AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Hyperosmolar hyperglycemic state (HHS) is one of two serious metabolic derangements that occurs in patients with diabetes mellitus and can be a life-threatening emergency. The condition is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis. It less common than the other acute complication of diabetes, diabetic ketoacidosis (DKA), and usually presents in older patients with type 2 diabetes mellitus. HHS carries a higher mortality rate than DKA, estimated at approximately 15%.   

Most patients present with severe dehydration and focal or global neurologic deficits. In many cases, the clinical features of HHS and DKA overlap and are observed simultaneously (overlap cases). The diagnostic features of HHS may include the following:

• Plasma glucose level of 600 mg/dL or greater
• Effective serum osmolality of 320 mOsm/kg or greater
• Profound dehydration (8-12 L) with elevated serum urea nitrogen (BUN)-to-creatinine ratio
• Small ketonuria and absent-to-low ketonemia
• Bicarbonate concentration greater than 15 mEq/L
• Some alteration in consciousness

HHS was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC). However, the terminology was changed because coma is found in fewer than 10% of patients with HHS.

For other information, see Medscape’s Diabetes & Endocrinology Resource Center.

Pathophysiology

Hyperosmolar hyperglycemic state (HHS) most commonly occurs in patients with type 2 diabetes mellitus who have some concomitant illness that leads to a reduced fluid intake. Infection is the most common cause, but many other conditions can cause altered mentation, dehydration, or both. Frequently, the concomitant illness is not identifiable.

In patients with a preexisting lack of or resistance to insulin, a physiologic stress such as an acute illness can cause further net reduction in circulating insulin. The basic underlying mechanism of HHS is a reduction in the effective circulating insulin with a concomitant elevation of counter-regulatory hormones. Decreased renal clearance and decreased peripheral utilization of glucose lead to hyperglycemia. Hyperglycemia and hyperosmolarity result in an osmotic diuresis and an osmotic shift of fluid to the intravascular space, resulting in further intracellular dehydration. This diuresis also leads to loss of electrolytes, such as sodium and potassium.

Unlike patients with DKA, patients with HHS do not develop significant ketoacidosis, but the reason for this is not known. Contributing factors likely include the availability of insulin in amounts sufficient to inhibit ketogenesis but not sufficient to prevent hyperglycemia. Additionally, hyperosmolarity itself may decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis. Also, lower levels of counter-regulatory hormones have been found in patients with HHS compared with those with DKA.

Frequency

United States

The incidence of HHS is less than 1 case per 1000 person-years, making it significantly less common than DKA. As the prevalence of type 2 diabetes mellitus increases, the incidence of HHS will likely increase as well.

Mortality/Morbidity

The mortality rate is high (10-20%). The mortality rate of HHS increases with increasing age and with higher levels of serum osmolality.

Race

African Americans, Hispanics, and Native Americans are disproportionately affected.

Sex

The prevalence is slightly higher in females than in males.

Age

HHS has a mean age of onset early in the seventh decade of life. In contrast, the mean age for DKA is early in the fourth decade of life. Residents of nursing facilities who are elderly and demented are at the highest risk due to a lack of ability to care for themselves, but the syndrome has been reported in patients as young as 18 months. As rates of obesity increase amongst children, the prevalence of type 2 diabetes mellitus is also rising in this age group. Several cases of HHS have been reported in the pediatric population.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Most patients with hyperosmolar hyperglycemic state (HHS) have a known history of diabetes, which is usually type 2.
• In 30-40% of cases, HHS is the initial presentation of a patient’s diabetes.
• HHS usually develops over a course of days to weeks unlike DKA.
• Often, a preceding illness results in several days of increasing dehydration.
• Adequate oral hydration may be impaired by concurrent acute illness (eg, vomiting) or chronic comorbidity (eg, dementia, immobility).
• Patients may complain of polydipsia, polyuria, weight loss, weakness. Patients do not typically report abdominal pain, which is often seen in DKA.
• A wide variety of focal and global neurologic changes may be present, including the following:
• • Drowsiness and lethargy
  • Delirium
  • Coma
  • Focal or generalized seizures
  • Visual changes or disturbances
  • Hemiparesis
  • Sensory deficits

Physical

Examine the patient for evidence of HHS and for signs of its possible underlying causes.

