Approach
The main goals of treatment are:
Restoration of volume deficits
Resolution of hyperglycemia and ketosis/acidosis
Correction of electrolyte abnormalities (potassium level should be >3.3 mEq/L before initiation of insulin therapy; use of insulin in a patient with hypokalemia may lead to respiratory paralysis, cardiac arrhythmias, and death)
Treatment of the precipitating events (e.g., sepsis, myocardial infarction, stroke) and prevention of complications.
It must be emphasized that successful treatment requires frequent monitoring of clinical and laboratory parameters to achieve resolution criteria. Individualized therapy is required based on these results as the presentation of DKA can be very variable.[3] A treatment protocol and a flow sheet for recording the treatment stages and laboratory data should be maintained.[1][46][47][48]
Initial and supportive treatment
The majority of patients present to the emergency department, where treatment should be initiated. There are several important steps that should be followed in early management:
Fluid therapy should be started immediately after initial laboratory evaluations.
Infusion of isotonic solution of 0.9% sodium chloride at a rate of 1.0 to 1.5 L/hour should be used for the first hour of fluid therapy.
Indications for admission to the intensive care unit (ICU) are hemodynamic instability or cardiogenic shock, altered mental status, respiratory insufficiency, severe acidosis, and hyperosmolar state with coma.
The diagnosis of hemodynamic instability should be made by observing for hypotension and clinical signs of poor tissue perfusion, including oliguria, cyanosis, cool extremities, and altered mental state. After admission to ICU, central venous and arterial lines are required, with continuous percutaneous oximetry. Oxygenation and airway protection are critical. Intubation and mechanical ventilation are commonly required, with constant monitoring of respiratory parameters. Nasogastric suctioning is always performed because of frequent ileus and danger of aspiration.
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Initial management in hemodynamically unstable patients includes fluid resuscitation to correct hypovolemia and hypotension, close monitoring, and vasopressor therapy under specialist supervision.[1][52]
Fluid therapy
Fluid deficit averages 6 liters.[53] After the initial management, continuous fluid therapy should be started. The goal is the restoration of fluid loss. Correction of fluid deficits should be undertaken gradually over 12-24 hours, as overly rapid correction can result in the patient developing cerebral edema.[54][55] After initial therapy with 1.0 to 1.5 L of isotonic solution (0.9% NaCl) for the first hour of admission in all patients, hydration status should be evaluated clinically. The presence of orthostatic hypotension or supine hypotension with dry mucous membranes and poor skin turgor indicates severe volume depletion, which should be treated by infusion of 0.9% NaCl at the rate of 1.0 L/hour until signs of severe volume depletion are resolved.[10][56] These patients then continue to receive fluid therapy as for mild volume depletion, based on the corrected serum sodium level.
In patients with mild volume depletion (characterized by an absence of hypotension), corrected serum sodium level should be evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016 [glucose (mg/dL) - 100]).
In hyponatremic patients: 0.9% NaCl should be started at 250-500 mL/hour and when the plasma glucose reaches 200 mg/dL, fluid therapy should be changed to 5% dextrose with 0.45% NaCl at 150-250 mL/hour.[1][10][57]
In hypernatremic or eunatremic patients, 0.45% NaCl at 250-500 mL/hour is recommended and when plasma glucose reaches 200 mg/dL, it should be changed to 5% dextrose with 0.45% NaCl at 150-250 mL/hour.[1][10][57]
Insulin therapy
The goal is the steady but gradual reduction of serum glucose and plasma osmolality by low-dose insulin therapy, in order to reduce the risk of treatment complications including hypoglycemia and hypokalemia.
