Diabetic ketoacidosis

Introduction

Diabetic ketoacidosis (DKA) is a serious and potentially life-threatening complication of diabetes mellitus. It results from severe insulin deficiency combined with increased counter-regulatory hormones, leading to hyperglycemia, ketone production, and metabolic acidosis. Prompt recognition and management are critical to prevent morbidity and mortality.

Definition and Epidemiology

Definition

Diabetic ketoacidosis is characterized by the triad of hyperglycemia, ketosis, and metabolic acidosis. It typically occurs in patients with type 1 diabetes but can also be seen in type 2 diabetes under stress conditions.

• Clinical definition: triad of high blood glucose, ketone accumulation, and acid-base disturbance
• Biochemical criteria: blood glucose >250 mg/dL, arterial pH <7.3, serum bicarbonate <18 mEq/L, elevated serum or urine ketones

Incidence and Prevalence

DKA is a common acute complication of diabetes worldwide, with varying incidence depending on age, type of diabetes, and healthcare access.

• Global incidence: approximately 4 to 8 episodes per 1000 patients with type 1 diabetes annually
• More common in children and young adults with type 1 diabetes
• Increasing recognition in type 2 diabetes, especially during severe illness or stress
• Mortality rates vary by region, typically less than 5% in developed countries but higher in resource-limited settings

Pathophysiology

Insulin Deficiency and Counter-Regulatory Hormones

The development of DKA is primarily due to absolute or relative insulin deficiency, which disrupts normal glucose and fat metabolism. This deficiency is compounded by increased levels of counter-regulatory hormones including glucagon, cortisol, catecholamines, and growth hormone.

• Absolute vs relative insulin deficiency: inability to utilize glucose effectively
• Role of counter-regulatory hormones: promote gluconeogenesis, glycogenolysis, lipolysis, and ketogenesis

Metabolic Consequences

The hormonal imbalance in DKA leads to a cascade of metabolic disturbances that affect multiple organ systems.

• Hyperglycemia and osmotic diuresis: excessive glucose in blood draws water and electrolytes from tissues, causing dehydration
• Lipolysis and ketogenesis: breakdown of fat releases free fatty acids converted to ketone bodies in the liver
• Electrolyte imbalances: losses of sodium, potassium, and phosphate due to osmotic diuresis
• Acid-base disturbances: accumulation of ketone bodies results in metabolic acidosis

Etiology and Precipitating Factors

DKA is often triggered by factors that increase insulin requirements or reduce insulin availability. Identifying and addressing these precipitating factors is crucial in both treatment and prevention.

• Infection: bacterial or viral infections commonly precipitate DKA
• Non-compliance with insulin therapy: missed doses or insufficient insulin administration
• New-onset diabetes: initial presentation of type 1 diabetes can manifest as DKA
• Acute medical conditions: myocardial infarction, stroke, surgery, or trauma
• Medications: corticosteroids, SGLT2 inhibitors, and other drugs affecting glucose metabolism

Clinical Presentation

Signs and Symptoms

Patients with diabetic ketoacidosis often present with a combination of systemic and metabolic symptoms. The severity can range from mild dehydration to life-threatening complications affecting multiple organs.

• Polyuria, polydipsia, and weight loss: due to osmotic diuresis from hyperglycemia
• Nausea, vomiting, and abdominal pain: common gastrointestinal manifestations
• Dehydration and hypotension: resulting from fluid losses and electrolyte imbalance
• Altered mental status and lethargy: from metabolic acidosis and dehydration
• Kussmaul respiration and fruity odor of breath: compensatory hyperventilation and acetone accumulation

Laboratory Findings and Diagnosis

Biochemical Parameters

Laboratory evaluation is essential for confirming DKA, assessing severity, and guiding management. Key parameters include blood glucose, ketone levels, electrolytes, and acid-base status.

• Blood glucose levels: typically >250 mg/dL, but can vary
• Serum ketones and urine ketones: elevated due to ketogenesis
• Arterial blood gases: metabolic acidosis with pH <7.3 and low bicarbonate
• Electrolytes: sodium, potassium, chloride, and phosphate disturbances are common
• Anion gap calculation: helps confirm high-anion-gap metabolic acidosis

Diagnostic Criteria

Establishing the diagnosis of DKA involves integrating clinical findings with laboratory values to differentiate it from other hyperglycemic emergencies.