• Vital signs
• • Fingerstick glucose should be checked immediately and is usually greater than 600 mg/dL.
  • Tachycardia is an early indicator of dehydration; hypotension is a later sign suggestive of profound dehydration due to volume loss secondary to osmotic diuresis.
  • Orthostatic vital signs are neither sensitive nor specific.
  • Tachypnea may be seen due to respiratory compensation for metabolic acidosis in overlap cases.
• General appearance and hygiene may provide clues to the state of hydration, presence of chronic illness, and reduced level of mentation.
• Perform a thorough skin examination. Skin turgor is another clue to hydration status.
• Examine the head, eyes, ears, nose, and throat (HEENT).
• • Examination may reveal altered hydration status (eg, sunken eyes, dry mouth).
  • Cranial neuropathies, visual field losses, and nystagmus may be appreciated, which are symptoms of HHS. They are usually reversible with therapy.
• Neck examination may reveal enlarged lymph nodes or meningismus. 
• The extremities may give evidence of peripheral volume sequestration or of dehydration.
• Evidence of underlying triggers of HHS on examination:
• • Vital signs
  • • Assess core temperature rectally. Abnormally high or low temperatures suggest sepsis as an underlying cause. Hypothermia is a poor prognostic factor.
    • Hypoxemia can be a concurrent problem affecting mentation. 
  • Skin examination
  • • Warm, moist skin suggests early sepsis.
    • Cool, dry skin suggests late sepsis.
    • Can reveal sources of infection, such as cellulitis or abscess.
  • HEENT
  • • Potential foci of infection may be revealed (eg, middle ear, sinuses, oropharynx).
    • Palpation of the thyroid may reveal evidence of thyrotoxicosis. Thyrotoxicosis needs to be considered in the differential of HHS as it can also cause tachycardia, fever, and dehydration.
  • The pulmonary and cardiac examinations may reveal signs of pneumonia or of cardiac diseases.
  • Check for costovertebral angle tenderness as a sign of pyelonephritis.
  • Look for Kernig and Brudzinski signs, which may suggest meningitis.
  • A careful abdominal examination can help to rule out an intraperitoneal infection.
  • Rectal examination can screen for prostatitis, perirectal abscess, and GI hemorrhage.
  • Pelvic examination is indicated in women with lower abdominal pain or purulent discharge.
  • During neurologic examination, evaluate overall mental status, cranial nerves, strength, sensation, reflexes, cerebellar function, stance, and gait. Focal findings may prompt further studies such as CT scan and/or lumbar puncture (LP).

Causes

• In general, any illness that predisposes to dehydration may lead to HHS. A wide variety of major illnesses may trigger HHS by limiting patient mobility and free access to water.
• A preceding or intercurrent illness is common, but the underlying cause may be difficult to ascertain. Pneumonia and urinary tract infections (UTIs) are the most common underlying causes of HHS.
• Stress response to any acute illness tends to increase hormones that favor elevated glucose levels. Cortisol, catecholamines, glucagon, and many other hormones have effects that tend to counter those of insulin. Examples of such acute conditions are as follows:
• • Stroke
  • Intracranial hemorrhage
  • Silent myocardial infarction
  • Pulmonary embolism
• Patients with underlying renal dysfunction and/or congestive heart failure are at greater risk.
• Drugs that raise serum glucose level, inhibit insulin, or cause dehydration may cause HHS.
• • Diuretics
  • Beta-blockers
  • Histamine 2 (H2) blockers
  • Antipsychotics (clozapine, olanzapine)
  • Alcohol and cocaine
  • Dialysis, total parenteral nutrition, and fluids that contain dextrose
• Elder abuse and neglect also may contribute to underhydration.
• Noncompliance with oral hypoglycemics or insulin therapy can result in HHS.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Alcoholic ketoacidosis
Delirium
Dementia
Overdose
Thyrotoxicosis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Serum electrolytes including sodium, potassium, chloride, bicarbonate, calcium, magnesium, and phosphate
• • Hyponatremia or hypernatremia may be present. In the setting of hyperglycemia, pseudohyponatremia is common due to the osmotic effect of glucose drawing water into the vascular space. Measured serum sodium level can be corrected upward 1.6 mEq/L for every 100 mg/dL increase in serum glucose level to give an estimate of what the serum sodium level would be in the absence of hyperglycemia and its associated osmotic effect.
  • Hyponatremia or hypernatremia may be present. Serum potassium concentration 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 level suggests profound total body losses, and patients should be placed on cardiac monitoring. Serum magnesium levels are also a poor indicator of true total body magnesium. In the presence of hypokalemia, concomitant hypomagnesemia should be assumed and treated.
  • The calculated anion gap is usually less than 12. However, an anion gap metabolic acidosis may be present because of dehydration (lactic acidosis) but usually is less profound than that observed in DKA.
  • Some patients who have primarily a hyperosmolar hyperglycemic state may have a component of DKA; therefore, a small amount of ketoacidosis may contribute to the anion gap acidosis.
• Renal function (BUN and creatinine levels)
• • BUN and creatinine levels are likely to be elevated initially due to dehydration.
  • When possible, they should be compared to previous values, as many patients with diabetes have renal insufficiency at baseline.
• Serum glucose level usually is elevated dramatically, often to greater than 800 mg/dL.
• Serum osmolarity usually is greater than 320 mOsm/dL.
• • Osmolarity can be measured directly. Predicted osmolarity is calculated using the following formula: Osm = (2 X Na) + (BUN/2.8) + (glucose/18)
  • If the calculated value is significantly lower than the measured value, consider toxic alcohol ingestion as a source of unmeasured osmoles that can trigger HHS.
• Serum ketones can be normal to small in pure HHS, but mild-to-moderate ketosis can be present when the disease has features both of HHS and of DKA ("overlap cases").
• Creatine phosphokinase (CPK) with isoenzymes should be measured routinely because both MI and rhabdomyolysis can trigger HHS, and both can be secondary complications of HHS.  
• Coagulation studies (prothrombin time [PT] and activated partial thromboplastin time [aPTT]) are useful as part of a screen for disseminated intravascular coagulation (DIC).
• Blood cultures should be obtained to search for bacteremia.
• Arterial blood gas analysis
• • ABG is the most accurate indicator of serum pH.
  • A venous blood gas (VBG) may be substituted in patients with normal oxygen saturation on room air. Venous blood gases provide comparable information (assuming that oxygenation and ventilation are adequate) and are easier and less painful to draw.
  • In most cases of HHS, the pH is greater than 7.30.
• Urinalysis can reveal elevated specific gravity (evidence of dehydration), glucosuria, small ketonuria, and evidence of UTI.
• Urine cultures are useful because UTIs may be underdetected by urinalysis alone, particularly in patients with diabetes mellitus.
• 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 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.
• Send for cultures of stool, cervical mucus, and other substances when clinical evidence suggests a potential area of infection.
• Although not useful in the acute phase of therapy, hemoglobin A1C (glycosylated hemoglobin) may be obtained as an indicator of the patient's glucose control over the previous several weeks.

