# Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

## Overview

DKA and HHS are the two most serious acute metabolic complications of diabetes mellitus. DKA results from absolute or relative insulin deficiency leading to ketosis and acidosis, occurring most commonly in Type 1 diabetes but increasingly recognized in Type 2. HHS involves severe hyperglycemia with hyperosmolality and dehydration without significant ketosis, occurring in Type 2 diabetes. Overlap syndromes exist in which patients exhibit features of both conditions. Mortality for DKA is below 1% with appropriate treatment, while HHS carries mortality of 5-20%, reflecting the older age and comorbidities of affected patients.

## Diabetic Ketoacidosis (DKA)

### Diagnostic Criteria

DKA is diagnosed when blood glucose exceeds 250 mg/dL (though it can be lower in euglycemic DKA), arterial pH is below 7.3 or serum bicarbonate is below 18 mEq/L, anion gap exceeds 12, and serum ketones are positive (beta-hydroxybutyrate above 3 mmol/L is preferred over urine ketones).

### Severity Classification

| DKA Severity | pH | Bicarbonate (mEq/L) | Mental Status |
|-------------|-----|--------------------:|--------------|
| Mild | 7.25-7.30 | 15-18 | Alert |
| Moderate | 7.00-7.24 | 10-14 | Alert or drowsy |
| Severe | <7.00 | <10 | Stupor or coma |

Mild DKA features pH 7.25-7.30, bicarbonate 15-18, and an alert patient. Moderate DKA has pH 7.00-7.24, bicarbonate 10-14, with an alert or drowsy patient. Severe DKA shows pH below 7.00, bicarbonate below 10, with stupor or coma.

### Precipitating Factors -- The 5 I's

The five main precipitants are Infection (the most common), Insulin non-compliance or inadequate dosing, Infarction (MI, stroke, mesenteric ischemia), Intoxication or drugs (cocaine, SGLT2 inhibitors, corticosteroids), and Initial presentation of Type 1 diabetes.

### Euglycemic DKA

Euglycemic DKA presents with blood glucose below 250 mg/dL. Causes include SGLT2 inhibitors (the most important modern cause), pregnancy, starvation, alcohol use, and low-carbohydrate diets. It is easily missed when glucose is not dramatically elevated, and ketones and ABG should be checked when clinical suspicion exists.

<image>Pathophysiology of DKA showing insulin deficiency leading to lipolysis, ketogenesis, and metabolic acidosis with concurrent hyperglycemia and osmotic diuresis</image>

### DKA Management

#### 1. Fluid Resuscitation

Resuscitation begins with 0.9% normal saline at 15-20 mL/kg/h (1-1.5 L in the first hour), followed by 250-500 mL/h of 0.9% NS or 0.45% NS based on the corrected sodium. When glucose reaches 200-250 mg/dL, fluids are switched to D5 0.45% NS to prevent hypoglycemia while continuing insulin. The average fluid deficit in DKA is 5-7 liters.

#### 2. Insulin Therapy

The standard protocol uses regular insulin at 0.1-0.14 units/kg/h as a continuous IV infusion, with an optional 0.1 units/kg IV bolus at initiation (which some protocols omit). The target glucose reduction is 50-70 mg/dL per hour. When glucose reaches 200-250 mg/dL, the drip is reduced to 0.02-0.05 units/kg/h and dextrose is added to fluids. Critically, insulin must not be started if potassium is below 3.3 mEq/L; potassium must be replaced first.

#### 3. Potassium Replacement

Total body potassium is always depleted in DKA, even when serum potassium appears initially normal or elevated. | Serum K+ | Action |
| --- | --- | --- |
| <3.3 mEq/L | HOLD insulin; replace K+ aggressively at 20-40 mEq/h IV |  |
| 3.3-5.3 mEq/L | Add 20-40 mEq KCl per liter of IV fluids |  |
| >5.3 mEq/L | Hold K+ replacement; recheck every 2 hours |  |

If potassium is below 3.3, insulin is held and potassium is replaced aggressively at 20-40 mEq/h IV. If potassium is 3.3-5.3, 20-40 mEq KCl per liter of IV fluids is added. If potassium exceeds 5.3, replacement is held and rechecked every 2 hours. Potassium should be monitored every 1-2 hours during treatment.

#### 4. Bicarbonate

Bicarbonate is administered only if pH falls below 6.9, using NaHCO3 100 mEq in 400 mL sterile water at 200 mL/h. Routine bicarbonate is not recommended because it can worsen hypokalemia and paradoxically worsen intracellular acidosis.

#### 5. Phosphate

Phosphate is replaced if levels fall below 1.0 mg/dL or if signs of cardiac or respiratory muscle weakness are present. Potassium phosphate 20-30 mEq over 24 hours serves the dual purpose of replacing both potassium and phosphate.

### Resolution Criteria for DKA

DKA is considered resolved when glucose falls below 200 mg/dL and at least two of the following are present: serum bicarbonate of 15 mEq/L or above, venous pH above 7.3, or anion gap of 12 or below. The patient must be eating before transition to subcutaneous insulin.

