AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Calcium channel blockers (CCBs) were initially introduced for use in the United States in 1981. Sustained-release formulations were available 10 years later. Indications for use of these drugs are angina, hypertension, arrhythmias, and migraine prophylaxis.

Calcium channel blocker overdose is rapidly emerging as the most lethal prescription drug ingestion. Overdose by short-acting agents is characterized by rapid progression to cardiac arrest. Overdose by extended-relief formulations result in delayed onset of arrhythmias, shock, sudden cardiac collapse, and bowel ischemia.

Pathophysiology

Calcium channel blockers have the following 4 cardiovascular effects:

1. Peripheral vasodilatation
2. Negative chronotropy (decreased heart rate)
3. Negative inotropy (decreased cardiac contractility)
4. Negative dromotropy (decreased cardiac conduction)

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.

Frequency

United States

In 1996, the American Association of Poison Control Centers (AAPCC) reported 8555 exposures to calcium channel blockers resulting in 58 fatalities and 225 major outcomes.

In 1997, the AAPCC reported 9077 exposures to calcium channel blockers, resulting in 44 fatalities and 232 major outcomes.

In 1998, the AAPCC reported 8666 exposures to calcium channel blockers, resulting in 61 fatalities and 277 major outcomes.

In 1999, the AAPCC reported 8844 exposures to calcium channel blockers, resulting in 61 fatalities and 243 major outcomes.

In 2000, the AAPCC reported 8975 exposures to calcium channel blockers, resulting in 44 fatalities and 317 major outcomes.

In 2001, the AAPCC reported 9264 exposures to calcium channel blockers, resulting in 60 fatalities and 286 major outcomes.

In 2002, the AAPCC reported 9585 exposures to calcium channel blockers, resulting in 68 fatalities and 365 major outcomes.

In 2003, the AAPCC reported 9650 exposures to calcium channel blockers, resulting in 57 fatalities and 339 major outcomes.

In 2004, the AAPCC reported 10,513 exposures to calcium channel blockers, resulting in 62 fatalities and 356 major outcomes.

Mortality/Morbidity

Premature discharge of patients with calcium channel blocker overdose, especially extended-release formulations, may result in severe morbidity or mortality.

• In 1996, the AAPCC reported 58 fatalities and 225 major outcomes.
• In 1997, the AAPCC reported 44 fatalities and 232 major outcomes.
• In 1998, the AAPCC reported 61 fatalities and 277 major outcomes.
  
• In 1999, the AAPCC reported 61 fatalities and 243 major outcomes.
  
• In 2000, the AAPCC reported 44 fatalities and 317 major outcomes.
  
• In 2001, the AAPCC reported 60 fatalities and 286 major outcomes.
  
• In 2002, the AAPCC reported 68 fatalities and 365 major outcomes.
  
• In 2003, the AAPCC reported 57 fatalities and 339 major outcomes.
  
• In 2004, the AAPCC reported 62 fatalities and 356 major outcomes.

Age

• In the last 10 years, there has only been a minimal decline in the percentage of pediatric exposures to CCBs of all cases called to Poison Centers nationally.
• In 1996, with 8555 total exposures reported, 2299 exposures occurred in children younger than 6 years (27% of reported cases).
• In 1997, with 9077 total exposures reported, 2560 exposures occurred in children younger than 6 years (28% of reported cases).
• In 1998, with 8666 total exposures reported, 2197 exposures occurred in children younger than 6 years (25% of reported cases).
• In 1999, with 8844 total exposures reported, 2304 exposures occurred in children younger than 6 years (26% of reported cases).
• In 2000, with 8975 total exposures reported to calcium channel blockers, 2201 exposures occurred in children younger than 6 years (25% of reported cases).
• In 2001, with 9264 total exposures reported to calcium channel blockers, 2249 exposures occurred in children younger than 6 years (24% of reported cases).
• In 2002, with 9585 total exposures to calcium channel blockers, 2256 exposures occurred in children younger than 6 years (24% of reported cases).
• In 2003, with 9650 total exposures to calcium channel blockers, 2198 exposures occurred in children younger than 6 years (23% of reported cases).
• In 2004, with 10,513 total exposures to calcium channel blockers, 2378 exposures occurred in children younger than 6years (23% of reported cases).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Generally, patients with calcium channel blocker overdose present with empty pill bottles or a witnessed ingestion. When a history is unavailable, patients present with a cardiodepressive toxidrome and decreased heart rate and blood pressure.

