Euglycemic diabetic ketoacidosis (EDKA) is a form of diabetic ketoacidosis (DKA) characterized by a relatively normal glucose level (<200 mg/dL [11.1 mmol/L]) [1]. In response to the increasing incidence of EDKA, several leading organizations, including the American Diabetes Association (ADA), convened a panel of internists and diabetologists in 2024 to revise the ADA consensus statement on hyperglycemic crises in adults with diabetes. The updated consensus emphasizes that all three diagnostic components—ketosis, metabolic acidosis, and diabetes—must be present to diagnose DKA. Notably, the definition of hyperglycemia as a diagnostic criterion was revised from a glucose threshold of >250 mg/dL (13.9 mmol/L) to either a serum glucose ≥200 mg/dL (11.1 mmol/L) or the presence of an established diagnosis of diabetes, regardless of the presenting glucose level [2]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which block glucose reabsorption in the proximal renal tubules, thereby inducing glucosuria, modest weight loss, and a reduction in blood pressure, have been implicated in the development of EDKA. Despite this risk, clinical evidence supports their benefits in heart failure, both with reduced and preserved ejection fractions, and in chronic kidney disease, underpinning their recommendation in major international guidelines. Other factors contributing to EDKA include prolonged fasting and physiological stress. The pathophysiology of EDKA involves insulin deficiency accompanied by an increase in counter-regulatory hormones such as glucagon, cortisol, catecholamines, and growth hormone [3]. Patients undergoing neurosurgery often present with altered metabolic demands, a limited ability to communicate symptoms, and overlapping clinical signs, making early recognition of EDKA particularly challenging. By drawing attention to the risks posed by SGLT2 inhibitors in this vulnerable population, this case report underscores the need for heightened vigilance, careful medication reconciliation, and tailored glycemic management protocols in neurosurgical care. Management primarily focuses on the correction of the anion gap, fluid resuscitation to restore intravascular volume, and the reversal of the underlying metabolic disturbances [4].

A man in his early seventies with a medical history of poorly controlled type 2 diabetes, reflected by a hemoglobin A1c of 10.8% measured a month prior to presentation, presented to the emergency department with worsening headaches and altered mental status. He was admitted to the surgical intensive care unit (ICU) following an emergent craniectomy and intracranial abscess debridement. His past medical history was notable for inconsistent insulin therapy; inconsistent use of empagliflozin since initiation 1 year prior to presentation, although it was taken consistently over the past month, including the day of surgery; dementia; and a prior left-sided ischemic stroke resulting in persistent right-sided hemiparesis. Over the past 3 years, he had undergone multiple craniotomies for recurrent right middle fossa/sphenoid wing meningiomas. His most recent surgical course, a year prior to this admission, was complicated by a methicillin-resistant Staphylococcus aureus (MRSA) wound infection and dehiscence, requiring removal of the duraplasty and extended antibiotic therapy.

Upon admission to the ICU, the patient required vasopressor support to maintain a mean arterial pressure of >65 mm Hg. His oxygen saturation was 95% while receiving 4 L of supplemental oxygen administered via a nasal cannula. He was tachypneic, with a respiratory rate of 24 breaths per minute, and tachycardic, with a heart rate of 105 beats per minute. He was initially slow to respond but remained alert and oriented to person and time. He complained of nausea and dizziness. Physical examination revealed a stable, chronic right-sided weakness. He appeared clinically dehydrated, with notably dry mucous membranes, and exhibited increased work of breathing. Initial laboratory tests revealed serum sodium, bicarbonate, anion gap, and glucose levels of 144 mmol/L, 12 mmol/L, 25 mmol/L, and 134 mg/dL (7.4 mmol/L), respectively. Given his volume depletion and intraoperative diuretic use, 1,500 mL of intravenous normal saline was administered. A sliding-scale insulin regimen was initiated, and empiric antibiotic coverage with ceftriaxone and vancomycin was started because of a high suspicion for sepsis.

The patient became progressively tachycardic, with a heart rate of 110–120 beats per minute; hypertensive, with a blood pressure of 152/86 mm Hg; off vasopressors; increasingly tachypneic, with a respiratory rate of >30 breaths per minute; and requiring escalating oxygen support. He also demonstrated increased work of breathing, including the use of accessory muscles, and became increasingly agitated, with worsening nausea, prompting an urgent brain computed tomography scan. The imaging findings were stable and showed only the expected postoperative changes. The patient’s clinical status remained relatively unchanged overnight; however, he continued to exhibit signs of respiratory distress and tachypnea, raising concerns about impending respiratory failure. Laboratory results worsened over the next several hours, with a bicarbonate level of 8 mmol/L, an anion gap of 28 mmol/L, and a glucose level of 204 mg/dL (11.3 mmol/L). The following morning, repeat laboratory tests showed a bicarbonate level of 11 mmol/L, an anion gap of 23 mmol/L, and a glucose level of 163 mg/dL (9.1 mmol/L) (Table 1). Arterial blood gas analysis revealed a pH of 7.29, a partial pressure of carbon dioxide of 26.3 mm Hg, and a base deficit of 12.4 mmol/L. The patient's chemistry panel, including sodium (141 mmol/L), chloride (107 mmol/L), and albumin (3.1 g/dL), was consistent with mixed primary high anion gap metabolic acidosis and metabolic alkalosis.

