symptomatic bradycardia
  10. Gastrointestinal decontamination is usually indicated in patients presenting within 1 hour after ingestion when there are no contraindications; whole-bowel irrigation with polyethylene glycol may be indicated for ingestions involving sustained-release products
  11. Treatment options for patients with mild toxicity include additional fluid resuscitation with IV fluid bolus, calcium, and glucagon administration in a sequential pattern to determine response to individual measures
  12. Treatment options for patients with moderate to severe toxicity often require multiple interventions at once, including high-dose insulin euglycemic therapy, vasopressor support, and lipid emulsion therapy, in addition to treatment options employed in mild toxicity
  13. Monitor closely for clinical changes or deterioration, treatment effects, and emergence of possible metabolic abnormalities during course of toxicity
  14. Asymptomatic patients with possible accidental ingestion of non–sustained-release product require observation for at least 6 to 8 hours; ingestion of sustained-release products requires observation for at least 24 hours
  15. Any calcium channel blocker overdose has propensity for mortality; severe ingestions are associated with an extremely high mortality rate. In general, mortality may be higher from nondihydropyridines compared with dihydropyridines
  16. Early use of more aggressive treatment options (eg, high-dose insulin euglycemic therapy) improves outcomes compared with delayed use

Pitfalls

  • Early consultation with medical toxicologist is particularly advised before or while initiating specific therapy (eg, gastrointestinal decontamination, high-dose insulin euglycemic therapy) to ensure appropriate dosing and monitoring
    • Hemodynamic instability is an absolute contraindication to administration of whole-bowel irrigation; cessation of whole-bowel irrigation is required if hemodynamic instability develops during administration
  • Diligent clinical monitoring of all patients with potential toxicity is warranted, including those who are asymptomatic 
    • Anticipate precipitous clinical deterioration; initially asymptomatic and seemingly stable patients may rapidly deteriorate to severe shock
  • Begin aggressive measures early in patients with manifestations of significant toxicity; benefit of early initiation of high-dose insulin euglycemic therapy is crucial
  • Patients with significant toxicity ideally should be managed in setting with advanced capabilities (eg, extracorporeal membrane oxygenation) in case standard measures fail
  • Calcium channel blocker toxicity may cause vasodilation, decreased inotropy (ie, contractility), decreased dromotropy (ie, conduction), and/or decreased chronotropy (ie, heart rate); overdose is characterized by hypotension, bradycardia, and potentially death 
  • Toxicity may occur after intentional or accidental overdose; calcium channel blockers are associated with highest risk of fatality among poisonings from all other cardiovascular agents 

Classification

  • 2 classes of drugs can lead to calcium channel blocker toxicity
    • Dihydropyridines (eg, nifedipine, nicardipine, amlodipine; names end with the suffix -pine) 
      • Common clinical use includes treatment of hypertension and angina 
      • Selective for vascular smooth muscle at therapeutic dosing; result in vasodilation of systemic arteries and main coronary arteries 
      • Lack significant myocardial depressant activity on conduction or contractility at therapeutic doses 
      • More likely to cause hypotension and reflex tachycardia in overdose
    • Nondihydropyridines (eg, verapamil, diltiazem; cardioselective)
      • Common clinical use includes treatment of tachycardia, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia, hypertension, and angina 
      • Selective for myocardial and pacemaker cells at therapeutic dosing; result in decreased contractility, rate of atrioventricular nodal conduction, and heart rate 
      • More likely to cause cardiac toxicity with bradycardia, conduction delays, arrhythmias, and decreased contractility leading to cardiogenic shock in overdose 

Diagnosis

Clinical Presentation

History

  • Patients may present with history of overdose/exposure
    • Medication name, formulation (immediate-release, sustained-release, extended-release), and approximate dose ingested may help risk stratify overdose
    • Patient may admit to coingestants or have access to additional medications that may confound cardiovascular effects
    • Common setting is therapeutic error (eg, double dose)
  • When history of an overdose is absent, strongly suspect calcium channel blocker toxicity with:
    • Children with bradycardia, hypotension, and/or depressed mental status with possible exposure to medications (eg, calcium channel blockers in the home)
    • Adult with bradycardia, hypotension, and hyperglycemia
      • Altered mental status in adults does not occur initially from calcium channel blocker toxicity alone, but as a complication of severe cardiovascular effects
    • Adults or older adults (eg, those aged 65 years or older) receiving therapeutic dose experiencing increase in fatigue, palpitations, or orthostatic symptoms, particularly after addition of another cardioactive medication
  • Time course of presenting features
    • Patients should develop symptoms within 6 hours for immediate-release forms and within 24 hours for modified-release forms 
    • 1 characteristic presenting pattern includes absence of symptoms at presentation, followed by precipitous deterioration to shock
  • Symptoms may include: 
    • Lightheadedness and syncope
    • Nausea and vomiting
    • Weakness
    • Diaphoresis
    • Shortness of breath (secondary to development of pulmonary edema)
    • Mental status changes
      • Preserved mental status despite significantly abnormal vital signs is a common manifestation in isolated ingestions 
      • In adults, mental status is usually intact unless poor cerebral perfusion develops; confusion, lethargy, and seizures may ensue with development of poor cerebral perfusion 
      • Children may develop depressed mental status in the setting of normal hemodynamics 

