Diabetic ketoacidosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

This topic covers the management of diabetic ketoacidosis (DKA) in adults.

The main goals of treatment are:[1][4]

Restoration of circulatory volume deficits
Resolution of hyperglycemia and ketosis/acidosis
Correction of electrolyte abnormalities (potassium level should be >3.5 mEq/L [>3.5 mmol/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.

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.[1] A treatment protocol and a flow sheet for recording the treatment stages and laboratory data should be maintained.[79][80][81]

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. In adults without renal or cardiac compromise, start an infusion of isotonic saline (0.9% sodium chloride) or balanced crystalloid solution at a rate of 500-1000 mL/hour for the first 2-4 hours of fluid therapy.[1]

The fluid choice for initial resuscitation should be determined by local availability, cost and resources.[1] Most clinical guidelines recommend isotonic saline as the initial resuscitation fluid because of its widespread availability, low cost, and efficacy in restoring circulating volume in clinical studies.[1] While effective, however, its use in large volumes may be associated with hyperchloremic normal anion gap metabolic acidosis and prolonged length of intensive care unit (ICU) and hospital stay.[1] Emerging evidence suggests that the administration of balanced crystalloid solutions (e.g., Ringer lactate or Plasma-Lyte®) is at least comparable in terms of outcomes, and may result in faster DKA resolution, shorter hospital length of stay and less frequent development of hyperchloremic metabolic acidosis.[82][83][84][85][86][87]

Indications for admission to the 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.

Initial management in hemodynamically unstable patients includes fluid resuscitation to correct hypovolemia and hypotension, close monitoring, and vasopressor therapy under specialist supervision.[88]

After admission to ICU, central venous and arterial lines are required, as well as Swan-Ganz catheterization and 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.

Tracheal intubation: animated demonstration

How to insert a tracheal tube in an adult using a laryngoscope.

Bag-valve-mask ventilation: animated demonstration

How to use bag-valve-mask apparatus to deliver ventilatory support to adults. Video demonstrates the two-person technique.

Fluid therapy

Fluid deficit averages 6 liters.[92] After the initial management, hydration status should be evaluated clinically and continuous fluid therapy started at an an appropriate rate to correct the deficit. Correction should be undertaken gradually over 24-48 hours, as overly rapid correction can result in the patient developing cerebral edema.[1]

Severe hypovolemia

The presence of orthostatic hypotension or supine hypotension with dry mucous membranes and poor skin turgor indicates severe volume depletion.

The Joint British Diabetes Societies for Inpatient Care (JBDS-IP) advise that a systolic blood pressure (SBP) cut-off of 90 mmHg may be used in assessing the severity of dehydration (with patients who have SBP <90 mmHg on admission considered to have severe hypovolemia), caveating that age, gender and concomitant drugs should also be taken into account.[66]

Severe hypovolemia should be treated by infusion of isotonic saline (or other crystalloid) at the rate of 1 L/hour until signs of severe volume depletion have resolved.[1][14]

Once SBP is ≥90 mmHg or other methods of clinical assessment indicate resolution of severe hypovolemia, patients should continue to receive fluid therapy as for mild hypovolemia.

Mild hypovolemia

Mild to moderate volume depletion is indicated by the absence of orthostatic hypotension or supine hypotension, dry mucous membranes, and poor skin turgor.

