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Introduction

  1. Pharmacology
    1. Insulin, a hormone secreted by the beta islet cells of the pancreas, promotes cellular uptake of glucose into skeletal and cardiac muscles and adipose tissue. Insulin shifts potassium intracellularly.
    2. There are several mechanisms by which high-dose insulin (hyperinsulinemia-euglycemia [HIE]) therapy may improve cardiac output:
      1. In calcium channel blocker and beta-adrenergic blocker overdose, myocardial metabolism shifts from free fatty acid to carbohydrate metabolism; insulin increases myocardial uptake of glucose, lactate, and oxygen.
      2. High-dose insulin increases calcium-dependent inotropic effects.
      3. High-dose insulin enhances nitric oxide synthase activity, which dilates coronary, pulmonary, and systemic blood vessels, leading to improved cellular perfusion.
    3. Human regular insulin is biosynthetically prepared with recombinant DNA technology. The onset of action of subcutaneous regular insulin is approximately 30 minutes to 1 hour, and the duration of action is 5-8 hours. The onset of action for high-dose insulin is not known but is frequently stated to be 15-45 minutes. The serum half-life of regular insulin at normal doses is 4-5 minutes after IV administration.
  2. Indications
    1. Diabetes management, hyperglycemic emergencies.
    2. Severe hyperkalemia.
    3. Administration with dextrose for hemodynamic compromise from calcium channel blockers and beta-adrenergic blockers. Improved hemodynamics and an association with survival have been reported in observational studies of patients with calcium channel blocker toxicity and case reports of beta-adrenergic blocker overdose.
  3. Contraindications. Hypersensitivity to insulin or its formulation.
  4. Adverse effects
    1. Hypoglycemia.
    2. Hypokalemia.
    3. Lipohypertrophy or lipoatrophy at injection site.
    4. Fluid overload and hyponatremia with high-dose insulin infusion. Consider using concentrated solutions of insulin and dextrose, given via a central line. Hypomagnesemia and hypophosphatemia are also possible.
    5. Use in pregnancy: FDA Category B (Introduction). Human insulin does not cross the placenta and is considered safe in pregnancy.
  5. Drug or laboratory interactions
    1. Hypoglycemia may be potentiated by ethanol, antidiabetic agents, beta blockers, fluoroquinolones, and salicylates.
    2. Corticosteroids, glucagon, and epinephrine (via beta-adrenergic effects) may antagonize the effects of insulin.
  6. Dosage and method of administration
    1. Hyperglycemic emergencies: Administer regular insulin 0.14 U/kg/h IV infusion or 0.1 U/kg IV bolus followed by 0.1 U/kg/h IV infusion (children: 0.1 U/kg/h IV infusion; bolus is contraindicated).
    2. Hyperkalemia. Administer regular insulin 0.1 U/kg IV with 50 mL of 50% dextrose (children: 0.1 U/kg insulin with 2 mL/kg of 25% dextrose).
    3. Hemodynamic compromise from calcium channel blockers and beta-adrenergic blockers: Hyperinsulinemia-euglycemia (HIE) therapy.
      1. Bolus of regular human insulin 1 U/kg IV. If blood glucose is below 200 mg/dL, give 0.5 g/kg of 50% dextrose IV (children: 0.25 g/kg of 25% dextrose).
      2. Continuous infusion. Wide variations in insulin dose and duration have been reported. Doses as high as 20 U/kg/h have been administered. The most commonly recommended infusion rate is 1-10 U/kg/h. Start at 1 U/kg/h. If refractory to initial therapies, increase by 1-2 U/kg/h every 10 minutes as needed to maintain satisfactory perfusion of vascular beds. Because of the vasodilation associated with HIE therapy, do not make dose adjustments based on the blood pressure alone.
      3. Insulin solutions are often made at a concentration of 1 U/mL. However, to avoid fluid overload, a concentrated insulin infusion up to 16 U/mL may be used.
      4. Maintain euglycemia with boluses and infusions of dextrose as needed. D10W may be given by peripheral IV line if no central line is available. Typically, at insulin doses greater than 5-10 U/kg/h, more concentrated dextrose solutions given via central line are needed to maintain euglycemia and avoid fluid overload.
      5. Monitoring
        1. Measure blood glucose at least every 15 minutes while titrating the insulin infusion upward or downward, until blood glucose has remained in the 100-200 mg/dL range for several hours; glucose testing may then be decreased to every 60 minutes. Blood glucose monitoring should be continued for at least 24 hours after the HIE infusion has been discontinued. Supplemental dextrose has been required for up to 45 hours beyond discontinuation of HIE.
        2. Monitor potassium hourly initially, then at least every 4-6 hours after HIE infusion and the patient's potassium level has stabilized. Replete potassium as needed to maintain potassium above 3.0 mEq/L. Rebound hyperkalemia has been reported after discontinuation of HIE. Monitor magnesium and phosphorus levels.
      6. Duration of therapy. Duration of insulin-dextrose treatment has varied from a single insulin bolus to infusions lasting hours to days. Average insulin infusion duration is 24-31 hours.
      7. Note: There are currently no studies illustrating the best way to decrease HIE therapy. Once hemodynamic parameters have stabilized, the infusion may be gradually tapered and discontinued.