Physical examination

  • Patients may present with vital signs within reference range and normal mental status, then precipitously and rapidly deteriorate; alternatively, patient may present in cardiac arrest 
  • Hypotension
  • Bradycardia
    • Common with nondihydropyridine (cardioselective) calcium channel blockers (eg, verapamil, diltiazem)
    • May occur after high-dose exposure to dihydropyridines (eg, nifedipine, nicardipine, amlodipine)
  • Tachycardia
    • Compensatory tachycardia secondary to vasodilation is more often seen with dihydropyridines such as nifedipine and nicardipine
  • Signs of vasodilation (warm extremities and strong pulse)
  • Mental status changes
    • Preserved mental status despite significantly abnormal vital signs is a common finding in isolated ingestions 
    • Children are more likely to have nonspecific lethargy and confusion despite hemodynamic parameters within reference range 
    • Precipitous change in mental status (eg, decreased level of consciousness, delirium, agitation) may develop in adults in association with poor cerebral perfusion 
  • Signs of congestive heart failure may develop as cardiac output diminishes
    • Pulmonary rales
    • Jugular venous distention
    • Peripheral edema
    • Hepatomegaly

Causes

  • Calcium channel blocker overdose or exposure
    • Overall effect of calcium channel blocker toxicity is dependent on drug class, dose, formulation, exposure to coingestions, and preexisting disease 
      • Class
        • Dihydropyridines
          • Preferentially inhibit vascular smooth muscle L-type calcium channels at therapeutic dosing; primary result is vascular smooth muscle relaxation (eg, vasodilation) associated with reflex tachycardia
          • Receptor selectivity is lost in large overdoses; may effect myocardium and conduction system, resulting in bradycardia and decreased contractility with escalating dose ingestion 
        • Nondihydropyridines
          • Preferentially inhibit myocardial L-type calcium channels at therapeutic dosing; primary result is prolonged depolarization time, leading to depressed cardiac contractility, conduction, and pacing
          • Receptor selectivity is lost in large overdoses; may affect vascular smooth muscle, resulting in vasodilatation with escalating dose ingestion 
      • Pharmacokinetics/pharmacodynamics
        • General principles
          • Most are rapidly and well absorbed from gastrointestinal tract 
          • Most are highly protein-bound and have a large volume of distribution; limits role of extracorporeal removal 
          • Metabolism is completed by liver cytochrome P450 system, leading to risk for drug interactions 
          • Many have low bioavailability, owing to extensive hepatic first-pass metabolism; however, in overdose, enzyme saturation occurs, allowing for greater systemic absorption and prolonged toxicity 
        • Immediate-release preparations
          • Onset of effect is about 1 hour; peak plasma concentration is achieved in 30 to 120 minutes; half-life about 2 to 7 hours after a single dose (may be longer with repetitive dosing, with liver failure, or in overdose) 
        • Delayed-release preparations (eg, sustained-release, extended-release) 
          • Result in delayed and prolonged toxicity; absorption is somewhat unpredictable and duration of toxicity is prolonged
          • Peak plasma concentration is usually achieved in about 6 to 12 hours after a single dose of sustained-release product (may be longer with repetitive dosing, with liver failure, or in overdose) 
          • Onset of toxicity in overdose may be delayed 12 to 16 hours and peak plasma concentration delayed up to 24 hours with sustained-release preparations 
        • Amlodipine
          • Pharmacokinetics are unique with more intermediate-release profile; slow onset and long duration of action are characteristic
          • Peak plasma concentration is observed between about 6 to 9 hours after a single dose, with mean retention time of about 13 to 24 hours 
      • Toxic dose
        • Adults: toxicity can result after ingestion of any supratherapeutic dose; doses 2- to 3-fold higher than therapeutic dose can result in profound toxicity in susceptible patients 
        • Children: toxicity can result after ingestion of as little as 1 tablet; death can occur after ingestion of 1 to 2 tablets in children 
        • Any calcium channel blocker overdose has propensity for mortality
        • Nondihydropyridine overdose is associated with an overall higher mortality rate than dihydropyridine overdose
          • Verapamil overdose is associated with highest mortality risk 
  • Common causes of acute toxicity and overdose include: 
    • Accidental ingestion of calcium channel blocker medications, usually in children
    • Therapeutic error such as wrong dose or wrong patient
    • Intentional ingestion (ie, self-harm)
    • Interaction with drugs that affect cardiac conduction, inotropy, or metabolism (via cytochrome P450 system)

Risk factors and/or associations

Age
  • Children and elderly adults are at higher risk of toxicity
    • Children may experience toxicity with as low as 1 tablet exposure 
    • Elderly patients may be more sensitive to effects of calcium channel blockers and more prone to toxicity 
Other risk factors/associations
  • Patients with underlying cardiovascular disease are more vulnerable to toxicity 
  • Coingestion of other medications—especially other cardiovascular agents (eg, digoxin, β-blockers, tricyclic antidepressants)—may aggravate toxicity

Diagnostic Procedures

Primary diagnostic tools

  • Suspect calcium channel blocker toxicity clinically according to history and physical examination
    • Most patients presenting with significant toxic ingestion will present with bradycardia, poor perfusion, and potentially hypotension 
    • Important parameters to establish include time of ingestion, amount ingested, formulation (immediate- or extended-release product), and possibility of coingestions 
  • Obtain the following tests in every patient with confirmed or suspected symptomatic calcium channel blocker toxicity:
    • ECG and continuous cardiac monitoring 
    • Serum glucose measurement 
    • Electrolytes with calcium, magnesium, and phosphorus measurements; renal function testing 
  • Additional diagnostic evaluations are required on the basis of clinical presentation
    • Echocardiography to assess ejection fraction and gross contractility
    • Chest radiograph in any person with clinical presentation concerning for pulmonary congestion
  • Obtain routine studies in patients with intentional ingestion, including:
    • Acetaminophen concentration to evaluate for treatable concomitant coingestion
    • Urine β-hCG level in women of childbearing age
    • Consider further work-up (eg, head CT, ethanol level, serum osmolality) in patients with unexplained mental status depression
  • Obtain additional laboratory parameters in critically ill patients as indicated (eg, blood gas test, lactate level) 