Isotonic saline or other crystalloid should be given at a clinically appropriate rate, with the aim of replacing 50% of the estimated fluid deficit in the first 8-12 hours.[1]
When glucose reaches <250 mg/dL (<13.9 mmol/L), 5% or 10% dextrose should be added to the isotonic saline or crystalloid to avoid hypoglycemia.[1]

Caution should be exercised in the following groups:

Young people ages 18-25 years
Elderly people
Pregnant people
People with heart or kidney failure
People with other serious comorbidities

In these situations admission to an intermediate care unit should be considered. Fluids should be replaced cautiously with close hemodynamic monitoring.[1][66]

Insulin therapy

Insulin therapy is the cornerstone of DKA management and should be started as soon as possible after diagnosis.[1] 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 short-acting regular insulin after exclusion of hypokalemia (potassium level should be >3.5 mEq/L [>3.5 mmol/L] before initiation of insulin therapy).[1]

Insulin treatment protocol[1]

A fixed-rate intravenous infusion of short-acting regular insulin at 0.1 units/kg/hour should be started. If there is a delay in setting up the infusion (e.g., if a delay in obtaining venous access is anticipated), an intravenous bolus of short-acting regular insulin 0.1 units/kg (or intramuscularly if intravenous administration is not possible) should be given, followed by the intravenous infusion.
Once blood glucose falls below 250 mg/dL (<13.9 mmol/L), 5% or 10% dextrose should be added to the isotonic saline/crystalloid infusion and the insulin infusion rate should be reduced to 0.05 units/kg/hour.
Thereafter, the insulin infusion should be adjusted to maintain glucose levels between 150 and 200 mg/dL (8.3 and 11 mmol/L) and continued until the ketoacidosis is resolved.

Subcutaneous insulin as an alternative to intravenous insulin

Patients with mild to moderate DKA that is not complicated by acute myocardial infarction, congestive heart failure, end-stage renal or hepatic failure, corticosteroid use, or pregnancy, may be given rapid-acting insulin analogs subcutaneously as an alternative to intravenous short-acting regular insulin, with studies showing no significant difference in outcomes when using either approach alongside aggressive fluid management for mild or moderate DKA.[1][4][93][94][95][96] [ ] 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.[4]

Continuous intravenous infusion of short-acting 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).[4] However, if there are prolonged waiting times for ICU admission or limited medical resources, the use of rapid-acting insulin analogs for the treatment of mild or moderate uncomplicated DKA episodes can be considered for outpatients, in general floors, or in emergency departments.[4] The use of rapid-acting subcutaneous insulin analogs is not recommended for the treatment of severe and complicated DKA.[1]

Potassium therapy

Insulin therapy and correction of acidemia and hyperosmolality will drive potassium into cells, which may cause serious hypokalemia. Within 48 hours of hospital admission, potassium levels typically decline by 1-2 mEq/L (1-2 mmol/L).[1] Severe hypokalemia ≤2.5 mEq/L (≤2.5 mmol/L) during treatment of DKA has been reported to be associated with a threefold increase in mortality.[1] The goal, therefore, is to correct the actual potassium deficits and thereby prevent fatal complications of hypokalemia, including respiratory paralysis and cardiac dysrhythmia. To avoid hypokalemia, serum potassium should be checked 2 hours after starting insulin administration and every 4 hours thereafter until the resolution of DKA.[1]

Potassium replacement should be started after serum levels fall below 5 mEql/L (5 mmol/L) to maintain a potassium level of 4-5 mEq/L (4-5 mmol/L). Give 10-20 mmol of potassium in each liter of intravenous fluid as needed.[1]

Low-normal or low potassium levels (<3.5 mEq/L [<3.5 mmol/L]) are present on admission in 5% to 10% of patients with DKA.[1] In such cases, potassium replacement should begin at a rate of 10 mEq/hour (10 mmol/hour) and insulin therapy should be delayed until the potassium level increases to >3.5 mEq/L (>3.5 mmol/L).[1] Likewise, if plasma potassium falls below 3.5 mEq/L (3.5 mmol/L) at any point during therapy, insulin should be stopped and potassium replaced intravenously.

