Calcium Channel Blocker Overdose Research Articles

Terlipressin for refractory hypotension following angiotensin‐II receptor antagonist overdose

A 54-year-old female presented to the Emergency Department following the ingestion of 32 tablets containing a combination of irbesartan 300 mg and hydrochlorothiazide 12.5 mg (CoAprovel, Bristol-Myers Squibb, Uxbridge, UK) and an unknown quantity of diazepam, paracetamol and alcohol. She had a past history of hypertension and alcohol dependency. On admission her arterial pressure was 95/50 mmHg and she had a sinus tachycardia (105 min−1). Seven hours after ingestion she became profoundly hypotensive and despite 2 litres of fluid her arterial pressure was 72/35 mmHg, with a central venous pressure of 13 mmHg. The patient developed 4 mm ST segment depression in leads V2-V5 but remained asymptomatic. She was administered ephedrine 30 mg with no response, and was transferred to ICU, where an infusion of phenylephrine 0.6 μg.kg−1.min−1 was started, with little improvement. The phenylephrine was stopped and norepinephrine and dobutamine were commenced, but despite increasing these to 0.25 μg.kg−1.min−1 and 10 μg.kg−1.min−1, respectively, she remained hypotensive. We decided to administer terlipressin 1 mg (Glypressin, Ferring, Malmö, Sweden) by slow intravenous bolus. Within 2 h her arterial pressure was within normal limits and she could be weaned off all vasopressors and inotropes. She remained normotensive, enabling transfer to the ward the following day, during which her observations were satisfactory. She was discharged home 2 days later after a psychiatric consultation. Patients who have been chronically treated with angiotensin receptor antagonists (AIIR1) have been shown to exhibit hypotension after induction of anaesthesia, which is often refractory to classical vasoconstrictor therapy [1]. As both the sympathetic and renin-angiotensin systems are blunted, the role of the vasopressin in restoring arterial pressure in these cases has been proposed [2]. Arginine-vasopressin, a postpituitary nine amino-acid peptide, stimulates vasopressin receptors – notably the vascular V1a receptors, to cause marked arterial constriction and has been used for septic and catecholamine resistant shock [3, 4]. It has also been shown to improve cerebral blood flow in resuscitation and is included in American Heart Association resuscitation guidelines [5, 6]. Terlipressin (triglycycl–lysine vasopressin) is a drug precursor slowly metabolised to lysine-vasopressin by plasma esterases. It has been reported to be effective in the treatment of vasodilatory shock secondary to calcium-channel blocker overdose and bupivacaine intoxication [7, 8]. Terlipressin was shown to be effective in rapidly restoring arterial pressure with no concomitant impairment in the left ventricular function in patients chronically treated with AIIR1 antagonists who presented with refractory hypotension after induction of anaesthesia [2]. Although our patient was not under general anaesthesia, the normal physiological mechanisms involved in maintaining blood pressure were blunted by the supranormal dose of AIIR1 antagonists. The resulting hypotension would have been caused by vasodilation and decrease in vascular adrenergic receptor sensitivity limiting the clinical effect of adrenergic drugs. Terlipressin results in limited postoperative hypertension and tachycardia [3]. A report of cardiac ischaemia following terlipressin used for treating intra-operative hypotension was associated with an acute increase in left ventricular afterload [9]. We feel that myocardial ischaemia on ECG in our patient was caused by a decrease in perfusion pressure in the coronary arteries. Following the administration of terlipressin there was resolution of the ST segment depression and a cardiac troponin assay was negative, indicating absence of significant myocardial ischaemic injury in this case. In conclusion, we suggest terlipressin may be used for the treatment of refractory hypotension secondary to angiotensin receptor antagonist overdose if conventional vasopressors have been unsuccessful.

Hyperinsulinemia-euglycemia therapy: a useful tool in treating calcium channel blocker poisoning

Hyperinsulinemia-euglycemia (HIE) therapy, when initiated promptly and aggressively, may offer considerable advantages in the treatment of calcium channel blocker poisoning. Although its mechanism of action is uncertain, HIE improves the efficiency with which the poisoned myocardium uses metabolic fuel, the end result of which is improvements in inotropy and other cardiovascular parameters. Although HIE is not universally accepted, the reports included in the previous issue of Critical Care should prompt clinicians to consider HIE an appropriate therapy specifically for calcium channel blocker poisoning.