Laboratory

  • Serum glucose level
    • Hyperglycemia is characteristic of overdose; caused by decreased insulin release from pancreatic β cells 
    • In overdoses of nondihydropyridines (eg, verapamil, diltiazem), higher serum glucose levels may correlate with increasingly severe toxicity (measured by need for vasopressors or pacing, or outcome of death) 
      • Severe toxicity (median measurements)
        • Initial serum glucose level: about 190 mg/dL
        • Peak serum glucose level: 360 mg/dL
        • Increase in glucose over course of toxicity: about 70%
      • Less severe toxicity (median measurements)
        • Initial serum glucose level: about 130 mg/dL
        • Peak serum glucose level: 145 mg/dL
        • Increase in glucose over course of toxicity: 0
  • Electrolyte, calcium, magnesium, phosphorus, creatinine, and BUN levels
    • Renal impairment may lead to accumulation of active metabolites of some calcium channel blockers (eg, diltiazem, verapamil) 
    • Increased anion gap metabolic acidosis can occur from lactic acidosis secondary to poor perfusion 
    • Hypokalemia often exacerbates cardiovascular toxicity; anticipate intracellular shift of potassium with insulin treatment
    • Hypocalcemia and hypomagnesemia may exacerbate cardiovascular toxicity
    • Monitor calcium levels when calcium salts are used for treatment

Imaging

  • Chest radiograph
    • Indicated in patients with hypoxia, pulmonary findings, or respiratory distress
    • Pulmonary edema (cardiogenic and noncardiogenic) may occur; presence may limit fluid administration during treatment 

Functional testing

  • ECG
    • Normal sinus rhythm with normal interval conduction may be present and does not exclude suspected or potential toxicity
    • Predominant findings depend on class of drug ingested
      • Dihydropyridines (eg, nifedipine) typically cause reflex tachycardia secondary to hypotension rather than conduction abnormalities 
      • Nondihydropyridines (eg, verapamil, diltiazem) typically cause severe bradycardias and variable heart blocks 
    • Common abnormal findings can include:
      • Rhythm disturbances
        • Sinus tachycardia
        • Bradydysrhythmias
      • Conduction abnormalities
        • PR prolongation
        • QT prolongation
        • QRS prolongation
          • At high doses, inhibition of sodium channels may occur, mimicking effects of class IA antiarrhythmics and cyclic antidepressants 
        • Variable atrioventricular blocks
        • Bundle branch blocks
      • Arrhythmia
        • Junctional rhythms
    • Serial ECG monitoring may be necessary in patients with significant toxicity, during treatment with calcium, and when significant electrolyte abnormalities are present (eg, hypokalemia)
    • Worsening degrees of heart block appear to correlate with increased severity of toxicity and potentially worsening prognosis 
  • Echocardiography
    • Bedside or formal echocardiography can help characterize shock as cardiogenic, distributive, or hypovolemic 
    • Knowledge of precise pathophysiology may help target specific therapy (eg, aid in vasopressor selection) 

Differential Diagnosis

Most common

  • β-blocker toxicity
    • Presenting features of β-blocker and calcium channel blocker toxicity are virtually indistinguishable (eg, hypotension, bradycardia)
    • Hypoglycemia is most characteristic of β-blocker toxicity, whereas hyperglycemia is characteristic of calcium channel blocker toxicity
    • Mental status depression is more often noted in patients with β-blocker toxicity; preserved mental status is more characteristic of calcium channel blocker toxicity
    • Differentiate using clinical presentation; distinguishing between the 2 is not vital to management because management of both poisonings is very similar
  • Clonidine toxicity
    • Central α₂-adrenergic agonist that may present similarly with bradycardia and hypotension
    • Differences include characteristic central nervous system findings (eg, central nervous system depression, miosis, hypotonia, hyporeflexia) usually present in patients with clonidine toxicity; significant respiratory depression may develop, mimicking opioid toxicity
    • Additional differentiating features include good response to supportive care (eg, atropine, fluid boluses, vasopressors) as compared with often poor clinical response to supportive care in calcium channel blocker toxicity
    • Differentiate using clinical presentation and response to supportive measures
  • Digoxin toxicity 
    • Presents similarly with delayed cardiac conduction (eg, bradycardia, atrioventricular block); hemodynamic compromise may develop
    • Gastrointestinal (eg, nausea, vomiting, diarrhea, abdominal pain) and central nervous system manifestations (eg, confusion, seizures, ataxia, coma, headaches, dizziness, color changes in vision) may develop in patients with digoxin toxicity
    • Presence of increased automaticity (eg, premature ventricular contractions) and certain arrhythmias (eg, paroxysmal atrial tachycardia with block, junctional tachycardia, bidirectional ventricular tachycardia) suggest digoxin toxicity rather than calcium channel blocker toxicity
    • Hyperkalemia is a hallmark of toxicity and no change in glucose level is anticipated in patients with digoxin toxicity
    • Use of digoxin is associated with characteristic ECG findings (eg, changes in T-wave morphology, QT interval shortening, scooped and depressed ST segment, increased U-wave amplitude, prolonged PR interval)
    • Confirm diagnosis with elevated digoxin concentration (greater than 2 ng/mL in postdistribution phase) in association with cardiac or noncardiac clinical manifestations of toxicity
  • Acute coronary syndromes
    • May present similarly with sudden onset of hypotension associated with cardiogenic shock
    • Differentiate by symptoms (eg, chest pain), presence of ECG changes (T-wave inversions, ST depression, ST elevation), and elevated troponin and creatine kinase–MB levels
    • Other means to diagnose include nuclear perfusion study and cardiac catheterization
  • Sepsis
    • May present similarly with hypotension, peripheral vasodilatation, and reflex tachycardia
    • Antecedent symptoms may suggest diagnosis (eg, cough with pneumonia, headache with meningitis)
    • Temperature instability and abnormal indices of inflammation (eg, elevated C-reactive protein level, abnormalities in WBC counts) suggests sepsis rather than calcium channel blocker toxicity; bradycardia is uncommon in patients with sepsis
    • Diagnosed by clinical presentation, clinical course, and microbiologic culture results
  • Anaphylaxis
    • Represents an acute, severe allergic reaction in response to a trigger (eg, medication, food, insect venom) that presents with a combination of variable findings (eg, bronchospasm, orofacial and/or laryngeal swelling, rash, vomiting, cardiovascular collapse) 
    • Underlying history of atopic disease is a significant risk factor for development of anaphylaxis 
    • Findings similar to calcium channel toxicity include presence of distributive shock (peripheral vasodilation, hypotension, tachycardia) and possibly pulmonary edema
    • Differs from calcium channel toxicity by clinical manifestations of angioedema, urticarial or erythematous pruritic rash, bronchospasm responsive to albuterol, and stridor from laryngeal edema
    • Differentiate using clinical presentation and absence of conduction abnormality on ECG and cardiac monitoring
    • Diagnosis is primarily clinical and confirmed by response to treatment (eg, epinephrine, corticosteroids, fluids); serial increase in blood tryptase and/or histamine levels can help support diagnosis of anaphylaxis 

