Definition

Diabetic ketoacidosis is defined by the presence of the following: hyperglycemia (blood glucose > 250 mg/dL), metabolic acidosis (arterial blood pH < 7.3 or bicarbonate < 16 mEq/L), and ketonemia (serum ketones ≥ 1:2 dilution) (Table 82.1). Although most patients with DKA have type 1 diabetes, DKA may also occur in patients with type 2 diabetes. African-American patients with type 2 diabetes appear to be particularly vulnerable, as evidenced by rising rates of DKA in this population. DKA remains a significant source of morbidity, accounting for as many as 9% of hospital admissions among patients with an established diagnosis of diabetes.

The presence of DKA leads to a new diagnosis of diabetes in up to 20% of patients. Fortunately, mortality attributable to DKA is generally less than 5% with appropriate treatment. Notably, geriatric patients are vulnerable to adverse outcomes, particularly when coexisting illnesses such as sepsis and myocardial infarction are also present.

Pathogenesis

Diabetic ketoacidosis occurs when insulin deficiency and counter-regulatory hormone excess are present simultaneously. Glucagon is the most important counter-regulatory hormone, but other hormones in this category include cortisol, growth hormone, and epinephrine (Figure 82.1). As a result of this hormonal imbalance, there is increased glucose production via gluconeogenesis and glycogenolysis while glucose utilization in peripheral tissues is impaired. The hormonal milieu also favors the liberation of fatty acids that are subsequently oxidized to form ketones. The ketones, β-hydroxybutyrate and acetoacetate, account for the anion gap metabolic acidosis that is characteristic of DKA (Chapter 83). As glucose and ketones accumulate in the bloodstream, the reabsorptive threshold of the renal tubule is surpassed, resulting in glucosuria and ketonuria, respectively. The ensuing osmotic diuresis results in the loss of sodium, potassium, and water in the urine. Nonadherence with an insulin regimen frequently causes DKA, but other triggers must be sought. Infections, particularly urinary tract infections (UTIs), and pneumonia, myocardial ischemia, stroke, pancreatitis, drugs, and alcohol consumption commonly precipitate DKA.

Evaluation

A thorough but rapid history is essential to determine the severity and duration of symptoms as well as to identify any precipitating events or comorbid illnesses. A schematic diagram for evaluation of the patient admitted to the ICU for DKA is shown in Figure 82.2. Presenting symptoms include polyuria and polydipsia that are a consequence of the hyperglycemia-induced osmotic diuresis. Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain are common and are thought to be due to a combination of metabolic acidosis and ileus. Some patients may also report dyspnea due to the acidosis-induced increase in respiratory drive, which produces Kussmaul breathing/respirations.

The physical examination is usually notable for signs of volume depletion—namely, dry mucous membranes, loss of normal skin turgor, tachycardia, and orthostatic hypotension. Deep and rapid respirations (Kussmaul respirations) may be evident. Mild abdominal tenderness is common, but focal abdominal pain or peritoneal signs warrant immediate evaluation. Temperature is normal or mildly hypothermic. Thus, the presence of fever should prompt an evaluation for concurrent infection. Acetone causes a fruity odor that may be detected on the patient’s breath. Importantly, acetone can be present in other disorders (e.g., alcoholic or starvation ketoacidosis and isopropyl alcohol ingestion). Altered sensorium is not characteristic of DKA and, if present, should trigger further evaluation.

Laboratory analysis demonstrates hyperglycemia. The serum glucose level is usually between 250 and 600 mg/dL (14 to 33 mmol/L). Profound hyperglycemia does not usually occur in DKA because the acidosis causes symptoms that prompt patients to seek medical care relatively early. Hyperglycemia causes an osmotic diuresis resulting in volume depletion, often with a concomitant free water deficit. As renal perfusion and the glomerular filtration rate (GFR) fall, the kidney excretes less glucose, which exacerbates the hyperglycemia.

The acute metabolic acidosis of DKA typically is accompanied by an acute respiratory compensation. Although the acidosis is most commonly an anion gap acidosis, a simultaneous anion gap and nonanion gap acidosis may coexist; or rarely a pure nonanion gap acidosis may be found (see Chapter 83 on metabolic acidoses). The type of acidosis depends on the intravascular volume of the patient. If fluid intake is adequate and GFR preserved, the kidney excretes ketones, thus reducing accumulation of unmeasured anions that would contribute to the serum anion gap. The observed nonanion gap metabolic acidosis is due to ketonuria, which is akin to the loss of bicarbonate equivalents in the urine. On the other hand, patients who are volume depleted have less ketonuria and accumulate more serum ketones, resulting in an anion gap metabolic acidosis. Depending on the volume status, patients with DKA can fall anywhere along this spectrum.

Serum ketones are present in a 1:2 dilution or higher. β-Hydroxybutyrate predominates with a concentration threefold higher than acetoacetate. The assay for ketones relies on the nitroprusside reaction, which only measures acetoacetate. Because acetoacetate only accounts for a small proportion of the ketones that are present, the assay for ketones may be negative early on. The test for ketones may become increasingly positive during the course of treatment, but this reflects a shift from β-hydroxybutyrate to acetoacetate rather than worsening ketonemia. Occasionally, drugs such as captopril can interfere with the assay for ketones, causing a false-positive result.