Patients should receive a continuous intravenous infusion of regular insulin after exclusion of hypokalemia (i.e., potassium level should be >3.3 mEq/L before initiation of insulin therapy).[1] This is the standard of care in critically ill and mentally obtunded patients with DKA.[3] Two alternative low-dose regimens are recommended by the American Diabetes Association (ADA).[1] The first option is a continuous intravenous infusion of regular insulin at a dose of 0.14 units/kg/hour (approximately 10 units/hour in a 70 kg patient) with no initial bolus.[1] This is based on studies that show the use of low-dose regular insulin administered by intravenous infusion is sufficient for the treatment of DKA, provided the dose is above 0.1 units/kg/hour. The alternative regimen involves an initial intravenous bolus dose of 0.1 units/kg followed by a continuous infusion at a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasma glucose concentration at a rate of 50 to 75 mg/dL/hour.[1]
If plasma glucose does not fall by at least 10% or 50 mg/dL in the first hour of insulin infusion, then a dose of 0.14 units/kg of regular insulin should be administered as an intravenous bolus and the continuous insulin infusion rate should be continued (either 0.1 units/kg/hour or 0.14 units/kg/hour depending on the regimen selected).[1][53] Insulin injection by a sliding scale is no longer recommended. When serum glucose is <200 mg/dL, the infusion can be reduced to 0.02 to 0.05 units/kg/hour, at which time dextrose may be added to the intravenous fluids.[1][53] The rate of insulin infusion (or the dextrose concentration) should then be adjusted to maintain a plasma glucose level of between 150-200 mg/dL.[1]
Patients with severe DKA (plasma glucose >250 mg/dL, arterial pH <7.00, serum bicarbonate <10 mEq/L), hypotension, anasarca (severe generalized edema), or associated severe critical illness should be managed with intravenous regular insulin in the ICU using the regimen described above.[1][58][59][60]
Patients with mild to moderate DKA (plasma glucose >250 mg/dL, arterial pH 7.00 to 7.30, serum bicarbonate 10-18 mEq/L) that is not complicated by acute myocardial infarction, congestive heart failure, end-stage renal or hepatic failure, steroid use, or pregnancy, may be given rapid-acting insulin subcutaneously as an alternative to intravenous regular insulin (with no significant difference in outcomes when using either approach alongside aggressive fluid management for mild or moderate DKA).[3][61][62][63]
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]
A suggested protocol would be an initial subcutaneous injection of rapid-acting insulin at a dose of 0.3 units/kg, followed 1 hour later by another subcutaneous injection of 0.2 units/kg. Thereafter, they should receive 0.2 units/kg every 2 hours until blood glucose becomes <250 mg/dL. At this point, the insulin dose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[59] Patients treated with subcutaneous insulin should receive adequate fluid replacement, frequent bedside blood glucose testing, and appropriate treatment of underlying causes to avoid recurrent DKA.[3] Continuous intravenous infusion of regular insulin should, however remain the preferred route in all patients with DKA because of intravenous insulin's short half-life and easy titration (compared with the delayed onset of action and prolonged half-life of subcutaneously administered insulin). However, if there are prolonged waiting times for ICU admission or limited medical resources, the use of insulin analogs for the treatment of mild or moderate uncomplicated DKA episodes can be considered for outpatients, in general floors, or in emergency departments.[3]
[Figure caption and citation for the preceding image starts]: Management of adult DKA. Abbreviations: blood glucose (BG); diabetic ketoacidosis (DKA); hour (h); intravenous (IV); subcutaneous (SC)Image created BMJ Knowledge Centre based on Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2014;7:255-64. [Citation ends].
Once DKA has resolved and the patient can tolerate oral intake, transition to subcutaneous insulin needs to be initiated. The ADA recommends using a transition protocol (as this is associated with reduced morbidity and costs), and advises that administration of basal insulin is required 2 to 4 hours before stopping intravenous insulin to prevent recurrence of DKA and rebound hyperglycemia.[3] The ADA further directs towards emerging evidence that administration of a low-dose basal insulin analog (0.15 to 0.3 units/kg) in addition to intravenous insulin infusion may reduce infusion duration and length of hospital stay, whilst preventing rebound hyperglycemia (without an increased risk of hypoglycemia).[3] Intermediate- or long-acting insulin is recommended for basal use and short-acting insulin for prandial glycemic control. If a patient used insulin to manage diabetes prior to DKA, the same dose can be re-started. Otherwise, the following regimen is recommended: total daily insulin dose of 0.5 to 0.8 units/kg/day, with 30% to 50% of the total daily dose given as basal long-acting insulin, usually at night as a single dose, and the remainder of the total daily dose given as divided doses of fast-acting insulin before each meal.[1][59][60] The ADA mentions that the total daily subcutaneous insulin dose can also be calculated from the rate of the insulin infusion in the previous 6-8 hours when stable glucose levels were attained.[3]
Potassium therapy
Insulin therapy and correction of acidemia and hyperosmolality will drive potassium into cells, which may cause serious hypokalemia. The goal, therefore, is to correct the actual potassium deficits and thereby prevent fatal complications of hypokalemia, including respiratory paralysis and cardiac dysrhythmia.
