Diabetic ketoacidosis – a clinical update

ANF iFOLIO CLINICAL UPDATE: ANFClinical Updates Diabetic ketoacidosis: a clinical update Diabetic ketoacidosis – a clinical update Read this article and complete the quiz to earn 1 iFolio hour Read this article and complete the quiz to earn 1 iFolio hour

Diabetic ketoacidosis (DKA) is a serious and potentially life-threatening complication of diabetes mellitus.1 DKA more commonly occurs in patients with type 1 diabetes, however it can also affect patients with type 2 diabetes.1

DKA is a complex metabolic disturbance characterised by hyperglycaemia, ketonaemia, and metabolic acidosis.2 It occurs as a result of insulin deficiency accompanied by an elevation of counterregulatory hormones, such as catecholamines, adrenaline, cortisol, and glucagon.2 Insulin deficiency may be absolute (during lapses in the administration of exogenous insulin) or relative (when usual insulin doses do not meet metabolic needs during physiologic stress).2,3

The annual incidence of DKA is 4-8 episodes per 1000 patient admissions with diabetes.4 Rates of admissions are increasing due to the increasing incidence of diabetes in the population.5 Diabetes is the fastest growing chronic condition in Australia; 280 Australians develop diabetes every day.6

While mortality from DKA remains relatively low in developed countries, less than 1%, it is the leading cause of death in patients with type 1 diabetes under 58 years of age.7 DKA is a medical emergency, it should be diagnosed promptly and managed intensively.7

PATHOPHYSIOLOGY

Insulin reduces blood glucose levels by increasing the uptake of glucose from the bloodstream into the cells and decreasing hepatic glucose production by inhibiting glycogenolysis and gluconeogenesis.1,5

In DKA insulin deficiency leads to impaired glucose uptake and utilisation, increased gluconeogenesis, and accelerated glycogenolysis, resulting in hyperglycaemia.1,8 The increased concentrations of counterregulatory hormones activates hormone-sensitive lipase in adipose tissue, and the resulting enhanced lipolysis releases large quantities of free fatty acids and glycerol into the circulation.1,8 The free fatty acids are oxidised in the hepatic mitochondria to form ketone bodies (acetone, beta-hydroxybutyrate and acetoacetate).1,8 Concurrent with the increased production of ketones, the clearance of ketoacids β-hydroxybutyrate and acetoacetate is reduced, resulting in an accumulation of in ketoacids in the blood, a decrease in serum bicarbonate concentration, and the development of metabolic acidosis.8

The severity of hyperglycaemia and the high concentrations of ketoacids cause osmotic diuresis leading to hypovolaemia, which leads to further increases in counterregulatory hormone levels, further aggravating hyperglycaemia.8 As insulin also maintains potassium concentrations within the intracellular fluid, insulin deficiency causes potassium to move into the extracellular space leading to electrolyte imbalance.8

CAUSES AND RISK FACTORS

The most common precipitating factors for DKA are inadequate or inappropriate insulin therapy and infection.1,2

Inadequate or inappropriate insulin therapy may occur due to missing or inadequate insulin doses, recent medicine titration, or undiagnosed or recently diagnosed diabetes.2,5

The physiologic stress associated with infection stimulates the release of counterregulatory hormones, causing insulin resistance, increased lipolysis, ketogenesis, and volume depletion, which may contribute to hyperglycaemic crises.2,5

Other precipitating factors for developing DKA include:1,2

• Acute illnesses, such as myocardial infarction, stroke, pancreatitis, acromegaly,

Cushing’s syndrome, and hyperthyroidism • Bariatric surgery • Medications, such as corticosteroids, thiazide diuretics, second-generation antipsychotics, immune checkpoint inhibitor therapy, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors • Eating disorders • Alcohol and illicit drug use. SIGNS AND SYMPTOMS

Common signs and symptoms of DKA include (see Illustration 1):2,9

• Increased thirst • Abdominal pain • Polyuria • Weight loss • Excessive tiredness • Nausea • Vomiting • Ketone breath (breath smells like sweet acetone) • Dehydration • Confusion • Reduced consciousness. Increasing acidosis is associated with Kussmaul respiration (rapid, deep, laboured breathing).1,2 Severe and prolonged DKA is also associated with hypothermia as a result of peripheral vasodilation.5 DIAGNOSIS

The varied presentations of DKA can make diagnosis difficult.1 It is important to exclude other causes of ketoacidosis, such as alcohol ketoacidosis, lactic acidosis, uraemic acidosis, and starvation ketosis.1,2,7

DKA is generally diagnosed using a combination of preliminary clinical assessment and serological tests to measure glucose levels, ketone levels, and venous blood gas.1,2 Diagnosing DKA requires the presence of all of the following:2,7

Glucose: blood glucose level greater than 11mmol/L or known diabetes.

