Insulin Therapy

Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS) are acute metabolic emergencies that require swift and precise treatment to prevent morbidity and mortality. Intravenous insulin administration serves as the cornerstone of therapy in these conditions, orchestrating a complex interplay that facilitates the resolution of ketosis and acidosis. However, the initiation and titration of insulin must be conducted with caution to avoid potential adverse effects. This guide aims to provide a comprehensive, evidence-based analysis of insulin therapy for the advanced clinical pharmacist and other healthcare professionals involved in the treatment of DKA and HHS.

Pharmacokinetics and Pharmacodynamics of Insulin

• Regular Insulin (IV)
  • Onset: Immediate
  • Peak: None (steady-state)
  • Duration: 15-30 minutes post-infusion cessation
• Rapid-Acting Insulin Analogs (e.g., Lispro, Aspart)
  • Onset: 10-20 minutes
  • Peak: 1-1.5 hours
  • Duration: 3-5 hours

Prerequisites for Initiating Insulin Therapy

• Potassium Management
  • Insulin therapy can exacerbate hypokalemia, which may trigger arrhythmias.
  • The American Diabetes Association (ADA) advises delaying insulin until serum potassium is ≥3.3 mmol/L.
  • Achieve this by administering IV fluids to expand extracellular volume and increase renal potassium excretion.
  • Initiate potassium supplementation at rates of 20-30 mEq/hour or 40 mEq/hour based on serum potassium levels.

Initial Insulin Dosing

• ADA Recommended Strategies
  • Option 1: 0.1 units/kg IV bolus followed by an infusion of 0.1 units/kg/hour.
  • Option 2: No bolus, with an infusion starting at 0.14 units/kg/hour.

 

Insulin Infusion Titration Protocol

• Initial Hourly Targets
  • Aim for a glucose reduction of 50-70 mg/dL/hour.
• Titration Steps
  • Scenario 1: If glucose decreases <50-70 mg/dL in the first hour:
    • Administer another 0.1-0.14 units/kg bolus.
    • Continue the existing infusion rate.
  • Scenario 2: If glucose decreases >70-100 mg/dL/hour:
    • Reduce the infusion rate by 50%.
  • Scenario 3: When glucose reaches 200-250 mg/dL:
    • Lower the infusion rate to 0.05-0.1 units/kg/hour.
• Monitoring
  • Frequent serum potassium checks are mandatory, with adjustments made to avoid hypokalemia.

 

Transitioning to Subcutaneous Insulin

• Criteria for Transition
  • Anion gap is closing.
  • Patient is alert and can tolerate oral intake.
  • Potassium is stable without the need for aggressive repletion.
• Transition Steps
  • 1-2 hours before stopping the infusion, administer a full dose of long-acting basal insulin (e.g., glargine at 0.5 units/kg).
  • At the next mealtime, administer rapid-acting insulin based on carbohydrate intake.

 

Clinical Pearls

• Always reassess the effectiveness of the insulin regimen based on dynamic changes in glucose, ketones, and acid-base balance.
• Avoid rapid correction of hyperglycemia to prevent cerebral edema.
• Be cautious with fluid and electrolyte management, particularly in patients with cardiac or renal complications.

---

Early Basal Insulin in DKA

The ADA guidelines recommend administering long-acting basal insulin only after resolution of DKA. However, earlier initiation of basal insulin is increasingly being advocated. The rationale includes:

• Smoother transition from IV to subcutaneous insulin, which may prevent recurrence of hyperglycemia or DKA after stopping the infusion.
• Newer basal insulin analogs like glargine and detemir reach peak action after over 4 hours, so the 2-hour overlap with IV insulin may be inadequate.
• Mitigating prolonged use of high-risk IV insulin infusions.
• Allowing faster discontinuation of IV insulin and potentially earlier discharge from ICU.

Recent evidence supports improved outcomes with early basal insulin. A prospective RCT by Hsia et al found lower rates of rebound hyperglycemia when glargine was started within 12 hours of IV insulin. Other RCTs showed early glargine reduced time to DKA resolution without increasing hypoglycemia. Retrospective data associated delays in glargine administration with longer time to DKA resolution and IV insulin duration.

However, maximal benefits were seen when glargine was given very early, even before complete DKA resolution. This aligns with UK guidelines advocating immediate basal insulin upon DKA diagnosis. Typical dosing is 0.25-0.4 units/kg, capped at a reasonable maximum dose.

In summary, early basal insulin is a safe practice that facilitates IV to subcutaneous transition and may accelerate DKA resolution. Glargine or detemir should be started as soon as feasible at an appropriate weight-based dose. Further high-quality studies are still needed to confirm optimal timing and dosing.