Insulin therapy should be withheld until the serum potassium level reaches 3.3 mEq/L. Likewise, if plasma potassium falls below 3.3 mEq/L at any point during therapy, insulin should be stopped and potassium replaced intravenously. In all patients with a serum potassium level <5.3 mEq/L and an adequate urine output of >50 mL/hour, 20-30 units (mEq) of potassium should be added to each liter of infusion fluid to prevent hypokalemia caused by insulin therapy. If potassium level is >5.3 mEq/L, replacement is not needed but potassium level should be checked every 2 hours.[1]
Bicarbonate therapy
Bicarbonate use in DKA remains controversial. The ADA advises that a number of studies have failed to show any difference in acidosis resolution or time to discharge in people with DKA when bicarbonate was used, and it is usually not recommended.[3] At arterial blood pH >7.0, administration of insulin blocks lipolysis and resolves ketoacidosis without the need to add bicarbonate. Administering bicarbonate therapy in these patients may result in increased risk of hypokalemia, decreased tissue oxygen uptake, and cerebral edema.
Bicarbonate therapy may be used in adult patients with an arterial blood pH <7 in DKA, although data are limited.[64] Based on studies in adult patients with an arterial blood pH of 6.9 to 7.0, 50 mmol sodium bicarbonate in 200 mL sterile water with 10 mEq potassium chloride (KCl) may be administered over 1 hour until pH is >7.0.
In adult patients with pH <6.9, it is recommended that 100 mmol sodium bicarbonate in 400 mL sterile water (an isotonic solution) with 20 mEq KCl be administered at a rate of 200 mL/hour for 2 hours until pH >7.0. For monitoring of treatment, venous pH is sufficient and should be checked at least each hour in this setting. Treatment should be repeated every 2 hours until pH >7.0.
Bicarbonate therapy as well as insulin therapy lowers serum potassium; therefore, KCl is added to isotonic bicarbonate infusion.[1][65][Figure caption and citation for the preceding image starts]: Algorithm for the management of potassium and bicarbonateModified from: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43 [Citation ends].
Phosphate therapy
Despite total body phosphate deficits in DKA that average 1.0 mmol/kg of body weight, serum phosphate is often normal or increased at presentation, but decreases with insulin therapy. Previous studies have failed to show any beneficial effects of phosphate replacement in DKA patients. Therefore, routine replacement of phosphate is not recommended.
However, to avoid cardiac, respiratory, and skeletal muscle dysfunction, careful phosphate therapy may be indicated in patients with cardiac dysfunction (e.g., with signs of left ventricular dysfunction), symptomatic anemia, or respiratory depression (e.g., decreased oxygen saturation), and in those with confirmed hypophosphatemia (serum phosphate concentration <1.0 mg/dL).[1]
Monitoring of therapy
Monitoring of respiratory parameters and hemodynamic status are essential in hemodynamically unstable patients.
Subsequent to initial laboratory evaluation, serum glucose and electrolytes are measured at least hourly; calcium, magnesium, and phosphate are checked every 2 hours, and BUN, creatinine, and ketones every 2-6 hours, depending on the patient's clinical condition and response to therapy.
Serial beta hydroxybutyrate (BOHB) measurements may aid monitoring of the response to treatment in DKA. However, measurement of ketone bodies, in the absence of a meter with capacity to measure BOHB, is not recommended. BOHB is converted to acetoacetate, which is detected by the nitroprusside method, during the treatment of DKA. Therefore, the increase in acetoacetate during DKA treatment may mistakenly indicate a worsening of ketonemia.
Present evidence suggests monitoring bicarbonate, anion gap, and pH to reflect the response to therapy. A flow sheet classifying these findings as well as mental status, vital signs, insulin dose, fluid and electrolytes therapies, and urine output allows easy analysis of response to therapy and resolution of crises. Metabolic panel measurement during DKA therapy provides dynamic information on the changes in renal function and sodium level.
Management and monitoring should continue until resolution of DKA. The criteria for resolution are:[1]
plasma glucose is <200 mg/dL (at this point, insulin can be decreased by 50%)
serum bicarbonate is >18 mEq/L
venous pH is >7.3
anion gap is <10.
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