What is the recommended management of severe hyperglycemia (plasma glucose >300 mg/dL) with or without diabetic ketoacidosis?

Management of Severe Hyperglycemia (Plasma Glucose >300 mg/dL)

For severe hyperglycemia with plasma glucose >300 mg/dL, initiate continuous intravenous insulin infusion at 0.1 units/kg/hour after excluding hypokalemia (K+ ≥3.3 mEq/L), combined with aggressive isotonic saline rehydration at 15-20 mL/kg/hour for the first hour. 1

Initial Assessment and Stabilization

Immediate Laboratory Evaluation

• Obtain arterial blood gases, complete blood count, urinalysis, plasma glucose, electrolytes (especially potassium), blood urea nitrogen, creatinine, serum osmolality, and electrocardiogram immediately upon presentation 1
• Measure serum ketones (β-hydroxybutyrate preferred) and calculate effective serum osmolality: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 1
• Correct serum sodium for hyperglycemia by adding 1.6 mEq to sodium value for each 100 mg/dL glucose above normal 1

Determine Clinical Severity

• Diabetic ketoacidosis (DKA): Blood glucose ≥250 mg/dL, venous pH <7.3, bicarbonate <15 mEq/L, moderate ketonuria or ketonemia 1
• Hyperosmolar hyperglycemic state (HHS): Blood glucose ≥600 mg/dL, venous pH ≥7.3, bicarbonate ≥15 mEq/L, effective serum osmolality ≥320 mOsm/kg, altered mental status or severe dehydration 1
• Patients with severe hyperglycemia (≥300 mg/dL) without acidosis but with symptoms (polyuria, polydipsia, weight loss) require immediate treatment 1

Fluid Resuscitation Protocol

First Hour Management

• Begin isotonic saline (0.9% NaCl) at 15-20 mL/kg body weight/hour for the first hour in all patients with severe hyperglycemia and dehydration 1
• Total fluid replacement should approximate 1.5 times the 24-hour maintenance requirements (approximately 5 mL/kg/hour after initial resuscitation) 1
• Monitor for fluid overload, which can lead to symptomatic cerebral edema, particularly in pediatric patients 1

Subsequent Fluid Management

• After the first hour, adjust fluid rate based on hydration status, electrolyte levels, and urine output 1
• When plasma glucose reaches 250 mg/dL in DKA or 300 mg/dL in HHS, switch to dextrose-containing fluids (D5W with 0.45-0.75% NaCl) while continuing insulin infusion 1

Insulin Therapy

Critical Pre-Insulin Check

• Do not start insulin if serum potassium is <3.3 mEq/L—this is an absolute contraindication that can cause life-threatening cardiac arrhythmias and death 1, 2
• If hypokalemia is present, aggressively replete potassium first with 20-40 mEq/L in IV fluids until K+ ≥3.3 mEq/L 1

Standard Insulin Infusion Protocol (Moderate-Severe Cases)

• Administer IV bolus of regular insulin at 0.1 units/kg body weight (alternatively 0.15 units/kg in some protocols) 1
• Immediately follow with continuous IV infusion of regular insulin at 0.1 units/kg/hour (typically 5-7 units/hour in adults) 1
• Only regular (short-acting) insulin should be used for IV infusion; rapid-acting analogs must not be administered intravenously 2
• Prepare insulin by adding 100 units regular insulin to 100 mL normal saline (concentration 1 unit/mL) 2

Pediatric Considerations

• In pediatric patients (<20 years), omit the initial insulin bolus and start continuous infusion at 0.1 units/kg/hour directly 1
• Some protocols suggest even lower doses (0.05 units/kg/hour) in malnourished children to reduce hypokalemia risk 3

Monitoring and Adjusting Insulin Rate

• Target glucose decline of 50-75 mg/dL per hour 1
• If plasma glucose does not fall by 50 mg/dL in the first hour, verify adequate hydration status; if acceptable, double the insulin infusion rate every hour until achieving steady glucose decline of 50-75 mg/dL/hour 1
• Check blood glucose every 2-4 hours and measure serum electrolytes, venous pH, bicarbonate, and anion gap every 2-4 hours 1

Alternative Subcutaneous Approach (Mild-Moderate Cases Only)

• For hemodynamically stable, alert patients with mild-moderate hyperglycemia (glucose 250-400 mg/dL, pH >7.25), subcutaneous rapid-acting insulin analogs at 0.15 units/kg every 2-3 hours combined with aggressive fluid replacement can be as effective and more cost-effective than IV insulin 1, 4, 3
• This approach requires adequate fluid replacement, frequent bedside glucose monitoring, and appropriate follow-up 1

Potassium Management

Critical Monitoring

• Hypokalemia occurs in approximately 50% of patients during treatment of hyperglycemic crises and severe hypokalemia (<2.5 mEq/L) is associated with increased mortality 1, 5
• Insulin stimulates potassium movement into cells, potentially causing life-threatening hypokalemia, respiratory paralysis, ventricular arrhythmia, and death 2

