Hyperosmolar Hyperglycemic State Workup

  • Author: Robin R Hemphill, MD, MPH; Chief Editor: George T Griffing, MD  more...
Updated: Aug 03, 2016

Approach Considerations

On the basis of the consensus statement published by the American Diabetes Association, diagnostic features of hyperosmolar hyperglycemic state (HHS) may include the following[3, 5] :

  • Plasma glucose level of 600 mg/dL or greater
  • Effective serum osmolality of 320 mOsm/kg or greater
  • Profound dehydration, up to an average of 9 L
  • Serum pH greater than 7.30
  • Bicarbonate concentration greater than 15 mEq/L
  • Small ketonuria and absent-to-low ketonemia
  • Some alteration in consciousness

HHS should be considered in children presenting with hyperglycemia and hyperosmolarity without significant ketoacidosis. It is particularly important to distinguish HHS from diabetic ketoacidosis (DKA) in children, because younger persons are at higher risk for the development of cerebral edema as a complication of aggressive fluid repletion.

An arterial line provides access for repeated blood draws, particularly in patients who are intubated or require admission to the intensive care unit (ICU).


Blood Studies

Hemoglobin and hematocrit values are usually elevated because of volume contraction. Leukocytosis is frequently present, with white blood cell (WBC) counts often exceeding 20,000/µL. Stress, dehydration, and demargination of leukocytes contribute to leukocytosis. Given that infections commonly precipitate HHS, consider leukocytosis secondary to an infectious process until proven otherwise. Obtain a chest radiograph and urine and blood cultures from all patients with leukocytosis.

Serum glucose

A fingerstick blood sugar measurement with a reflectance meter is the simplest first step in the evaluation. The serum glucose level usually is elevated dramatically, often to greater than 800 mg/dL. Many patients present with glucose concentrations greater than 1000 mg/dL. Blood sugar levels of 65-250 mg/dL exclude significant glycemic derangement and should prompt a search for other causes of mental status changes.

The concentration of glucose in the plasma is directly proportional to the degree of dehydration. Higher concentrations of glucose relate to higher degrees of dehydration, higher plasma osmolality, and a worse prognosis.

Monitor the plasma glucose concentration hourly during the first 24-48 hours of treatment.

Hemoglobin A

Although hemoglobin A1c (glycosylated hemoglobin) levels are not useful in the acute phase of therapy, they may be obtained as an indicator of the patient’s glucose control over the previous several weeks.

Serum osmolarity or osmolality

Normal serum osmolality ranges from 280 to 290 mOsm/kg. A serum osmolality of 320 mOsm/kg or higher defines HHS. Rarely, serum osmolality may exceed 400 mOsm/kg. In HHS, higher serum osmolality relates to greater impairment of the level of consciousness. Osmolality can be measured directly by means of freezing point depression or osmometry. Alternatively, serum osmolality may be calculated from sodium, blood urea nitrogen (BUN), and glucose values, as follows:

Osm = (2 × Na) + (glucose/18) + (BUN/2.8)

Urea is freely permeable across cell membranes and therefore does not create an osmotic gradient between the intracellular and extracellular fluids. The last term of the serum osmolality equation above thus may be dropped, giving the effective serum osmolality. The effective serum osmolality may be used to calculate a patient’s osmolality quickly at the bedside but should be confirmed by a measured value.

The osmole gap is the difference between the measured osmolality and the calculated osmolality (at low solute concentrations, they are nearly equivalent measures). Although the measured osmolality is very high in patients with HHS, the osmole gap should be unimpressive, because the calculated osmolality includes the elevated serum glucose concentration. If the osmole gap is very large, consider toxic alcohol ingestion.

Blood gases

Document arterial plasma pH early in the treatment of patients with hyperglycemia presenting with an altered level of consciousness. Arterial blood gas (ABG) values are obtained to measure serum pH. In most cases of HHS, the blood pH is greater than 7.30.

