Presentation and Diagnosis

The presentation and diagnosis of DKA relies on a thorough patient history, focused physical examination, and appropriate laboratory analysis. Patients typically report a history of poor glucose control and symptoms associated with hyperglycemia, such as polyuria, polydipsia, dehydration, weakness, weight loss, and lethargy that may progress over the course of days to weeks. Nausea, vomiting, and abdominal pain are also common presenting complaints and frequently signify the progression from symptomatic hyperglycemia to overt DKA. Interestingly, there is a strong correlation between severity of metabolic acidosis (HCO₃ <8 mMol/L and pH 7.12) and the presence of abdominal pain (20). In absent of such, abdominal pain secondary to intra-abdominal pathology should be investigated instead of attributing it to hyperglycemic-induced abdominal pain (20). The physical examination may reveal evidence of dehydration—for example, tachycardia, hypotension, prolonged capillary refill time, poor skin turgor, dry mucous membranes, and weight loss. In the setting of infection, the patient could be normothermic or hypothermic due to peripheral vasodilation. Additionally, Kussmaul respiration—very deep, gasping breaths taken in response to severe metabolic acidosis—an acetone or fruity breath odor, depressed mental status, and even focal neurologic deficits or coma may also be seen.

Laboratory analysis is usually confirmatory of DKA in these patients (Table 137.2). A complete blood count with differential, blood glucose, serum electrolytes, serum osmolality, serum lactate, blood urea nitrogen, serum creatinine, arterial or venous blood gas, serum, and urinary ketones should be ordered in patients with suspected DKA. In addition, an electrocardiogram and cardiac enzymes should be requested, with a workup for infection if infectious triggers of DKA are suspected. Caution should be exercised when using the serum sodium levels in patients with DKA, as the reported laboratory value can be artificially low, normal, or elevated, depending upon the spurious effects of glucose and triglycerides in these patients and the relative loss of water compared to sodium. In the presence of hyperglycemia, serum sodium measurement can be corrected by adding 1.6 mg/dL to the measured serum sodium for each 100 mg/dL increase in glucose above 100 mg/dL (21). Other tests, such as serum lactate, β-human chorionic gonadotropin (β-HCG), chest radiography, and computed tomography may be indicated, depending on the clinical scenario. Potassium is frequently faulty elevated secondary to the extracellular shift caused by academia while hypokalemia may indicate severe total-body potassium deficit that might contribute to arrhythmia.

Elevated plasma anion gap–associated metabolic acidosis (AGMA) is typically seen in laboratory analysis of patients with DKA, as ketosis and ketone body accumulation are responsible for an increase in the anion gap. Although the degree of plasma glucose levels in DKA has no correlation with degree of acidosis, in up to 11% of patients a nongap hyperchloremic metabolic acidosis may ensue (22,23). Typically, the normal anion gap is between 7 and 9 mEq/L and reflects unmeasured ions in the serum. In patients with DKA, an elevated anion gap—more than 10 to 12 mEq/L—occurs because of the high ketone concentration. Other causes of AGMA, which must be excluded during DKA evaluation, include alcoholic ketoacidosis, starvation ketoacidosis, lactic acidosis, and renal failure. In patients with possible DKA, these other causes of AGMA should be excluded through further history and laboratory analysis. For example, alcoholic ketoacidosis may present with profound metabolic acidosis, but typically has a characteristic history, an elevated blood alcohol content, and only mildly elevated serum glucose concentration. Likewise, starvation ketosis is accompanied by a significant history and only mild acidosis (serum bicarbonate is usually >18 mMol/L). Furthermore, AGMA secondary to salicylate ingestion, paraldehyde, methanol, and ethylene glycol should be considered. Ingesting of these alcohol derivatives results in an increased osmolar gap in addition to elevated anion gap; this may be a clue to the diagnosis.