Treatment Goals

  • Prevent absorption through gastrointestinal decontamination measures when indicated
  • Provide supportive measures to preserve tissue perfusion by improving cardiac output and peripheral vascular tone

Admission criteria

Admit all symptomatic patients for treatment and monitoring 

Patients ingesting sustained-release products require observation for at least 24 hours 

Patients ingesting amlodipine require observation for at least 12 hours

Admit patients with intentional or malicious ingestion with intent to cause harm 

Criteria for ICU admission
  • Many experts recommend continuous cardiac monitoring and management of all symptomatic ingestions in a high level of care setting (eg, ICU, critical care unit, step-down unit) 
  • Admit patients in whom moderate to severe toxicity is suspected to ICU; ideally, they should be managed in setting with advanced capabilities (eg, extracorporeal membrane oxygenation) in case standard measures fail 
  • Patients with symptomatic bradycardia, hypotension, dysrhythmias, or conduction abnormalities require heightened level of monitoring and aggressive care

Recommendations for specialist referral

  • Consult medical toxicologist and/or regional poison control center for all patients with possible exposure for monitoring and treatment recommendations

Treatment Options

Initial resuscitation measures

  • Airway management; specific considerations include:
    • Rapid sequence intubation induction agents
      • Ketamine may be preferred agent given sympathomimetic effects when there are no contraindications; fentanyl may be acceptable choice unless multiple ingestions are suspected owing to risk for hypotension with coingestion 
      • Maintain care and consider avoidance of induction agents that may worsen hypotension and bradycardia (eg, propofol, thiopental, benzodiazepines, dexmedetomidine) during rapid sequence intubation 
    • Paralytics
      • Avoid paralytic agents with potential to cause hyperkalemia, bradycardia, and other arrhythmias (eg, succinylcholine) 
      • Rocuronium (short-acting), vecuronium (intermediate-acting), and pancuronium (longer-acting) may be preferred agents owing to advantageous cardiovascular profiles in patients with calcium channel blocker toxicity 
  • IV fluid resuscitation
    • Administer IV fluid bolus as first response for patients with manifestations of toxicity (eg, poor perfusion, hypotension, bradycardia) 
  • Atropine trial for symptomatic bradycardia
    • Administer as per advanced life support protocol for symptomatic bradycardia (eg, altered mental status, poor perfusion, hypotension) 
    • Often ineffective; may increase heart rate with resultant transient increase in cardiac output; not anticipated to affect stroke volume or vasomotor tone
  • Prepare to aggressively institute multiple interventions simultaneously in patients with initially poor perfusion and hypotension (significant manifestations of toxicity)
    • Simultaneous management strategies may include a combination of repeat IV fluid bolus, calcium, glucagon, high-dose insulin euglycemic therapy, vasopressors (norepinephrine), and lipid emulsion

Consult medical toxicologist and/or regional poison control center in all cases of exposure 

  • Early consultation is advised before or while initiating specific therapy (eg, gastrointestinal decontamination, high-dose insulin euglycemic therapy) to ensure appropriate dosing and monitoring

