Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

Catherine T. Jamin and Jeffrey Manko

BACKGROUND

Diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) are two potentially devastating complications of diabetes. Although the number of patients diagnosed with DKA or HHS has nearly doubled in recent decades, the age-adjusted mortality of these patients has declined by almost half within the same time period.¹^,² This improvement in outcomes is due in large part due to the early recognition and therapeutic interventions delivered in the emergency department.

DKA and HHS are characterized by an imbalance between the effective action of insulin and of counterregulatory hormones such as glucagon, cortisol, catecholamines, and growth hormone.³ This imbalance results in increased gluconeogenesis, impaired peripheral glucose utilization, lipolysis, and increased ketoacid production. In DKA, this produces the triad of hyperglycemia, ketonemia, and metabolic acidosis. In HHS, it is thought that there is sufficient effective insulin to limit lipolysis and ketogenesis, but not enough to facilitate glucose uptake in the tissues (Fig. 42.1). In both conditions, patients undergo a significant osmotic diuresis—HHS with total body water (TBW) deficit of 8 to 10 L and DKA with a TBW deficit of 3 to 6 L—resulting in dehydration and electrolyte shifts.

FIGURE 42.1 Pathogenesis of DKA and HHS. Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Information updated from Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335. From American Diabetes Association. FFA, free fatty acids.

HISTORY AND PHYSICAL EXAM

Classically reported findings in a patient with DKA or HHS include polyuria, polydipsia, weakness, and dehydration. The onset of HHS is usually insidious, occurring over days to weeks, while DKA tends to manifest over a period of hours. Patients with DKA may complain of abdominal pain, nausea, or vomiting, while HHS patients often report mental status changes or confusion. The physical exam in both conditions will reveal evidence of hypovolemia, including hypotension, tachycardia, decreased capillary refill, and poor skin turgor. Patients with DKA will commonly demonstrate deep breathing or Kussmaul respirations, a fruity odor to their breath, and abdominal tenderness. Patients with HHS may present with profound neurologic changes including focal deficits, seizures, or coma. The most common insult precipitating both conditions is infection. Other triggers include insufficient insulin, drugs, and other severe physiologic stresses such as myocardial ischemia, stroke, and pancreatitis.³

DIAGNOSTIC EVALUATION

When DKA or HHS is suspected, the laboratory evaluation should include plasma glucose, basic metabolic panel, serum osmolarity, venous blood gas, serum lactate, and detection of ketones. A complete blood count, urinalysis, blood and urine cultures, chest radiograph, and electrocardiogram may help detect coexisting or triggering illness.

Hyperglycemia is a cardinal feature of both conditions and is typically more profound in patients with HHS (Table 42.1). Patients with DKA may however present with serum glucose <300 mg/dL; therefore, in a patient clinically suspected of having DKA, laboratory evaluation should always include calculation of the anion gap (AG) and serum ketones.³^,⁴

TABLE 42.1 Diagnostic Criteria for DKA and HHS

^aNitroprusside reaction method.

^bEffective serum osmolality: 2[Measured Na⁺ (mEq/L)] + Serum Glucose (mg/dL)/18.

^cAnion gap: Na⁺ − [(Cl⁻ + HCO₃⁻ (mEq/L)]. Na⁺, sodium; Cl−, chloride; HCO₃−, bicarbonate.

Adapted from Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore). 1986;65(3):163.

Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Information updated from Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335. From American Diabetes Association.

Ketones

In the patient with DKA, hepatic fatty acid oxidation produces ketone bodies, specifically acetoacetic acid, beta-hydroxybutyric acid, and acetone. The standard laboratory test used to detect serum ketones uses a nitroprusside reagent. While widely available, this test does not detect beta-hydroxybutyric acid and thus may yield a false-negative result. To avoid false-negative results, serum beta-hydroxybutyric acid should be measured directly, when possible.

Anion Gap Metabolic Acidosis

Patients with DKA will have a metabolic acidosis, with an arterial pH, by definition, of <7.3, and an elevated AG.