Patients may have hyperkalemia. This occurs due to insulin deficiency and acidosis, both of which favor a transcellular shift of potassium into the extracellular fluid. Despite the initial elevation in serum potassium level, the majority of patients have total body potassium depletion. The osmotic diuresis causes obligate potassium loss in the urine, and gastrointestinal losses may also contribute to the potassium deficit, averaging 3 to 5 mEq/kg. Initiation of insulin may unmask the potassium deficit as insulin drives potassium intracellularly. An analogous process occurs with phosphate—that is, phosphate levels may be elevated initially, but they typically drop with treatment. Mild leukocytosis is common in DKA, but white blood cell counts greater than 25,000/μL should raise suspicion of an underlying infection.

Treatment

The treatment and management of DKA are outlined in Figure 82.3. The following treatment steps are the cornerstones of management: (1) volume resuscitation, (2) reversal of hyperglycemia, (3) inhibition of ketogenesis, and (4) repletion of electrolytes.

Volume Resuscitation

The average volume deficit is 3 to 4 L. At least 1 to 2 L of isotonic fluid (usually normal saline) should be administered rapidly. Patients with hemodynamic compromise should continue to receive volume resuscitation at a rate of 1 L/hour while their volume status is simultaneously monitored very closely. After adequate repletion of intravascular volume (as judged clinically), patients with a low serum sodium concentration should continue to receive isotonic fluid, but at a slower rate. Fluids are infused at 4 to 14 mL/kg/h, depending on the clinical assessment of volume status. On the other hand, if the serum sodium concentration is normal or elevated, the patient almost certainly has a concomitant free water deficit and the intravenous fluid therapy should be changed to 0.45% saline, also infused at a rate of 4 to 14 mL/kg/h. Serum osmolality should be corrected no faster than 3 mOsm per hour to avoid iatrogenic cerebral edema. The importance of frequent reassessments of volume status cannot be overemphasized, particularly for patients with a history of heart or renal failure.

Reversal of Hyperglycemia

Insulin therapy should begin only after initial volume replacement. Hyperglycemia serves to “drag” water into the extracellular fluid (ECF) space (due to its contribution to osmotic pressure in the ECF) and helps maintain blood pressure, even in the face of significant volume deficits. If the volume deficit is not addressed first, insulin administration can precipitate vascular collapse as hyperglycemia resolves and extravascular water moves intracellularly. This occurs more commonly in patients with hyperglycemic hyperosmolar state (HHS) due to the profound hyperglycemia, but it can also occur in patients with DKA. Further, volume resuscitation alone may improve GFR and glucose excretion. Because there is no convincing evidence that withholding insulin for the first 15 to 30 minutes of volume resuscitation has any adverse effects, insulin administration should be delayed during this critical period.

After initial volume repletion, a bolus of 0.15 units/kg of insulin should be given intravenously and a maintenance infusion begun at 0.1 units/kg/h. Capillary blood glucose should be monitored hourly and verified by frequent measurements of serum glucose. If blood glucose does not fall by 50 to 70 mg/dL/h, the insulin drip should be adjusted accordingly. Most ICUs have a protocol for insulin drip titration.

Inhibition of Ketogenesis

Insulin is required to inhibit lipolysis and ketone generation. Because the serum glucose normalizes before ketoacid production stops, it is important to continue the insulin drip until the anion gap has “closed” (i.e., returned to a normal gap of 7 to 12 mmol/L). Premature discontinuation of insulin will lead to worsening acidosis. If serum glucose falls to ≤ 250 mg/dL (14 mmol/L) before the anion gap closes, intravenous fluids should be changed to include 5% dextrose. On occasion, 10% dextrose is necessary to maintain blood glucose between 150 and 200 mg/dL. Once dextrose is included in the intravenous fluids, the insulin infusion should be decreased to 0.05 to 0.1 units/kg/h. It may be necessary to decrease the infusion to 2 to 4 units/hour to avoid hypoglycemia.

The acidosis should be monitored every 2 to 4 hours by following the anion gap and serum bicarbonate. Ketones may appear to increase as the β-hydroxybutyrate is converted to acetoacetate as only the latter is detected by the assay. It is more important to follow the anion gap than the ketonemia. As insulin shuts off production of ketoacids and the kidney excretes those already present, the anion gap normalizes and a non-anion-gap metabolic acidosis becomes evident. As the kidney regenerates bicarbonate over 12 to 24 hours, the acidosis resolves. When it is evident that ketoacid production has been suppressed and the bicarbonate is normalizing, the insulin infusion can be discontinued. At least 0.5 hour before stopping the infusion, however, the patient should be given subcutaneous insulin to prevent the recurrence of the acidosis.

Despite significant acidosis, bicarbonate therapy is rarely, if ever, necessary. Even with severe acidemia (pH 7.0 to 7.2), there is no clear evidence supporting the use of bicarbonate therapy. In fact, bicarbonate infusions can be detrimental because they may delay ketoacid metabolism, unmask hypokalemia, and cause intracellular acidosis. Increased bicarbonate drives PaCO₂ production while simultaneously inhibiting respiratory drive, the result of which is intracellular acidosis. Bicarbonate therapy can be considered if the pH is < 7 but should be used judiciously.