TABLE 137.2 Diagnostic Criteria for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Nonketotic Syndrome

Ketonemia and ketonuria can both be assessed semiquantitatively with the nitroprusside reaction test. This test estimates the relative levels of acetoacetate and acetone in the blood, but does not detect the presence of the main metabolic product in ketoacidosis, β-hydroxybutyrate (β-OHB), which could contribute to underestimating the degree of ketosis. Because the ratio of β-OHB to acetoacetate may increase from 1:1 to as much as 5:1 during the development of DKA, an increase in β-OHB may represent the predominant ketone during that illness (24). Of note, β-OHB monitoring may significantly improve the diagnostic specificity in DKA patients with euglycemia or only mild hyperglycemia—as with prolonged vomiting, starvation, pregnancy, hepatic insufficiency, or following insulin administration—where blood glucose levels can be misleading (25). Leukocytosis may be explained by the stress response from DKA; however, a WBC greater than 25,000 cells/µL is unlikely and warrants a further workup (26). Elevation of pancreatic enzymes does not correlate with the degree of gastrointestinal symptoms or the presence of pancreatitis (27).

Management

Management of DKA includes initial resuscitation, correction of hyperglycemia and resolution of ketosis, and treatment of any precipitating causes (Figs. 137.2 and 137.3). Following these phases, it is essential also to provide chronic therapy to prevent repeated episodes and secondary sequelae of DM.

DKA can cause loss of protective airway reflexes, hypoxia, and hyperventilation. In patients with a severely depressed mental status, appropriate care should be taken to protect the airway so that pulmonary aspiration of gastric contents does not occur. If the patient’s Glasgow Coma Scale is 8 or less, or in situations that require sedation and transport away from the acute care environment for further evaluation, tracheal intubation may be necessary to ensure adequate airway protection and ventilation. Because these patients have a high incidence of gastroparesis, the placement of a decompressive gastric tube may also be warranted in the presence of an altered level of consciousness, and elevation of the head of bed to 30 and 40 degrees may serve to prevent passive regurgitation. Mechanical ventilation, if utilized, should be set to maintain respiratory compensation of the accompanying severe metabolic acidosis initially and adjusted appropriately as the acidosis corrects.

Following airway and respiratory care, initial therapy should be directed at restoring adequate blood volume and organ perfusion with intravascular volume resuscitation. In addition to correcting the hemodynamic insults associated with severe hypovolemia, appropriate volume administration can also decrease CRH levels and plasma glucose concentration (28,29). The goal during this phase is to replace the fluid deficit over the first 24 hours, half of which should be replaced in the first 6 to 8 hours. Estimation of fluid deficit can be based on body weight or general guidelines and response characteristics. Typically, 1 to 2 L (15 to 20 mL/kg body weight) of isotonic saline in the first 1 to 2 hours is sufficient for initial resuscitation; however, in more severe cases the resuscitation may require larger volumes, and some prefer to add colloids. The following clinical estimations of volume deficit using orthostatic blood pressure and heart rate may also be used to guide initial fluid replacement, although these criteria may be less reliable in patients with neuropathy and/or impaired cardiovascular reflexes (18).

• An increase in pulse without change in blood pressure with orthostatic position change indicates approximately a 10% decrease in extracellular volume (i.e., 2 L).
  
• A decline in blood pressure (>15/10 mmHg) with position change indicates approximately a 15% to 20% decrease in extracellular volume (i.e., 3 to 4 L).
  
• Supine hypotension indicates a decrease of more than 20% in extracellular fluid volume (i.e., >4 L).

After the initial resuscitation phase, both the rate of infusion and type of intravenous fluid must be adjusted. Current recommendations are to decrease the infusion rate to 250 mL/hr or to 4 to 14 mL/kg/hr, depending on the patient’s hydration status and to maintain adequate urine output of approximately 0.5 mL/kg/hr or, in a normal adult about 50 mL/hr. Depending on the patient’s corrected serum sodium, isotonic saline is continued or changed to hypotonic saline. If the patient’s corrected serum sodium is low, 0.9% saline solution should be continued as the replacement fluid; however, if the patient’s corrected serum sodium is normal or elevated, the fluid should be changed to 0.45% saline solution in order to continue free water deficit replacement. In general, resolution of hyperglycemia is faster than ketoacidosis (30). Additionally, once plasma glucose levels reach 250 mg/dL, 5% or even 10% dextrose solution should be added to the replacement fluids to maintain serum glucose levels between 150 and 200 mg/dL and allow the insulin infusion to continue until ketosis is reversed, defined as closing the anion gap and negative ketonemia, and to prevent the too rapid correction of serum glucose levels.

