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Pediatric Emergency Care:
Special Features: Toxicology Reviews

Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning

BOYER, EDWARD W. MD, PhD; DUIC, PETER A. MD; EVANS, ADELAIDE MD

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From the Departments of Emergency Medicine, University of Massachusetts—Memorial Health Center, Worcester, Massachusetts (E.W. Boyer), and Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (P.A. Duic, A. Evans).

Address for reprints: Edward W Boyer, MD, PhD, Department of Emergency Medicine, University of Massachusetts—Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655.

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INTRODUCTION

Calcium channel blocker (CCB) overdose remains a significant cause of poisoning death (1). Conventional therapy consisting of intravenous (IV) fluids, calcium, dopamine, dobutamine, norepinephrine, and glucagon often fails to improve hemodynamic parameters in severely intoxicated patients (2). Because of these failures, efforts have focused on the development of novel treatments for this poisoning (3,4). One, hyperinsulinemia/euglycemia (HIE) therapy, has produced striking benefit (5,6). This review provides a synopsis of pediatric and adult CCB-poisoned patients treated with this therapy, describes its mechanism of action, and proposes indications and dosing for HIE therapy.

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CASES

Patient 1.

A 5-month-old female weighing 5.5 kg was inadvertently given 20 mg of nifedipine. The infant developed systolic blood pressures of 50 mmHg within 20 minutes and required ventilatory assistance. The patient received calcium chloride, glucagon, dopamine, epinephrine, phenylephrine, and milrinone. Despite these treatments, the patient remained hypotensive with a systolic blood pressure of 50 mmHg; her arterial pH was 7.05. A continuous insulin infusion was begun at 1 U/kg/h. One half hour after starting the insulin infusion, the patient’s systolic blood pressure increased to 80 to 90 mmHg. Glucagon and phenylephrine were discontinued at 30 minutes and 2 hours, respectively, and epinephrine, dopamine, and milrinone were discontinued by 72 hours, 90 hours, and 90 hours, respectively. After 96 hours, insulin was discontinued. The patient developed anuric renal failure, but this condition resolved within 30 days (7).

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Patient 2.

A 14-year-old female ingested 30 mg/kg of sustained release verapamil over a 6-hour period. Upon presentation, her blood pressure was 69/24 mmHg, and her pulse was 56 with a 3rd degree heart block. She received activated charcoal; after an initial response to calcium gluconate and atropine, hypotension returned. She received insulin (a 10 U bolus, followed by a continuous infusion at a rate of 12 U/h) and 6g/h of a dextrose infusion. After 2 hours, the insulin infusion rate was increased to 20 U/h. Her blood pressure increased to 120 mmHg. She received no other medications. The insulin and dextrose infusions were discontinued at 9 and 12 hours, respectively. A serum verapamil concentration, drawn upon presentation, was 1094 ng/mL; a corresponding norverapamil level was 1253 ng/mL (therapeutic concentration: 100–600 ng/mL) (6).

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Patient 3.

A 48-year-old nondiabetic male with hypertension, chronic obstructive pulmonary disease, congestive heart failure, and depression, ingested an unknown amount of extended-release diltiazem in a witnessed ingestion. He became hemodynamically unstable in the emergency department, failing to respond to calcium, IV fluids, dopamine, and dobutamine. He received an insulin infusion at a rate of 75 IU/kg/h, which improved his blood pressure to 115/60 mmHg. All pressors were discontinued within 30 minutes of insulin administration. The patient received the insulin infusion for 5 hours. The patient also received 10 g/h of glucose supplementation (5).

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Patient 4.

A 34-year-old nondiabetic female with hypertension and renal failure ingested 0.86 mg/kg amlodipine tablets. One hour after the ingestion, she became hypotensive with a systolic blood pressure of 40 mmHg and pulse of 60. Because of her history of renal failure, treating physicians did not administer calcium, providing instead activated charcoal, IV fluids, dopamine, dobutamine, norepinephrine, and glucagon. She received 35 U/h of insulin as a continuous IV infusion. Because her initial capillary glucose was 325 mg/dL, she received no supplemental dextrose. Instead, her serum glucose was measured every 15 minutes for 1 hour, and every 30 minutes thereafter. Her blood pressure rose to 150/60 mmHg within 30 minutes of the insulin infusion. When dopamine, norepinephrine, and glucagon were stopped 45 minutes after HIE therapy began, her blood pressure remained unchanged. The insulin infusion was discontinued after 6 hours (5).

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Patient 5.

A 31-year-old male ingested 71 mg/kg of sustained release verapamil. The patient’s had systolic blood pressure 70 mmHg with a pulse of 50; an EKG demonstrated 3rd degree block. The patient, who was orotracheally intubated, was estimated to have an ejection fraction of 10% based upon an echocardiogram. He received activated charcoal, IV fluids, calcium chloride, glucagon, and atropine. Along with 8g/h of dextrose, insulin was administered (10 U bolus, followed by a continuous infusion of up to 10 U/h). Blood pressure increased to 150/70 mmHg, the ejection fraction improved to 50%, and the patient converted to normal sinus rhythm with a rate of 84 beats per minute. Because of oliguria, dopamine was infused at a rate of 2.5 ug/kg/h. Dopamine and insulin infusions were discontinued at 18 and 22 hours, respectively. A peak serum verapamil concentration was 3710 ng/mL, and a norverapamil concentration was 487 ng/mL (6).