• Typical thresholds for DKA: blood glucose >250 mg/dL, pH <7.3, bicarbonate <18 mEq/L, ketonemia or ketonuria
• Differentiation from hyperosmolar hyperglycemic state (HHS): absence of significant ketosis and more severe hyperosmolarity in HHS

Management and Treatment

Fluid Therapy

Fluid replacement is the first step in treating DKA, aiming to restore perfusion, correct dehydration, and improve hemodynamics.

• Initial resuscitation: rapid infusion of isotonic saline to restore intravascular volume
• Maintenance fluids: adjusted according to ongoing losses, dehydration severity, and electrolyte status

Insulin Therapy

Insulin administration is critical to reduce hyperglycemia, suppress ketogenesis, and correct metabolic acidosis.

• Continuous intravenous insulin infusion: preferred in moderate to severe DKA for tight glucose control
• Transition to subcutaneous insulin: once ketosis resolves and patient can tolerate oral intake

Electrolyte Replacement

Electrolyte imbalances, particularly potassium deficiency, are common and can be life-threatening if not corrected.

• Potassium supplementation: initiated before or during insulin therapy depending on serum potassium
• Phosphate and magnesium correction: indicated in cases of significant depletion

Treatment of Precipitating Factors

Identifying and addressing the underlying cause of DKA is essential to prevent recurrence and improve outcomes.

• Infection management: antibiotics for bacterial infections or antiviral therapy if indicated
• Other underlying causes: treatment of myocardial infarction, stroke, or medication-induced DKA

Complications

Diabetic ketoacidosis can lead to multiple complications if not recognized and treated promptly. Monitoring and prevention are critical during therapy.

• Cerebral edema: more common in children, can be life-threatening
• Hypokalemia and cardiac arrhythmias: result from potassium shifts during insulin therapy
• Acute kidney injury: due to severe dehydration and hypoperfusion
• Thromboembolic events: increased risk due to hypercoagulable state in DKA

Prevention and Patient Education

Preventing recurrent episodes of DKA is an essential aspect of diabetes management. Patient education plays a critical role in early recognition and timely intervention.

• Insulin adherence and monitoring: maintaining prescribed insulin regimens and self-monitoring of blood glucose
• Sick-day rules and ketone monitoring: adjusting insulin and fluid intake during illness, checking ketone levels regularly
• Regular follow-up and diabetes education: structured programs to reinforce knowledge of DKA warning signs and proper diabetes management

Prognosis

The prognosis of DKA has improved significantly with early recognition and appropriate management. Outcomes depend on the severity of the episode, underlying health, and rapidity of treatment.

• Factors affecting outcomes: age, comorbidities, severity of dehydration, and timely initiation of therapy
• Mortality rates: typically less than 5% in developed countries, higher in resource-limited settings
• Long-term prognosis: most patients recover fully with proper diabetes management, but recurrent episodes indicate the need for intensive follow-up

References

1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.
2. American Diabetes Association. 15. Diabetes Care in the Hospital: Standards of Medical Care in Diabetes. Diabetes Care. 2023;46(Suppl 1):S184-S194.
3. Wolfsdorf JI, Glaser N, Agus M, Fritsch M, Hanas R, Rewers A, et al. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2009;10(Suppl 12):154-179.
4. Umpierrez GE, Korytkowski M. Diabetic emergencies: ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol. 2016;12(4):222-232.
5. Fujita Y, Kaneko H, Furuichi T. Diabetic ketoacidosis: pathophysiology, diagnosis and management. J Diabetes Investig. 2020;11(2):251-261.
6. Chiang JL, Maahs DM, Garvey KC, Hood KK, Laffel LM, Weinzimer SA, et al. Type 1 diabetes in children and adolescents: a position statement by the American Diabetes Association. Diabetes Care. 2018;41(9):2026-2044.
7. Kitabchi AE, Nyenwe EA. Diabetic ketoacidosis. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth: MDText.com, Inc.; 2024.
8. Rafique A, Malik F, Ahmed J. Diabetic ketoacidosis: clinical features, precipitating factors and outcomes. J Coll Physicians Surg Pak. 2018;28(11):869-873.
9. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin dependent diabetes 1990-96. Arch Dis Child. 1999;81(4):318-323.
10. Kitabchi AE, Nyenwe EA, Umpierrez GE. Management of hyperglycemic crises in patients with diabetes. Diabetes Spectrum. 2006;19(1):28-36.