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Basic Information ⬇

AUTHOR: Jessica E. Shill, MD

Definition

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, all in the absence of significant ketoacidosis.

Synonyms

HHS

Hyperosmolar hyperglycemic syndrome

Diabetic hyperosmolar syndrome

Hyperglycemic hyperosmolar nonketotic syndrome

Hyperglycemic hyperosmolar nonketotic coma

Hyperosmolar hyperglycemic state

Nonketotic hyperosmolar syndrome

ICD-10CM CODES
E08.00Diabetes mellitus due to underlying condition with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHC)
E08.01Diabetes mellitus due to underlying condition with hyperosmolarity with coma
E09.00Drug or chemical induced diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHC)
E09.01Drug or chemical induced diabetes mellitus with hyperosmolarity with coma
E11.00Type 2 diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHC)
E11.01Type 2 diabetes mellitus with hyperosmolarity with coma
E13.00Other specified diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHC)
E13.01Other specified diabetes mellitus with hyperosmolarity with coma
Epidemiology & Demographics

HHS is a rare condition that most commonly affects patients with type 2 diabetes mellitus. Approximately 20% of patients have no history of diabetes.1 Older adults with new-onset diabetes or those who have poorly controlled type 2 diabetes and are predisposed to extracellular fluid volume depletion (dehydration) are at increased risk for HHS. Social and racial-ethnic disparities are remarkable with Black race/ethnicity and lower income individuals at heightened risk of HHS.2 Mortality from HHS 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.

Physical Findings & Clinical Presentation1

  • 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
Etiology

HHS can be precipitated by various conditions1:

  • Infection is the most common precipitant (especially pneumonia, urinary tract infections, and COVID-19)
  • 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, heat stroke)
  • Drugs (e.g., steroids, thiazides, beta blockers, atypical antipsychotics, sympathomimetics including cocaine, alcohol, and pentamidine)

A relative insulin deficiency provides enough insulin to inhibit ketogenesis but is insufficient to inhibit hepatic gluconeogenesis and glycogenolysis or to promote peripheral glucose uptake, resulting in consequent hyperglycemia. With underlying illness, counterregulatory hormone excess leads to further blood glucose elevation. The resultant extreme hyperglycemia leads to osmotic diuresis.3,4 If adequate hydration is not maintained, dehydration and worsening renal function ensue. In patients with inadequate fluid intake due to altered thirst mechanisms or the inability to access fluids, as may be seen in older adults, the risk of severe dehydration further increases. Diminished renal filtration further impairs glucose excretion, thus exacerbating the hyperglycemia, dehydration, and hyperosmolality and increasing the risk for cardiovascular collapse.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Diabetic ketoacidosis
  • Stroke (especially in older adults with neurologic abnormalities)
  • Hypovolemic or septic shock
  • Encephalopathy
Workup

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

Laboratory Tests

  • Hyperglycemia: Blood glucose >600 mg/dl (Box 1)5
  • 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 level for every 100 mg/dl increase in serum glucose >100 mg/dl and <400 mg/dl, and then increase the sodium level by 4 mmol/L for each glucose increment of 100 mg/dl above 400 mg/dl.6 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 leukocytosis of 10,000 to 15,000 mm3 is expected from the stress of illness alone1
  • Urinalysis, urine/sputum/blood cultures as indicated based on physical exam findings to evaluate the precipitating illness and other comorbidities

BOX 1 Diagnostic Testing Criteria for Patients With Hyperglycemic Hyperosmolar State5

Glucose higher than 600 mg/dl

Normal pH (classically, however, patients are often mildly acidotic)

No significant ketosis∗

Serum osmolarity

  • >320 mOsm/L with any mental status changes, or
  • >350 mOsm/L

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

Imaging Studies

Electrocardiogram (ECG), chest radiograph, and other imaging studies as indicated to evaluate the precipitating causes

∗Serum acetoacetate is often present, typically an absent or low β-hydroxybutyrate level.

Treatment ⬆ ⬇

Acute General Rx134

Aggressive fluid resuscitation, intravenous insulin, and electrolyte correction are the mainstays of treatment. The initial goal of HHS 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 HHS 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 HHS 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/h 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/h 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/h 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/h.

Insulin

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 and 300 mg/dl until resolution of HHS.

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 h 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 h 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 h 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.

Disposition

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

Pearls & Considerations ⬆ ⬇

Comments

  • When patients with end-stage renal disease experience development of HHS, special management considerations are needed.7 Aggressive fluid resuscitation is unnecessary in anuric end-stage renal disease 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 patients with end-stage renal disease 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 long-term care facilities regarding optimal glycemic control, limiting modifiable risk factors for HHS, and prevention of dehydration is paramount.

Related Content ⬆

    1. Kitabchi A.E. : Hyperglycemic crises in adult patients with diabetesDiabetes Care. ;32(7):1335-1343, 2009.
    2. McCoy R.G. : Sociodemographic, clinical, and treatment-related factors associated with hyperglycemic crises among adults with type 1 and type 2 diabetes in the United States, 2014-2020JAMA Netw Open 1. ;4(9), 2021.
    3. French E.K. : Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patientsBMJ. ;365, 2019.
    4. Muneer M, Akbar I: Acute metabolic emergencies in diabetes: DKA, HHS and EDKA, Adv Exp Med Biol 85-114, 2020.
    5. Graber MN: Diabetes and hyperglycemia. In Adams JG et al: Emergency medicine: clinical essentials 2:1378:e1-1396, 2013.
    6. Verbalis J.G. : Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendationsAm J Med. ;126(10):S1-S42, 2013.
    7. Schaapveld-Davis C.M. : End-stage renal disease increases rates of adverse glucose events when treating diabetic ketoacidosis or hyperosmolar hyperglycemic stateClin Diab. ;35(4):202-208, 2017.