Venous blood gas (VBG) values may be substituted in patients with normal oxygen saturation on room air. Venous blood gases provide comparable information, are easier to draw, and are less painful to the patient. The pH measured by a VBG assessment is 0.03 pH units less than the pH measured by ABG assessment.[14]

ABG values also indicate underlying diseases associated with HHS. Hypoxemia may be observed in association with cardiac or pulmonary diseases. Hypocarbia may be due to respiratory alkalosis as a compensatory mechanism to a primary metabolic acidosis. Hypocarbia also may be due to tachypnea in response to an elevated alveolar-arterial oxygen gradient from pulmonary disease. A low plasma bicarbonate level is commonly observed in persons with HHS, but very low levels (< 15 mEq/L) indicate DKA.

Serum electrolytes

Early in the course of HHS, before significant osmotic diuresis has occurred, the elevated plasma glucose level exerts an osmotic drag. This results in the movement of water from the intracellular to the extracellular space, with dilution of all electrolytes in the plasma. Patients with renal insufficiency who may not establish an osmotic diuresis may effectively present with hyponatremia and hypochloremia.

As HHS progresses and osmotic diuresis occurs, electrolytes are lost in the urine. All electrolytes are extremely deficient at the time of presentation, at which time the relative deficiencies of water and electrolytes determine their plasma concentrations. Additionally, the presence of hypertriglyceridemia affects the concentration of electrolytes. Triglycerides also exert an osmotic drag and displace electrolytes in the plasma.

Hyponatremia or hypernatremia may be present. In the setting of hyperglycemia, pseudo-hyponatremia is common as a result of the osmotic effect of glucose drawing water into the vascular space. The measured serum sodium concentration can be corrected upward in proportion to increases in serum glucose to yield an estimate of what the serum sodium level would be in the absence of hyperglycemia and its associated osmotic effect.

Bartoli et al described a mathematical model and formulas designed to improve estimation of the plasma sodium concentrations that patients will have after treatment of hyperosmolar coma.[15, 16] Such estimations are important for avoiding sodium imbalances after coma treatment. The model estimates the amount of glucose added to the plasma, along with associated water loss, but excludes concomitant sodium loss.

Hypokalemia or hyperkalemia may be present. Serum potassium may be elevated due to an extracellular shift caused by insulin deficiency. However, total body potassium is likely low regardless of its serum value; a low measured serum potassium suggests profound total body losses, and patients should be placed on cardiac monitoring. During treatment, insulin drives potassium into cells, and intravenous (IV) hydration dilutes potassium in the circulation. Aggressively replace potassium to maintain plasma levels in the normal range during treatment.

Serum magnesium levels are also a poor indicator of true total body magnesium. In the presence of hypokalemia, concomitant hypomagnesemia should be presumed and treated.

The bicarbonate concentration in a patient with HHS may be greater than 15 mEq/L.

The anion gap is calculated according to the following formula:

(Na+ + K+) – (Cl + HCO3)

The calculated anion gap is usually less than 12 mmol/L. A wide anion gap is observed in most patients with HHS, reflecting mild metabolic acidosis. The mild acidosis in HHS is often multifactorial and results, in part, from the accumulation of ketoacids in the absence of effective insulin activity. Some patients with profound dehydration may have high anion gaps, reflecting the additional contribution of lactic acid produced by hypoperfusion of tissues. Underlying renal disease with uremia also may contribute to a high anion gap.

Monitor plasma electrolyte levels at least every 4 hours during the first 24-48 hours of treatment.

Serum ketones

A mild degree of ketosis is usually observed in any patient who is dehydrated. In those with HHS, despite the significant degree of dehydration, ketosis is mild and responds readily to treatment. Profound ketosis that does not respond readily to IV rehydration is the norm in persons with DKA. Mild-to-moderate ketosis can be present when the disease has features of both HHS and DKA (overlap cases).

BUN and creatinine

Patients with HNS present with prerenal azotemia. Initially, BUN and creatinine concentrations are likely to be elevated, and the BUN-to-creatinine ratio may exceed 30:1. When possible, these values should be compared with previous values; many patients with diabetes have baseline renal insufficiency. The renal function of many patients does not normalize after treatment; this indicates irreversible or underlying renal damage.

Serum enzymes

Dehydration causes a rise in the plasma levels of albumin, amylase, bilirubin, calcium, total protein, lactate dehydrogenase, transaminases, and creatine kinase (CK). Up to two thirds of patients with HHS have elevated serum enzyme levels. Accordingly, serum levels of CK and isoenzymes should be measured routinely because both MI and rhabdomyolysis can trigger HHS and both can be secondary complications of HHS.[17]

Avoid the assumption that enzyme level elevation is due to dehydration. Exclude underlying disease associated with each of these abnormal blood levels in patients with HHS. This is especially true in the case of CK elevations.

Blood culture

Blood cultures should be obtained to search for bacteremia.


Urine Studies

Urinalysis can reveal elevated specific gravity (evidence of dehydration), glycosuria, small ketonuria, and evidence of urinary tract infection (UTI). Urine for analysis may be difficult to obtain in a severely dehydrated patient with HHS. Catheterization of the urinary bladder may be necessary.

Urinalysis may provide further information about the patient’s metabolic state. Ketones are rarely present in persons with HHS, mostly because of dehydration. Gross proteinuria suggests underlying renal disease. Urinary osmolality and the urine specific gravity should be very high in patients with HHS. Occasionally, a patient presents with a low urine specific gravity. This is diagnostic of coexisting diabetes insipidus, prompts a more thorough evaluation of pituitary and renal function, and warrants aggressive fluid resuscitation and central pressure monitoring.

Urethral catheterization is useful for obtaining a clean urine specimen. This is especially important if the urine dipstick shows signs of infection. An indwelling Foley catheter indicates urine output and response to fluid therapy.

Urine cultures are useful because UTIs may be underdetected by urinalysis alone, particularly in patients with diabetes mellitus (DM). Send cultures as clinically indicated.


Cerebrospinal Fluid Studies

Cerebrospinal fluid (CSF) cell count, glucose, protein, and culture are indicated in patients with an acute alteration of consciousness and clinical features suggestive of possible central nervous system (CNS) infection. Patients who are immunocompromised may require additional studies of the CSF, such as polymerase chain reaction (PCR) for herpes simplex virus (HSV) and cryptococcal antigen.

When meningitis or subarachnoid hemorrhage is suspected, lumbar puncture (LP) is indicated. If meningitis is suspected clinically, do not withhold antibiotics while waiting for the LP to be completed.


Radiography of Chest and Abdomen

In the initial evaluation of patients with HHS, a chest radiograph is almost always advisable to exclude pneumonitis. Radiographic findings may be falsely negative at first because of the profound dehydration in some patients, and serial studies may document the pneumonitis process as rehydration proceeds. Cardiomegaly in the presence of dehydration implies a severely compromised heart, which is probably affected by cardiomyopathy.

Abdominal radiographs are indicated if the patient has abdominal pain or is vomiting.


Computed Tomography of Head

Patients with HHS who present with altered mental status may have an underlying CNS disease. Computed tomography (CT) of the head is indicated in many patients with focal or global neurologic changes to help exclude hemorrhagic strokes, subdural hematoma, subarachnoid bleeding, intracranial abscesses, and intracranial masses. It may be useful for patients who show no clinical improvement after several hours of treatment, even in the absence of clinical signs of intracranial pathology.

Repeat CT scanning is indicated if cerebral edema is a concern during the treatment of HHS.



Electrocardiography (ECG) is indicated in all patients with HHS because myocardial infarction (MI) and pulmonary embolism (PE) frequently precipitate HHS.

The height of the T waves in the ECG tracings may point to a potassium derangement. The duration of the QT interval may be abnormal as a consequence of calcium abnormalities.

Contributor Information and Disclosures

Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine

Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.


Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Joseph Michael Gonzalez-Campoy, MD, PhD, FACE Medical Director and CEO, Minnesota Center for Obesity, Metabolism, and Endocrinology

Joseph Michael Gonzalez-Campoy, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, Association of Clinical Researchers and Educators (ACRE), and Minnesota Medical Association

Disclosure: Nothing to disclose.

George T Griffing, MD Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, InternationalSocietyfor Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Lewis S Nelson, MD, FACEP, FAACT, FACMT Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York University Medical Center and New York Harbor Healthcare System

Lewis S Nelson, MD, FACEP, FAACT, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center

David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine

Disclosure: Nothing to disclose.

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society

Disclosure: Nothing to disclose.

Paulina B Sergot, MD Staff Physician, Department of Emergency Medicine, New York University/Bellevue Hospital Center

Paulina B Sergot, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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