Diabetic Ketoacidosis : DKA Protocol

What is Diabetic Ketoacidosis?

Omission of insulin and infection are the most common triggers of diabetic ketoacidosis (DKA). Noncompliance with insulin therapy accounts for up to 44% of DKA cases, while infection is observed less frequently.

Acute medical conditions involving the cardiovascular system (e.g., myocardial infarction, stroke, acute thrombosis), gastrointestinal system (e.g., bleeding, pancreatitis), endocrine axis (e.g., acromegaly, Cushing’s syndrome, hyperthyroidism), and recent surgical procedures can contribute to DKA. These conditions cause dehydration, increase insulin counter-regulatory hormones, and worsen peripheral insulin resistance.

Certain medications, including diuretics, beta-blockers, corticosteroids, second-generation antipsychotics, anticonvulsants, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and immune checkpoint inhibitors, may disrupt carbohydrate metabolism and fluid balance, precipitating DKA. SGLT-2 inhibitors, in particular, are linked to euglycemic DKA, where glucose levels are <250 mg/dL.

Other contributing factors include psychological disorders, eating disorders, insulin pump malfunction, and drug abuse. New-onset type 2 diabetes mellitus (T2DM) can also manifest with DKA, particularly in obese individuals of African American or Hispanic descent who have undiagnosed hyperglycemia, impaired insulin secretion, and insulin resistance. Additionally, cocaine use has been identified as an independent risk factor for recurrent DKA.

What is the Pathophysiology of DKA?

DKA arises from insulin deficiency, increased insulin counter-regulatory hormones (e.g., cortisol, glucagon, growth hormone, catecholamines), and peripheral insulin resistance. These factors lead to hyperglycemia, dehydration, ketosis, and electrolyte imbalances.

Figure 1. Role of Insulin in Glucose, Fat and Protein Metabolism

Hyperglycemia results from increased gluconeogenesis, glycogenolysis, and decreased glucose utilization caused by absolute insulin deficiency. Importantly, DKA associated with SGLT-2 inhibitors may occur without significant hyperglycemia, resulting in euglycemic DKA.

Figure 2. Regulation of metabolism by insulin (intracellular processes)

Lipolysis increases while lipogenesis decreases, leading to elevated free fatty acids, which are converted into ketone bodies: β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. Hyperglycemia-induced osmotic diuresis, coupled with inadequate fluid intake, causes dehydration, hyperosmolarity, and electrolyte losses. A decline in renal function further exacerbates hyperglycemia and hyperosmolality. Impaired insulin action and hyperosmolality hinder potassium uptake by skeletal muscles, resulting in intracellular potassium depletion. Potassium loss through osmotic diuresis adds to the total body potassium deficiency. Consequently, patients may have normal, low, or high serum potassium levels at presentation, but insulin therapy and hyperglycemia correction often lead to hypokalemia.

Diagnosis of DKA

Diagnostic criteria and classification of DKA

*Nitroprusside reaction method.

Serum osmolality formula: 2[measured Na⁺ (mEq/L)] + glucose (mg/dL)/18 = mOsm/kg.

*Anion gap formula: [(Na⁺) – (Cl⁻ + HCO₃⁻) (mEq/L)].

What Are The Clinical Features of DKA?

Patients with diabetic ketoacidosis (DKA) often present with polyuria, polydipsia, weight loss, vomiting, and abdominal pain. Abdominal pain is closely associated with acidosis and typically resolves with treatment. Physical examination findings such as hypotension, tachycardia, poor skin turgor, and weakness indicate dehydration, a hallmark of DKA. Mental status changes may occur and are often proportional to the severity of acidosis or hyperosmolarity.
In the emergency room, a thorough search for symptoms of precipitating factors—such as infections, vascular events, or substance abuse—should be initiated. Patients in hyperglycemic crises can present with hypothermia due to peripheral vasodilation and reduced utilization of metabolic substrates.

Differential Diagnoses of DKA

• Hyperglycemic hyperosmolar state (HHS): Not associated with ketosis.
• Starvation or alcoholic ketoacidosis: Characterized by normoglycemia (<200 mg/dL) and bicarbonate levels >18 mEq/L.
• Lactic acidosis: Suspected in cases of hypotension, impaired renal function, and metformin use, with a lactic acid level >7 mmol/L.
• Toxic ingestions: Methanol, isopropyl alcohol, or paraldehyde ingestion may alter the anion gap or osmolality and require investigation.

