Patients with mild DKA are alert and have pH levels between 7.25 and 7.30 and beta-hydroxybutyrate levels of 3–4 mmol/L; those with moderate ketoacidosis are either alert or a little drowsy and have pH levels between 7.0 and 7.24 and beta-hydroxybutyrate levels of 4–8 mmol/L; and those with severe ketoacidosis are stuporose and have a pH < 7.0 and beta-hydroxybutyrate levels of greater than 8 mmol/L. Those with mild ketoacidosis can be treated in the emergency department, but those with moderate or severe ketoacidosis require admission to the ICU or step-down unit. Therapeutic goals are to restore plasma volume and tissue perfusion, reduce blood glucose and osmolality toward normal, correct acidosis, replenish electrolyte losses, and identify and treat precipitating factors. Gastric intubation is recommended in the comatose patient to prevent vomiting and aspiration that may occur as a result of gastric atony, a common complication of DKA. An indwelling urinary catheter may also be necessary. In patients with preexisting heart or kidney failure or those in severe cardiovascular collapse, a central venous pressure catheter should be inserted to evaluate the degree of hypovolemia and to monitor subsequent fluid administration.
A comprehensive flow sheet that includes vital signs, serial laboratory data, and therapeutic interventions (eg, fluids, insulin) should be meticulously maintained by the clinician responsible for the patient’s care. Plasma glucose should be recorded hourly and electrolytes and pH at least every 2–3 hours during the initial treatment period. Bedside glucose meters should be used to titrate the insulin therapy. The patient should not receive sedatives or opioids in order to avoid masking signs and symptoms of impeding cerebral edema.
In most patients, the fluid deficit is 4–5 L. Initially, 0.9% saline solution is the solution of choice to help reexpand the contracted vascular volume and should be started in the emergency department as soon as the diagnosis is established. The saline should be infused rapidly to provide 1 L/h over the first 1–2 hours. After the first 2 L of fluid have been given, the intravenous infusion should be at the rate of 300–400 mL/h. Use 0.9% (“normal”) saline unless the serum sodium is greater than 150 mEq/L, when 0.45% (“half normal”) saline solution should be used. The volume status should be very carefully monitored clinically. Failure to give enough volume replacement (at least 3–4 L in 8 hours) to restore normal perfusion is one of the most serious therapeutic shortcomings adversely influencing satisfactory recovery. Excessive fluid replacement (more than 5 L in 8 hours) may contribute to acute respiratory distress syndrome or cerebral edema. When blood glucose falls to approximately 250 mg/dL (13.9 mmol/L), the fluids should be changed to a 5% glucose-containing solution to maintain serum glucose in the range of 250–300 mg/dL (13.9–16.7 mmol/L). This will prevent the development of hypoglycemia and will also reduce the likelihood of cerebral edema, which could result from too rapid decline of blood glucose.
Immediately after initiation of fluid replacement, regular insulin can be given intravenously in a loading dose of 0.1 unit/kg as a bolus to prime the tissue insulin receptors. Following the initial bolus, intravenous doses of insulin as low as 0.1 unit/kg/h are continuously infused or given hourly as an intramuscular injection; this is sufficient to replace the insulin deficit in most patients. A prospective randomized study showed that a bolus dose is not required if patients are given hourly insulin infusion at 0.14 unit/kg. Replacement of insulin deficiency helps correct the acidosis by reducing the flux of fatty acids to the liver, reducing ketone production by the liver, and also improving removal of ketones from the blood. Insulin treatment reduces the hyperosmolality by reducing the hyperglycemia. It accomplishes this by increasing removal of glucose through peripheral utilization as well as by decreasing production of glucose by the liver. This latter effect is accomplished by direct inhibition of gluconeogenesis and glycogenolysis as well as by lowered amino acid flux from muscle to liver and reduced hyperglucagonemia.