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DISCUSSION

The clinical features of CCB toxicity arise from blockade of L-type calcium channels in myocardial cells, smooth muscle cells in the vasculature, and beta-islet cells of the pancreas (8). Antagonism of these channels produces conduction delay, bradycardia, peripheral vasodilatation, hypoinsulinemia, and hyperglycemia. Metabolic acidosis, a common clinical finding, is due to lactic acid and arises from poor perfusion or deranged metabolism of lactate (9,10).

Hypoinsulinemia appears to be a critical factor in CCB overdose (11). Myocytes, in an unstressed aerobic state, oxidize free fatty acids for metabolic energy (8,6). In shock states, such as in CCB toxicity, myocytes switch to glucose utilization for fuel (8,6). Hypoinsulinemia may prevent glucose uptake by myocytes, with ensuing loss of inotropy and decreased peripheral vascular resistance (6). As tissue perfusion falls, the decreased delivery of glucose deprives myocytes of needed fuel. Continuation of this cycle leads to hemodynamic deterioration, shock, and ultimately death.

The exact mechanism of action of HIE therapy is poorly defined. Hyperinsulinemia/euglycemia therapy improves inotropy and peripheral vascular resistance and reverses acidosis, possibly by improving carbohydrate uptake and utilization by myocytes (8,6). In addition, HIE therapy may promote the metabolism of lactate, thereby limiting the metabolic acidosis common in CCB poisoning. In general, the effectiveness of HIE therapy is limited to improvements in arterial blood pressure and acidosis, with beneficial effects frequently occurring within 20 to 45 minutes of insulin administration.

Insulin has a variable effect on cardiac conduction. Among reported cases, only 2 patients converted from 3rd degree heart block to normal sinus rhythm after this therapy was begun (6). Unfortunately, the temporal relationship between HIE and conversion is unclear. Because HIE often fails to correct bradycardia, heart block, and intraventricular conduction delay, other therapeutic modalities such as calcium administration should be aggressively pursued in patients with conduction disturbances.

Cases describing the failure of HIE therapy are infrequent (12,13). In both, HIE therapy was not begun until late in the patients’ courses, with 1 patient not receiving HIE until after ACLS protocols had been exhausted (13). These findings suggest that HIE therapy should not be delayed, although specific data to confirm this recommendation are lacking.

Because each of these cases is drawn from case reports and poorly controlled case series, considerable variation exists in the indications for therapy, insulin dosing and duration, as well as for glucose and potassium supplementation. Our recommendations for the indications and dosing of HIE therapy are presented in Table 1. It must be noted, however, that these guidelines are proposals only; they have not been validated by clinical trials. At present, HIE is reserved as an adjunct to conventional therapy and should be used only after an inadequate response to fluid resuscitation, high-dose calcium salts, and pressors.

Table 1
Table 1
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Hypoglycemia and hypokalemia secondary to insulin infusion remain significant, although inconsistent, effects of this therapy. Among reported cases, several patients who were hyperglycemic at the onset of HIE remained so despite insulin infusions of up to 0.5 U/kg/h. Similarly, hypokalemia arose in only 4 of 11 patients. Of those who developed hypokalemia, all remained asymptomatic, and most of these patients went untreated (6). There have been no reports of rebound in serum potassium concentrations once the insulin infusion is stopped. Because these patients are not thought to have globally depleted stores of potassium, aggressive repletion of K+ in asymptomatic patients may offer limited benefit.

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CONCLUSIONS

As other reports have suggested, HIE is a safe and effective therapy for the treatment of calcium channel blocker intoxications (6). At present, HIE is reserved as an adjunct to conventional therapy. Future studies will determine if HIE therapy should be advanced to initial therapy for calcium channel blocker poisoning.

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REFERENCES

1. Litovitz TL, Klein-Schwartz W, White S, et al. 1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2000; 18:517–574.

2. Enyeart JJ, Price WA, Hoffman DA, et al. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol 1983; 2:1228–1231.

3. Buckley N, Dawson AH, Howarth D, et al. Slow-release verapamil poisoning: Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993; 158:202–204.

4. Bania TC, Blaufeux B, Hughes S, et al. Calcium and digoxin vs. calcium alone for severe verapamil toxicity. Acad Emerg Med 2000; 7:1089–1096.

5. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med 2001; 344:1721–1722.

6. Yuan TH, Kerns 2nd, WP Tomaszewski CA, et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999; 37:463–474.

7. Morris-Kukoski C, Biswas A, Parra M, et al. Insulin “euglycemia” therapy for accidental nifedipine overdose. J Toxicol Clin Toxicol 2000; 38:577.

8. Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995; 23:1251–1263.

9. Buss WC, Savage DD, Stepanek J, et al. Effect of calcium channel antagonists on calcium uptake and release by isolated rat cardiac mitochondria. Eur J Pharmacol 1988; 152:247–53.

10. Rafael J, Patzelt J. Binding of diltiazem and verapamil to isolated rat heart mitochondria. Basic Res Cardiol 1987; 82:246–251.

11. Ohta M, Nelson D, Nelson J, et al. Effect of Ca++ channel blockers on energy level and stimulated insulin secretions in isolated rat islets of Langerhans. J Pharmacol Exp Ther 1993; 264:35–40.

12. Herbert J, O’Malley C, Tracey J, et al. Verapamil overdosage unresponsive to dextrose/insulin therapy. J Toxicol Clin Toxicol 2001; 39:293–294.

13. Boyer EW. 2000 Poisoning Data. Boston: Massachusetts Poison Control Center; 2000.

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Keywords:

Hyperinsulinemia; euglycemia; calcium channel blockers; overdose; poisoning

© 2002 Lippincott Williams & Wilkins, Inc.

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