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Featured Clinical Topic-Endocrinology: Management of Diabetic Ketoacidosis in Critically Ill Patients

24 Jan 2018 3:56 PM | MSHP Office (Administrator)

Management of Diabetic Ketoacidosis in Critically Ill Patients

Authors: Anahit R. Simonyan, PharmD Candidate 2018, St. Louis College of Pharmacy
Gabrielle A. Gibson, PharmD, BCPS, BCCCP: Barnes-Jewish Hospital

It is estimated that patients with diabetes are more likely to be hospitalized and experience longer hospital stays than those without diabetes.1 Additionally, severe hyperglycemia can lead to either diabetic ketoacidosis (DKA) and/or hyperosmolar hyperglycemic state (HHS), which are two of the most serious acute complications of diabetes associated with significant morbidity and mortality. Diabetic ketoacidosis is an acute complication of diabetes, responsible for over 500,000 hospital stays per year.2 The remainder of this paper will be focused on the management of DKA.

The pathophysiology of DKA can be explained by an absolute insulin deficiency leading to ketosis. The decrease in effective insulin concentration causes an increase in production of counterregulatory hormones. These hormones cause a decrease in glucose utilization, increase in gluconeogenesis, and increase in glycogenolysis. The characteristic finding of ketoacidosis is due to upregulation of lipolysis and availability of free fatty acids. The liver converts the free fatty acids to ketone bodies, resulting in ketonemia and acidosis. Diabetic ketoacidosis can be precipitated by several factors, including infection, non-adherence to therapy, concomitant illnesses, and medications such as corticosteroids and sympathomimetic agents. Although DKA may present with symptoms ranging from abdominal pain to severe polyuria, polydipsia, or polyphagia, diagnosis of DKA is based on abnormal pH and serum bicarbonate values, an elevated anion gap with additional fluid and electrolyte abnormalities, and positive urine and serum ketones.1,2

Goals of DKA treatment include improvement of organ perfusion through increasing circulatory volume, gradual reduction of osmolality and serum glucose, clearance of both serum and urine ketones, and normalization of electrolytes. The three main treatments for DKA are fluid therapy, reversal of hyperglycemia, and correction of electrolyte abnormalities while concomitantly identifying and treating the underlying cause.

Management: Intravenous (IV) fluids1,2
Administration of IV fluids is utilized in the treatment of DKA in order to correct hypovolemia. In the absence of cardiac compromise, all patients should receive normal saline (0.9% NaCl) for intravascular volume repletion. The initial isotonic saline should be infused at a rate of 15-20 mL/kg/hr or 1-1.5 L during the first hour. Subsequent choices of fluid are determined by the patient’s volume and hemodynamic status, corrected sodium, and the patient’s urine output in addition to cardiac and renal function. Fluids may then be changed to include dextrose once the patient’s serum glucose reaches an acceptable level of 200 mg/dL. As patients become volume resuscitated, monitoring for improved renal function, blood pressure, lab values, and clinical exam should occur within the first 24 hours.

The cornerstone of DKA treatment lies with administration of insulin. The optimal initial treatment regimen for DKA patients is IV regular insulin. A randomized, prospective study performed by Fisher and colleagues evaluated 45 patients with DKA to determine the most efficacious route of insulin administration. The group receiving IV regular insulin had a statistically significant faster decrease in plasma glucose (two hours vs four hours, P<0.01) and ketone bodies (4 hours versus 6 hours, P<0.05) compared to subcutaneous or intramuscular insulin. About 90% of participants receiving IV insulin had a decrease in plasma glucose by at least 10% in the first hour, compared to only 30-40% of the participants in the subcutaneous and intramuscular insulin groups. Thus, the administration of continuous IV regular insulin infusions are preferred because of the short half-life and ability to easily titrate.

Guideline recommendations suggest a bolus of 0.1 units/kg of regular insulin with subsequent continuous infusion of regular insulin at 0.1 units/kg/hour. The patient can be transitioned to subcutaneous short-acting insulin once the hyperglycemic crisis has resolved and certain criteria have been met. A patient must have a blood glucose <200 mg/dL in addition to two of the following: serum bicarbonate >15 mEq/L, pH >7.3, or calculated anion gap <12 mEq/L. In order to prevent hyperglycemia, the short-acting subcutaneous injection should be overlapped with the infusion by 1-2 hours. In the case that patients are to remain NPO, a regular insulin infusion should be continued with appropriate IV fluids. Hypoglycemia is one of the most common complications from treatment of DKA, thus it is imperative that these patients have frequent blood glucose monitoring at least every 1-2 hours to prevent and manage hypoglycemia.

Patients with DKA may experience elevations in potassium as a result of insulin deficiency and metabolic acidosis. Potassium is stored in the intracellular compartment, and in the presence of acidosis the potassium shifts from the intracellular to the extracellular space. This causes an increase in serum potassium, despite the fact that most patients have a total body deficit of potassium. With insulin and fluid therapy, and subsequent correction of acidosis and volume status, a decrease in serum potassium may occur. Supplementation may be initiated once the serum potassium < 5.2 mEq/L. It is rare to have a patient present with hypokalemia, but if this does occur, insulin therapy should be held until the serum potassium is restored to >3.3 mEq/L, to avoid arrhythmias and respiratory muscle weakness.

At presentation of DKA, levels of phosphate may be elevated. However, patients receiving insulin therapy for treatment of DKA will have decreased phosphate levels. In order to avoid cardiac dysfunction, muscle weakness, and respiratory distress secondary to hypophosphatemia, vigilant monitoring and replacement of phosphate must be employed. In those with a serum phosphate <1.0 mg/dL, supplementation with 20-30 mEq of potassium phosphate should be administered in addition to IV fluids. Correction of phosphate should not exceed 4.5 mmol/hour in order to prevent severe hypocalcemia and further complications.

The American Diabetes Association (ADA) does not recommend the routine use of bicarbonate therapy unless the patient has extreme acidosis (pH <6.9) with severe systemic complications, such as impaired myocardial contractility. Duhon and colleagues performed a retrospective analysis to determine whether the use of IV bicarbonate therapy led to improved outcomes in DKA patients. The primary outcome was the time it took to resolve acidosis, with secondary outcomes of hospital length of stay, and additional therapy requirements within the first 24 hours of admission. The study showed no statistically significant difference in the time it took to resolve acidosis between the two groups. The only statistically significant difference found was an increase in insulin and fluid requirements in those receiving bicarbonate therapy than those not receiving it. However, this study is limited by its retrospective nature and its small sample size with 40 patients included in each group.

It is imperative to treat the manifestations of DKA in order to prevent complications and reduce mortality in critically ill patients. Appropriate IV fluid, insulin, and correction of electrolyte abnormalities is necessary for the safe and effective treatment of DKA. Patients should be educated on how to prevent DKA, including the medications and conditions that may precipitate its occurrence. Pharmacists can play a vital role in the education and prevention process, and should promote awareness to diabetic patients regarding this condition.

1. Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32:1119–1131.
2. Kitabchi AE, Guillermo UE, Miles JM, Fisher JN. Hyperglycemia Crises in Adult Patients with Diabetes. Diabetes Care. 2009;32:1335-1343.
3. Fisher JN, Shahshahani MN, Kitabchi AE, et al. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977;297(5):238-241.
4. Finfer S, Blair D, Bellomo R, et al. Intensive versus Conventional Glucose Control in Critically Ill Patients (NICE-SUGAR). N Engl J Med. 2009;360(13):1283-1297.
5. Duhon B, Attride RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother. 2013;47(8):970-975.

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