Concomitant with aggressive fluid resuscitation, insulin therapy should be instituted to decrease glucose production and increase glucose utilization with subsequent improvements in ketosis, acidosis, and hyperglycemia. Most experts recommend low-dose insulin infusion in all but the mildest cases of DKA over intermittent intravenous or subcutaneous administration, as the former is more physiologic, more therapeutically reliable, and decreases the risk of hypoglycemia and hypokalemia (31–35).

For continuous insulin infusion, many experts recommend an initial bolus of regular insulin 0.1 U/kg followed by an infusion at 0.1 U/kg/hr, with a goal of decreasing plasma glucose levels by 10% in the first hour. If the plasma glucose level does not respond appropriately after the first hour, and if the intravascular volume status is adequate, additional bolus of 0.14 unit/kg and the infusion rate may be doubled every hour until a constant decline in plasma glucose level is achieved. As previously mentioned, once the plasma glucose concentration reaches 11.1 mMol/L (200 mg/dL), the insulin infusion rate should be decreased to 0.02 to 0.05 U/kg/hr and dextrose should be added to the replacement fluid to maintain the plasma glucose level between 8.3 and 11.1 mMol/L (150 and 200 mg/dL) until anion gap acidosis is resolved.

In addition to serum glucose and bicarbonate levels, the American Diabetic Association recommends evaluation of β-OHB levels as the preferred method for rapid diagnosis and monitoring of DKA. Typically, β-OHB concentrations are less than 1 mMol/L; however, in patients with DKA, plasma β-OHB concentration can be elevated to concentrations in excess of 4 to 12 mMol/L (mean, 7 mMol/L). Adequate DKA treatment should allow β-OHB concentration to decrease by approximately 1 mMol/L/hr and eventfully return to baseline (<1 mMol/L) (24,36–39). As has been documented, serum bicarbonate levels are slower to correct while β-OHB is a more appropriate measure of therapy. Notably, as adequate treatment progresses, β-OHB is oxidized to acetoacetate, which can be detected by the nitroprusside reaction test leading to incorrect conclusions. Hence, it is recommended to measure directly β-OHB for diagnosis and monitoring treatment of DKA (19,40).

Despite massive potassium losses (3 to 5 mEq/kg) in patients presenting with DKA, the serum potassium concentration may be normal due to intravascular volume contraction and intracellular electrolyte shifts, and should not be used as an indicator of potassium homeostasis in the early phases of treatment. As insulin is provided, and acidosis is corrected, potassium may quickly shift back into the intracellular compartment. Additionally, initial resuscitation with normal saline may lower the serum potassium concentration. Severe hypokalemia may potentially cause life-threatening cardiac dysrhythmias and respiratory muscle weakness (41–43). Particular attention should be directed to help prevent hypokalemia during DKA treatment. If serum potassium is less than 3.3 mMol/L (3.3 mEq/L), it is recommended not start insulin because the reduction in plasma glucose levels and acidosis can cause significant intracellular fluid and potassium shifts that may worsen cardiovascular function to the point of collapse (18,44). Potassium replacement should begin once the serum potassium concentration is less than 3.3 mMol/L (3.3 mEq/L), assuming adequate urine output, using the following guidelines:

• If the serum potassium is less than 3.3 mMol/L (3.3 mEq/L), 40 to 60 mEq of potassium should be added to each liter of IV fluid. Initiate replacement at 10 mEq/hr through a peripheral venous access or, preferably, 20 to 30 mMol/hr through a CVL, until the serum potassium level is more than 3.3 mMol/L.
  
• If the serum potassium is 3.3 to 4 mMol/L, 30 to 40 mEq of potassium should be added to each liter of IV fluid.
  
• If the serum potassium is 4 to 5 mMol/L, 20 to 30 mEq of potassium should be added to each liter of IV fluid.
  
