At a Glance

Both diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious complications of diabetes that develop as a consequence of too little insulin, coupled with an increase in concentration of counter-regulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone. DKA occurs when ketones are produced during hepatic metabolism of free fatty acids for energy in the absence of glucose, secondary to absolute or relative insulin deficiency. Patients suffering from DKA are typically younger, lean patients with type I diabetes, although type II diabetics can also be affected. Presentation with DKA may be the first symptom of previously undiagnosed diabetes.

Signs and symptoms of DKA occur quickly (<24 hours)and can mimic those of the flu, including nausea and vomiting, abdominal pain, loss of appetite, weakness, or fatigue. Additional symptoms include polydipsia, polyuria, polyphagia, Kussmaul’s respirations, fruity-scented breath, and a mental state ranging from lethargic to comatose (<20% of hospitalized patients). Physical examination may reveal evidence of dehydration, such as decreased skin turgor and dry mouth. Cases of severe dehydration may result in decreased blood pressure and tachycardia, secondary to a decrease in circulating blood volume. Although infection is a common trigger of DKA and HHS, patients can be either normothermic or hypothermic due to peripheral vasodilation.

Patients suffering from HHS are typically older and obese with a known history of type II diabetes, although, in 30-40% of cases, HHS is the patient’s initial presentation of diabetes. HHS can take days or weeks to develop. Similar to DKA, patients suffering from HHS may also present with polyruia, abdominal pain with nausea and vomiting, polydipsia (often absent in elderly patients with HHS), and dehydration (typically more pronounced in HHS). On physical examination, these patients may also show signs of weakness, tachycardia, altered sensorium, and hypotension.

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In addition to inadequate or inappropriate insulin therapy, infections, pancreatitis, myocardial infarction, cerebrovascular accident, and drugs are common triggers of DKA and HHS.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Initial laboratory tests for DKA and HHS should include evaluations of plasma glucose, blood urea nitrogen/creatinine, phosphorus, serum ketones, electrolytes with calculated anion gap and effective osmolality, urinalysis, urine ketones by dipstick, complete blood count (CBC) with differential, and an electrocardiogram

The three defining features of DKA are acidosis, ketosis, and hyperglycemia. The current diagnostic criteria for DKA include a plasma glucose level greater than or equal to 250 mg/dL (14 mmol/L); an arterial pH less than or equal to 7.3; a serum bicarbonate less than or equal to 15 mEq/L (mmol/L), although less severe cases of DKA may present with bicarbonate levels between 15 and 18 mmol/L; an effective serum osmolality of less than or equal to 320 mmol/kg; anion gap greater than 12 mmol/L (Na
+– [Cl + HC03]); moderate to high serum ketones; and moderate to high urine ketones. A pH level, bicarbonate level, and mental status are used as indicators of the severity of DKA.

When available, testing for the presence of beta-hydroxybutyrate is the preferred method for monitoring response of DKA patients to treatment. Values greater than 3 mg/dL (>0.5 mmol/L) are considered abnormal, and levels of 3 mmol/L correlate with the need for treatment. In addition to having water shortages of approximately 6 L in adults, DKA patients also typically have shortages in sodium, potassium, chloride, phosphate, magnesium, and calcium.

Patients with DKA are typically admitted to the hospital for intravenous treatment of fluid loss, correction of hyperglycemia by insulin infusion, and correction of electrolyte disturbances and acid-base balance. In addition, it is important to identify and treat any concurrent infection, if present, that may have been the underlying cause of DKA.

HHS is characterized by little to no ketoacid accumulation, a serum glucose concentration greater than 34 mmol/L (600 mg/dL), an arterial pH greater than 7.3, a serum bicarbonate level greater than 15 mmol/L, an effective serum osmolality greater than 320 mmol/kg, and negative serum or urine kethones. Adult patients with severe dehydration may have water shortages of up to 8-12 L. All patients diagnosed with HHS require hospitalization for treatment and close monitoring. Glucose concentrations should be checked every hour, and electrolytes and venous blood gasses should be measured every 2-4 hours or as clinically indicated.

