Hyperglycemic Hyperosmolar Syndrome

Hyperglycemic Hyperosmolar Syndrome 

Hyperglycemic hyperosmolar syndrome (HHS) is a life-threatening complication of diabetes mellitus characterized by marked hyperglycemia, dehydration, electrolyte derangements, and hyperosmolality with or without mental obtundation, in the absence of significant ketoacidosis.


  • Hyperosmolar hyperglycemic syndrome
  • Diabetic hyperosmolar syndrome
  • Hyperglycemic hyperosmolar nonketotic syndrome
  • Hyperglycemic hyperosmolar nonketotic coma
  • Hyperosmolar hyperglycemic state
  • Nonketotic hyperosmolar syndrome

Epidemiology & Demographics

Hyperglycemic Hyperosmolar Syndrome is a rare condition that most commonly affects patients with type 2 diabetes mellitus.

Approximately 20% of patients have no history of diabetes.

Elderly individuals with new-onset diabetes or those with poorly controlled type 2 diabetes predisposed to extracellular fluid volume depletion (so-called dehydration) are at increased risk for Hyperglycemic Hyperosmolar Syndrome.

Mortality from Hyperglycemic Hyperosmolar Syndrome is estimated at 5% to 20%, a greater mortality rate than for diabetic ketoacidosis.

Prognosis is determined by several factors, including age, degree of dehydration, and presence of other comorbidities.

What are the Symptoms of Hyperglycemic Hyperosmolar Syndrome – Physical Findings & Clinical Presentation

Here are the symptoms of Hyperglycemic Hyperosmolar Syndrome

  • •Polyuria, polydipsia, weight loss, weakness
  • •Mental status changes that can range from full alertness to coma
  • •Focal neurologic signs (e.g., hemiplegia, hemianopsia) or seizures (focal or generalized), aphasia, visual hallucinations
  • •Symptoms of coexisting illnesses or comorbidities that may have precipitated the event
  • •Signs of extracellular fluid volume depletion, including dry mucous membranes, poor skin turgor, sunken eyes, hypotension, and tachycardia
  • •Normothermia or hypothermia despite the presence of infection, due to peripheral vasodilation

What causes this condition?

Hyperglycemic Hyperosmolar Syndrome can be precipitated by various conditions:

  • •Infection (most common precipitant, especially pneumonia and urinary tract infections)
  • •Insulin deficiency (undiagnosed diabetes, inadequate insulin, or medication nonadherence)
  • •Inflammatory conditions (e.g., acute pancreatitis, acute cholecystitis)
  • •Ischemia/infarction (e.g., myocardial infarction, stroke, bowel ischemia)
  • •Kidney failure
  • •Severe dehydration (e.g., burns, heatstroke)
  • •Drugs (e.g., steroids, thiazides, beta blockers, atypical antipsychotics, sympathomimetics including cocaine, alcohol, pentamidine)

A relative insulin deficiency provides enough insulin to inhibit ketogenesis but is insufficient to inhibit hepatic gluconeogenesis, glycogenolysis, or promote peripheral glucose uptake, with consequent hyperglycemia.

With underlying illness, counterregulatory hormone excess leads to further blood glucose elevation.

The resultant extreme hyperglycemia leads to osmotic diuresis.

If adequate hydration is not maintained, dehydration and worsening renal function ensue. In those with inadequate fluid intake due to altered thirst mechanisms or the inability to access fluids, as may be seen in the elderly population, the risk of severe dehydration further increases.

Diminished renal filtration further impairs glucose excretion, thus exacerbating the hyperglycemia, dehydration, and hyperosmolality, and increases the risk for cardiovascular collapse.

Differential Diagnosis

  • •Diabetic ketoacidosis
  • •Stroke (especially in the elderly with neurologic abnormalities)
  • •Hypovolemic or septic shock
  • •Encephalopathy

How is this condition diagnosed?

After the initial history is obtained, perform a physical exam that includes immediate evaluation of airway, breathing, circulation, mental status, volume status, and signs suggestive of precipitating event including infection, myocardial infarction, or stroke.

Laboratory Tests

  • •Hyperglycemia: Blood glucose >600 mg/dl 

Diagnostic Testing Criteria for Patients with Hyperglycemic Hyperosmolar State

From Adams JG et al (eds): Emergency medicine: clinical essentials, ed 2, Philadelphia, 2013, Saunders.

