Diagnostic Criteria for Hyperosmolar Hyperglycemic State (HHS)
HHS is diagnosed when all of the following metabolic criteria are met: blood glucose ≥600 mg/dL, effective serum osmolality ≥320 mOsm/kg, arterial pH ≥7.30, serum bicarbonate ≥15 mEq/L, and small or absent ketones in urine and serum. 1, 2
Core Metabolic Thresholds
The American Diabetes Association establishes five mandatory criteria that must ALL be present simultaneously for HHS diagnosis: 1, 2
- Blood glucose ≥600 mg/dL (33.3 mmol/L) 1, 2, 3
- Effective serum osmolality ≥320 mOsm/kg H₂O, calculated as: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 1, 2
- Arterial pH ≥7.30 (distinguishes from diabetic ketoacidosis) 1, 2
- Serum bicarbonate ≥15 mEq/L 1, 2
- Small or absent ketones in both urine and serum (ketonemia ≤3.0 mmol/L) 1, 2, 3
Critical Calculation Requirements
Corrected serum sodium must be calculated by adding 1.6 mEq/L to the measured sodium for each 100 mg/dL glucose elevation above normal, as this affects the osmolality calculation and treatment decisions. 2, 3
The effective osmolality formula excludes urea because it freely crosses cell membranes and does not contribute to osmotic gradient, though some guidelines include it: [(2×Na+) + glucose + urea]. 3
Clinical Presentation (Not Diagnostic Requirements)
Altered mental status is a common clinical feature but NOT a mandatory diagnostic criterion. 2 This is a critical distinction that prevents missed diagnoses:
- Mental status can range from full alertness to profound lethargy or coma 1, 2
- The degree of mental obtundation typically correlates with severity of hyperosmolarity 2
- Patients meeting metabolic thresholds warrant HHS management regardless of alertness 2
- The absence of altered mental status does not exclude HHS diagnosis when other criteria are met 2
In pediatric protocols, HHS requires "altered mental status OR severe dehydration," indicating mental status change alone is not mandatory if severe dehydration is present. 2
Essential Initial Laboratory Evaluation
Upon suspicion of HHS, immediately obtain: 2
- Plasma glucose and serum electrolytes with calculated anion gap
- Serum osmolality (calculated and measured if available)
- Blood urea nitrogen and creatinine
- Serum ketones (β-hydroxybutyrate preferred over nitroprusside method)
- Arterial blood gases
- Complete blood count with differential
- Urinalysis with urine ketones by dipstick
- Electrocardiogram
- HbA1c
Bacterial cultures (blood, urine, throat) and chest X-ray should be obtained if infection is suspected, as infection is the most common precipitant of HHS. 2
Distinguishing HHS from Other Conditions
DKA vs. HHS Overlap
Approximately 10% of hyperglycemic crises present with mixed DKA-HHS features. 1 The key differentiators are:
- DKA: pH <7.3, bicarbonate <15 mEq/L, moderate to large ketones, glucose typically >250 mg/dL 1, 4
- HHS: pH ≥7.3, bicarbonate ≥15 mEq/L, minimal ketones, glucose ≥600 mg/dL 1, 4
Other Differential Diagnoses
- Starvation ketosis: Mildly elevated glucose (rarely >250 mg/dL), bicarbonate usually not <18 mEq/L 2
- Alcoholic ketoacidosis: Variable glucose (can be hypoglycemic to mildly elevated), profound acidosis possible 2
Common Pitfalls to Avoid
Do not rely solely on mental status changes to diagnose HHS—this leads to missed diagnoses in alert patients with severe metabolic derangement. 2 Suspect HHS based on metabolic criteria even if mental status is preserved. 2
Monitor calculated effective osmolality, not just individual components, to ensure accurate diagnosis and management. 2 A patient may have marked hyperglycemia but not meet HHS criteria if osmolality is <320 mOsm/kg.
The nitroprusside method for ketone measurement only detects acetoacetic acid and acetone, not β-hydroxybutyrate (the predominant ketoacid), which can lead to underestimation of ketosis. 1 Direct measurement of β-hydroxybutyrate in blood is preferred. 1
Timeline and Precipitating Factors
HHS develops over days to a week (unlike DKA which evolves over hours to days), typically presenting with polyuria, polydipsia, weight loss, and progressive dehydration before mental status changes occur. 2, 5
Most common precipitants include: 2
- Infection (most frequent)
- Acute cerebrovascular accident
- Myocardial infarction
- Medications affecting carbohydrate metabolism (diuretics, corticosteroids, SGLT2 inhibitors)