We performed a comprehensive evaluation of the causes of high anion gap metabolic acidosis. The lactic acid level was within normal limits (0.7 mmol/L), effectively ruling out lactic acidosis. Renal function was normal, with a creatinine level of 0.8 mg/dL (0.071 mmol/L) and a blood urea nitrogen of 21 mg/dL (7.5 mmol/L), excluding uremia as the cause. The serum beta-hydroxybutyrate (BHB) level was 8.5 mmol/L, narrowing the differential diagnosis to ketoacidosis. These findings, together with the patient’s perioperative fasting state, relatively normal glucose levels, and recent empagliflozin use, supported the diagnosis of EDKA.

Management included initiating an insulin infusion with concurrent administration of 5% dextrose in normal saline, following institutional ketoacidosis protocols. The protocol adjusts insulin and dextrose infusion rates based on serum glucose levels. The choice of isotonic over hypotonic fluids was guided by the patient’s intravascular depletion, which also contributed to the observed metabolic alkalosis. Within 8 hours of initiating treatment, the patient's bicarbonate level improved to 18 mmol/L and the anion gap narrowed to 11 mmol/L. By the following morning, metabolic acidosis was fully resolved. Insulin infusion was subsequently discontinued after the patient was transitioned to subcutaneous glargine insulin (Fig. 1). The patient’s mental status improved concurrently with improvement in his acid-base status. Despite normalization of the acid-base status, persistent glucosuria was observed on urinalysis for up to 48 hours after insulin discontinuation.

EDKA resolved without complications. His anion gap and bicarbonate levels normalized before being transferred from the ICU to the general medical floor. Intraoperative cultures confirmed the presence of MRSA. As a result, ceftriaxone was discontinued, and vancomycin was switched to ceftaroline based on antibiotic sensitivity. At the time of discharge, the patient was scheduled for follow-up with his primary care provider to optimize long-term diabetes management given his persistently elevated hemoglobin A1c.

EDKA is a rare but increasingly recognized diabetes complication, particularly in patients on SGLT2 inhibitors. SGLT2 inhibitor– associated DKA occurs at rate of 0.16–0.76 events per 1,000 patient-years in patients with type 2 diabetes. Blau et al. [5] estimated that SGLT2 inhibitors increase the risk of DKA in this population by approximately sevenfold. Erondu et al. [6] reported an overall incidence of DKA related to SGLT2 inhibitor therapy of approximately 0.1%. Along with empagliflozin, other medications, such as corticosteroids and octreotide, have also been implicated in the development of EDKA. SGLT2 inhibitors contribute to EDKA by promoting urinary glucose excretion, which lowers blood glucose levels and masks hyperglycemia, a key diagnostic feature of typical DKA. This reduction in plasma glucose leads to decreased insulin secretion and a relative insulin-deficient state, while simultaneously stimulating glucagon release. This combination promotes lipolysis and hepatic ketogenesis, resulting in elevated ketone levels and metabolic acidosis. Additionally, SGLT2 inhibitors may increase renal ketone reabsorption, which further exacerbates ketosis. In this context, EDKA is often triggered by stressors such as surgery, fasting, infection, or reduced insulin dosing [7]. A thorough medication review is essential to identify precipitating agents. In this case, recent SGLT2 inhibitor use, combined with surgical stress and fasting, was the likely trigger [8].

Clinical presentation can range from mild symptoms, such as dry mucous membranes and fatigue, to severe manifestations, including vomiting, Kussmaul respirations, encephalopathy, or coma. In patients with baseline neurologic impairment, such as the current patient with pre-existing dementia and a brain abscess, the diagnosis may be delayed or obscured. The cornerstone of diagnosis is identifying the characteristic biochemical triad: an elevated anion gap, normal to mildly elevated glucose levels, and the presence of ketones. Although BHB is a more sensitive early marker of ketoacidosis, it is not routinely measured in many hospitals, including ours. For peripheral tissues to utilize ketones as an energy source, insulin must be present and BHB must be converted to acetoacetate. Therefore, as DKA resolves, the concentration of BHB decreases, while the concentration of acetoacetate increases [9]. Management includes the prompt initiation of insulin and dextrose-containing fluids to resolve acidosis and close the anion gap. Unlike traditional DKA management, EDKA requires the early addition of 5% dextrose to intravenous fluids because of the typically normal or mildly elevated serum glucose levels (<250 mg/dL [13.9 mmol/L]). If ketosis persists despite treatment with 5% dextrose, increasing the dextrose concentration to 10% may be necessary to prevent hypoglycemia and facilitate resolution of ketoacidosis [10]. Electrolytes, particularly potassium, must be closely monitored during treatment due to insulin-driven intracellular shifts [11]. Potassium supplementation is essential if serum potassium drops below 3.3 mmol/L. Although bicarbonate therapy is sometimes considered for severe acidosis (pH <6.9), current evidence does not support its routine use owing to the lack of demonstrated benefit. Glucosuria may persist for days following the resolution of EDKA because of ongoing SGLT2 inhibitor effects, which was consistent with this patient’s post-treatment course [12].

This case illustrates the importance of recognizing EDKA in the perioperative setting, particularly in patients undergoing neurosurgery who are on SGLT2 inhibitors. Diagnosis of EDKA can be easily missed or delayed because patients do not present with the hallmark severe hyperglycemia of typical DKA. This is especially concerning in patients undergoing neurosurgery because altered mental status, tachypnea, and acidosis may be misattributed to intracranial pathology or postoperative complications. Early identification and appropriate treatment can prevent complications and reduce morbidity. Discontinuing SGLT2 inhibitors well before surgery remains a key preventive measure, and current guidelines recommend stopping canagliflozin, dapagliflozin, and empagliflozin at least 3 days before surgery, and ertugliflozin at least 4 days before scheduled surgery [13].