Although not useful in the initial stages of therapy, hemoglobin A1C may provide useful information in determining whether this is an acute episode in a previously undiagnosed or poorly controlled diabetic or is a truly acute episode in a well-controlled diabetic.(Table 1)

Table 1.
Diagnostic Criteria Normal Range DKA HHS
Mild Moderate Severe
Plasma glucose level, mg/dL (mmol/L) 75-115 (4.2-6.4) >250 (14) >250 (14) >250 (14) >600 (34)
Arterial pH 7.35-7.45 >7.25-7.30 >7.00-7.25 <7.00 >7.30
Serum bicarbonate level, mmol/L 22-28 15-18 10 to <15 <10 >15
Effective Serum osmolality, mmol/kg 275-295 ≤320 ≤320 ≤320 >320
Anion gap*, mmol/L <12 >10 >12 >12 <12
Serum ketones Negative Positive Positive Positive Small
Urine ketones Negative Positive Positive Positive Small
Mental status Alert Alert/drowsy Stupor/coma Stupor/coma

*Calculation Na+ – (Cl + HCO3)

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Serum creatinine levels may be falsely elevated because of dehydration or interference from ketone bodies (if a colorimetric method is used).

Most laboratory tests for ketone bodies use nitroprusside-based methods that measure only acetoacetate, not the primary ketone body beta-hydroxybutyrate. In DKA patients suffering from severe complications, such as lactic acidosis, there is significantly more beta-hydroxybutyrate than acetoacetate, resulting in a negative or weakly positive nitroprusside test. As ketosis improves, beta-hydroxybutyrate is converted to acetoacetate. Thus, subsequent nitroprusside testing may falsely indicate that ketosis is increasing.

Drugs with sulfhydryl groups, such as captopril, which is used to treat hypertension and diabetic nephropathy, may also interfere with reagents in the nitroprusside test, resulting in a false negative.

What lab results are absolutely confirmatory?

The laboratory results used to confirm diagnosis are also used for confirmation.

Additional Issues of Clinical Importance

Treatment of DKA or HHS is usually a three-prong approach, involving fluid replacement (orally or intravenously), intravenous electrolyte replacement, and insulin therapy. Overzealous treatment of DKA and HHS with insulin may result in hypoglycemia and hypokalemia. Hypokalemia may also be induced as a consequence of treatment of acidosis with bicarbonate.

Although rare, cerebral edema is a frequently fatal complication of DKA, occurring in approximately 0.7-1.0% of children. The mechanism underlying cerebral edema is currently unknown, but studies suggest that a gradual replacement of sodium and water deficits in patients who are hyperosmolar, followed by the addition of dextrose once blood glucose reaches 200 mg/dL (11.1 mmol/L) in DKA and 300 mg/dL (16.6 mmol/L) in HHS, may prevent development of this complication. A glucose level of 200-250 mg/dL (11.1-14.4 mmol/L) should be maintained in cases of HHS until the patient becomes clinically stable.

Resolution of DKA is defined by a blood glucose level less than 200 mg/dL (11.1 mmol/L), the normalization of blood acidity (pH > 7.3), the absence of ketones in the blood or urine, a serum bicarbonate level greater than 18 mmol/L, an anion gap less than 12 mmol/L, and the ability to tolerate oral nutrition and fluids. HHS is considered resolved when osmolarity is less than 320 mmol/kg and there is a gradual recovery to mental alertness.

Errors in Interpretation

The conditions causing the three metabolic abnormalities characteristic of DKA (i.e., hyperglycemia, ketosis, and acidosis) overlap. Alcoholism and starvation can result in ketosis, whereas, in some instances, the effect of lactic acidosis, chronic renal failure, or ingestion of drugs, such as salicylate, methanol, ethylene glycol, and paraldehyde, is high anion gap metabolic acidosis. The key diagnostic feature distinguishing between diabetic and alcohol-induced ketoacidosis is the plasma glucose level. Patients with decreased food intake (<500 kcal/day) may also present with ketosis; however, starvation ketosis is rarely accompanied by a serum bicarbonate concentration less than 18 mEq/L.