• Children can become symptomatic with as little as one tablet. In young children, calcium channel blockers have the potential to be fatal with single tablet ingestions. Delayed onset of hypotension has been reported in children with extended-release tablet ingestion. All children with suspected calcium channel blocker ingestions of any amount should be evaluated in a health care facility and monitored in an ICU setting for signs of delayed toxicity.
• Carefully question the caretakers of children who present with depressed blood pressure or heart rate to see if anyone in the household is taking blood pressure or heart medicine.
• In adults, deliberate overdoses are more likely to involve multiple medications, and alcohol is frequently a co-ingestant.
• Establishing the complete list of medications that the patient may have had access to is important.

Physical

Focus the physical examination on mental status and cardiovascular assessment.

• Hypotension
• Bradycardia, with variable degrees of heart block
• Altered mental status or seizures secondary to hypotension
• Occasional cases of bowel infarction caused by mesenteric underperfusion

Causes

• Verapamil (eg, Calan, Isoptin), a phenylalkylamine, produces hypotension and heart block.
• • Several extended-release formulations are available (eg, Isoptin SR, Calan SR, Verelan, Covera-HS).
  • All extended-release formulations require longer observation periods to ensure that no delayed onset of toxicity occurs.
• Nifedipine (eg, Procardia, Procardia XL, Adalat, Adalat CC) is representative of the dihydropyridine class, which produces profound hypotension with less heart block.
• • Overdoses with CCBs in this class may present with reflex tachycardia.
  • Other drugs in the dihydropyridine class of calcium channel blockers act similarly; they include nicardipine (eg, Cardene, Carden SR), nimodipine (Nimotop), nitrendipine, isradipine (DynaCirc, DynaCirc SR), amlodipine (Norvasc), felodipine (Plendil), and nisoldipine (Sular).
  • Amlodipine has a particularly long half-life of 45 hours.
  • All dihydropyridines exert their greatest effect on vascular smooth muscle, producing vasodilatation.
  • The sustained-release or controlled-release preparations also need prolonged observation for the same reasons prolonged observation is required for extended-release formulations.
• Diltiazem (Cardizem), the only CCB in the benzothiazepine class, produces significant antidromotropic effects.
• • Patients ingesting diltiazem typically present with heart block and lesser degrees of hypotension.
  • Delayed-release formulations include Cardizem CD, Cardizem SR, Dilacor XR, Tiamate, Teczem, and Tiazac. These require longer observation periods to insure no delayed onset of toxicity.
• Bepridil (Vascor), used for refractory angina, is a unique calcium channel blocker with some sodium channel blocking activity.
• • Bepridil has been shown to prolong the QTc interval through its potassium channel blocking effect; therefore, it may cause torsade de pointes.
  • About 1% of patients treated with this drug experienced ventricular arrhythmias.
• Mibefradil (Posicor), was a novel selective T-channel calcium channel blocker, which was alleged to have less negative inotropy at therapeutic concentrations; however, it has been removed from the worldwide market after multiple adverse drug interactions were reported.
• • Mibefradil is proarrhythmic and may increase levels of tricyclic antidepressants and many other medications through competitive inhibition of cytochrome P450 C4A.
  • When patients are taking mibefradil, drugs that prolong the QTc interval (eg, terfenadine) should be used cautiously or not at all.
  • Soon after mibefradil's release, a box warning was added to the package insert; it warned that AV block and bradycardia has occurred with standard use, especially if the drug is taken in conjunction with beta-blockers or other calcium channel blockers.
  • On June 8, 1998, the drug was withdrawn from the US market because of adverse drug interactions with 26 other medications. A report by Mullins et al detailed 4 life-threatening cases of cardiogenic shock when mibefradil was used at recommended doses with calcium channel blockers and beta-blockers.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The most likely differential diagnostic problems for a cardiodepressive toxic syndrome are as follows:

Calcium channel blocker overdose
Beta-blocker overdose
Digitalis overdose
Clonidine overdose
Acute myocardial infarction with cardiogenic shock

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Hyperglycemia may occur as calcium channel blockade inhibits insulin release.
• Lactic acidosis may occur and an arterial blood gas (ABG) may suggest acidemia.
• Blood levels are generally not available with any reasonable turn around time. Treatment must be instituted based on symptoms. Blood levels are available to confirm elevated levels if the diagnosis is in doubt.