Imaging Studies

• A chest radiograph is useful to screen for pneumonia. Abdominal radiographs are indicated if the patient has abdominal pain or is vomiting.
• CT scan of the head
• • CT scan is indicated in many patients with focal or global neurologic changes.
  • 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.
  • Indications for head CT scans are controversial.

Procedures

• Venous access
• • Large-bore intravenous (IV) or central venous access is used, especially in cases in which hemorrhage is a precipitant and blood products are likely to be required or when inotropic agents may be necessary.
  • Central venous pressure (CVP) may be helpful in monitoring intravascular volumes.
• Urethral catheterization is useful to obtain 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.
• An arterial line provides access for repeated blood draws, particularly in patients who are intubated or require admission to the ICU.
• 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

Standard care for dehydration and altered mental status is appropriate, including airway management, intravenous access, crystalloid, and any medications routinely given to coma patients.

• Airway management is the top priority. In comatose patients in whom airway protection is of concern, endotracheal intubation may be indicated. Cervical spine immobilization is necessary if head or neck injury is a possibility.
• Intravenous access, large bore if possible, is useful, provided that attempts to obtain it do not significantly delay transfer to the nearest ED.
• Bolus of 500 mL isotonic saline is appropriate for nearly all adults who are clinically dehydrated. A 250-mL bolus may be more appropriate in patients with a history of CHF, renal insufficiency, or both.
• Basic medications given to coma patients in the field may include thiamine 100 mg IV, dextrose (50 mL of D50), and naloxone (0.05-0.4 mg IV). This combination is of benefit to many comatose patients with few adverse effects.
• When possible, fingerstick glucose measurement is obtained prior to dextrose administration. In any case in which fingerstick glucose measurement is unavailable or likely to be delayed, empiric D50 must be administered to comatose patients without delay. Undiagnosed and untreated hypoglycemia, which may present with signs and symptoms very similar to those of HHS, is readily reversible but can be rapidly lethal if not treated promptly.
• Whenever possible, contact the receiving facility while en route to ensure preparation for a comatose, dehydrated, and/or hyperglycemic patient.
• Notify the facility of possible brain attack when appropriate.
• Use antibiotics as indicated based on clinical situation and likelihood of infection.