Gastrointestinal decontamination

  • Gastric lavage is not routinely indicated
    • Consider with massive, life-threatening ingestion in patients presenting with recent exposure (within 1 hour) by providers with expertise in procedure 
    • Strongly consider potential for vagal stimulation with worsening bradycardia if procedure is attempted; consider pretreatment with atropine 
  • Activated charcoal
    • Consider administration in consultation with medical toxicologist in patients presenting within 1 hour after ingestion
      • Administration after 1 to 2 hours may be recommended in patients coingesting drug that may delay gastric emptying (eg, anticholinergic agent) 
      • Concurrent administration of activated charcoal and whole-bowel irrigation may decrease effectiveness of charcoal; however, clinical relevance of interaction is not definitively known 
    • Strongly consider potential for rapid decompensation with large ingestions before administration; rapid decompensation may lead to unprotected airway and life-threatening aspiration of charcoal
    • Contraindicated in presence of altered mental status or seizure with unprotected airway and in patients with vomiting or ileus 
  • Whole-bowel irrigation with polyethylene glycol for ingestion involving sustained-release product
    • Consider early administration in consultation with medical toxicologist (before hemodynamic compromise) 
    • May be indicated in hemodynamically stable patients after ingestion of potentially toxic dose of sustained-release product, particularly in patients presenting more than 2 hours after ingestion when activated charcoal is less effective 
    • Contraindicated in bowel obstruction, perforation, ileus, emesis, compromised unprotected airway, and hemodynamic instability
    • Theoretical benefit with sustained-release ingestion is often outweighed by practical risks involved with administration owing to hemodynamic instability

Specific treatment based on degree of toxicity in consultation with medical toxicologist

  • Mild toxicity
    • Attempt interventions in a sequential pattern in relatively stable patients; continually monitor and reassess response to individual interventions 
    • Repeat IV fluid bolus
      • Exercise caution to avoid excessive administration of fluids owing to the risk of fluid overload and pulmonary edema in patients with underlying comorbidity (eg, congestive heart failure) 
    • Calcium
      • Recommended as a first line agent; however, evidence regarding efficacy is limited 
      • May benefit contractility and vasomotor tone 
      • Unlikely to affect heart rate or conduction; administration is associated with risk for development of hypercalcemia, particularly with repeated dosing
    • Glucagon
      • Considered a mainstay in treatment; however, evidence regarding efficacy is somewhat limited 
      • May increase heart rate and contractility in some patients when used early in course of poisoning; expect minimal effect on mean arterial pressure 
      • Improvement in heart rate may be optimal in the presence of ionized calcium levels within reference range 
      • Pretreatment with antiemetic (eg, ondansetron) may help diminish common adverse effects of nausea and vomiting 
  • Moderate to severe toxicity
    • Often requires multiple interventions simultaneously; in addition to treatments used for mildly symptomatic patients (IV fluid boluses, atropine, calcium, glucagon), institute a combination of the following treatments in unstable patients in consultation with medical toxicologist: high-dose insulin euglycemic therapy, vasopressors, lipid emulsion therapy 
    • Titrate therapy to improve clinical perfusion; therapy escalation is indicated with evidence of inadequate tissue perfusion. Lower blood pressures are tolerable in the absence of signs of severe hypoperfusion 
    • High-dose insulin euglycemic therapy
      • First line intervention for patients with suspected or documented cardiogenic shock and patients with suspected large ingestion 
      • Start treatment early because maximum effects may be delayed up to 1 hour; early institution of treatment improves outcomes 
      • Begin in patients with cardiogenic shock unresponsive to initial measures (eg, IV fluid boluses, atropine, calcium, glucagon)
      • Improves hemodynamics by increasing cardiac contractility 
    • Vasopressor treatment
      • Guide selection of most appropriate vasopressor by hemodynamic parameters based on clinical examination, echocardiography findings, and invasive monitoring results 
        • Norepinephrine may be preferred agent in setting of vasodilatory shock to increase blood pressure 
        • Epinephrine may be preferred agent in the setting of cardiogenic shock to increase contractility and heart rate; dobutamine may be preferred agent in the setting of confirmed myocardial dysfunction 
        • Expert consensus recommends avoiding use of dopamine 
        • Use of vasopressors necessitates invasive blood pressure monitoring to effectively titrate medications 
      • Expected hemodynamic benefits may be unpredictable owing to myocardial depression caused by calcium channel blockers; higher than standard dosing may be required 
        • Maintain awareness that arrhythmogenic effects of most vasopressor agents increase at higher doses
      • Some experts recommend weaning off vasopressors before high-dose insulin therapy when patient requires both treatments; this decision should be made in consultation with medical toxicologist 
    • Lipid emulsion therapy
      • May provide alternative energy source for myocardial cells and/or lipid sink to partition circulating drug away from target tissues
      • Use for patients in near–cardiac arrest and hemodynamic instability not responding to other standard therapy, including high-dose insulin euglycemic therapy and vasopressor support 
        • Toxicologist may make recommendation to initiate this therapy using lipid solubility/partition coefficient of the specific calcium channel blocker ingested
      • May result in improved hemodynamics; data in humans are inconclusive and limited to case reports and animal studies
      • Treatment interferes with accuracy of many laboratory tests including glucose, magnesium, creatinine, and lipase measurements; however, potassium levels remain accurate 
      • Lipid emulsions may interfere with extracorporeal membrane oxygenation; however, failed lipid emulsion is not an absolute contraindication for extracorporeal membrane oxygenation 
  • Treatment of toxicity refractory to standard measures
    • Extracorporeal membrane oxygenation for refractory shock 
    • Transthoracic or transvenous cardiac pacing for refractory bradycardia and high-grade atrioventricular block; goal heart rate is 50 to 60 beats per minute 
    • Other treatment options may include use of methylene blue, intra-aortic balloon pump, and molecular adsorbent recirculating systems 

Monitor closely for clinical deterioration, treatment effects, and emergence of possible metabolic abnormalities

  • Frequent clinical reassessment is paramount because clinical status may change precipitously
  • Patients on high-dose insulin and glucose therapy require close monitoring of glucose and potassium concentrations
  • Patients receiving calcium boluses require close monitoring of calcium concentrations

