Hyperglycemic Hyperosmolar State

How to Cite This Chapter: Rodríguez-Gutiérrez R, Vélez-Viveros CA, Portillo-Sánchez P, Quintanilla-Siller A, Lavalle-Gonzalez FJ, Sieradzki J, Płaczkiewicz-Jankowska E. Hyperglycemic Hyperosmolar State. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.13.3.2 Accessed September 30, 2020.
Last Updated: June 11, 2019
Last Reviewed: June 11, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia, increased plasma osmolality, dehydration, and often prerenal azotemia (water loss is significantly higher than in diabetic ketoacidosis [DKA]). Despite the very high blood glucose levels, no ketosis or acidosis is observed, which is explained by residual insulin secretion that does not protect against hyperglycemia but is sufficient to inhibit ketone production; in addition, hyperosmolality inhibits lipolysis.

HHS develops mainly in patients with type 2 diabetes mellitus, most frequently as a result of its delayed diagnosis or inappropriate treatment, especially in the elderly. However, it may also develop in patients with type 1 diabetes. The risk of HHS increases with the presence of precipitating factors, including severe infections (the most common precipitating factor, especially with dehydration), acute cardiovascular conditions (myocardial infarction, stroke), alcohol poisoning, use of diuretics or psychotropic drugs, and renal failure. The prognosis in HHS, in comparison with DKA, is markedly worse.

Clinical FeaturesTop

Signs and symptoms of HHS are very similar to DKA. However, the clinical course of HHS is characterized by an onset of days before hospital admission and altered mental status is almost always present (≥90% of patients). In addition, compared with DKA, patients with HHS are usually more dehydrated and do not develop a rapid and deep breathing pattern (Kussmaul) or abdominal pain.

Symptoms including manifestations of the underlying condition from altered mental status to coma.

Signs including tachycardia, tachypnea, shallow or deep respirations, features of extreme dehydration (reduced skin turgor, dry mucous membranes, and reduced eyeball turgor), facial redness, and hypotension. Neurologic signs, such as abnormal movements, seizures, hemiparesis and hemianopia, may occur.


The initial evaluation is the same as in DKA.

Diagnostic Criteria

Diagnosis is based on laboratory test results (Table 5.2-7).

Differential Diagnosis

1. DKA with concomitant hyperosmolality.

2. Coma due to a primary neurologic condition (hyperosmolality is not a constant feature).

3. Hepatic or uremic coma (no severe hyperglycemia is seen; patients with hepatic coma may even have hypoglycemia).

4. Poisoning or intoxication.

5. Dehydration secondary to other causes (diabetes insipidus, excessive use of diuretics, polyuria).


1. Fluid replacement: Similarly to DKA, in HHS, due to the severe dehydration, fluid replacement therapy is considered the most critical part of treatment. The rate of infusion and type of saline solution (0.45% vs 0.9% vs balanced crystalloid solutions) depend on serum sodium and chloride levels, plasma osmolality, and cardiac function. The rate of correction of plasma osmolality should not be >3 mOsm/kg H2O/h. Use 0.45% saline until normal plasma osmolality is restored. The starting point for a reasonable regimen of fluid resuscitation may be as follows:

1) Administer 1000 mL of 0.9% saline IV over the first hour in severe hypovolemia.

2) Administer 500 mL of 0.45% or 0.9% saline IV per hour for the subsequent 4 to 6 hours.

3) Administer 250 mL 0.45% or 0.9% saline per hour until the correction of water deficit is achieved.

4) When serum glucose reaches ≤16.6 mmol/L (300 mg/dL), change to 5% glucose (dextrose) with 0.45% NaCl at a rate of 150 to 250 mL/h.

5) In patients with heart failure it may be necessary to reduce the infusion rates.

6) In case of hypotension use 0.9% saline or a balanced isotonic solution.

2. Reduce hyperglycemia: Start insulin IV (use a short-acting insulin)Evidence 1 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, indirectness, and lack of further recent studies. Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977 Aug 4;297(5):238-41. PubMed PMID: 406561.:

1) Start with approximately 0.1 IU/kg (usually 4-8 IU) in an IV injection bolus and start a continuous insulin infusion at a rate of ~0.14 IU/kg/h as a follow-up to bolus or as a direct step, without the bolus.

2) Adjust the dose as required to achieve a serum glucose level ≤16.6 mmol/L (300 mg/dL).

3) Once serum glucose reaches 16.6 mmol/L (300 mg/dL), reduce the infusion rate of IV insulin to between 0.02 and 0.05 IU/kg/h, maintain the serum glucose level between 11.1 and 16.6 mmol/L (200-300 mg/dL), then switch from the IV infusion to a subcutaneous insulin regimen. In insulin-naive patients, start with 0.5 to 0.8 IU/kg/d of human insulin (our pattern of practice is to use two-thirds of insulin isophane and one-third of regular insulin), maintaining the insulin infusion for 1 to 2 hours after the subcutaneous regimen begins and the patient has eaten. In patients previously treated with insulin, a prior insulin regimen can be restarted.

3. Correct potassium deficit as in DKA.

4. Search for the precipitating cause and treat appropriately.


Follow-up is similar to DKA.

The criteria of resolution are normal osmolality and normal mental status. There is no need to monitor serum phosphate, calcium, or ketone levels. In patients in whom acidosis has been excluded, arterial blood gas analysis may be done only as otherwise indicated.

Complications and prognosisTop

Rhabdomyolysis resulting from severe hyperosmolality, gastroparesis, and venous thromboembolism (common; thromboprophylaxis with subcutaneous heparin is recommended: see Primary Prevention of Venous Thromboembolism).

The estimated mortality rate in HHS is ~20% and is 10 times higher than in DKA. Prognosis depends on the presence of comorbidities, age, and severity of dehydration, with infants and elderly being the most affected.


Table 5.2-7. Diagnostic criteria for hyperglycemic hyperosmolar state (HHS)


Values typical for HHS

Blood glucose level in mmol/L (mg/dL)

≥33.3 (600)



Serum bicarbonate level

>15 mmol/L

Urine ketone bodies/serum ketone bodies


Effective serum osmolality

>320 mOsm/kg H2Oa

Altered mental status

Altered level of consciousness to lack of response (coma)

Anion gap


a Reference range: 280 to 290 mOsm/kg H2O.

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