Imaging Studies

• A chest x-ray may be helpful to determine heart size and presence or absence of congestive heart failure. In patients with CHF, aggressive fluid boluses to treat hypotension may exacerbate heart failure or cause acute pulmonary edema.
• If bowel obstruction is suspected, abdominal radiography is recommended. Color flow vascular ultrasonography of the intra-abdominal arterial supply may confirm bowel infarction.

Other Tests

• Obtain a 12-lead electrocardiogram (ECG) for all cases and perform continuous cardiac monitoring until stable.
• Cardiac biomarkers, such as troponin I, may help differentiate drug-induced bradycardia from ischemic causes.

Procedures

• Transcutaneous or transvenous pacing may be required if hemodynamically unstable heart block fails to respond to medical therapy.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Rapid transport before the patient deteriorates is crucial. Empiric use of glucagon (5-15 mg IV) may be warranted for patients with an unknown overdose presenting with bradycardia or hypotension. Consider using calcium only if a witness confirms a calcium channel blocker overdose; calcium may induce fatal arrhythmias in digoxin overdose, which can present with similar findings. Treat hypotension with fluid boluses. If profound hypotension fails to respond to fluid resuscitation, administer a dopamine or norepinephrine drip, if permitted by local protocol. If the patient deteriorates to cardiac arrest from a calcium channel blocker overdose, perform prolonged cardiopulmonary resuscitation (CPR) in the field because patients have survived neurologically intact after an hour of CPR.

• Establish ABCs, obtain IV access, provide oxygen, and monitor closely.
• Avoid ipecac syrup.
• Administer IV glucagon if hypotension is present. Administer fluid bolus of normal saline if no evidence of decompensated congestive heart failure exists.
• Atropine may be tried if hemodynamically significant bradycardia occurs; however, heart block is usually resistant to atropine in calcium channel blocker toxicity. Mid-dose dopamine (5-10 mcg/kg/min) may improve heart rate and contractility.
• Administer IV calcium chloride (up to 4 g) and/or glucagon (up to 15 mg) if hypotension persists.
• Consider dopamine or norepinephrine infusion if a long transport time is likely, as permitted by local prehospital care protocols.

Emergency Department Care

Aggressive cardiovascular support is necessary for managing the massive calcium channel blocker overdose. While calcium chloride in high doses (4-6 g) may overcome some of the adverse effects of CCBs, it rarely restores normal cardiovascular status. According to many case reports, glucagon and inamrinone (formerly amrinone) have been used with good results. However, vasopressors are frequently necessary for adequate resuscitation and should be started early if hypotension occurs (see Medication). Additional basic overdose management includes airway protection, gastric lavage, and activated charcoal.

• Gastric decontamination
• • Gastric lavage may be useful in early presentations (<1-2 h postingestion), especially in cases of extended- or delayed-release tablet ingestion.
  • Activated charcoal (50-100 g PO) should be administered after gastric lavage.
  • Completely asymptomatic patients may be treated with activated charcoal and close observation.
  • Whole bowel irrigation with polyethylene glycol solution (eg, GoLYTELY, NuLytely, Colyte) may be useful in extended-release preparations. However, be sure that ileus, bowel obstruction, and bowel ischemia have not occurred; case reports of bowel ischemia and infarction have appeared with calcium channel blocker overdose.
• Medications
• • Administer glucagon (5-15 mg IV bolus) followed by an infusion after fluid resuscitation is performed for persistent hypotension. Recommended infusion rate for adults is 10-15 mg/h. Recommended pediatric dose is 50 mcg/kg IV over 5 minutes, followed by an infusion at 0.07 mg/kg/h.
  • Calcium chloride (1-4 g IV, slowly) can be administered for hypotension or heart block.
  • Thirty milliliters of 10% calcium gluconate can be administered over 10-15 minutes. Boluses may be repeated every 15-20 minutes for a total of 3 doses. After the third bolus, the ionized calcium level should be checked. Recommended pediatric dose of calcium gluconate is 60 mg/kg, with a maximum dose of 1 g.
  • Vasopressor support to maintain blood pressure and cardiac output is critical. In the hypotensive patient, administer dopamine at medium-to-high doses early for cardiac contractility for heart rate support and norepinephrine for blood pressure support. Inamrinone may be of additional benefit in profound cardiac contractile failure (see Medication).
  • In a series of case reports, high dose insulin infusion (0.1-1 U/kg/h) with dextrose infusion (usually D10W-D25W) to maintain normal serum glucose levels have been successful for stabilizing cardiac output. When using this technique frequent monitoring of glucose and potassium every 20-30 minutes is necessary.
• Anecdotal efficacy of cardiopulmonary bypass exists in cases of severe poisoning resistant to aggressive medical treatments, such as patients failing glucagon and norepinephrine infusions.
• A patient developing acute respiratory distress syndrome (ARDS) has been successfully treated with partial liquid ventilation; however, this procedure is no longer available.

Consultations

• Consult an AAPCC certified regional poison control center or a medical toxicologist in all cases to assist in management because several options for treatment exist and each case is unique.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Aggressive cardiovascular support is necessary for management of massive calcium channel blocker overdose. While calcium may overcome some adverse effects of CCBs, it rarely restores normal cardiovascular status. According to many case reports, glucagon and inamrinone (formerly inamrinone) have been used with good results. However, vasopressors are frequently necessary for adequate resuscitation and should be started early if hypotension occurs. Recent case reports suggest that use of high dose insulin, with maintenance of euglycemia by dextrose infusion, may be efficacious.

Drug Category: GI decontaminants

Used to minimize systemic absorption of ingested calcium channel blockers.

Drug Category: Antidotes

Used to reverse calcium channel blockade or counteract the effects of reduced intracellular calcium.

Some animal models and human case reports suggest a significant response in cardiac output with hyperinsulinemic therapy with concomitant maintenance of euglycemia with supplemental dextrose. No prospective human trials exist to verify this result.

Drug Category: Cardiovascular agents

Vasopressors augment blood pressure by alpha stimulation induced vasoconstriction.

Atropine rarely helps significant bradycardia or heart block; isoproterenol has an adverse cardiovascular hemodynamic profile greatly diminishing its potential for use in bradycardia. Use these agents only after considering the above factors.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit all ingestions to ICU monitoring for 6-12 hours in standard-release preparation overdose and for 24-36 hours in extended-release or once-a-day preparation overdose.

Further Outpatient Care

• If patient is hemodynamically stable, observation may occur in observation units if available to the ED.
• • Adequate ICU capabilities must be present in the observation unit because these patients may require intubation, pacemaker placement, or vasopressor support.
  • Only asymptomatic ingestions should be watched in an observation unit, and if cardiodepressive symptoms occur, transfer the patient to an ICU setting.
• After adequate observation time, the asymptomatic patient may be referred for psychiatric evaluation.

Transfer

• Patients must be completely asymptomatic to be transferred and should only be transferred with units capable of advanced cardiac life support (ACLS), including intubation and pacing.

Complications

• Anoxic encephalopathy from prolonged CNS hypoxia
• Bowel infarction from underperfusion of mesenteric circulation
• Adult respiratory distress syndrome

Prognosis

• The patient has a reasonable prognosis if treated aggressively, as long as they do not deteriorate to cardiogenic shock.
• • However, even with deterioration, prolonged attempts at resuscitation of the toxin-induced cardiac arrest are warranted.
  • Anecdotal cases of prolonged CPR with aggressive vasopressor support have yielded neurologically intact survivors.

Patient Education

• Advise older patients to keep all medications away from children and to use child-resistant caps if children live in or visit their home.
• Educate grandparents who keep pills in easy-to-open pill-tenders of the risks to their grandchildren, who can easily open these types of containers.
• Advise adults to keep the number of the nearest poison control center near the phone and to call them even for a single tablet ingestion by children.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Extended-release tablets have a delayed onset of up to 12 hours. Releasing a patient who has ingested an extended-release tablet too soon places them in jeopardy.

Special Concerns

• Bepridil is a unique calcium channel blocker with antiarrhythmic activity. It is also proarrhythmic, even at therapeutic doses, and may cause torsade de pointes.
• Mibefradil, which has been taken off the market, has been associated with profound cardiogenic shock and fatality when switching to another CCB after stopping mibefradil.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jan 8, 2007