Ketoacidosis
In this case report, ketonemia was timely identified (ketone levels: 1.4mmol/L) and managed such that no metabolic acidosis occurred (blood pH: 7.38). Nonetheless, it is crucial to keep in mind management strategies when managing a patient with a high risk of developing diabetic ketoacidosis.
The most prevalent cause of ketoacidosis is DKA. Other types of ketoacidosis include EDKA, alcoholic ketoacidosis (AKA) and starvation ketoacidosis (SKA). DKA most commonly occur in patients with poorly-controlled DM and is precipitated by an acute infection that triggers uncontrolled hyperglycemia. Other risk factors of DKA include T1DM, non-compliance to insulin or OHGAs and acute major illnesses such as acute myocardial infarction, stroke, sepsis or pancreatitis and surgery. Table 1 summarizes the three types of KA, associated laboratory findings as well as appropriate management strategies.
Table 1
Differentiation between the three different types of ketoacidosis: DKA, AKA and SA. (11)
| DKA | AKA | SKA |
ETIOLOGY | Diabetes is uncontrolled, and there is hyperglycemia, with relative or absolute insulin deficiency. Risk factors that can precipitate extreme hyperglycemia: • Infection • Non-adherence to insulin therapy • Acute major illnesses | Chronic alcohol abuse, liver disease and acute alcohol ingestion | Body is deprived of glucose as the primary source of energy for a prolonged period. |
EPIDEMIOLOGY | Occurs more frequently in T1DM; 10–30% of cases occur in T2DM especially in the background of extreme physiologic stress or acute illness. | Correlates with the incidence of alcohol abuse and can occur at any age. Occurs mainly in chronic alcoholics but rarely in binge drinkers. | Mild ketosis usually develops after a 12–14 hours fast but if prolonged such as in cases of extreme socio-economic deprivation or eating disorders, ketoacidosis will progressively develop. May present in cachexia due to underlying malignancy, post-operative or post-radiation dysphagia. |
CLINICAL PRESENTATION | • Abdominal pain • Nausea, vomiting • Hypovolemia • Rapid and deep respiratory effort • Distinct fruity odor to breath due to acetone production |
(Symptoms associated with hyperglycemia) • Polyuria • Polydipsia • Unintentional weight loss • Weakness • Mentation changes • Lethargy • Obtundation | • Signs associated with alcohol withdrawal such as hypertension and tachycardia | • Signs of muscle wasting including poor muscle mass, minimal body fat, obvious bony prominences, tooth decay, sparse, thin and dry hair • Low blood pressure • Low body temperature |
LABORATORY FINDINGS | • pH < 7.3 • Serum bicarbonate < 18mmol/L • Elevated anion gap values > 12mEq/L |
• Hyperglycemia – blood glucose > 125mg/dL (fasting) • Leukocytosis – WBC > 11.0x109/L • Serum sodium may be relatively low • Serum potassium may be elevated (> 5.2mmol/L) | Hypoglycemia – blood glucose < 70mg/dL (fasting) |
• Hypokalemia < 3.5mmol/L • Elevated transaminases and hyperbilirubinemia due to possible concurrent alcoholic hepatitis | • Hypomagnesemia and hypophosphatemia • Multiple electrolyte abnormalities due to chronic malnutrition • Vitamin deficiencies |
TREATMENT | • Standard initial stabilization – airway, breathing and circulation • Monitoring and replacement of electrolytes (especially potassium) • Correction of hypovolemia with IV fluids |
Monitoring and replacement of electrolytes (especially potassium), correction of hypovolemia with IV fluids, correction of hyperglycemia with IV insulin | • Monitoring and replacement of electrolytes, correction of hypovolemia with IV fluids and IV dextrose (for induction of endogenous insulin and reduction in counter-regulatory hormones) • Monitoring and replacement of magnesium and phosphate |
Thiamine replacement should be done parenterally and then maintained orally | • Monitor for refeeding syndrome |
*Insert: Table 1. Differentiation between the three different types of ketoacidosis: DKA, AKA and SA. (11)
EDKA is defined as ketoacidosis (pH < 7.3 or serum bicarbonate < 18mmol/L) with a normal or close-to-normal plasma glucose (11-14mmol/L) (12, 13). Clinically, patients may not appear to be dehydrated due to the absence of polyuria and polydipsia. However, patients may instead have non-specific symptoms such as nausea, vomiting, abdominal pain, lethargy and tachypnea due to ketonemia and concurrent ketoacidosis. EDKA has a similar presentation to DKA except for the fact that patients generally present with relatively lower blood glucose. A lack of hyperglycemia can mask the underlying DKA, delaying its diagnosis and hence treatment outcomes.