  • Glucose higher than 600 mg/dl
  • Normal pH (classically, however, patients are often mildly acidotic)
  • No significant ketosis ∗Serum acetoacetate is often present, typically an absent or low β-hydroxybutyrate level.
  • Serum osmolarity
    • •>320 mOsm/L with any mental status changes, or
    • •>350 mOsm/L
  • Serum osmolality: Usually >320 mOsm/kg
  • •Complete metabolic panel: Serum creatinine, blood urea nitrogen (BUN), electrolytes, glucose
  • •Serum sodium: May be low, normal, or high. Hyperglycemia increases plasma osmolality that translocates intracellular water to the extracellular compartment, decreasing serum sodium. Serum sodium can be corrected by adding 1.6 mmol/L to the measured serum sodium for each 100 mg/dl rise in serum glucose above 100 mg/dl. Marked osmotic diuresis induced by hyperglycemia may cause the serum sodium level to be normal or high
  • •Serum potassium and phosphate: Total body potassium and phosphate deficits typically occur due to urinary losses from osmotic diuresis. However, these levels may be acutely normal or high due to extracellular shift secondary to insulin deficiency and hyperosmolality
  • •Anion gap and serum lactate: Anion gap may be normal or elevated in the setting of lactic acidosis
  • •Arterial blood gas: pH >7.30
  • •Serum and urine ketones: Negative or small
  • •Serum bicarbonate: >15 mmol/L
  • •Hemoglobin A1c (if not performed in past 3 mo)
  • •Complete blood count with differential (may indicate presence of underlying infection [leukocytosis >25,000 mm3], inflammatory condition, hemoconcentration. A leukocytosisof 10,000 to 15,000 mm3 is expected from the stress of illness alone)
  • •Urinalysis, urine/sputum/blood cultures as indicated based on physical exam findings to evaluate the precipitating illness and other comorbidities

Imaging Studies

ECG, chest radiograph, and other imaging studies as indicated to evaluate the precipitating causes of Hyperglycemic Hyperosmolar Syndrome

How is Hyperglycemic Hyperosmolar Syndrome treated?

Acute General Treatment

Aggressive fluid resuscitation, intravenous insulin, and electrolyte correction are the mainstays of treatment.

The initial goal of Hyperglycemic Hyperosmolar Syndrome treatment includes restoring the water deficit with intravenous fluids.

This will help to normalize the plasma hyperosmolality, improve renal perfusion and insulin resistance, reduce the counterregulatory hormone release, and eventually correct hyperglycemia.

Selecting the appropriate type of fluid is important to prevent complications related to dysnatremia.

Improper management of plasma sodium concentration and plasma osmolality during treatment of Hyperglycemic Hyperosmolar Syndrome has been associated with the life-threatening complication of cerebral edema.

Aggressive Intravenous Fluid Replacement

Due to trivial ketonemia and the insulin sensitivity of most Hyperglycemic Hyperosmolar Syndrome patients, initial treatment is intravenous fluid alone without insulin.

Insulin used prior to intravenous hydration or early in resuscitation risks a precipitous drop in serum osmolality.

In the absence of cardiac compromise or end-stage renal disease, infuse 0.9% normal saline (NS) at an initial rate of 1 L/hr for the first hour.

This is then followed by adjustments in the rate of infusion based on electrolyte values and hemodynamics.

A lower rate of 250 to 500 ml/hr may be adequate in the absence of severe dehydration. If the corrected serum sodium is elevated, 0.45% NS may be infused instead.

Reassess corrected sodium needs by frequent checks and calculation. Recommended sodium decline is 0.5 mmol/L/hr and should not surpass 10 to 12 mmol/L per day. Use measured or calculated osmolality to guide the rate of fluid resuscitation for gradual normalization of osmolality.

Recommended serum osmolality decline is 3 mOsm/kg per hour. Once serum glucose decreases to 300 mg/dl, change the intravenous fluid to 5% dextrose with 0.45% NS at 150 to 250 ml/hr.


Once glucose is no longer significantly improving with fluids alone, reassess patient’s fluid status and initiate intravenous insulin.

Administer initial bolus of intravenous regular insulin 0.1 units/kg followed by 0.1 units/kg per hour infusion or a continuous infusion of 0.14 units/kg per hour without initial bolus.

If serum glucose declines by less than 50 to 75 mg/dl in the first hour, increase the insulin infusion rate every hour until a decline is noted.