The AG reflects the difference between measured cations and anions and is elevated in DKA due to the presence of the ketoacids. Normal AG values are 7 to 11, with >12 considered elevated. Patients with hypoalbuminemia will have a factitiously lower AG due to the partial loss of negatively charged albumin particles.⁵ The AG should be corrected in patients with hypoalbuminemia using the following calculation:

Arterial versus Venous Blood Gas

Recent studies demonstrate that peripheral venous blood gas (VBG) samples can be used to accurately assess the degree of acidosis in patients presenting to the emergency department.⁶^–⁸ Compared with an arterial blood gas (ABG), the VBG will be lower by approximately 0.02 to 0.04 pH units. In general, VBGs and ABGs agree, but periodic correlation should be performed if serial VBGs are being used to monitor a patient’s acid–base status.

Osmolarity

Unlike patients with DKA, patients with HHS will present with significantly elevated serum osmolarity. Hyperosmolarity is primarily due to the marked free water loss associated with glucose-induced osmotic diuresis. Serum osmolarity is calculated as follows:

A serum osmolarity >320 can result in mental status changes, including stupor and coma. In patients with HHS presenting with neurologic impairment but normal serum osmolarity, a rigorous search for alternative explanations of their altered mental status is required.⁹^,¹⁰

Potassium

Despite presenting with elevated serum potassium levels, patients with DKA and HHS will often have a potassium deficit ranging between 3 and 5 mg/kg.¹¹^,¹² The potassium deficit is multifactorial and can be attributed to decreased intake and increased urinary and gastrointestinal losses.¹² Elevated serum potassium is mechanistically related to insulin deficiency, hyperglycemia, and acidosis, which decrease its regular cellular uptake.¹² As patients receive treatment for DKA and HHS, potassium uptake resumes and serum levels will rapidly fall, placing patients at risk for cardiac dysrhythmias and respiratory muscle weakness. Potassium levels should be followed closely at every stage of treatment to prevent these treatment complications.¹¹ Protocols for management of DKA (Table 42.2) include components for potassium replacement and to withhold insulin therapy until serum potassium levels are >3.3 mEq/L.³

TABLE 42.2 Management Guidelines

DKA diagnostic criteria: blood glucose 250 mg/dL, arterial pH < 7.3, bicarbonate 15 mEq/L, and moderate ketonuria or ketonemia. HHS diagnostic criteria: serum glucose >600 mg/dL, arterial pH > 7.3, serum bicarbonate > 15 mEq/L, and minimal ketonuria and ketonemia.

^a15–20 mL/kg/h.

^bSerum Na should be corrected for hyperglycemia (for each 100 mg/dL glucose > 100 mg/dL, add 1.6 mEq to sodium value for corrected serum value).

Bwt, body weight; IV, intravenous; SC, subcutaneous.

Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Information updated from Kitabchi, AE, Umpierrez, GE, Miles, JM, Fisher, JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335. From American Diabetes Association.

Sodium

The hyperglycemia present in both DKA and HHS will initially create an osmotic gradient that draws water from the cellular space, effectively lowering the measured serum sodium. This osmotic effect of glucose on serum sodium should be corrected using the following calculation:

The finding of hypernatremia in either DKA or HHS indicates that a significant free water deficit exists.

Phosphate

Serum phosphate may be normal or elevated in patients with DKA or HHS due to extracellular shifts; however, patients are typically phosphate depleted due to urinary loss and decreased intake.¹³ As with potassium, insulin therapy will unmask this deficit as it drives phosphate back into the cells. Although phosphate replacement has yet to demonstrate clinical benefit in patients with DKA, patients should be administered phosphorus when cardiac dysfunction, anemia, or respiratory depression is present, or when phosphate levels are <1 mg/dL.³^,¹⁴^,¹⁵

DIFFERENTIAL DIAGNOSIS

Other diagnoses to consider when evaluating a patient with an elevated AG acidosis include lactic acidosis, starvation or alcoholic ketoacidosis, uremic acidosis, and toxic ingestion. Patents with DKA may produce lactate, but will have a predominance of ketone bodies and a less significant elevation of lactate when compared to patients with primary lactic acidosis (e.g., the septic patient). Patients with starvation or alcoholic ketoacidosis will have detectable ketones but without hyperglycemia or glycosuria. Patients with uremic acidosis or toxic ingestion may present with an elevated AG acidosis but will not have the accompanying hyperglycemia, ketonemia, or glycosuria.

MANAGEMENT GUIDELINES

Fluid

All patients with DKA or HHS will be volume depleted and require fluid resuscitation. The free water deficit should be replaced within 24 hours and is calculated as follows: