From the Guidelines
The primary reason for the persistent anion gap and elevated bicarbonate levels during diabetic ketoacidosis (DKA) treatment is the phenomenon of "delayed anion gap closure," where ketoacid anions are metabolized more slowly than the rate at which bicarbonate is administered or regenerated, as supported by recent studies 1.
Physiological Mechanisms
The treatment of DKA involves several physiological mechanisms that contribute to the persistence of anion gap and elevated bicarbonate levels. These include:
- Delayed anion gap closure: Ketoacid anions (beta-hydroxybutyrate and acetoacetate) are metabolized more slowly than the rate at which bicarbonate is administered or regenerated, creating a transitional state where both the anion gap remains elevated and bicarbonate levels rise.
- Hyperchloremic metabolic acidosis: Large volumes of chloride-rich fluids (normal saline) administered during treatment can lead to chloride retention, which maintains acidosis even as ketosis resolves.
- Renal handling: The kidneys preferentially excrete ketone bodies while retaining bicarbonate during recovery.
- Volume contraction: Decreased glomerular filtration rate limits the kidney's ability to excrete excess bicarbonate.
- Insulin therapy: Promotes both ketoacid metabolism (closing the anion gap) and bicarbonate regeneration simultaneously.
Treatment Implications
The use of bicarbonate in patients with DKA has been shown to make no difference in the resolution of acidosis or time to discharge, and its use is generally not recommended 1. Instead, management goals should focus on restoration of circulatory volume and tissue perfusion, resolution of hyperglycemia, and correction of electrolyte imbalance and acidosis. Continuous intravenous insulin is the standard of care for critically ill and mentally obtunded individuals with DKA or hyperosmolar hyperglycemia. Successful transition from intravenous to subcutaneous insulin requires administration of basal insulin 2–4 h before the intravenous insulin is stopped to prevent recurrence of ketoacidosis and rebound hyperglycemia 1.
From the Research
Reasons for Persistent Anion Gap and Elevated Bicarbonate Levels
The reasons for a persistent anion gap and elevated bicarbonate (HCO3) levels during diabetic ketoacidosis (DKA) treatment are multifaceted. Some key factors include:
- Inadequate insulin treatment: Failure to continue insulin treatment until the anion gap has normalized can lead to inadequate reversal of ketoacid production by the liver 2.
- Incomplete replacement of electrolytes: Failure to recognize the magnitude of total-body potassium depletion and to begin replacement despite an initially normal serum potassium level may lead to complications, including persistent anion gap metabolic acidosis 2.
- Presence of underlying infections or illnesses: Infections, such as urinary tract infections and pneumonia, can precipitate DKA and contribute to a persistent anion gap 3.
- Volume depletion: Volume depletion, such as that induced by tirzepatide, can affect interstitial fluid glucose levels and lead to closed-loop insulin infusion system failure, precipitating DKA 4.
- Non-compliance with insulin therapy: Non-compliance with insulin therapy can contribute to the development of DKA and a persistent anion gap 3.
Factors Affecting Bicarbonate Levels
Elevated bicarbonate levels during DKA treatment may be influenced by:
- The use of bicarbonate therapy: Although bicarbonate therapy is not generally regarded as a standard treatment for DKA, its use may affect bicarbonate levels 5.
- The severity of the metabolic acidosis: The severity of the metabolic acidosis, as indicated by the pH level, can influence the bicarbonate level 5.
- The effectiveness of treatment: The effectiveness of treatment, including insulin and fluid replacement, can impact the normalization of bicarbonate levels 2.
Precipitating Causes
Precipitating causes of DKA, such as infections, non-compliance with insulin therapy, and psychological stress, can contribute to a persistent anion gap and elevated bicarbonate levels 3. Identifying and addressing these underlying causes is crucial for effective treatment and prevention of DKA 6, 3.