HHS: Hyperglycemic hyperosmolar state.

BUN: Blood urea nitrogen.

Acetest and Ketostix measure acetoacetic acid only; results may underestimate total ketones, especially early in DKA.

Diagnostic Tests

Initial Tests:

• Basic metabolic panel, osmolality, ketones, β-hydroxybutyrate (β-OH)
• Complete blood count with differential
• Urinalysis and urine ketones (dipstick)
• Arterial blood gases

Additional Tests:

• Electrocardiogram (ECG)
• Chest X-ray
• Tissue cultures (as needed)
• Hemoglobin A1c (HbA1c)

Key Considerations:

• Anion Gap Acidosis: Anion gap = [Na+] – (Cl⁻ + HCO₃⁻). Correct for hypoalbuminemia.
• HCO₃⁻ Level: Typically, HCO₃⁻ >18-20 mEq/L rules out metabolic acidosis.
• Serum Ketones: β-OH is an early and dominant ketone in DKA, better reflecting ketosis than acetoacetate.
• Serum Osmolality: Direct measurement or derived: 2[Na⁺] + glucose/18.
• Infection Indicators: White blood cell count >25,000 suggests infection.
• Creatinine Levels: May be falsely elevated due to acetoacetate interference in the assay.

Treatment Goals and Protocol For DKA

Goals of DKA Management:

1. Optimize volume status.
2. Address hyperglycemia and ketosis/acidosis.
3. Correct electrolyte imbalances.
4. Identify and treat precipitating factors.

Steps in Early Management:

1. Start IV fluids after collecting blood samples for biochemical analysis.
2. Ensure potassium levels >3.3 mEq/L before initiating insulin therapy. Supplement potassium as needed.
3. Begin insulin therapy only after addressing fluid and potassium deficits.

Criteria for DKA Resolution:

• Plasma glucose: <200–250 mg/dL
• Serum bicarbonate: >18 mEq/L
• Venous blood pH: >7.3
• Anion gap: <10

Treatment arms

• Fluid Therapy: Replace ~6 L fluid deficit over 24–36 hours. Aim for 50% replacement within the first 12 hours.
• Insulin Therapy: Transition to subcutaneous insulin with long-acting insulin given 2 hours before stopping IV insulin.
• Bicarbonate Therapy: If pH <7.0 or HCO₃⁻ <5 mEq/L, administer 100 mmol of bicarbonate in 200 mL water with 20 mEq KCl over 2 hours.

Common Complications

1. Hypoglycemia and Hypokalemia:
   • These are the most frequent complications of diabetic ketoacidosis (DKA).
   • They can be avoided by timely adjustment of insulin dosages and frequent monitoring of potassium levels.
2. Non-Anion Gap Hyperchloremic Acidosis:
   • Occurs due to urinary loss of ketoanions (necessary for bicarbonate regeneration) and preferential chloride reabsorption in the proximal renal tubule.
   • Contributing factors include intensive administration of chloride-containing fluids and low plasma bicarbonate levels.
   • This condition typically resolves spontaneously and does not require changes to the treatment plan.
3. Cerebral Edema:
   • Primarily reported in young adult patients.
   • Symptoms include headache, lethargy, papillary changes, and seizures.
   • This condition carries a mortality rate of up to 70%.
   • Treatment involves mannitol infusion and mechanical ventilation as needed.
4. Rhabdomyolysis:
   • May occur due to hyperosmolality and hypoperfusion during DKA.
5. Pulmonary Edema:
   • Can result from excessive fluid replacement, particularly in patients with chronic kidney disease (CKD) or congestive heart failure (CHF).

Outpatient Treatment Plan

1. Diabetes Education:
   • Ensure the patient understands the basics of diabetes management, including glucose monitoring and symptom recognition.
2. Insulin Regimen:
   • Prescribe an appropriate insulin regimen that is both understandable and affordable for the patient.
3. Home Supplies:
   • Provide a complete set of supplies for the initial insulin administration and glucose monitoring at home.

Proper education and planning are crucial to prevent recurrence and ensure long-term disease management.

Reference

Karslioglu French E, Donihi AC, Korytkowski MT. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ. 2019 May 29;365:l1114