Bench-to-bedside review: Hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers

Hyperinsulinaemia/euglycaemia therapy (HIET) consists of the infusion of high-dose regular insulin (usually 0.5 to 1 IU/kg per hour) combined with glucose to maintain euglycaemia. HIET has been proposed as an adjunctive approach in the management of overdose of calcium-channel blockers (CCBs). Indeed, experimental data and clinical experience, although limited, suggest that it could be superior to conventional pharmacological treatments including calcium salts, adrenaline (epinephrine) or glucagon. This paper reviews the patho-physiological principles underlying HIET. Insulin administration seems to allow the switch of the cell metabolism from fatty acids to carbohydrates that is required in stress conditions, especially in the myocardium and vascular smooth muscle, resulting in an improvement in cardiac contractility and restored peripheral resistances. Studies in experimental verapamil poisoning in dogs have shown that HIET significantly improves metabolism, haemodynamics and survival in comparison with conventional therapies. Clinical experience currently consists only of a few isolated cases or short series in which the administration of HIET substantially improved cardiovascular conditions in life-threatening CCB poisonings, allowing the progressive discontinuation of vasoactive agents. While we await further well-designed clinical trials, some rational recommendations are made about the use of HIET in severe CBB overdose. Although the mechanism of action is less well understood in this condition, some experimental data suggesting a potential benefit of HIET in β-adrenergic blocker toxicity are discussed; clinical data are currently lacking.

Metaraminol (Aramine®) in the management of a significant amlodipine overdose

To report a patient with a significant amlodipine self-poisoning who failed to clinically respond to conventional treatment and was managed with metaraminol (Aramine). A 43-year old male presenting after ingestion of 560 mg amlodipine, who failed to respond clinically to treatment with fluid resuscitation, calcium salts, glucagon and norepinephrine/epinephrine inotropic support. Following a loading bolus of 2 mg and intravenous infusion (83 microg/min) of metaraminol (Aramine) there was improvement in his blood pressure, cardiac output and urine output. This is the first case report of the beneficial use of metaraminol (aramine) in the management of significant amlodipine poisoning unresponsive to conventional therapy.

High-Dose Insulin Therapy for Calcium-Channel Blocker Overdose

To evaluate the evidence for using high-dose insulin therapy with supplemental dextrose and potassium in calcium-channel blocker (CCB) overdose. Evidence of efficacy for high-dose insulin therapy with supplemental dextrose and potassium was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996-2003 were also reviewed. Identified articles, including animal studies, case reports, and case series, were evaluated for this review. No clinical trials were available. Animal models of CCB overdose demonstrate that high-dose insulin with supplemental dextrose and potassium was a more effective therapy than calcium, glucagon, or catecholamines. High-dose insulin appears to enhance cardiac carbohydrate metabolism and has direct inotropic effects. Published clinical experience is limited to 13 case reports where insulin was used after other therapies were failing; 12 of these patients survived. High-dose insulin therapy was beneficial for CCB-induced hypotension, hyperglycemia, and metabolic acidosis. Bradycardia and heart block resolved in some patients, but persisted in others. Based on animal data and limited human experience, as well as the inadequacies of available alternatives for patients with significant poisoning, high-dose insulin therapy warrants further study and judicious use in patients with life-threatening CCB poisoning.

Calcium Channel Blocker Ingestion: An Evidence-Based Consensus Guideline for Out-of-Hospital Management

In 2003, U.S. poison control centers were consulted after 9650 ingestions of calcium channel blockers (CCBs), including 57 deaths. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System database that were associated with cardiovascular drugs and emphasizes the importance of developing a guideline for the out-of-hospital management of calcium channel blocker poisoning. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of calcium channel blockers alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. The panel's recommendations follow. The grade of recommendation is in parentheses. 1) All patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately regardless of the amount ingested (Grade D). 2) Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D). 3) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see Table ), would warrant consideration of referral to an emergency department (Grade D). 4) Do not induce emesis (Grade D). 5) Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D). 6) For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D). 7) Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).

A fatal case of amlodipine poisoning

A fatal overdose of amlodipine, a calcium channel blocker, in a 50-year-old man is described. Biological samples obtained at autopsy were screened for common drugs and narcotics. The amlodipine determination was made by HPLC with diode-array detection and a post-mortem blood concentration of 2.3 mg/kg was determined. The only other drug detected was a blood alcohol concentration of 0.008%. The presence of amlodipine was confirmed in other tissues and in the stomach content. The overdose is assumed to be an accumulation of amlodipine due to the long half-life of this drug.

Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review

We present a case report of successful treatment of shock induced by the calcium channel blocker (CCB) diltiazem. A 75-year-old woman took a combination of tablets, including diltiazem. Soon after arrival, she developed haemodynamic shock which persisted despite treatment with fluids, dopamine, dobutamine, norepinephrine (noradrenaline), calcium gluconate and glucagon. Haemodynamic stability was not achieved until an insulin infusion and glucose administration was started. We review the literature and the updated guidelines for the treatment of CCB intoxication, with particular emphasis on situations where insulin and glucose infusions can be live saving.

Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review.

Glucagon is usually accepted as part of the standard treatment in the management of patients with beta-blocker and calcium channel blocker overdoses. A systematic review was done in order to evaluate the evidence supporting glucagon use in beta-blocker and calcium channel blocker overdoses. Studies evaluating glucagon for those uses were identified using the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, MedLine, ToxLine, and EMBASE searches, as well as reviewing medical toxicology textbooks and references of identified articles. Only controlled studies of human or animal studies were included, the latter only when it was an in vivo model of acute poisoning. The quality of the included studies was assessed. The search found no study in humans but identified 30 in animals. In the five studies of animal models of beta-blocker overdose included, glucagon appeared to consistently increase the heart rate at least transiently but appeared to have no effect on mean arterial pressure even though it possibly increased cardiac output. Its effect on the survival rate in animal models of beta-blocker overdose was unclear. In the six studies of animal models of calcium channel blocker overdose included, glucagon appeared to increase heart rate and cardiac output and reverse second and third degree AV blocks, all at least transiently. There appeared to be no effect of glucagon on mean arterial pressure although it did increase in one model. Glucagon appeared to have no effect on survival rate. The included studies for both overdoses were not blinded, had limited numbers of animals, and some had inadequate glucagon regime. The evidence supporting the use of glucagon in the management of patients with beta-blocker and calcium channel blocker overdoses is limited to animal studies.

Continuous Calcium Chloride Infusion for Massive Nifedipine Overdose

A 37-year-old woman presented with persistent hypotension and noncardiogenic pulmonary edema after massive nifedipine overdose. Judicious use of continuous and prolonged high-dose IV calcium infusion was administered to provide sustained increases in serum ionic calcium level (approximately 2 mmol/L) and was able to improve the hemodynamic status without any major adverse reaction.

Utilization of a glucagon infusion in the management of a massive nifedipine overdose

This case report describes a continuous i.v. infusion of glucagon used to reverse the cardiovascular manifestations of a nifedipine overdose in a patient who presented after a massive nifedipine extended-release tablet ingestion. In this patient, glucagon appeared to be effective in the management of this toxicologic emergency.

Twelfth Annual Meeting of the Society for Pediatric Anesthesia, Orlando, Florida, October 16, 1998

Twelfth Annual Meeting of the Society for Pediatric Anesthesia, Orlando, Florida, October 16, 1998

Amlodipine overdose causes prolonged calcium channel blocker toxicity

Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.

Approach to the cardiac effects of beta blocker and calcium channel blocker overdose

Beta adrenergic blocking agents and calcium channel blockers are two of the most frequently used cardiac/antihypertensive medications that can be quite lethal in an overdose setting. Glucagon should be considered in the treatment of both agents, although calcium therapy alone has met with variable success in calcium channel blocker overdose. These drug overdoses should be managed in the intensive care unit.

Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration

Aims The purpose of this study was to investigate the effect of activated charcoal on the absorption of amlodipine, with special reference to delayed charcoal administration. Methods Thirty‐two healthy volunteers, eight subjects in four parallel groups, ingested 10 mg of amlodipine on an empty stomach. Activated charcoal (25 g in 300 ml of water) was ingested either immediately afterwards or 2 h or 6 h after amlodipine, or amlodipine was ingested with 300 ml of water only (control). Plasma concentrations and the cumulative excretion of amlodipine into urine were measured by GC‐MS for 96 h and 72 h, respectively. In addition, adsorption of amlodipine to charcoal was studied in vitro. Results Activated charcoal administered immediately after amlodipine reduced the amlodipine AUC(0,96 h) and the 72‐h urinary excretion by 99% (P<0.0005). After a delay of 2 h in charcoal administration the AUC(0,96 h) was reduced by 49% (P=0.001), but after a delay of 6 h the reduction was 15% only (P=NS). At a charcoal: drug ratio of 5:1, about 90% of amlodipine was adsorbed by charcoal in vitro; at ratios of 10:1 and 20:1, adsorption was practically complete. Conclusions Activated charcoal almost completely prevented amlodipine absorption when administered immediately after amlodipine ingestion. Charcoal also markedly reduced amlodipine absorption when given 2 h after amlodipine; in amlodipine overdose, administration of charcoal may be beneficial even later. We conclude that administration of activated charcoal is the method choice to prevent absorption of amlodipine in amlodipine overdose.

Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration

The purpose of this study was to investigate the effect of activated charcoal on the absorption of amlodipine, with special reference to delayed charcoal administration. Thirty-two healthy volunteers, eight subjects in four parallel groups, ingested 10 mg of amlodipine on an empty stomach. Activated charcoal (25 g in 300 ml of water) was ingested either immediately afterwards or 2 h or 6 h after amlodipine, or amlodipine was ingested with 300 ml of water only (control). Plasma concentrations and the cumulative excretion of amlodipine into urine were measured by GC-MS for 96 h and 72 h, respectively. In addition, adsorption of amlodipine to charcoal was studied in vitro. Activated charcoal administered immediately after amlodipine reduced the amlodipine AUC(0.96 h) and the 72-h urinary excretion by 99% (P < 0.0005). After a delay of 2 h in charcoal administration the AUC(0.96 h) was reduced by 49% (P = 0.001), but after a delay of 6 h the reduction was 15% only (P = NS). At a charcoal:drug ratio of 5:1, about 90% of amlodipine was adsorbed by charcoal in vitro; at ratios of 10:1 and 20:1, adsorption was practically complete. Activated charcoal almost completely prevented amlodipine absorption when administered immediately after amlodipine ingestion. Charcoal also markedly reduced amlodipine absorption when given 2 h after amlodipine; in amlodipine overdose, administration of charcoal may be beneficial even later. We conclude that administration of activated charcoal is the method of choice to prevent absorption of amlodipine in amlodipine overdose.

Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride

Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride

Massive verapamil overdose complicated by noncardiogenic pulmonary edema

We describe two cases of pulmonary edema, bradycardia, and hypotension associated with massive verapamil overdose. A noncardiogenic etiology of the pulmonary edema was indicated in one patient by normal thermodilution cardiac output and pulmonary artery occlusion pressure, and in the other patient by a normal echocardiogram. We hypothesize that calcium channel blocker overdose predisposes patients to develop pulmonary edema.

Effect of calcium chloride and 4-aminopyridine therapy on desipramine toxicity in rats.

Hypotension is a major contributor to mortality in tricyclic antidepressant overdose. Recent data suggest that tricyclic antidepressants inhibit calcium influx in some tissues. This study addressed the potential role of calcium channel blockade in tricyclic antidepressant-induced hypotension. Two interventions were studied that have been shown previously to improve blood pressure with calcium channel blocker overdose. CaCl2 and 4-aminopyridine. Anesthetized rats received the tricyclic antidepressant desipramine IP to produce hypotension, QRS prolongation, and bradycardia. Fifteen min later, animals received CaCl2, NaHCO3, or saline. In a second experiment, rats received tricyclic antidepressant desipramine IP followed in 15 min by 4-aminopyridine or saline. NaHCO3 briefly (5 min) reversed hypotension and QRS prolongation. CaCl2 and 4-aminopyridine failed to improve blood pressure. The incidence of ventricular arrhythmias (p = 0.004) and seizures (p = 0.03) in the CaCl2 group was higher than the other groups. The administration of CaCl2 or 4-aminopyridine did not reverse tricyclic antidepressant-induced hypotension in rats. CaCl2 therapy may possibly worsen both cardiovascular and central nervous system toxicity. These findings do not support a role for calcium channel inhibition in the pathogenesis of tricyclic antidepressant-induced hypotension.

Intestinal Infarction Due to Nifedipine Overdose

The first case of intestinal infarction associated with nifedipine overdose is presented. This is also the first reported case of an overdose with an extended release nifedipine preparation. The formation of a large gastric concretion of nifedipine tablets may have enhanced its local vasodilatory effects thereby producing mesenteric hypoperfusion, ischemia, and infarction.