Hyperosmolar Hyperglycemic State

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 differs in the magnitude of dehydration, ketosis, and acidosis. HHS usually presents in older patients with type 2 diabetes mellitus and carries a higher mortality rate than DKA, estimated at approximately 15%.

Most patients present with severe dehydration and focal or global neurologic deficits.^{[1, 2, 3]} In as many as one third of cases, the clinical features of HHS and DKA overlap and are observed simultaneously (overlap cases). Based on the consensus statement published by the American Diabetic Association, diagnostic features of HHS may include the following:^[1]

• 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 9L
• 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 was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC). However, the terminology was changed because coma is found in fewer than 20% of patients with HHS.^[2]

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Pathophysiology

Hyperosmolar hyperglycemic state (HHS) most commonly occurs in patients with type 2 diabetes mellitus who have some concomitant illness that leads to reduced fluid intake. Infection is the most common cause, but many other conditions can cause altered mentation, dehydration, or both. The concomitant illness may not be 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, such as glucagon, catecholamines, cortisol, and growth hormone.^{[1, 2]} 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.^{[1, 2, 3]}

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.^{[1, 2, 3]}

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Epidemiology

Frequency

United States

The incidence of hyperosmolar hyperglycemic state (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.^[2]

Mortality/Morbidity

The mortality rate is high (10-20%) and usually due to a comorbid illness The mortality rate of HHS increases with increasing age and with higher levels of serum osmolality.^{[2, 3]}

Race

African Americans, Hispanics, and Native Americans are disproportionately affected due to an increased prevalence of type 2 diabetes mellitus.^[2]

Sex

The prevalence is slightly higher in females than in males.

Age

Hyperosmolar hyperglycemic state (HHS) has a mean age of onset early in the seventh decade of life. In contrast, the mean age for diabetic ketoacidosis (DKA) is early in the fourth decade of life.^{[2, 3]} Residents of nursing facilities who are elderly and demented are at the highest risk due to a lack of ability to care for themselves.

As rates of obesity increase amongst children, the prevalence of type 2 diabetes mellitus is also rising in this age group and may lead to an increased incidence of HHS in this population.^{[4, 5]} HHS should be considered in children presenting with hyperglycemia and hyperosmolarity without significant ketoacidosis. It is particularly important to distinguish HHS from DKA in children, as they are at higher risk for the development of cerebral edema as a complication of aggressive fluid repletion. The mortality due to HHS in children also appears to be higher as compared to DKA, but there have been too few reported cases to calculate mortality accurately.^{[4, 5]}

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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 patient's initial presentation of diabetes.^[3]
• HHS usually develops over a course of days to weeks unlike DKA, which develops more rapidly.
• 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, a complaint that is often noted in patients with 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

   

  

   

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Physical

Examine the patient for evidence of hyperosmolar hyperglycemic state (HHS), focusing on hydration status, mentation, and signs of possible underlying causes, such as a source of infection.

• 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 for volume status.
  • Tachypnea may occur due to respiratory compensation for metabolic acidosis in overlap cases.
  • Assess core temperature rectally.
    • Abnormally high or low temperatures suggest sepsis as an underlying cause.
    • Lack of fever does not rule out infection.
    • Hypothermia is a poor prognostic factor.
  • Hypoxemia can be a concurrent problem affecting mentation.

   

  

   
• 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.

   

  

   
• The extremities may manifest evidence of peripheral volume sequestration or of dehydration.

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Causes

• In general, any illness that predisposes to dehydration may lead to hyperosmolar hyperglycemic state (HHS).^{[2, 3]} A wide variety of major illnesses may trigger HHS by limiting patient mobility and free access to water.
• A preceding or intercurrent infection 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.^[2]
• 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 levels, inhibit insulin, or cause dehydration may cause HHS. Examples include the following:

  • Diuretics
  • Beta-blockers
  • Atypical antipsychotics (clozapine, olanzapine)
  • Alcohol and cocaine
  • 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.

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Laboratory Studies

• Serum electrolytes including sodium, potassium, chloride, bicarbonate, calcium, magnesium, and phosphate

  • Hyponatremia or hypernatremia may be present. In the setting of hyperglycemia, pseudo-hyponatremia is common due to the osmotic effect of glucose drawing water into the vascular space. The measured serum sodium concentration 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.
  • Hypokalemia or hyperkalemia 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 concentration 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 presumed and treated.
  • The calculated anion gap is usually less than 12 mmol/L. However, an elevated anion gap metabolic acidosis may be present because of dehydration but usually is less profound than that observed in diabetic ketoacidosis (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 concentrations)

  • BUN and creatinine concentrations are likely to be elevated initially due to dehydration.
  • When possible, they should be compared to previous values, as many patients with diabetes have baseline renal insufficiency.