Once the serum glucose reaches 300 mg/dl, decrease the insulin infusion rate to 0.02 to 0.05 units/kg per hour to maintain serum glucose between 200 to 300 mg/dl until resolution of Hyperglycemic Hyperosmolar Syndrome.

Potassium Replacement

Insulin therapy shifts potassium intracellularly, frequently causing hypokalemia. If serum potassium at presentation is between 3.3 and 5.2 mmol/L, infuse 20 to 30 mmol of potassium chloride (KCl) with each liter of intravenous fluid to maintain serum potassium between 4 and 5 mmol/L.

If the serum potassium concentration at presentation is <3.3 mmol/L, replace potassium by administering KCl infusion at 20 to 30 mmol/h, and withhold insulin until the serum potassium concentration is >3.3 mmol/L.

If the serum potassium at presentation is >5.2 mmol/L, monitor serum potassium level every 2 hours without intravenous potassium supplementation.

Phosphorus and Magnesium Replacement

  • •Phosphorus and magnesium replacement are not routinely recommended. There are no studies of the utility of phosphate administration during treatment of HHS. Very low phosphorus levels may limit adenosine triphosphate (ATP) generation, thus limiting adequate diaphragm function. In patients with cardiac dysfunction, respiratory depression, or anemia and serum phosphate <1 mg/dl, add 20 to 30 mmol/L potassium phosphate to intravenous fluids.
  • •Monitor serum glucose hourly and serum electrolytes, BUN, and creatinine every 2 to 4 hours until resolution of HHS.

Transition to Subcutaneous Insulin

Normalization of serum osmolality and mental status indicates resolution of HHS.

At this point, a transition to subcutaneous insulin should be performed. Overlap the initiation of subcutaneous intermediate- or long-acting insulin and discontinuation of intravenous insulin by 2 to 4 hours to ensure adequate insulin levels and prevent rebound hyperglycemia.

In patients with a known history of diabetes, their home insulin regimen may be initiated if adequate prior to presentation.

In patients with poorly controlled diabetes, the subcutaneous insulin dose can be determined based on their stable insulin drip requirement.

Insulin-naive patients may be started on basal-bolus insulin therapy either by calculation of total daily dose of 0.5 to 0.8 units/kg (split as half-basal and half-bolus; administer one-third total bolus for each meal) or by their individual stable insulin drip requirements.

Further subcutaneous insulin dose titration is based on subsequent blood glucoses. Resolution of glucotoxicity and inciting condition(s) will decrease insulin requirements. The underlying infection/inflammatory condition or precipitating event must be adequately treated.

Chronic Therapy

Most patients will need insulin at discharge, at least short term.

Patients whose diabetes was previously well controlled on oral agents may resume oral therapy after blood glucose stabilization by insulin.


Most patients require management in an emergency care setting, such as the intensive care unit or in a step-up facility.

Pearls & Considerations

  • •When patients with ESRD experience development of HHS, special management considerations are needed. Aggressive fluid resuscitation is unnecessary in anuric ESRD patients, because most patients cannot produce the osmotic diuresis associated with normal kidney function. Note that urinary potassium and phosphorus losses will not occur, thereby limiting the need for supplementation. Lower continuous insulin infusion rates are required in ESRD patients because of decreased insulin clearance. Hemodialysis is typically delayed until serum glucoses are corrected. Precipitous decreases in serum glucose from insulin administration and hemodialysis may result in rapid shifts in tonicity, predisposing cerebral edema.
  • •Education of the patient, family, and caregivers at chronic care facilities regarding optimal glycemic control, limiting modifiable risk factors for HHS, and prevention of dehydration is paramount.

Suggested Readings

  • French E.K., et al.: Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ 2019; 365: pp. I1114.
  • Kitabchi A.E., et al.: Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32: pp. 1335-1343.
  • Muneer M., Akbar I.: Acute metabolic emergencies in diabetes: DKA, HHS and EDKA. In Crusio W.E., et al. (eds): editors: advances in experimental medicine and biology. 2020. Springer, New York pp. 1-30.
  • Schaapveld-Davis C.M., et al.: End-stage renal disease increases rates of adverse glucose events when treating diabetes ketoacidosis or hyperosmolar state. Clin Diabetes 2017; 35 (4): pp. 202-208.

Sign up to receive the trending updates and tons of Health Tips

Join SeekhealthZ and never miss the latest health information

Scroll to Top