### Transition to Subcutaneous Insulin

Subcutaneous basal insulin should be given 2-4 hours before discontinuing the IV insulin drip. The home regimen is resumed (or a new basal-bolus regimen calculated if newly diagnosed). This overlap period prevents rebound ketoacidosis. If the patient was on an SGLT2 inhibitor, it is held during acute illness and restarted cautiously.

<image>DKA management protocol flowchart showing parallel pathways for fluid resuscitation, insulin therapy, potassium replacement, and monitoring with transition criteria to subcutaneous insulin</image>

## Hyperosmolar Hyperglycemic State (HHS)

### Diagnostic Criteria

HHS is diagnosed when blood glucose exceeds 600 mg/dL, serum osmolality exceeds 320 mOsm/kg, pH is above 7.3 with bicarbonate above 18 (no significant acidosis), ketonemia is minimal or absent, and altered mental status is present (correlating with osmolality).

### Key Differences from DKA

HHS typically affects older adults with Type 2 diabetes. Onset is more insidious (days to weeks versus hours to days for DKA). Dehydration is more severe (average deficit 8-10 L versus 5-7 L in DKA). Mortality is higher (5-20%) due to advanced age, comorbidities, and thromboembolic complications. Residual insulin is sufficient to prevent ketosis but not to control glucose.

### Precipitating Factors

Infection (UTI, pneumonia) is the most common precipitant. Other causes include new diabetes diagnosis (often unrecognized Type 2), medication non-compliance, cerebrovascular accident or MI, medications (corticosteroids, thiazide diuretics), and inadequate fluid intake in nursing home residents or cognitively impaired individuals.

### HHS Management

Fluid resuscitation is the primary treatment and is often more critical than insulin initially. Treatment starts with 0.9% NS at 15-20 mL/kg/h in the first hour, followed by 250-500 mL/h, switching to 0.45% NS when corrected sodium normalizes. Slower, more cautious rehydration is necessary in patients with heart failure or CKD. Insulin is given at lower doses (0.05-0.1 units/kg/h) and may be deferred initially in favor of fluids, as fluids alone reduce glucose significantly. The target glucose reduction is 50-70 mg/dL per hour. Potassium replacement follows the DKA protocol. VTE prophylaxis is essential because hyperviscosity creates high thromboembolic risk. Osmolality is monitored, and mental status should improve as it normalizes; if it does not, other causes should be investigated.

<image>Comparison table of DKA versus HHS showing differences in glucose level, pH, ketones, osmolality, fluid deficit, insulin requirements, onset, and mortality</image>

## Monitoring During Treatment

Glucose is checked every 1-2 hours. Electrolytes (potassium, sodium, chloride, bicarbonate) are monitored every 2-4 hours. Venous blood gas is obtained every 2-4 hours until resolution. Beta-hydroxybutyrate, if available, is more reliable than urine ketones for monitoring DKA resolution. Corrected sodium is calculated using the glucose level to track true sodium status: corrected Na equals measured Na plus 1.6 multiplied by (glucose minus 100) divided by 100 (some use a correction factor of 2.4 for glucose above 400).

## Complications of Treatment

Hypoglycemia is the most common complication, resulting from excessive insulin relative to glucose. Hypokalemia results from insulin-driven intracellular shift and renal losses. Cerebral edema occurs primarily in pediatric patients and is rare in adults, associated with overly rapid fluid resuscitation or glucose correction. Pulmonary edema can result from aggressive fluid resuscitation in patients with cardiac or renal dysfunction. Non-anion gap metabolic acidosis can develop during recovery as ketoacid anions are cleared and replaced by chloride.

## Clinical Pearls

Beta-hydroxybutyrate is the dominant ketone in DKA but is not detected by the urine ketone dipstick (which measures acetoacetate), and urine ketones can paradoxically increase during treatment as beta-hydroxybutyrate converts to acetoacetate. The corrected sodium must always be calculated in DKA/HHS because a "normal" measured sodium in the setting of severe hyperglycemia actually represents significant hypernatremia once glucose is corrected. The anion gap, not glucose, is the best marker of DKA resolution. SGLT2 inhibitor-associated euglycemic DKA is easily missed, and clinicians should have a low threshold to check ketones in any acutely ill patient on an SGLT2 inhibitor. Patients with HHS are at high risk for DVT/PE, and VTE prophylaxis must always be ensured. Recurrent DKA most commonly results from insulin non-adherence, and barriers to insulin access (cost, education, psychosocial factors) should be addressed before discharge.

## References

- Kitabchi AE, et al. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care. 2009;32:1335-1343.
- Umpierrez GE, et al. Diabetic Emergencies -- Ketoacidosis, Hyperglycaemic Hyperosmolar State and Hypoglycaemia. Nat Rev Endocrinol. 2016;12:222-232.
- Dhatariya KK, Vellanki P. Treatment of DKA/HHS. Endocrinol Metab Clin North Am. 2020;49:621-633.
- American Diabetes Association. Standards of Care in Diabetes -- 2024: Diabetes Care in the Hospital. Diabetes Care. 2024;47(Suppl 1):S295-S306.
- Palmer BF, Clegg DJ. Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy. Clin J Am Soc Nephrol. 2021;16:1284-1291.