Ketones: blood ketones greater than 3mmol/L or ketonuria on a standard urine dipstick. Acidosis: venous pH less than 7.3 and/or bicarbonate level less than 15mmol/L.

Rarely, some patients may present with euglycaemic DKA and have a normal blood glucose level.2 Patients treated with SGLT-2 inhibitors are at increased risk of developing euglycaemic DKA.1

The presence of one or more of the following criteria may indicate severe DKA:2,7

• Blood ketones greater than 6mmol/L • Bicarbonate level less than 5.0mmol/L • Venous pH less than 7.0 • Hypokalaemia • Glasgow Coma Scale (GCS) score of less than 12 • Oxygen saturation below 92% on air (assuming normal baseline respiratory function) • Systolic blood pressure below 90mmHg • Pulse over 100 or below 60 beats per minute. TREATMENT

Treatment of DKA consists of fluid resuscitation and maintenance, insulin therapy, electrolyte replacement, and supportive care (see Table 1 for treatment pathway).1 The most urgent goals of treatment are rapid intravascular volume repletion, correction of hyperglycaemia and acidosis, suppression of ketogenesis, and prevention of hypokalaemia.3,7 Identifying and treating precipitating factors is also important.3

Ketonaemia and acidosis should resolve within 24 hours.7 Biochemical markers, ketones, bicarbonate, pH, glucose, and potassium, should be regularly monitored.2 The recommended metabolic treatment targets are:7

• Reduction of blood ketone concentration by 0.5mmol/L/hour • Increase in venous bicarbonate by 3.0mmol/L/hour

• Dry mouth • Thirst

• Frequent urination • Shortness of breath • Difficulty breathing

• Tachycardia • Arrhythmia

• Nausea • Vomiting • Abdominal pain

• Reduction of capillary blood glucose concentration by 3.0mmol/L/hour • Maintain serum potassium concentration of 4.0-5.5mmol/L.

Fluid resuscitation and maintenance

Intravenous fluids (IV) should be started as soon as DKA is confirmed.2,10 The main aims of fluid replacement are restoration of circulatory volume, clearance of blood ketones, restoration of tissue perfusion, and correction of electrolyte imbalance.1,7 Intravenous fluids also dilute glucose levels and circulating counterregulatory hormones concentrations.1,2

Insulin therapy

Insulin therapy should be started about one hour after IV fluid replacement is started as insulin may be more dangerous and less effective before some fluid replacement has been obtained.2 Insulin therapy suppresses ketogenesis, reduces blood glucose, and corrects electrolyte disturbances.7

Insulin therapy should be commenced as a fixed rate intravenous insulin infusion (FRIII) at a dose of 0.1units/kg body weight, or according to local protocols.10 Caution should be exercised if the dose is calculated to exceed 15units/hour.10

The FRIII should be continued until the following targets are achieved:10

Glucose: blood glucose level less than 14mmol/L . Ketones: blood ketones less than 0.6mmol/L.

Acidosis: venous pH greater than 7.3 and/or bicarbonate level greater than 15mmol/L.

A supplemental glucose or dextrose infusion may be administered concurrently as a substrate for the insulin to reduce the risk of hypoglycaemia.7

Electrolyte replacement

Hypokalaemia and hyperkalaemia are common in DKA.1 While serum potassium is often high on admission, insulin therapy causes an intracellular shift and lowers potassium levels, potentially resulting in severe hypokalaemia.1,7 Hypokalaemia is also commonly associated with hypomagnesemia.1

Electrolytes should be monitored and supplemented as required.10

PREVENTION

The risk of DKA can be decreased by patients with diabetes:11

• Regularly checking blood glucose levels • Following their treatment plan • Staying hydrated • Checking with a health professional before taking new medicines • Developing and following a plan for when they are ill.