The insulin infusion should be “piggy-backed” into the fluid line so the rate of fluid replacement can be changed without altering the insulin delivery rate. If the plasma glucose level fails to fall at least 10% in the first hour, a repeat loading dose (0.1 or 0.14 unit/kg) is recommended. Rarely, a patient with immune insulin resistance is encountered, and this requires doubling the insulin dose every 2–4 hours if hyperglycemia does not improve after the first two doses of insulin. The insulin dose should be adjusted to lower the glucose concentration by about 50–70 mg/dL/h (2.8–3.9 mmol/L). If clinical circumstances prevent use of an insulin infusion, then the insulin can be given intramuscularly. An initial 0.15 unit/kg of regular insulin is given intravenously, and at the same time, the same size dose is given intramuscularly. Subsequently, regular insulin is given intramuscularly hourly at a dose of 0.1 unit/kg until the blood glucose falls to around 250 mg/dL, when the insulin can be given subcutaneously. Patients who normally take insulin glargine or insulin detemir can be given their usual maintenance doses during the initial treatment of their DKA. The continuation of their subcutaneous basal insulins means that lower doses of intravenous insulin will be needed, and there will be a smoother transition from intravenous insulin infusion to the subcutaneous regimen.
Total body potassium loss from polyuria and vomiting may be as high as 200 mEq. However, because of shifts of potassium from cells into the extracellular space as a consequence of acidosis, serum potassium is usually normal to slightly elevated prior to institution of treatment. As the acidosis is corrected, potassium flows back into the cells, and hypokalemia can develop if potassium replacement is not instituted. If the patient is not uremic and has an adequate urinary output, potassium chloride in doses of 10–30 mEq/h should be infused during the second and third hours after beginning therapy as soon as the acidosis starts to resolve. Replacement should be started sooner if the initial serum potassium is inappropriately normal or low and should be delayed if serum potassium fails to respond to initial therapy and remains above 5 mEq/L, as in cases of chronic kidney disease. Occasionally, a patient may present with a serum potassium level less than 3.5 mEq/L, in which case insulin therapy should be delayed until the potassium level is corrected to greater than 3.5 mEq/L. An ECG can help monitor the patient’s potassium status: High peaked T waves are a sign of hyperkalemia, and flattened T waves with U waves are a sign of hypokalemia. Foods high in potassium content should be prescribed when the patient has recovered sufficiently to take food orally. Tomato juice has 14 mEq of potassium per 240 mL, and a medium-sized banana provides about 10 mEq.
The use of sodium bicarbonate in the management of DKA has been questioned since clinical benefit was not demonstrated in one prospective randomized trial and because of the following potentially harmful consequences: (1) development of hypokalemia from rapid shift of potassium into cells if the acidosis is overcorrected; (2) tissue anoxia from reduced dissociation of oxygen from hemoglobin when acidosis is rapidly reversed (leftward shift of the oxygen dissociation curve); and (3) cerebral acidosis resulting from lowering of cerebrospinal fluid pH. It must be emphasized, however, that these considerations are less important when very severe acidosis exists. Therefore, it is recommended that bicarbonate be administered in DKA if the arterial blood pH is 7.0 or less, with careful monitoring to prevent overcorrection. One or two ampules of sodium bicarbonate (one ampule contains 44 mEq/50 mL) should be added to 1 L of 0.45% saline with 20 mEq KCl or to 400 mL of sterile water with 20 mEq KCl and infused over 1 to 2 hours. (Note: Addition of sodium bicarbonate to 0.9% saline would produce a markedly hypertonic solution that could aggravate the hyperosmolar state already present.) It can be repeated until the arterial pH reaches 7.1, but it should not be given if the pH is 7.1 or greater since additional bicarbonate would increase the risk of rebound metabolic alkalosis as ketones are metabolized. Alkalosis shifts potassium from serum into cells, which could precipitate a fatal cardiac arrhythmia.
