PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of thijCurrent IssueSee also Cardiovascular Diseases Journal in PMCSubscribeSubmissionsTHI Journal Website
 
Tex Heart Inst J. 2012; 39(4): 575–578.
PMCID: PMC3423274
Hyperinsulinemia Euglycemia Therapy for Calcium Channel Blocker Overdose
A Case Report
Anushree Agarwal, MD, Siegfried W. Yu, MD, Abdul Rehman, MD, and Joseph Q. Henkle, MD
From: Department of Internal Medicine (Drs. Agarwal, Rehman, and Yu), and Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine (Dr. Henkle), Southern Illinois University School of Medicine, Springfield, Illinois 62702
We report the case of a patient with calcium channel blocker toxicity who was treated successfully with hyperinsulinemia euglycemia therapy, without prior use of vasopressors. The patient was a 60-year-old man with schizoaffective disorder who presented with severe hemodynamic compromise after an intentional overdose of 5,400 mg of extended-release diltiazem. He had been admitted to the hospital twice before for attempted suicide with diltiazem and nifedipine, respectively. During the previous admissions, conventional treatments were used, and complications included hemodynamic compromise, ischemic bowel requiring ileostomy, and a prolonged hospital stay. During the current admission, the patient's clinical condition failed to improve after treatment with charcoal, fluid resuscitation, calcium, and glucagon. Eight hours after admission, hyperinsulinemia euglycemia therapy was initiated; 3 hours later, the patient's hemodynamic status showed sustained improvement. His bradycardia and hypotension resolved without cardiac pacing or vaso-pressors.
Hyperinsulinemia euglycemia therapy is a potentially life-saving treatment for calcium channel blocker toxicity. We suggest that such therapy should be considered early, in conjunction with conventional therapy, for the treatment of calcium channel blocker overdose in patients not responding to initial treatment.
Key words: Calcium channel blockers, diltiazem, hyperinsulinemia euglycemia therapy, insulin/therapeutic use
Calcium channel blocker (CCB) overdose is emerging as one of the most common causes of prescription drug-related fatalities in the United States. In 2009, the American Association of Poison Control Centers reported that, of 1,158 human substance-exposure fatalities, those that involved pharmaceutical drugs were the most common, accounting for 925 of the deaths (79.9%).1 Among those, deaths from cardiovascular drugs were second only to those from analgesics in frequency, and CCBs accounted for 64.2% of the cardiovascular drugs.1 The use of CCBs as an antihypertensive therapy is increasing worldwide,2,3 leading to a parallel increase in potential CCB overdoses.
Conventional treatments for CCB overdose include intravenous (IV) fluids, calcium salts, dopamine, dobutamine, norepinephrine, phosphodiesterase inhibitors, and glucagon. Most of these therapies are intended to increase transmembrane calcium flow (calcium salts) or increase cyclic adenosine monophosphate (cAMP) concentration by stimulating production of adenylate cyclase (with norepinephrine and glucagon) or by inhibiting production of phosphodiesterase (with amrinone and milrinone). However, the conventional therapies are unsuccessful in reversing the cardiovascular toxicity of CCB, so they commonly fail to improve the hemodynamic condition of the patient. Blockade of the L-type calcium channels that mediate the antihypertensive effect of CCBs also decreases the release of insulin from pancreatic β-islet cells and reduces glucose uptake by tissues (insulin resistance). These, in turn, may be the most important factors in CCB-mediated attenuation of cardiac inotropism and peripheral vascular resistance. By targeting this insulin-mediated pathway, hyperinsulinemia euglycemia therapy (HIET) appears to have a distinct role, and its clinical potential is underrecognized in the management of severe CCB toxicity.4
We describe the clinical course of a 60-year-old man who was effectively treated with HIET after developing severe toxicity from an intentional overdose of diltiazem in a suicide attempt. This was his 3rd hospital admission resulting from an intentional CCB overdose. Review of the clinical courses of these 3 overdoses provides a unique opportunity to compare treatment strategies and to illustrate the distinct efficacy of HIET in conjunction with supportive treatment for reversing the life-threatening toxicity of CCB overdose.
A 60-year-old man was admitted to our hospital on 3 separate occasions after he attempted suicide with an overdose of CCB. His medical history included stable coronary artery disease, congestive heart failure with a documented left ventricular ejection fraction of 0.40 to 0.45, hypertension, peripheral vascular disease, and schizoaffective disorder. On 2 of these admissions, the overdose consisted of the same amount of the same drug, diltiazem, but the patient was given different treatments.