Replace and correct electrolyte abnormalities and acid-base disorders

  • Replace electrolytes to correct hypocalcemia and hypomagnesemia in standard fashion
  • Correct hypokalemia before initiation of insulin therapy, when possible 
    • Maintain care when correcting for serum hypokalemia during insulin therapy; temporary shift of potassium to intracellular compartment occurs during insulin therapy and aggressive correction of serum hypokalemia may lead to iatrogenic hyperkalemia when insulin is discontinued
    • Some experts advise gentle potassium replacement when levels fall below 2.5 mEq/L during treatment with high-dose insulin 
    • Maintain awareness that correction of hypokalemia is difficult with concomitant hypomagnesemia
  • Treat acidosis with bicarbonate and appropriate ventilator setting modifications to maintain target pH of at least 7.4 

Treat widened QRS interval (sodium channel blockade) with sodium bicarbonate 

  • Consider infusion if treatment response is appreciated

Drug therapy

  • Gastrointestinal decontamination
    • Activated charcoal (single administration) 
      • Activated Charcoal Oral suspension; Children: 1 to 2 g/kg/dose or 25 to 50 g/dose PO. Dosages can be repeated PRN, q4h to q6h.
      • Activated Charcoal Oral suspension; Adults and Adolescents: 50 g as a single dose; not recommended for multiple dosage regimens.
    • Whole-bowel irrigation
      • Polyethylene Glycol 3350 Oral solution: Children: 25 mL/kg/hour (up to 500 mL/hour) orally or by nasogastric tube until rectal effluent is clear.
      • Polyethylene Glycol 3350 Oral solution: Adolescents and Adults: 1.5 to 2 L/hour orally or by nasogastric tube until rectal effluent is clear or a total of 15 L has been passed.
  • Pharmacotherapy to treat effects of absorption
    • Atropine
      • Effects are short-lived
      • Atropine Sulfate Solution for injection; Infants, Children, and Adolescents: 0.02 mg/kg/dose IV (minimum dose: 0.1 mg); may repeat once. Max: 0.5 mg/dose.
      • Atropine Sulfate Solution for injection; Adults: 0.5 to 1 mg IV every 3 to 5 minutes as needed up to 3 mg.
    • Calcium
      • Administer calcium chloride only via central access; calcium gluconate can be administered through a secure peripheral line 
      • Calcium chloride contains 3 times the amount of ionized calcium per mL compared with calcium gluconate 
      • Recommendation regarding number of doses to be administered is not rigorously standardized
        • Some experts recommend only a single dose of calcium given uncertain efficacy and potential for harm from iatrogenic hypercalcemia 
        • Others suggest that bolus may be repeated to serum calcium concentration no greater than 15 mg/dL 
      • Beneficial effects are often short-lived and calcium alone may not significantly improve condition in severely poisoned patients 
      • Avoid calcium administration when coingestion of digoxin is suspected 
      • Calcium chloride
        • Calcium Chloride Solution for injection; Infants, Children, and Adolescents: 20 mg/kg/dose (0.2 mL/kg/dose of a 10% solution) (Max: 2 g/dose) IV over 5 to 10 minutes; if there is a beneficial effect, start 20 to 50 mg/kg/hour (0.2 to 0.5 mL/kg/hour) continuous IV infusion.
        • Calcium Chloride Solution for injection; Adults: 1,000 to 2,000 mg (10 to 20 mL of a 10% solution) IV over 5 minutes; may repeat every 10 to 20 minutes for an additional 3 to 4 doses or consider an infusion 20 to 50 mg/kg/hour (0.2 to 0.5 mL/kg/hour). Titrate to effect and administer additional boluses as needed.
      • Calcium gluconate
        • Calcium Gluconate Solution for injection; Infants, Children, and Adolescents: 60 to 100 mg/kg/dose (Max: 3 g/dose) IV/IO (0.6 to 1 mL/kg); may repeat if needed. Calcium chloride is preferred salt.
        • Calcium Gluconate Solution for injection; Adults: 1,500 to 3,000 mg (15 to 30 mL of a 10% solution) IV over 2 to 5 minutes; may repeat if needed.
    • Glucagon
      • Consider pretreatment with antiemetic (eg, ondansetron) before administration to diminish adverse effects of nausea and vomiting 
      • Effects are noted within minutes and short-lived, lasting up to 15 minutes. Stack bolus doses in rapid succession to yield desired response; both boluses and infusions require titration to effect 
      • Glucagon Hydrochloride Solution for injection; Infants and Children: 0.03 to 0.15 mg/kg/dose IV (Max: 10 mg/dose); may repeat every 3 to 5 minutes as needed. May be followed by 0.05 to 0.1 mg/kg/hour continuous IV infusion if required. Initial max rate: 5 mg/hour. Titrate to clinical effect.
      • Glucagon Hydrochloride Solution for injection; Adolescents: 5 to 10 mg IV; repeat dose every 3 to 5 minutes as needed. May be followed by 1 to 5 mg/hour continuous IV infusion if required. Initial max rate: 5 mg/hour. Titrate to clinical effect.