Phosphate replacement is seldom required in treating DKA. However, if severe hypophosphatemia of less than 1 mg/dL (0.32 mmol/L) develops during insulin therapy, a small amount of phosphate can be replaced per hour as the potassium salt. Correction of hypophosphatemia helps restore the buffering capacity of the plasma, thereby facilitating renal excretion of hydrogen. It also corrects the impaired oxygen dissociation from hemoglobin by regenerating 2,3-diphosphoglycerate. Three randomized studies, though, in which phosphate was replaced in patients with DKA did not show any apparent clinical benefit from phosphate administration. Moreover, attempts to use potassium phosphate as the sole means of replacing potassium have led to a number of reported cases of severe hypocalcemia with tetany. To minimize the risk of inducing tetany from too-rapid replacement of phosphate, the average deficit of 40–50 mmol of phosphate should be replaced intravenously at a rate no greater than 3–4 mmol/h in a 60- to 70-kg person. A stock solution (Abbott) provides a mixture of 1.12 g KH2PO4 and 1.18 g K2HPO4 in a 5-mL single-dose vial (this equals 22 mmol of potassium and 15 mmol of phosphate). One-half of this vial (2.5 mL) should be added to 1 L of either 0.45% saline or 5% dextrose in water. Two liters of this solution, infused at a rate of 400 mL/h, will correct the phosphate deficit at the optimal rate of 3 mmol/h while providing 4.4 mEq of potassium per hour. (Additional potassium should be administered as potassium chloride to provide a total of 10–30 mEq of potassium per hour, as noted above.) If the serum phosphate remains below 2.5 mg/dL (0.8 mmol/L) after this infusion, a repeat 5-hour infusion can be given.
F. Hyperchloremic Acidosis During Therapy
Because of the considerable loss of keto acids in the urine during the initial phase of therapy, substrate for subsequent regeneration of bicarbonate is lost and correction of the total bicarbonate deficit is hampered. A portion of the bicarbonate deficit is replaced with chloride ions infused in large amounts as saline to correct the dehydration. In most patients, as the ketoacidosis clears during insulin replacement, a hyperchloremic, low-bicarbonate pattern emerges with a normal anion gap. This is a relatively benign condition that reverses itself over the subsequent 12–24 hours once intravenous saline is no longer being administered. Using a balanced electrolyte solution with a pH of 7.4 and 98 mEq/L chloride such as Plasma-lyte instead of normal saline (pH ~5.5; chloride 154 mEq/L) has been reported to prevent the hyperchloremic acidosis.
G. Treatment of Associated Infection
Antibiotics are prescribed as indicated (Table 30–5). Cholecystitis and pyelonephritis may be particularly severe in these patients.
H. Transition to Subcutaneous Insulin Regimen
Once the DKA is controlled and the patient is awake and able to eat, subcutaneous insulin therapy can be initiated. The patient with type 1 diabetes may have persistent significant tissue insulin resistance and may require a total daily insulin dose of approximately 0.6 unit/kg. The amount of insulin required in the previous 8 hours can also be helpful in estimating the initial insulin doses. Half the total daily dose can be given as a long-acting basal insulin and the other half as short-acting insulin premeals. The patient should receive subcutaneous basal insulin and rapid-acting insulin analog with the first meal and the insulin infusion discontinued an hour later. The overlap of the subcutaneous insulin action and insulin infusion is necessary to prevent relapse of the DKA. In patients with preexisting diabetes, giving their basal insulin by subcutaneous injection at initiation of treatment simplifies the transition from intravenous to subcutaneous regimen. The increased insulin resistance is only present for a few days, and it is important to reduce both the basal and bolus insulins to avoid hypoglycemia. A patient with new-onset type 1 diabetes usually still has significant beta cell function and may not need any basal insulin and only very low doses of rapid-acting insulin before meals after recovery from the ketoacidosis. Patients with type 2 diabetes and DKA due to severe illness may initially require insulin therapy but can often transition back to oral agents during outpatient follow-up.