1. Lizzo JM, Goyal A, Gupta V. Adult Diabetic

Ketoacidosis. 2021 [cited 2021 Oct 23]. In:

StatPearls [Internet]. Treasure Island (FL): StatPearls

Publishing LLC. Available from https://www.ncbi. nlm.nih.gov/books/NBK560723 2. BMJ Best Practice. Diabetic ketoacidosis [Internet].

London: BMJ Publishing Group Ltd; 2021 [cited 2021 Oct 23]. Available from: https://bestpractice. bmj.com/topics/en-gb/3000097/pdf/3000097/

Diabetic%20ketoacidosis.pdf 3. Diabetic Ketoacidosis (DKA). 2020 [cited 2021

Oct 21]. In: MSD Manual Professional Version [Internet]. Kenilworth (NJ): Merk Sharp & Dohme

Corp. Available from: https://www.msdmanuals. com/en-au/professional/endocrine-and-metabolicdisorders/diabetes-mellitus-and-disorders-ofcarbohydrate-metabolism/diabetic-ketoacidosisdka

4. Lee MH, Calder GL, Santamaria JD, Maclsaac RJ.

Diabetic ketoacidosis in adult patients: an audit of factors influencing time to normalisation of metabolic parameters. Intern Med J [Internet]. 2018 [cited 2021 Oct 23];48(5):529-534. doi: 10.1111/imj.13735 5. Broadley L, Clark K, Ritchie G. Prevention and management of hyperglycaemic crisis. Nurs Stand [Internet]. 2019 [cited 2021 Oct 16];37(7):75–82. doi: 10.7748/ns.2019.e11387

6. Diabetes Australia. About Diabetes [Internet].

Diabetes in Australia; c2021 [cited 2021 Oct 23].

Available from: https://www.diabetesaustralia.com. au/about-diabetes/diabetes-in-australia/

7. Joint British Diabetes Societies for Inpatient Care.

The Management of Diabetic Ketoacidosis in Adults [Internet]. London (UK): Joint British Diabetes

Societies for Inpatient Care; 2021 [cited 2021 Oct 16]. Available from: https://diabetes-resourcesproduction.s3.eu-west-1.amazonaws.com/ resources-s3/public/2021-06/JBDS%2002%20

DKA%20Guideline%20amended%20v2.pdf 8. Dhatariya KK, Glaser NS, Codner E, Umpierrez GE.

Diabetic ketoacidosis. Nat Rev Primers [Internet]. 2020 [cited 2021 Oct 24];6(40). doi: 10.1038/ s41572-020-0165-1

9. Ray-Barruel G, Kerr K. Avoiding diabetic ketoacidosis in perioperative and procedure settings. Aust Nurs Midwifery J [Internet]. 2021 [cited 2021 Oct 16];27(2):28-30. Available from: https://anmj.org.au/avoiding-diabetic-ketoacidosisin-perioperative-and-procedure-settings/ 10. Government of Western Australia WA Country

Health Service. Adult Diabetic Ketoacidosis (DKA)

Guideline [Internet]. Perth (Australia): Government of Western Australia; 2019 [cited 2021 Oct 16].

Available from: https://www.wacountry.health. wa.gov.au/~/media/WACHS/Documents/Aboutus/Policies/Adult-Diabetic-Ketoacidosis-DKA-

Guideline--South-West.pdf?thn=0 11. National Health Service. Health A-Z [Internet].

Diabetic Ketoacidosis; 2019 [cited 2021 Oct 23].

Available from: https://www.nhs.uk/conditions/ diabetic-ketoacidosis

Table 1: Treatment pathway7

Fluid replacement Insulin therapy Biochemical markers GCS

0-1 hour

Commence IV fluid replacement 1-6 hours Continue IV fluid replacement Commence FRIII

Continue FRIII

6-12 hours

Continue IV fluid replacement Continue FRIII Initial assessments Establish monitoring regime Ensure parameters improving Avoid hypoglycaemia Ensure parameters improving Avoid hypoglycaemia Initial assessment Regularly assess GCS score Regularly assess GCS score

12-24 hours

Continue IV fluids if patient not eating and drinking Move to variable rate infusion if patient not eating and drinking and no ketonaemia Ensure parameters normalised or improving Regularly assess GCS score Continue to treat as necessary Re-assess for complications (fluid overload, cerebral oedema)

Precipitating factors

Identify and treat as necessary

Continue to treat as necessary

Complications of treatment

Assess for complications (fluid overload, cerebral oedema)