*Hyperglycemic Hyperosmolar State

Chapter: Hyperglycemic Hyperosmolar State
McMaster Section Editor(s): Victor M. Montori, Juan P. Brito
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): René Rodríguez-Gutiérrez, Analy Velez-Viveros, Armando Quintanilla-Siller, Fernando J. Lavalle-Gonzalez
Author(s) in Interna Szczeklika: Jacek Sieradzki, Ewa Płaczkiewicz-Jankowska
Additional 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 (especially with dehydration), acute cardiovascular conditions (myocardial infarction, stroke), alcohol poisoning, use of diuretics or psychotropic drugs, and renal failure.

Clinical FeaturesTop

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

Symptoms include manifestations of the underlying condition and altered mental status to coma.

Signs include tachycardia, tachypnea, shallow respirations, features of extreme dehydration (reduced skin turgor, dry mucous membranes, reduced eyeball turgor), facial redness, and hypotension.


The initial evaluation is the same as in DKA.

Diagnostic Criteria

Diagnosis is based on laboratory test results (Table 1).

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. Poisonings.


1. Fluid replacement: Similarly as in 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 0.45% saline IV over the first hour.

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

5) 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 1Weak 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 U/kg (usually 4-8 U) in an IV injection bolus or start a continuous insulin infusion at a rate of about 0.15 U/kg/h as a direct step, without the bolus.

2) Immediately start a continuous IV infusion at a rate of 0.1 U/kg/h and 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 U/kg/h, maintain the serum glucose level between 11.1 and 16.6 mmol/L (200-300 mg/dL), and switch from the IV infusion to a subcutaneous insulin regimen. In insulin-naive patients, start with 0.5 to 0.8 U/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 nonnaive patients, a previous 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 the follow-up in patients with DKA. There is no need to serially monitor serum phosphate and calcium levels or ketone levels. In patients in whom acidosis has been excluded, arterial blood gas analysis may be done only as otherwise indicated.


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


Table 1. Diagnostic criteria for hyperglycemic hyperosmolar state (HHS)


Values typical for HHS



Serum bicarbonate level

>18 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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