Potassium Replacement Protocol

• Once serum potassium is ≥3.3 mEq/L and urine output is adequate, add 20-30 mEq/L potassium to each liter of IV fluid 1
• Use a combination of 2/3 KCl or potassium-acetate and 1/3 KPO₄ 1
• Maintain serum potassium between 4-5 mEq/L throughout treatment 1
• Monitor potassium levels closely every 2-4 hours, as intravenously administered insulin has rapid onset requiring increased attention to hypokalemia 2

Transition to Subcutaneous Insulin

Resolution Criteria

• DKA resolution requires all of the following: glucose <200 mg/dL, serum bicarbonate ≥18 mEq/L, venous pH >7.3, anion gap ≤12 mEq/L, and patient able to tolerate oral intake 1
• Ketonemia typically takes longer to clear than hyperglycemia; direct measurement of β-hydroxybutyrate is preferred over nitroprusside method (which only measures acetoacetic acid and acetone) 1

Critical Transition Protocol

• Administer long-acting basal insulin (glargine or detemir) subcutaneously 2-4 hours BEFORE discontinuing IV insulin infusion—this is the most common error leading to DKA recurrence 1, 4
• Continue IV insulin infusion for 1-2 hours after administering subcutaneous basal insulin to ensure adequate absorption and prevent rebound hyperglycemia 1
• Calculate basal insulin dose as approximately 50% of the total 24-hour IV insulin amount given as a single daily injection 6
• Divide the remaining 50% equally among three meals as rapid-acting prandial insulin 6

Glycemic Targets During Hospitalization

Critically Ill Patients (ICU)

• Target glucose concentration of 7.8-10.0 mmol/L (140-180 mg/dL) for the majority of critically ill patients 1
• Start therapy when blood glucose ≥8.3 mmol/L (150 mg/dL) and maintain glucose <10.0 mmol/L with strategies that minimize hypoglycemia risk 1
• Lower targets of 6.1-7.8 mmol/L (110-140 mg/dL) may be appropriate for selected ICU patients at centers with extensive experience and appropriate nursing support 1

Non-Critically Ill Patients

• Target pre-meal glucose <7.8 mmol/L (140 mg/dL) and random blood glucose <10.0 mmol/L (180 mg/dL) 1
• More recent guidelines suggest targeting glucose between 7.8-10.0 mmol/L (140-180 mg/dL) for most general medicine and surgery patients 1
• In terminally ill patients or those with severe comorbidities, higher glucose ranges up to 11.1 mmol/L (200 mg/dL) may be acceptable 1

Common Pitfalls and How to Avoid Them

Critical Errors to Prevent

• Never stop IV insulin abruptly without prior subcutaneous basal insulin administration—this causes DKA recurrence 1, 4
• Never hold insulin when glucose falls to target—instead add dextrose to IV fluids while maintaining insulin infusion to clear ketones 1, 4
• Never initiate insulin if potassium <3.3 mEq/L—replete potassium first to prevent fatal arrhythmias 1, 2
• Never rely solely on urine ketones for monitoring—they lag behind serum ketone clearance and do not measure β-hydroxybutyrate 1

Hypoglycemia Prevention

• Hypoglycemia is the most common adverse reaction of insulin therapy and may lead to unconsciousness, convulsions, temporary or permanent brain impairment, or death 2
• When plasma glucose reaches 250 mg/dL (DKA) or 300 mg/dL (HHS), add dextrose to IV fluids while continuing insulin at the same rate 1
• Adjust insulin dosage if patients change physical activity or meal plans; insulin requirements may be altered during illness, emotional disturbances, or other stresses 2

Monitoring for Complications

• Watch for cerebral edema (rare but frequently fatal, occurring in 0.7-1.0% of children with DKA), characterized by deterioration in consciousness level, lethargy, and decreased arousal 1
• Monitor for hyperchloremic acidosis from excessive saline administration 1
• Assess for fluid overload and pulmonary edema, particularly in patients with widened alveolo-arteriolar oxygen gradient or pulmonary rales 1

Special Populations

Pediatric Patients with Type 2 Diabetes

• Youth with marked hyperglycemia (blood glucose ≥250 mg/dL, A1C ≥8.5%) without acidosis who are symptomatic should be treated initially with basal insulin while metformin is initiated and titrated 1
• In patients with ketosis/ketoacidosis, initiate subcutaneous or IV insulin to rapidly correct hyperglycemia and metabolic derangement; once acidosis resolves, start metformin while continuing subcutaneous insulin 1
• In severe hyperglycemia (blood glucose ≥600 mg/dL), assess for hyperglycemic hyperosmolar nonketotic syndrome 1

Renal or Hepatic Impairment

• Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment 2