Diltiazem

Clinical Effects:

DILTIAZEM
  • USES: For the treatment of hypertension, dysrhythmias, and stable angina. PHARMACOLOGY: Binds to and antagonizes L-type calcium channels located on all types of muscle cells resulting in relaxation of vascular smooth muscle and arterial vasodilation as well as decreased force of cardiac contraction and decreased heart rate and conduction. TOXICOLOGY: Excessive doses cause bradycardia and conduction delays by suppression of the SA and AV nodes. Decreased contractility is less than that caused by verapamil and more than that caused by nifedipine. Vasodilation is less than that seen after nifedipine overdose. EPIDEMIOLOGY: Common overdose, which may result in significant morbidity and mortality. MILD TO MODERATE TOXICITY: Patients may have asymptomatic bradycardia or mild hypotension which may manifest as dizziness, fatigue, and/or lightheadedness. SEVERE TOXICITY: Can cause profound bradycardia and dysrhythmias (including complete heart block) and hypotension resulting in cardiogenic shock and end-organ dysfunction including lethargy, syncope, altered mental status, seizures, bowel ischemia, renal failure, metabolic acidosis, acute lung injury, coma, and death. Hyperglycemia generally develops in patients with severe poisoning. ADVERSE EFFECTS: COMMON: Minor gastrointestinal effects, headache, and rash are commonly reported.

Range of toxicity:

DILTIAZEM
  • TOXICITY: The following doses are considered to be potentially toxic: an adult with an inadvertent single ingestion of diltiazem greater than 120 mg immediate-release or a chewed sustained-release formulation, greater than 360 mg sustained-release formulation, or greater than 540 mg extended-release formulation, and greater than 1 mg/kg for a child. THERAPEUTIC DOSE: ADULT: ANGINA: 30 mg four times daily immediate release; 120 to 180 mg once daily, up to a MAX of 540 mg extended release. HYPERTENSION: 120 to 240 mg once daily, up to a MAX of 540 mg once daily extended release.

Treatment:

DILTIAZEM
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients who have asymptomatic bradycardia can be admitted and observed with telemetry. Obtain peripheral intravenous access and monitor ECG. Mild hypotension may only require treatment with intravenous fluid administration. MANAGEMENT OF SEVERE TOXICITY: Patients with bradycardia and hypotension require standard ACLS treatment. Place a central line and consider placement of an arterial line. Standard first line treatment includes atropine for bradycardia although in a serious poisoning it is rarely effective. High dose insulin and dextrose have been effective in animal studies and multiple case reports in patients with hypotension refractory to other modalities, and should be considered early in patients with significant hypotension. Use intravenous calcium in severe poisonings although in these cases, beneficial effects of calcium infusion may be very minimal or short-lived. Repeat bolus doses or a continuous intravenous infusion are often needed. Standard vasopressors should be administered to maintain blood pressure. Lipid emulsion has been successful in animal studies and a few case reports of patients with hypotension refractory to other therapies. Intravenous glucagon has been used with variable success. In a patient whose hemodynamic status continues to be refractory despite the treatment described above, extracorporeal membrane oxygenation or cardiopulmonary bypass should be considered. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
  • Decontamination: PREHOSPITAL: Not recommended because of the potential for abrupt deterioration. HOSPITAL: Because a diltiazem overdose can be life-threatening, all significant ingestions should receive activated charcoal. Patients with altered mental status should be intubated prior to administration. Gastric lavage should be considered in patients with recent large ingestions if the airway is protected. Late gastric lavage may be effective following sustained-release products. Whole bowel irrigation should be considered early for patients who can protect their airway or who are intubated who have ingested sustained-release formulations; it can limit absorption from possible concretions. Whole bowel irrigation should NOT be performed in patients who are hemodynamically unstable.
  • Airway management: Intubate patients with coma, mental status depression or significant hemodynamic instability.
  • Hypotensive episode: Treat initially with fluids (insert a central venous or pulmonary artery catheter to guide fluid therapy if hypotension persists). Consider inserting an arterial line in patients with refractory hypotension. Intravenous calcium, vasopressors, high dose insulin/dextrose, and glucagon may all be useful for refractory hypotension. Pacemakers (external or internal), intraaortic balloon pump, and cardiopulmonary bypass have been used in patients refractory to other modalities.
  • Calcium: Intravenous calcium infusions have been shown to be helpful, although response is often short lived. Optimal dosing is not established; start with an initial IV infusion of about 13 to 25 mEq of calcium (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) followed by either repeat boluses every 15 to 20 minutes up to 3 to 4 doses or a continuous infusion starting with 0.5 mEq/kg/hr of calcium (0.2 to 0.4 mL/kg/hr of 10% calcium chloride or 0.6 to 1.2 mL of 10% calcium gluconate) and titrate as needed. Calcium dosing should be titrated to hemodynamic response rather than serum calcium concentration alone; central venous or pulmonary artery catheters may be useful to guide therapy. Monitor ECG and ionized calcium concentration. Patients with severe overdose have tolerated significant hypercalcemia (up to twice the upper limit of normal) without developing clinical or ECG evidence of hypercalcemia.
  • Insulin: Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 unit/kg/hr, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 25 to 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hr in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued. Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
  • Vasopressin: Anecdotal reports suggest that epinephrine, vasopressin, metaraminol, or phenylephrine may occasionally be effective in patients who do not respond to dopamine or norepinephrine.
  • Fat Emulsion: Lipid emulsion has been successful in animal studies and several case reports of patients with hypotension refractory to other therapies. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. If possible, discontinue after 30 to 60 minutes. Longer periods of lipid therapy should be considered if the patient’s hemodynamic stability is dependent on continued lipid infusion.
  • Glucagon: DOSE: ADULT: Optimal dosing in calcium antagonist poisoning is not established. Initially, 3 to 5 mg IV, slowly over 1 to 2 minutes; may repeat treatment with a dose of 4 to 10 mg if there is no hemodynamic improvement within 5 minutes. CHILD: 50 mcg/kg; repeat doses may be used due to the short half-life of glucagon.
  • L-Carnitine: L-carnitine may be useful to treat hypotension in the setting of calcium channel blocker overdose. It is not well studied but an animal study and one human case report suggest efficacy. The dose used in the human case report was 6 g IV followed by 1 g IV every 4 hours.
  • Phosphodiesterase inhibitor: There are case reports where a phosphodiesterase inhibitor (inamrinone, enoximone) appeared to improve blood pressure in patients unresponsive to other modalities.
  • Monitoring of patient: Monitor vital signs frequently. Institute continuous cardiac monitoring and obtain serial ECGs. In patients with significant hypotension or bradycardia, monitor serum electrolytes, blood glucose, renal function, arterial or venous blood gas, and urine output. Obtain digoxin level in patients who also have access to digoxin. Monitor cardiac enzymes in patients with chest pain. Serum diltiazem levels are not readily available and not helpful to guide therapy.
  • Enhanced elimination procedure: Hemodialysis is not of value because of the high degree of protein binding and a large volume of distribution.
  • Patient disposition: HOME CRITERIA: According to the AAPCC guidelines, healthy, asymptomatic adults with a single diltiazem ingestion of 120 mg or less immediate-release or a chewed sustained-release formulation, 360 mg or less of a sustained-release formulation, or 540 mg or less extended-release formulation , and 1 mg/kg or less for a child can be monitored at home. OBSERVATION CRITERIA: Symptomatic patients, those with underlying cardiovascular disease, those taking beta blockers or another cardiodepressant drug, and those with deliberate ingestions should be referred to a health care facility for treatment, evaluation and monitoring. According to the AAPCC guidelines, an adult with an inadvertent single ingestion of diltiazem greater than 120 mg immediate-release or a chewed sustained-release formulation, greater than 360 mg sustained-release formulation, or greater than 540 mg extended-release formulation, and greater than 1 mg/kg for a child should be referred to a healthcare facility. Patients should be observed for at least 6 hours after ingestion of immediate-release and 18 to 24 hours after ingestion of sustained-release formulations. Patients who develop signs or symptoms of toxicity should be admitted to an intensive care setting. ADMISSION CRITERIA: Any patient with a history of ingestion of sustained release dosage forms or who become symptomatic should be admitted to a monitored setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist in cases of severe poisonings or in cases where there is a history of a large exposure.