During his first admission, the patient arrived at the emergency room 4 hours after taking 30 tablets of 180-mg extended-release diltiazem (5,400 mg). He was alert and oriented but hypotensive. He provided a full history of the incident and informed us that he had just ingested his 30-day supply of diltiazem after refilling the prescription from his pharmacy earlier in the day. The details of his toxic ingestion were supported by the pharmacy's records. His initial blood pressure was 68/58 mmHg, and his heart rate was 54 beats/min. Aggressive fluid resuscitation and IV calcium yielded no improvement. Vasopressor therapy with dopamine was started and titrated to maintain a systolic blood pressure between 90 and 100 mmHg. Twenty-four hours later, the patient developed abdominal distention. Computed tomography of the abdomen revealed large-bowel ischemia, which was attributed to prolonged hypotension in the setting of vasopressor therapy. The patient underwent immediate exploratory laparotomy with right hemicolectomy and ileostomy. Dopamine was discontinued after 36 hours of therapy. The patient left the hospital against medical advice on the 8th day.
One month later, the patient was readmitted with an intentional overdose of long-acting nifedipine (30 tablets of 60-mg nifedipine [1,800 mg]). He arrived at the emergency room 5 hours after ingestion. He was alert and oriented and again provided a complete history, informing us that he had ingested his 30-day supply of nifedipine after refilling the prescription from his pharmacy earlier in the day. The pharmacy's records supported his claim. Initially, the patient was normotensive, with a heart rate of 55 beats/min. Ten hours after admission, however, his systolic blood pressure dropped to 83 mmHg, which again prompted treatment with fluid resuscitation, IV calcium, subcutaneous glucagon, and dopamine infusion. This treatment was continued for 24 hours. Meanwhile, his course was complicated by acute renal failure and partial small-bowel obstruction, both of which subsequently resolved with supportive treatment to achieve hemodynamic stability. This time, he left the hospital against medical advice on the 2nd day of hospitalization.
Twenty days later, the patient returned to the emergency room 3 hours after intentionally ingesting 30 tablets of 180-mg extended-release diltiazem (5,400 mg). He was alert and oriented on presentation. The pharmacy records again showed that he had refilled his prescription earlier that day. In the emergency room, the patient was hypotensive, and his electrocardiogram showed first-degree atrioventricular block with a prolonged QTc interval of 480 ms. He was treated with fluid resuscitation, IV calcium, subcutaneous glucagon, and oral charcoal. His initial arterial blood gas and basic metabolic panel were normal, with a blood glucose level of 132 mg/dL. Results of a complete blood count, standard urinalysis, and serum toxicology were all normal.
Despite aggressive conventional therapy for approximately 8 hours after the patient's arrival at the emergency room, his hypotension and bradycardia failed to improve. At that time, his blood glucose level was 162 mg/dL and his potassium level was 3.4 mEq/L, and the decision was made to treat the patient with HIET (Fig. 1). The treatment was initiated with an IV bolus of regular insulin (0.1 U/kg), followed by a regular IV insulin drip at 0.2 U/kg/hr and 5% dextrose with half-normal saline (D5½NS) at 225 mL/hr. Eleven hours after his presentation at the emergency room, the patient's insulin drip was increased to 0.3 U/kg/hr and the D5½NS rate was increased to 300 mL/hr. Potassium and blood glucose levels were monitored every hour, and no significant hypokalemia or hypoglycemia was observed.
figure 24FF1
Fig. 1 Clinical course of the patient treated with hyperinsulinemia euglycemia therapy (HIET). At 8 hours, HIET was initiated with a regular insulin bolus (0.1 U/kg), followed by a regular insulin drip started at 0.2 U/kg/hr and 5% dextrose in (more ...)
Within 3 hours after HIET was begun, the patient's blood pressure and heart rate had improved. The HIET was continued for a total of 24 hours, resulting in reversal of the patient's hypotension and bradycardia, and resolution of his electrocardiographic abnormalities. He did not require vasopressors or pacing. Figure 1 provides details of his treatment and his systolic blood pressure and heart rate during this hospitalization. Echocardiog-raphy performed before discharge from the emergency room showed normal left ventricular function with an ejection fraction of 0.55. The patient was discharged to the psychiatry department on the 2nd hospital day for further treatment of his psychiatric illness.
The proposed mechanism of cardiovascular compromise in CCB toxicity involves the inhibition of L-type calcium channels, which are found in pancreatic β-cells, as well as in the myocardium and in vascular smooth-muscle cells. This inhibition leads to hypoinsulinemia and insulin resistance-induced decreases in cardiac inotropism and peripheral vascular resistance (Fig. 2). Hyperinsulinemia euglycemia therapy is an exciting development in the treatment of severe CCB toxicity, because it overcomes CCB-induced hypoinsulinemia and insulin resistance, thereby increasing the uptake of glucose by myocardial cells and improving cardiac inotropism and peripheral vascular resistance. In this way, HIET is able to break the cycle of hemodynamic deterioration.4 Insulin-induced hypokalemia may also provide a membrane-stabilizing effect, prolong repolarization, and allow calcium channels to remain open longer, thus facilitating calcium entry during systole.5–7
figure 24FF2
Fig. 2 Pathophysiology of calcium channel blocker toxicity and the action of insulin (developed from an explanation of hyperinsulinemia euglycemia therapy by iheureux and colleagues4).
