1. First-Line Insulin Regimens

Continuous intravenous (IV) regular insulin is the established standard of care for managing hyperglycemia in hemodynamically unstable or complex critically ill patients. As a patient’s clinical status improves and vasopressor requirements decrease, a carefully planned transition to a subcutaneous basal-bolus regimen is appropriate to maintain glycemic control while simplifying management.

1.1 Continuous Intravenous Infusion Protocols

An IV insulin infusion should be initiated when two consecutive blood glucose readings exceed 180 mg/dL. A typical protocol involves:

• Initiation: Start regular insulin at 0.14 units/kg/hr intravenously. A loading bolus is generally not recommended due to increased risk of hypoglycemia.
• Titration: Perform hourly glucose checks to guide rate adjustments based on a target range of 140–180 mg/dL.
  • If glucose >180 mg/dL: Increase rate by 1–2 units/hr for every 20 mg/dL above the target.
  • If glucose 140–180 mg/dL: Maintain the current rate.
  • If glucose 110–139 mg/dL: Decrease rate by 1 unit/hr.
  • If glucose <110 mg/dL: Hold the infusion, administer 10–25 g of IV dextrose, and resume at 50% of the prior rate once glucose is >110 mg/dL.
• Weaning: After achieving ≥4 consecutive in-target readings, consider reducing the infusion rate by 10–20% every 2–4 hours to test for stability.
• Transition: Plan for a 2–4 hour overlap with subcutaneous insulin before discontinuing the infusion.

1.2 Subcutaneous Insulin Algorithms and Overlap

Transitioning from IV to subcutaneous (SC) insulin requires a structured approach to prevent glycemic excursions. The process should only begin once vasopressors are weaned to low, stable doses and the patient’s clinical trajectory is improving.

1.3 Agent Selection Rationale and Comparative Profiles

2. Adjunctive and Alternative Therapies

While insulin is the cornerstone of ICU glycemic management, other agents play a critical role in rescuing refractory hypoglycemia and managing specific metabolic derangements. Non-insulin oral agents are generally contraindicated in the acute ICU setting.

2.1 Glucagon for Refractory Hypoglycemia

• Indication: Severe hypoglycemia (<70 mg/dL with altered mental status) in a patient without IV access or who is unresponsive to IV dextrose.
• Dose: 1 mg administered subcutaneously or intramuscularly; may be repeated once after 15 minutes if no response.
• Mechanism: Stimulates hepatic glycogenolysis to rapidly increase blood glucose.

2.2 DPP-4 Inhibitors and SGLT2 Inhibitors

These oral agents are generally not used for acute glycemic control in the ICU.

• DPP-4 Inhibitors (e.g., sitagliptin): While they have a low risk of hypoglycemia, there is limited evidence for their use in the ICU. They should be avoided in unstable patients.
• SGLT2 Inhibitors (e.g., canagliflozin): These agents are contraindicated in patients with hemodynamic instability or volume depletion due to the significant risk of precipitating euglycemic diabetic ketoacidosis (EDKA).

3. Pharmacokinetic and Pharmacodynamic Considerations

Critical illness profoundly alters insulin disposition and response. Organ dysfunction and supportive care technologies necessitate individualized dosing strategies and heightened vigilance.

3.1 Renal and Hepatic Dysfunction

• Renal Failure: Decreased insulin clearance prolongs its half-life, significantly increasing the risk of hypoglycemia.
• Hepatic Failure: Impaired gluconeogenesis and glycogenolysis reduce the body’s ability to counteract insulin, also increasing hypoglycemia risk.
• Practice: In patients with severe renal or hepatic failure, initiate insulin infusions at a lower rate (e.g., 0.05–0.10 units/kg/hr) and monitor glucose every 30-60 minutes until stable.

3.2 CRRT and ECMO Adjustments

• Continuous Renal Replacement Therapy (CRRT): Insulin may be adsorbed to the filter or cleared in the effluent, potentially increasing requirements. Consider an initial 10–20% increase in the infusion rate and verify with hourly checks.
• Extracorporeal Membrane Oxygenation (ECMO): Insulin can be sequestered in the circuit, especially a new one. Dosing must be individualized with frequent monitoring.

3.3 Corticosteroids, Vasopressors, and Inotropes

• Corticosteroids: These drugs increase hepatic glucose release and induce insulin resistance, often requiring a 20–50% increase in the insulin infusion rate.
• Vasopressors (e.g., norepinephrine): Alpha-adrenergic stimulation causes peripheral vasoconstriction, leading to erratic and unreliable absorption of SC insulin. An IV infusion is mandatory until vasopressors are weaned.
• Inotropes (e.g., epinephrine): These agents can increase gluconeogenesis, requiring transient adjustments to the insulin infusion.

4. Monitoring Strategies and Technologies

Accurate and timely glucose measurement is the foundation of safe insulin therapy. The choice of monitoring modality depends on the patient’s clinical stability and the intensity of the insulin regimen.

4.1 Capillary vs. Arterial Sampling

• Capillary Point-of-Care (POC): Prone to significant variance (up to 15%) compared to laboratory values. Accuracy is particularly compromised in patients with shock, peripheral edema, or those on high-dose vasopressors.
• Arterial/Venous Blood Gas Analyzers: Offer much higher accuracy and are the preferred method for guiding IV insulin therapy in critically ill patients with arterial line access.

4.2 Continuous Glucose Monitoring (CGM)

• Benefits: Provides real-time trend data, enabling early alerts for impending hypoglycemia or hyperglycemia. Studies suggest CGM can reduce hypoglycemic events by up to 30%.
• Requirements: Requires calibration against arterial or lab values every 6–12 hours. Avoid placing sensors on edematous sites or areas with poor perfusion.
• Integration: To be effective, CGM alarms must be integrated into EMR and pump systems, with clear nurse response protocols to prevent alarm fatigue.

4.3 Pharmacoeconomic Evaluation