Nonketotic Hyperosmolar Syndrome

Pathophysiology

• NKHS typically occurs in the elderly type II diabetic; although about half of the patients have no known prior history of diabetes. It may also occur in children (rare) and no diabetics in special circumstances. The classic scenario is that of an elderly, type II diabetic who encounters a stressful event.
• As with DKA, the underlying mechanism of NKHS is a relative insulin deficiency in the setting of elevated “stress”/counter regulatory hormones. In contrast to DKA, insulin levels are sufficient to prevent significant ketoacidosis. The result is severe hyperglycemia, osmotic diuresis, profound dehydration, and electrolyte depletion.
• The mortality rate of NKHS is higher than that of DKA. This can be explained by three reasons:
  1. more profound dehydration and electrolyte disturbances,
  2. older demographics,
  3. life-threatening precipitants and coexisting disease are more common.
  Coma and death are the end-result when left untreated.

Common Precipitants

• Infection (most common; usually Gram-negative pneumonia or sepsis)
• Ischemia/infarction (cardiac or CNS)
• Injury (trauma, burns)
• GI bleed
• Pancreatitis
• Pulmonary embolus
• Medications (ß-blockers, phenytoin, steroids, thiazide diuretics)
• Peritoneal dialysis, hyper alimentation (may precipitate NKHS in no diabetics)

Common Contributing Factors/Coexistent Disease

• Renal insufficiency (impaired elimination of glucose)
• Cardiac disease (CHF, A-fib, unstable angina or previous MI)
• Altered mental status/Altered thirst mechanism (Alzheimer’s, CVA; unable to keep up with fluid losses)
• Physical debilitation (unable to reach water)
• Diuretic medication (exacerbates fluid losses and thiazides promote hyperglycemia)

Diagnosis and Evaluation

• There are four basic diagnostic criteria:
  1. marked hyperglycemia (>600 mg/dl, often >1000 mg/dl);
  2. hyperosmolarity (>320 mosm/L);
  3. pH >7.3 (may be more acidotic secondary to coexistent illness; sepsis, lactic acidosis);
  4. minimal or absent ketosis.

Clinical Signs and Symptoms

• Polyuria, polydipsia, weight loss, fatigue and weakness often begin days to weeks before presentation. The average length of symptoms is 12 days in NKHS as opposed to 3 days for DKA.
• Signs and symptoms of dehydration are present: decreased skin turgor and sweating, dry mucous membranes, tachycardia, and, in the late stages, orthostatic, hypotension and shock. The average fluid deficit in NKHS is 8-12 L as opposed to 6 L in DKA.
• Urinary output (UOP) is not a good indicator of hydration status in NKHS as the osmotic diuresis inappropriately maintains urinary output in the face of severe dehydration.
• Neurologic signs and symptoms are usually present and correlate with the elevation of osmolarity. Mental status may range from mild drowsiness to lethargy and frank coma, myxedema coma. Focal neurologic deficits are often found including hemi paresis, hemianopsia, cranial nerve findings, aphasia and dysphasia, and focal seizures. The focal seizures are best treated with benzodiazepines.

Laboratories/Studies

• Hyperglycemia must be present for diagnosis. Serum glucose is usually >600, and often >1000.
• Hyperosmolarity is the cardinal laboratory indicator of NKHS. Osmolarity is always >320. Calculated osmolarity = 2 Na + glucose/18 + BUN/2.8 Effective osmolarity/tonicity = 2 Na + glucose/18 (urea is a freely permeable, “in affective” osmole).
• Mild anion gap acidosis often secondary to lactic acidosis from dehydration, infection, or cardiac failure is present.
• Potassium deficit secondary to osmotic diuresis occurs. The usual total body deficit is 5-10 meq/kg. Serum potassium levels may initially be normal or even high depending on extracellular shifts. Without significant acidosis, these shifts are less pronounced in comparison to DKA.
• Sodium deficit is present secondary to osmotic diuresis (5-10 meq/kg). Despite total body sodium depletion, the patient with NKHS is often hypernatremic (greater free water losses than Na losses). As in DKA, the laboratory value for sodium must be adjusted in the presence of hyperglycemia, thyroid storm, as it will be factitiously lowered. Corrected Na = serum Na + 1.6 ([serum glucose – 100] / 100).
• Magnesium and phosphorus losses occur secondary to osmotic diuresis.
• Complete blood count commonly reveals leukocytosis secondary to “stress” demargination and or infection, as well as elevated hematocrit secondary to dehydration.
• Hyperamylasemia: associated pancreatitis is common; it may precipitate NKHS or be caused by NKHS.
• Hypertriglyceridemia is common.
• CXR should be evaluated for signs of occult pneumonia or cardiac failure.
• EKG should be evaluated for signs of precipitant ischemia/infarction, as well as indications of hypokalemia.
• Head CT may be necessary in the setting of new altered mental status, seizures, or focal neurologic findings, although all may be explained by the hyperosmolarity of NKHS.

ED Management

The treatment of NKHS can be divided into four basic categories:

1. fluid replacement,
2. electrolyte correction,
3. insulin administration, and
4. treatment of the precipitant.

Fluid Replacement

• The first treatment objective is to establish hemodynamic stability with 0.9% NS as necessary. Usually 1-2 L of 0.9% NS over the first hour is required. Once hemodynamic stability is restored, switch to 0.45% NS as 0.9% NS may lead to or exacerbate hypernatremia.
• The average fluid deficit is 8-10 L or 20-25% of total body water. The goal is to replace 50% of losses over the first 12 h, with the remainder over the next 24 h.
• Fluid management with NKHS can be difficult and may require invasive monitoring, since most patients are elderly with preexisting renal and cardiac impairment.

Electrolyte Correction

• Anticipate and treat hypokalemia early. Begin replacement once potassium is in the normal range and the patient is making urine. Oral replacement is adequate and safer if patient able to tolerate it. Otherwise, replace intravenously at a rate of 10-20 meq/h.
• Magnesium replacement may be needed for effective replacement of potassium.
• As in DKA, replace phosphorus if < 1.0.

Insulin Administration

• In NKHS, insulin therapy is less important than in DKA. This seems counterintuitive, as glucose levels are higher with NKHS. However, in DKA the goal of insulin therapy is to stop lipolysis and, thereby, ketoacidosis. In NKHS there is already sufficient insulin to block lipolysis, and, therefore, the insulin requirement is generally lower.
• The attendant risks of insulin therapy are higher with NKHS than DKA.
  1. Hypoglycemia: many previously undiagnosed diabetics and those on oral regimens may be very sensitive to insulin and require slower infusion rates. The goal is to slowly lower glucose levels at a rate of ˜100 mg/dl.
  2. Hypotension: insulin should not be given until the patient is hemodynamically stable. Glucose osmotically maintains the intravascular compartment in the face of profound dehydration. An abrupt shift of glucose into the intracellular compartment post-insulin administration may cause sudden intravascular collapse.
  3. Hypokalemia: insulin should not be given prior to obtaining a potassium result or if the potassium level is < 3.5. Insulin should be given as an infusion of 5-10 u/h or 0.1 u/kg/h. Bolus insulin is potentially harmful.

Search for and Treat Acute Precipitants and Coexisting Disease

• Early diagnosis and treatment of infection with antibiotics, and appropriate management of cardiac and renal disease are extremely important in decreasing the morbidity and mortality of NKHS.

Admission Decision

• ICU admission is necessary for most patients. Very mild cases may be managed in a monitored observation setting. Admission decisions require evaluation of the severity of the NKHS, precipitating diseases, and concurrent conditions.