Although there have been randomized, controlled, prospective studies in animals to compare HIET with calcium chloride, epinephrine, or glucagon individually for the treatment of verapamil toxicity, there have been no prospective clinical trials of HIET in human beings.8,9 In animal models, Kline and colleagues8,9 showed that HIET significantly improves maximum elastance at end-systole, left ventricular end-diastolic pressure, and coronary artery blood flow, in contrast with other treatments, consequently improving survival rates after severe verapamil toxicity.4 These observations support the clinical efficacy of HIET shown in case reports.10–12
The severe hemodynamic consequences of CCB overdose toxicity can result in life-threatening hypotension and end-organ failure, and ineffective therapies can lead to potentially avoidable healthcare expenditures. Although our patient responded better to inotropic agents after the overdose with nifedipine, and the course was relatively less complicated, these results may be explained by the minimal influence of dihydropiridine CCB nifedipine on sinus and atrioventricular node function as opposed to the effects of the non-dihydropiridine CCB diltiazem.13
The optimal dose of insulin to be used in HIET is not known. Generally, the lower insulin doses used in patients with diabetic ketoacidosis are not considered to be effective.14 A review of the literature found no uniformity in the doses of insulin used in HIET, with doses ranging from 0.1 to 1 U/kg/hr. 5,7,10–12,15 Boyer and colleagues16 proposed a protocol for the initiation of HIET wherein an initial insulin bolus of as much as 1 IU/kg is given, followed by insulin infusions of 0.5 IU/kg/hr and 10% dextrose in half-normal saline. Blood glucose levels are monitored every 20 minutes for the first hour, and both potassium and glucose levels are monitored every hour thereafter. The duration of HIET is guided by hemodynamic values after the withdrawal of vasoactive agents.4,16
Our report differs from previous reports of CCB overdose in that we were able to compare 3 separate incidents with 3 different treatment methods in the same patient. The patient had a positive response much earlier in his 3rd admission, when HIET was added to conventional treatment. Furthermore, during the 3rd admission, we initiated HIET earlier in the course of treatment than is documented in other reports, and we achieved substantial improvement without prior or concomitant use of vasopressors. This suggests that earlier use of HIET may obviate the need for vasopressors and avoid the complications associated with prolonged vasopressor therapy.
In conclusion, HIET is an effective treatment for life-threatening CCB overdose with hemodynamic compromise. We suggest that it should be considered as an early, adjunctive therapy, rather than as a rescue therapy, in order to achieve its maximal benefit for CCB overdose and its associated toxicity. Further investigation is warranted, however, to evaluate the efficacy of this distinct therapy.
Footnotes
Address for reprints: Anushree Agarwal, MD, 3114 West American Drive, Milwaukee, Wl 53221
E-mail: anudr28/at/gmail.com
1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2009 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th annual report. Clin Toxicol (Phila) 2010;48(10):979–1178. [PubMed]
2. Jassim Al Khaja KA, Sequeira RP, Mathur VS. Rational pharmacotherapy of hypertension in the elderly: analysis of the choice and dosage of drugs. J Clin Pharm Ther 2001;26(1):33–42. [PubMed]
3. Odigie-Okon E, Zarich S, Okon E, Dufresne A. Antihypertensive therapy in African Americans: findings from an innercity ambulatory clinic. J Clin Hypertens (Greenwich) 2010; 12(3):187–92. [PubMed]
4. Lheureux PE, Zahir S, Gris M, Derrey AS, Penaloza A. Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers. Crit Care 2006;10(3):212. [PMC free article] [PubMed]
5. Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 2005;39(5):923–30. [PubMed]
6. Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 2004;23(4):215–22. [PubMed]
7. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37(4):463–74. [PubMed]
8. Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995;23(7):1251–63. [PubMed]
9. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993;267(2):744–50. [PubMed]
10. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med 2001; 344(22):1721–2. [PubMed]
11. Marques M, Gomes E, de Oliveira J. Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation 2003;57(2):211–3. [PubMed]
12. Patel NP, Pugh ME, Goldberg S, Eiger G. Hyperinsulinemic euglycemia therapy for verapamil poisoning: case report. Am J Crit Care 2007;16(5):520,518–9. [PubMed]
13. Santarelli P, Biscione F, Natale A, Manzoli A, Lanza GA. Electrophysiologic effects of amlodipine vs. diltiazem in patients with coronary artery disease and beta-blocking therapy. Cardiovasc Drugs Ther 1994;8(4):653–8. [PubMed]
14. Levine MD, Boyer E. Hyperinsulinemia-euglycemia therapy: a useful tool in treating calcium channel blocker poisoning. Crit Care 2006;10(4):149. [PMC free article] [PubMed]
15. Rasmussen L, Husted SE, Johnsen SP. Severe intoxication after an intentional overdose of amlodipine. Acta Anaesthesiol Scand 2003;47(8):1038–40. [PubMed]
16. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care 2002;18(1):36–7. [PubMed]
Articles from Texas Heart Institute Journal are provided here courtesy of
Texas Heart Institute