      • Glucagon Hydrochloride Solution for injection; Adults: 3 to 10 mg IV followed by 1 to 10 mg/hour continuous IV infusion.
    • High-dose insulin euglycemic therapy
      • Replace potassium if hypokalemia is present before beginning treatment 
      • Insulin Regular (Recombinant) Solution for injection; Adults and Adolescents: 1 unit/kg bolus followed by an initial infusion of 1 unit/kg/hour; titrate to mean arterial pressure that ensures adequate tissue perfusion; titrate up by 1 to 2 units/kg/hour every 10 to 15 minutes to a maximum of 10 units/kg/hour (doses up to 22 units/kg/hour have been used safely under the guidance of a toxicologist). 
      • Administer simultaneous dextrose to patients with glucose concentration less than 200 mg/dL; bolus with 25 to 50 g D50 in adults (or 0.5 g/kg) and 0.25 g/kg D10 to D25 in children, then follow with dextrose infusion at 0.5 g/kg/hour while monitoring glucose frequently; euglycemia is defined as blood glucose between 100 and 250 mg/dL 
        • Concentrated infusions of D25 to D50 through a central line may be required to limit fluid overload (80-kg adult would require 400 mL/hour of D10 to achieve glucose infusion rate of 0.5 g/kg/hour) 
      • Improvement in hemodynamics may take up to an hour to appreciate full effects at optimal dosing. Taper insulin slowly after improvement in hemodynamics is established; rapid taper may result in return of hemodynamic instability 
      • Monitor for potential complications (eg, hypoglycemia, hypokalemia) 
        • Check glucose concentration at least every 15 minutes until stable insulin dose and glucose infusion rate are established
        • Check potassium concentration every hour while insulin is being titrated, then every 2 to 6 hours once insulin dose and glucose infusion have stabilized
    • Vasopressors
      • Standard dosing may not be adequate; higher than standard dosing may be necessary along with use of multiple agents 
      • Norepinephrine
        • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion; titrate to clinical response (Usual Max: 2 mcg/kg/minute).
        • Norepinephrine Bitartrate Solution for injection; Adults: Initially, up to 8 to 12 mcg/minute, as an IV infusion. Infusions are typically initiated and titrated in increments of 0.02 mcg/kg/minute (or more in emergency cases). The usual maintenance dose is 2 to 4 mcg/minute. Patients with refractory shock may require dosages of 8 to 30 mcg/minute.
      • Dobutamine
        • Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Usual dosage range: 2 to 20 mcg/kg/minute.
        • Dobutamine Hydrochloride Solution for injection; Adults: Initially, 0.5 to 1 mcg/kg/minute as continuous IV infusion. Titrate every few minutes to attain hemodynamic goals. Usual dosage range: 2 to 20 mcg/kg/minute IV. Doses more than 20 mcg/kg/minute may increase heart rate.
      • Epinephrine
        • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Doses up to 5 mcg/kg/minute may be necessary.
        • Epinephrine Hydrochloride Solution for injection; Adults: 0.05 to 2 mcg/kg/minute continuous IV infusion; titrate every 10 to 15 minutes in increments of 0.05 to 0.2 mcg/kg/minute to achieve desired blood pressure goal.
    • Lipid emulsion therapy
      • Soybean Oil Emulsion for injection; Infants, Children, and Adolescents: 1 to 1.5 mL/kg IV bolus, repeated every 3 to 5 minutes as needed (Max cumulative bolus: 3 mL/kg) followed by 0.25 mL/kg/minute IV infusion for no more than 60 minutes. If a significant response occurs quickly, adjust infusion to 0.025 mL/kg/minute; increase infusion back to 0.25 mL/kg/minute or repeat bolus if instability re-emerges. Suggested Max: 10 mL/kg.
      • Soybean Oil Emulsion for injection; Adults: 1.5 mL/kg (lean body weight) IV bolus followed by 0.25 mL/kg/minute IV infusion for 30 to 60 minutes. If the patient remains unstable, rebolus once or twice and double the infusion rate. If a significant response occurs quickly, adjust infusion to 0.025 mL/kg/minute; increase infusion back to 0.25 mL/kg/minute or repeat bolus if instability re-emerges. Suggested Max: 10 to 12 mL/kg.
        • Decrease infusion rate to one-tenth of initial infusion rate (0.025 mL/kg/minute) if there is significant response to higher initial infusion rate
        • If hemodynamic instability redevelops at one-tenth initial infusion rate, increase rate back to 0.25 mL/kg/minute or repeat bolus in severe cases
    • Sodium bicarbonate
      • Indicated for wide QRS interval secondary to sodium channel blockade; consider infusion if QRS interval shortens 
      • Sodium Bicarbonate Solution for injection; Children: 1 mEq/kg by slow IV injection.
      • Sodium Bicarbonate Solution for injection; Adults and Adolescents: 2 mEq/kg by slow IV injection for QRS duration greater than 120 milliseconds. 