Emergency Department Care

• Manage the airway as needed, establish intravenous access, initiate vigorous fluid resuscitation, and obtain appropriate laboratory and radiographic studies.
• Fluid deficits in hyperosmolar hyperglycemic state (HHS) are large; the fluid deficit of an adult may be 10 L or more.
• • Administer 1-2 L of isotonic saline in the first 2 hours. A higher initial volume may be necessary in patients with severe volume depletion. Slower initial rates may be appropriate in patients with significant cardiac or renal disease or in those who are not urinating. Caution should be taken to not correct hypernatremia too quickly, as this could lead to cerebral edema.
  • After the initial bolus, some clinicians recommend changing to half-normal saline, while others continue with isotonic saline. Either fluid likely will replenish intravascular volume and correct hyperosmolarity; a good standard is to switch to half-normal saline once blood pressure and urine output are adequate.
  • Once serum glucose drops to 250 mg/dL, the patient must receive dextrose in the intravenous fluid.
• Initiate insulin therapy in the ED.
• • Although many patients with HHS respond to fluids alone, intravenous insulin in dosages similar to those used in DKA can facilitate correction of hyperglycemia.
  • Insulin used without concomitant vigorous fluid replacement increases risk of shock.
• Replete potassium and magnesium as needed.
• Detection and treatment of an underlying illness is critical. Antibiotics need to be administered early.
• Frequent reevaluation of the patient’s clinical and laboratory parameters is necessary.
• All patients diagnosed with HHS require hospitalization, usually to an intensive care unit for close monitoring.

Consultations

• Generally, no consultation is required to manage HHS in the ED. After ED management, refer the patient to a primary care physician, internist, or intensivist for further care.
• In occasional cases, endocrinology, neurology, or infectious disease consultation may be useful.
• Psychiatry consultation may be useful during the hospitalization.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Fluids, insulin, and electrolytes (especially potassium) are the cornerstones of management. Antipyretics, antiemetics, and antibiotics are added, when appropriate, to control fever and nausea/vomiting.

Drug Category: Insulin

Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in DKA can facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases risk of shock.

Drug Category: Electrolytes

These agents are used to replenish electrolytes depleted because of the presence of high blood glucose level.

Drug Category: Alkalinizing agent

No evidence is found that sodium bicarbonate provides any benefit to patients with HHS. It may be considered if a patient has significant acidosis (pH <7.0), particularly if inotropic agents are required to maintain blood pressure.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Continued management of the fluid, electrolyte, and glucose disturbances is necessary until these have resolved.
• Diabetic teaching is necessary to prevent recurrence.

Further Outpatient Care

• Primary care follow-up is necessary for additional diabetic teaching and any appropriate immunizations.
• Visiting home nurse referral may be necessary to enhance compliance.

In/Out Patient Meds

• Adjust insulin or oral hypoglycemic therapy on the basis of the patient's insulin requirement once serum glucose level has been relatively stabilized.

Transfer

• Transfer to appropriate level of care if the patient is critically ill.

Deterrence/Prevention

• Diabetic teaching, both in the hospital and after discharge, by the primary care physician and/or a visiting home nurse, is essential to modify behavior and enhance compliance.
• A home evaluation by a visiting nurse may be useful to identify factors limiting adequate access to water.

Complications

• Ischemia or infarction to any organ, including heart and brain
• Thromboembolism
• Acute respiratory distress syndrome (ARDS)/DIC or multiorgan dysfunction syndrome
• Cerebral edema (rare)

Prognosis

• The overall mortality rate is between 10% and 20% and is dependent on coexisting conditions and complications.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to manage the airway with endotracheal intubation when necessary
• Failure to provide adequate fluid resuscitation (leading to shock)
• Cerebral edema (more common in children) secondary to overly rapid hydration (especially with hypotonic fluids) or failure to add glucose to fluids when the level falls to less than 250 mg/dL
• Hypoglycemia due to excessive insulin use without the initiation of glucose-containing fluids
• Failure to replete potassium in patients who have a total body potassium deficit but an initially normal serum potassium level (On the other hand, administration of intravenous potassium has been associated with significant morbidity and death, especially with iatrogenic errors.)
• Failure to treat empirically and early with broad-spectrum antibiotics when sepsis appears to be a possible precipitant

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Mark Sagarin, MD, and Andrew McAfee, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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• Piniés JA, Cairo G, Gaztambide S, et al. Course and prognosis of 132 patients with diabetic non ketotic hyperosmolar state. Diabete Metab. Jan-Feb 1994;20(1):43-8. [Medline].
• Rosa EC, Lopes AC, Liberatori Filho AW, et al. Rhabdomyolysis due to hyperosmolarity leading to acute renal failure. Ren Fail. Mar 1997;19(2):295-301. [Medline].
• Singhi SC. Hyperglycemic hyperosmolar state and type 2 diabetes mellitus: yet another danger of childhood obesity. Pediatr Crit Care Med. Jan 2005;6(1):86-7. [Medline].
• Trence DL, Hirsch IB. Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin North Am. Dec 2001;30(4):817-31. [Medline].
• Umpierrez GE, Kelly JP, Navarrete JE, et al. Hyperglycemic crises in urban blacks. Arch Intern Med. Mar 24 1997;157(6):669-75. [Medline].
• Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med. Nov-Dec 1991;6(6):495-502. [Medline].

Article Last Updated: Jul 22, 2008