Bicarbonate therapy

Bicarbonate use in DKA remains controversial. The American Diabetes Association (ADA) guidelines note 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.[4] 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.[1]

Routine bicarbonate administration is not recommended.[1][4]
However, because severe metabolic acidosis may lead to adverse vascular effects, bicarbonate therapy should be considered in patients with arterial blood pH <7.0.[1]

If indicated, an isotonic solution of 100 mEq (100 mmol) sodium bicarbonate in 400 mL sterile water (8.4% solution) can be given every 2 hours until the pH is >7.0.[1]

Bicarbonate therapy as well as insulin therapy lowers serum potassium; therefore, based on expert opinion, potassium chloride should be added to the isotonic bicarbonate infusion.

Phosphate therapy

Despite the fact that total body phosphate deficits in DKA can be up to 1 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 patients with DKA. Furthermore, excessively rapid phosphate replacement may precipitate hypocalcemia.

Routine replacement of phosphate is not recommended.[1]
Phosphate should not be given unless there is muscle weakness, such as respiratory or cardiac compromise, and a phosphate level <3.1 mg/dL (<1 mmol/L).

If replacement is indicated, 20-30 mEq/L (20-30 mmol/L) of potassium phosphate should be added to replacement fluids.[1]

Monitoring of therapy

Monitoring of respiratory parameters and hemodynamic status are essential in hemodynamically unstable patients.

In all patients, capillary blood glucose testing should be performed during treatment every 1-2 hours using a hospital-calibrated glucose meter.[1]
Electrolytes, creatinine, beta-hydroxybutyrate (BOHB), and venous pH should be checked every 2-4 hours until stable.[1]

Serial 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 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.

Resolution

Management and monitoring should continue until resolution of DKA. The criteria for resolution are:[1]

plasma/capillary ketones <0.6 mmol/L AND
venous pH ≥7.3 or bicarbonate ≥18 mEq/L (≥18 mmol/L)

Ideally, plasma glucose should also be <200 mg/dL (<11.1 mmol/L). At this point, insulin dose can be decreased by 50%.

The anion gap should not be used as a criterion, as it may be misleading due to the presence of hyperchloremic metabolic acidosis caused by large volumes of isotonic saline solution.[1] Urinary ketone measurement should also be avoided as a criterion of DKA resolution.[1]

Once DKA has resolved and the patient can tolerate oral intake, transition to subcutaneous insulin needs to be initiated. To prevent the recurrence of hyperglycemia or ketoacidosis during the transition period to subcutaneous insulin, it is important to allow an overlap of 1-2 hours between the administration of subcutaneous insulin and the discontinuation of intravenous insulin.[1] Emerging evidence suggests 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, while preventing rebound hyperglycemia (without an increased risk of hypoglycemia).[1][4]

If a patient used insulin to manage diabetes prior to DKA, the same regimen can be restarted and adjusted as needed.[1] If there is concern for inadequate baseline insulin therapy (i.e., high hemoglobin A1c [HbA1c]) or any potentially precipitating drug as a contributing factor to the DKA, then the treatment regimen should be changed prior to hospital discharge.[1]

In those newly diagnosed with diabetes, a multidose insulin regimen with basal insulin and prandial rapid-acting insulin analogs should be started after the resolution of DKA.[1] This has been proposed as a more physiologic regimen compared with human insulins (i.e., short-acting regular insulin and neutral protamine Hagedorn [NPH] insulin), and has been reported to reduce the rate of hypoglycemia after transition from intravenous to subcutaneous insulin.[1] Human insulin regimens may also be used, but proper dosing should ensure 24 hour insulin coverage.[1] Although long-acting basal insulin analogs and NPH insulin are frequently administered once daily, greater flexibility and better coverage of basal insulin needs may be obtained if they are administered twice daily.[1] Rapid-acting insulin is added as needed, depending on nutritional intake and glucose levels.[1]

To transition from intravenous to subcutaneous insulin therapy, an estimation of the total daily dose (TDD) of insulin is needed. This may be calculated using several methods, each of which has limitations that must be considered when assessing overall insulin needs.[1]