With the rise in the use of SGLT2-i, there is an increase in published case reports on EDKA (14, 15). Other factors that increase the risk of EDKA include poor oral intake, pregnant women, and treatment with insulin (16). In view of the lack of hyperglycemia, serum ketones should be checked in patients with nausea, vomiting or malaise. Occasionally, low serum bicarbonate may be the first finding in patients with EDKA.
Considering that this patient was on SGLT2-i (Dapagliflozin) for DM, it was even more crucial to identify any precedents for development of EDKA. AKA was ruled out from history-taking.
Oral Hypoglycemic Agent – SLGT2-i In Relation To EDKA
SGLT2-i work by blocking SGLT2-i cotransporters in the early proximal renal tubule which is responsible for reabsorption of 80–90% of glucose filtered by the glomerulus. This results in glucosuria and subsequent decrease in blood plasma glucose concentration (8, 17). The mechanisms that propagate DKA in susceptible patients include: osmotic diuresis with glucosuria (resulting in a state of carbohydrate deficit), volume depletion and dehydration (15, 17). Carbohydrate deficit and hypovolemia promote glucagon release, increase glucagon-to-insulin ratio and trigger ketogenesis with euglycemia. There is also a direct effect of SGLT2 on pancreatic alpha cells which result in glucagon release and inhibition of ketone bodies excretion by kidneys (18, 19).
Although the precise incidence rate of SGLT2-i associated with DKA is unknown, clinical trials of SLGT2-i with T2DM have reported incidence of 0.16 to 0.76 events per 1000 patient-years (15, 20). Other studies have also proven that risk of DKA was almost three-fold higher with SGLT2-i than dipeptidyl peptidase-4 inhibitors. This was observed with dapagliflozin, empagliflozin and canagliflozin, suggesting a class effect (21).
Fasting In Relation To EDKA
Reduced nutritional intake especially with concurrent illnesses, such as odontogenic infections, in patients with T2DM can also precipitate EDKA (22, 23). Prolonged fasting results in a carbohydrate deficit state and reduction of glycogen stores, leading to the use of alternative energy sources like free fatty acids. Ketogenesis from lipolysis, combined with reduced glycogen store that maintain a euglycemic state, sparking off EDKA.
However, fasting-induced EDKA should be discerned from starvation ketosis where metabolic acidosis is not present (serum bicarbonate > 18mmol/L or serum pH > 7.3) (12, 24).
In our case report, it is evident that ketosis likely arose due to patient’s prolonged starvation (approximately 33 hours) instead of associated SGLT2-i use and the background of T2DM. This can be concluded from the fact that there was only mild ketosis that arose the day after the operation, with lack of evidence of metabolic acidosis as reflected by normal serum bicarbonate of 20.6mmol/L and normal blood pH of 7.38. Ketone levels were normal pre-operatively and the patient’s last dose of SGLT2-i was taken 2 days prior to the surgery. This significantly lowered the risk of developing EDKA peri-operatively.
Peri-Operative Considerations
In the peri-operative management of patients on SGLT2-i, it is crucial to ensure that the drug is withheld even when there are no other predisposing factors that might precipitate ketoacidosis such as dehydration and acute illness. Surgery itself poses a physiological stress that may be enough to result in development of DKA.
The American Diabetes Association recommends discontinuation of SGLT2-i 3 to 4 days before surgery (25) whereas the Australian Diabetes Society recommends for cessation at least 3 days pre-operatively (26). This is because the elimination half-life of SGLT2-i ranges from 11 to 13 hours and the pharmacodynamic effects may persist for multiple days. Hypoglycemic drugs should not be restarted until the patient is clinically well, normo-glycemic and able to resume normal nutritional intake.
SGLT2-i should be stopped immediately for patients who are undergoing emergency surgery (27). Post-operatively, these patients should preferably be admitted to a ward with the capability of early recognition and management of DKA.
In cases where there is insufficient time for SGLT2-i cessation prior to surgery, it is essential to monitor the patient post-operatively for any signs and symptoms of ketoacidosis. Studies have also supported that the use of intravenous insulin has helped to reduce risk of DKA in patients who are unable to stop their medications pre-operatively (28). This can be considered in emergency cases where SGLT2-i cannot be stopped in time, especially when patient is nursed in intensive care postoperatively.
Recognition of starvation ketonemia is also crucial, especially in patients who have fasted for prolonged periods of time prior to surgery. Although infrequently reported, in cases where patients have other diagnosed comorbidities, prolonged starvation can eventually culminate in metabolic ketoacidosis. Regardless, it would be useful to consider preoperative serum glucose and serum ketones for a patient with unexplained ketosis, to promptly manage any potential precedents for metabolic acidosis.