Nondrug and supportive care

Intentional ingestion

  • Obtain psychiatric evaluation after medical clearance for any patient with known or suspected intentional ingestion 
  • Patients with intentional ingestions require continuous observation to prevent further attempts at self-harm 

Comorbidities

  • Patients with preexisting heart failure are more prone to fluid overload; maintain care with fluid boluses when responding to hypotension to avoid fluid overload 

Monitoring

  • Monitoring asymptomatic patients after ingestion
    • Consultation with a medical toxicologist and/or regional poison control center is recommended because observation times and disposition can vary by medication, timing of ingestion, patient age, and comorbidities
    • General observation guidelines
      • Accidental ingestion of non–sustained-release product
        • Observe for at least 6- to 8-hour period
      • Accidental ingestion of amlodipine
        • Observe for at least 12-hour period
      • Accidental ingestion of sustained-release product 
        • Observe for at least 24-hour period
      • Asymptomatic patients are medically cleared and may be safely discharged home after appropriate observation period
    • Patients coingesting agents that may delay absorption (eg, anticholinergics, opioids) and patients with significant gastrointestinal disease or postsurgical changes may require prolonged observation beyond period recommended in general guidelines 
    • Intentional ingestions require psychiatric consultation to determine safest disposition and need for additional psychiatric intervention before formal disposition 
    • Older adults (eg, those aged 65 years or older) who have inadvertently taken medications incorrectly require evaluation for cognitive compromise and ability to care independently for themselves before consideration for discharge 
  • Monitoring of patient with symptomatic toxicity requiring treatment
    • Frequency of testing is determined on an individual basis according to severity of toxicity and clinical status
      • General monitoring parameters for all patients requiring treatment
        • Cardiac monitoring
          • Continuous cardiac monitoring and pulse oximetry 
          • Serial ECG testing to assess for conduction delays and electrolyte abnormality effects 
          • Follow-up echocardiography for refractory shock and when escalation of therapy is anticipated
        • Laboratory monitoring
          • Monitor serum glucose and electrolyte concentrations including calcium, magnesium, and phosphorus
        • Monitor for treatment effects and adequacy of perfusion
          • Monitor blood gas, lactate level, mental status, urine output, and other examination markers of perfusion (eg, capillary refill)
          • Evidence of cerebral hypoxemia, tissue hypoxemia, and acidosis indicate need for therapy escalation more than an absolute mean arterial blood pressure threshold 
        • Invasive hemodynamic monitoring
          • No gold standard is recommended for hemodynamic monitoring during resuscitation and treatment 
          • In general, invasive monitoring is indicated for patients with persistently unstable hemodynamic parameters despite initial treatment measures
          • May be most helpful to determine most appropriate choice of vasopressor by defining presence and degree of negative inotropy and vasodilation 
    • Patients receiving high-dose insulin and glucose therapy
      • Closely monitor glucose concentration at least every 15 minutes while titrating up on insulin to goal of improved perfusion; make adjustments in glucose infusion rate accordingly 
        • Target glucose concentration is between 100 and 250 mg/dL during insulin therapy 
        • For hypoglycemia, give 25 to 50 g in adults and increase dextrose infusion by 25 g/hour 
        • Space monitoring of glucose concentration to hourly intervals after stable dose of insulin and glucose infusion are achieved 
        • Continue monitoring glucose concentration after insulin drip is tapered to point of discontinuation; many patients require continuous glucose administration after cessation of insulin infusion 
      • Closely monitor potassium concentration every hour until patient is stabilized; space monitoring of potassium concentration to every 2 to 6 hours after stable dose of insulin and glucose infusion are achieved 
        • Target serum potassium concentration is 2.8 to 3.2 mEq/L while on insulin therapy 
        • Maintain care when correcting for serum hypokalemia during insulin therapy; temporary shift of potassium to intracellular compartment may occur. Aggressive correction of serum hypokalemia may lead to iatrogenic hyperkalemia when insulin is discontinued 
      • Monitor magnesium concentration every 4 to 6 hours, especially in patients with hypokalemia. Hypokalemia is difficult to correct with concomitant hypomagnesemia; replace magnesium as per standard protocols 
      • Monitor phosphorus concentration every 4 to 6 hours and replace per standard protocols 
      • Monitor calcium concentration (both total and ionized) every 1 to 2 hours in hemodynamically unstable patients with goal to maintain 1.5 to 2 times upper limit of reference range 
    • Patients receiving glucagon
      • Monitor for adverse effects (ie, vomiting, hyperglycemia)
    • Patients receiving lipid emulsion therapy
      • Monitor for possible adverse effects from hypertriglyceridemia
      • Monitor blood pressure, heart rate, and other available hemodynamic parameters at least every 15 minutes during infusion 
      • Maintain awareness that measurement of several laboratory values becomes inaccurate with therapy (eg, glucose, magnesium, creatinine, lipase); however, potassium measurements remain accurate
    • Patients receiving vasopressor support
      • Invasive blood pressure monitoring is recommended to accurately titrate infusions 
    • Patients receiving calcium therapy
      • Monitor serum calcium concentrations (both total and ionized) frequently during calcium administration; space monitoring to every 2 to 4 hours once no further calcium administration is warranted in hemodynamically unstable patients 
      • Monitor with serial ECGs

Complications

  • From inadequate perfusion or dysrhythmic events; includes:
    • Stroke
    • Ischemia (eg, bowel, limb)
    • Acute respiratory distress syndrome
    • Multiorgan failure
    • Death

Prognosis

  • Any calcium channel blocker overdose has propensity for mortality; severe ingestions are associated with an extremely high mortality rate 
    • In general, mortality may be higher from nondihydropyridines compared with dihydropyridines
      • Verapamil overdose is associated with highest risk of mortality; amlodipine overdose is also associated with high risk for mortality 
    • Intractable hypotension and asystole are usual mode of death 
    • Intentional overdose is associated with high risk of lethal dose exposure
  • Glucose concentrations may be more predictive of severe toxicity than initial vital signs for nondihydropyridines 
  • Worsening degrees of heart block appear to correlate with increased severity of toxicity and worsening prognosis 
  • Intentional overdose is associated with high risk of lethal dose exposure
  • Early use of more aggressive treatment options (eg, high-dose insulin euglycemic therapy) improves outcomes compared with delayed use 
  • Coingestion with other cardioactive agents (eg, calcium channel blockers, tricyclic antidepressants) is associated with higher cardiovascular morbidity

Prevention

  • Keep medications in original child-resistant containers and out of reach of children
  • Consider use of alternative pharmacotherapeutic agents in patients with potential for suicidal behavior

References

1: Tomassoni AJ et al: Emergency department treatment of beta blocker and calcium-channel blocker poisoning. Emerg Med Critical Care. 4(3), 2014

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