• If serum potassium level is above 5.5 mMol/L, insulin and intravenous fluids should be initiated, and potassium chloride infusion held with serum potassium level evaluated every 2 hours.

In addition to potassium, other electrolytes such as magnesium, phosphate, and calcium are also depleted in patients with DKA. Inadequate serum concentrations of these electrolytes may cause respiratory depression, cardiac dysfunction, and alteration of tissue oxygenation that can be avoided by diligent monitoring and appropriate replacement. Measurement of these electrolytes should be done at presentation to identify significant abnormalities in order to facilitate appropriate early correction as clinically indicated. They should be repeated as necessary, depending on the clinical scenario. Although several studies have failed to show an outcome benefit to phosphate replacement, some experts continue to recommend replacement of phosphate in those with serum phosphate concentration less than 1.0 mMol/L (0.323 mg/dL) by using potassium phosphate as a portion of the total potassium replacement (18,45,46). Of note, hypocalcemia may become problematic in the face of overaggressive phosphate replacement.

Adequate treatment of DKA—intravascular volume repletion with reversal of hyperglycemia and ketosis—is generally associated with improvements in both physiologic and laboratory parameters. Criteria for resolution of DKA include plasma glucose less than 11.1 mMol/L (200 mg/dL) and two of following parameters: serum bicarbonate concentration 15 mEq/L or more, venous pH greater than 7.3, anion gap 12 mEq/L or less, and, recently, β-OHB less than 1 mMol/L (25). After resolution of the DKA episode, when the patient is able to tolerate enteral nutrition, a multidose subcutaneous insulin regimen that includes a combination of short- and intermediate- or long-acting insulin should be instituted. To allow for sufficient insulin plasma level, intravenous insulin should be continued for 1 to 2 hours following the first dose of subcutaneous insulin. Patients with previously diagnosed diabetes may restart their previous insulin schedule with additional adjustment and coverage as needed. If the patient is not ready for oral intake, intravenous insulin should be continued as well as fluid resuscitation. Bicarbonate offers no benefit in improving cardiac or neurologic functions in DKA (47). However, the American Diabetic Association suggests selectively use in severe acidosis with pH less than 6.9 (10).

Treatments of DKA should ideally be provided in an environment that has adequate nursing care and monitoring capabilities, as well as a rapid turnaround of laboratory tests. Invasive monitoring should be provided as necessary; patients with mild-to-moderate DKA may require only noninvasive blood pressure monitoring, continuous electrocardiography, pulse oximetry, and a urinary catheter, whereas patients with the most severe disease states and comorbidities may, in addition, require arterial and central venous catheterization. Additionally, patients with oliguria or hypotension refractory to initial rehydration, mental obtundation, sepsis, respiratory insufficiency, pregnancy, or significant comorbidities or precipitating events such as myocardial infarction or decompensated congestive heart failure should be managed in a critical care environment (18,42).

Complications

Common complications encountered during DKA treatment include hypoglycemia and hyperglycemia, various electrolyte disturbances, lactic acidosis, intravascular volume overload, cerebral edema, acute respiratory distress syndrome (ARDS), coagulopathy, rhabdomyolysis, and thromboembolism (Table 137.3).

Hypoglycemia and hyperglycemia are common complications of DKA treatment. Because intensive intravenous insulin therapy intentionally decreases blood glucose levels, reverses ketone body formation, and improves insulin sensitivity, it also places the patient at significant risk for hypoglycemia. The latter is associated with serious complications, including significant cognitive dysfunction, coma, and death. The incidence of serious hypoglycemic episodes associated with DKA treatment can be substantially decreased with the institution of low-dose insulin protocols, the addition of dextrose containing solutions to intravenous fluid management when the blood glucose concentration reaches 250 to 300 mg/dL, and the institution of frequent blood glucose monitoring with frequent insulin infusion rate titration (6,42). Additionally, hyperglycemia—with the potential for DKA to recur—can be seen following the resolution of DKA, due in large part to abrupt termination of the intravenous insulin infusion without adequate overlap of nonintravenous therapies, including subcutaneous insulin.

TABLE 137.3 Complications of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Nonketotic Syndrome Treatment

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