   

  

   
• Serum glucose level usually is elevated dramatically, often to greater than 800 mg/dL.
• Serum osmolarity and/or osmolality are usually greater than 320 mOsm/L

  • Osmolality can be measured directly by freezing point depression or osmometry.
  • Predicted osmolarity is calculated using the following formula: Osm = (2 X Na) + (BUN/2.8) + (glucose/18)
  • The Osmol gap is the difference between the measured osmolality and the calculated osmolarity (at low solute concentrations they are nearly equivalent measures).
  • Although the measured osmolality is very high in patients with HHS, the osmol gap should be unimpressive since the calculated osmolarity includes the elevated serum glucose concentration.
  • If the calculated value is significantly lower than the measured value, and the osmol gap is very large, consider toxic alcohol ingestion.

   

  

   
• Serum ketones can be normal to small in pure HHS, but mild-to-moderate ketosis can be present when the disease has features of both HHS and 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.
• Blood cultures should be obtained to search for bacteremia.
• Arterial blood gas analysis (ABG)

  • ABG is obtained to measure 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, are easier to draw, and are less painful to the patient. The pH measured by a VBG is 0.03 pH units less than the pH on an ABG.^[6]
  • In most cases of HHS, the blood pH is greater than 7.30.

   

  

   
• Urinalysis can reveal elevated specific gravity (evidence of dehydration), glucosuria, small ketonuria, and evidence of urinary tract infection (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 cultures as clinically indicated.
• 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.

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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.

   

  

   

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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.

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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.
• Basic medications given to coma patients in the field may include dextrose (50 mL of D50). This 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 cerebrovascular accident when appropriate.

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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. 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. This may decrease the risk of developing cerebral edema.^[1]
  • In pediatric patients with suspected HHS, correcting fluid deficits over a longer time period (48 h) may be appropriate to reduce the risk of developing cerebral edema.^[4]

   

  

   
• 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. Use of insulin may exacerbate hypokalemia.
• 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. Recheck glucose concentrations every hour. Electrolytes and VBGs should be monitored every 2-4 hours or as clinically indicated.
• All patients diagnosed with HHS require hospitalization, usually to an intensive care unit for close monitoring.

Diagnosis and management guidelines for hyperglycemic crises are available from the American Diabetes Association.^[7]

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Consultations

• Generally, no consultation is required to manage HHS in the ED. Virtually all patients need admission to a monitored unit managed by medicine, pediatrics, or the ICU.
• In occasional cases, endocrinology, neurology, or infectious disease consultation may be useful.
• Psychiatry consultation may be useful during the hospitalization.

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Medication Summary

Fluids, insulin, and repletion of electrolytes (especially potassium) are the cornerstones of management. Antipyretics, antiemetics, and antibiotics are added, when appropriate, to control fever and vomiting, and treat an underlying infection if suspected.

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Class Summary

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.

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Insulin (Humulin, Humalog, Novolin)

• Dosing, Interactions, etc.

Clinical Context:  Used to reduce blood glucose levels and decrease ketogenesis. Some authors favor lower bolus and infusion dosages, with rationale that fluids are cornerstone of therapy and that disorder is more one of insulin resistance than of insulin deficiency. Furthermore, lowering serum glucose and serum osmolarity overly rapidly can result in complications.

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Class Summary

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

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Potassium chloride (Klor-Con, K-Dur, Micro-K)

• Dosing, Interactions, etc.

Clinical Context:  Initial serum potassium in even reference range suggests intracellular potassium depletion. In virtually all cases of HHS, supplemental potassium is necessary, as serum level drops secondary to insulin therapy and correction of metabolic acidosis.

Do not start until initial serum level is ascertained. Administer IV potassium cautiously, with attention to proper dosing and concentration. If patient can tolerate oral medications or has gastric tube in place, KCl can be repleted orally up to 60 mEq per dose, with dosing based upon frequently obtained lab values.

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Class Summary

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.

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Sodium bicarbonate (NaHCO3)

• Dosing, Interactions, etc.

Clinical Context:  Bicarbonate ion produced on dissociation neutralizes hydrogen ions and raises urinary and blood pH.

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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.

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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.

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Inpatient & Outpatient Medications

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

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Transfer

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

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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.

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Complications

• Ischemia or infarction to any organ, including the heart and brain
• Hypoglycemia
• Hypokalemia
• Cerebral edema (rare)
• Thromboembolism^[8]
• Rhabdomyolysis^[9]

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Prognosis

• The overall mortality rate is between 10% and 20% and is dependent on coexisting conditions and complications.^{[2, 3]}

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