A weight-based formula may be considered using 0.5 to 0.6 units/kg/day in insulin-naive patients, bearing in mind that body composition and/or insulin resistance may have an impact on this estimate. For people with risk factors for hypoglycemia, including kidney failure or frailty, a calculation using approximately 0.3 units/kg/day may be more appropriate.[1]
For patients who were already on insulin, consideration of the preadmission outpatient insulin regimen and HbA1c levels may help guide transition dosing needs. However, it is necessary to understand how drug-taking behaviors and dietary factors may have influenced outpatient insulin dosing recommendations.[1]
TDD may be also calculated by considering the hourly intravenous insulin infusion rate requirements, but with caution given the potential variation in insulin needs based on factors such as glucotoxicity, duration of treatment with intravenous insulin, concurrent dextrose infusion, drugs associated with hyperglycemia, and nutritional intake.[1] The ADA advises that the total daily subcutaneous insulin dose can also be calculated from the rate of the intravenous insulin infusion in the previous 6-8 hours when stable glucose levels were attained.[4]

Consensus guidelines recommend starting with 40% to 60% of the TDD given as basal insulin, with the remaining proportion divided into three mealtime doses of rapid-acting insulin. If patients are nil per os (NPO; not by oral administration), they recommend giving basal insulin with corrective dosing of rapid-acting insulin every 4-5 hours.[1]

Management considerations for DKA occurring in special populations

Frail or older adults

Patients have a high rate of preexisting comorbidities, as well as a high risk for hospital mortality, prolonged hospitalization, and DKA recurrences.[1] Isolated hyperglycemic hyperosmolar state (HHS) and mixed DKA/HHS occur more frequently than DKA.[1] It is important to evaluate for specific precipitating factors and concurrent diagnoses (such as cardiovascular events, infection, and drugs).[1] Fluid resuscitation and rate of fluid replacement need to account for comorbidities and acute precipitating events, and polypharmacy should be addressed where present.[1]

Patients on sodium-glucose cotransporter-2 (SGLT2) inhibitors and dual SGLT1/2 inhibitors

Patients may present with near-normal glucose concentrations or euglycemic DKA (glucose <200 mg/dL [<11.1 mmol/L]).[1] SGLT2 inhibitors and dual SGLT1/2 inhibitors should be stopped on admission. In euglycemic DKA, 5% to 10% dextrose should be added to intravenous fluids or started at the same time as the isotonic saline.[1] Initiation or continuation of SGLT2 or dual SGLT1/2 inhibitors after DKA resolution is not routinely recommended.[1]

End-stage kidney disease

Patients usually present with greater hyperglycemia, more frequent hyponatremia, higher osmolality, hyperkalemia, and lower ketone (BOHB) concentrations compared with patients without end-stage kidney disease.[1] Patients have a greater risk of cardiac complications.[1] Careful fluid administration and potassium replacement are needed.[1]

Pregnancy

Up to 2% of pregnant women with pregestational diabetes develop DKA. Most cases occur with preexisting type 1 diabetes.[1] DKA is rare in women with gestational diabetes.[1] Euglycemic DKA may occur and mixed acid-base disturbances may occur with hyperemesis, making the diagnosis challenging.[1] The significant feto-maternal risk requires immediate expert senior medical and obstetric intervention. Ideally patients should be cared for in delivery suites or high-dependency units.[1] Management guidelines in the emergency department or obstetric unit should include sections on the management of DKA in pregnancy as well as sick day rules.[1] Consult local guidelines.

Coronavirus disease 2019 (COVID-19)

A higher frequency of DKA was seen during the COVID-19 pandemic; those with preexisting type 2 diabetes who contracted COVID-19 were found to be particularly at risk of developing DKA.[1] Patients with COVID-19 who present with DKA have a higher risk for complications, need for ICU care, longer hospital stays and mortality.[1] Treatment of severe COVID-19 with corticosteroids may require higher doses of insulin to treat refractory ketonemia.[1]

Use of this content is subject to our disclaimer