Hrev_master [page 59] [Emergency Care Journal 2024; 20:12551] Emergency Care Journal 2024 volume 20:12551 Abstract Diabetic Ketoacidosis (DKA) is a potentially life-threatening condition that complicates diabetes mellitus. Euglycemic DKA (eDKA) is emerging as a variant in both type 1 and type 2 diabetes mellitus. The rise in its presentation is being caused by newer med- icines using SGLT-2 inhibitors, with a complex underlying patho- physiology. Here we report a case of a 70-year-old woman present- ing to the emergency department complaining of shortness of breath and abdominal pain. She suffers from type 2 diabetes mel- litus and is on oral therapy, including the SGLT-2 inhibitor empagliflozin. Further testing revealed a high-anion-gap metabolic acidosis without elevation of lactate levels and a glucose level of 160 mg/dL. CT imaging of the abdomen showed a small bowel perforation. The case required aggressive medical therapy before surgical repair in the operating room. EDKA is a medical emer- gency that can be challenging to identify due to its atypical presen- tation compared to the traditional DKA (which is hyperglycemic). These characteristics can delay effective and timely treatment. Case Report A 70-year-old woman presented to the emergency department complaining of abdominal pain for the past seven days and acute- onset shortness of breath. She suffered from hypertension and type 2 diabetes mellitus on empaglifozin/metformin therapy (with reported good compliance); she was not on insulin therapy. Her Body Mass Index (BMI) was 33. She claimed that she was await- ing elective surgery to repair an incisional hernia. She denied any allergy. On evaluation, she was awake and oriented, tachypneic (28 breaths/min) with an almost periodic breathing pattern, and a peripheral oxygen saturation above 95%. On auscultation, the lung sounds were clear without any abnormal findings. She was well perfused with no signs of congestion; the blood pressure was 120/80 mmHg and the heart rate was 110 bpm. The EKG showed sinus tachycardia without any other concerning signs. She was fully alert and oriented, with a GCS of 15. The pupils were equal in diameter and both reactive to light. Her cranial nerve examina- tion was completely normal. She had no speech or coordination deficits. The patient had no sensory or motor deficits in the limbs, but she complained of generalized weakness. She had no rigidity on the neck examination. The abdomen was tender in the lower quadrants, where the known incisional hernia was palpable and firm. She also complained of having a closed bowel for seven days, associated with nausea and persisting vomiting, resulting in lower caloric intake before presentation. The chest X-ray showed no signs of pulmonary pathology, and the abdomen X-ray (acquired in the supine position) showed signs of dilated small bowel without free air. The arterial blood gas showed a pO2 of 124 mmHg (room air) associated with a severe high anion gap metabolic acidosis (pH 7.2, pCO2 11 mmHg, HCO3 4.5 mmol/L, BE -22, anion gap 22, Lactate 1 mmol/L, glucose 160 mg/dL, Sodium 132 mmol/L, Potassium 2 mmol/L, Chloride 105 mmol/L). The anion gap was calculated by the point-of-care blood gas analyzer by subtracting the sum of bicarbonate and chloride from the sodium level (with- out accounting for the potassium level). Laboratory exams revealed a mild leukocytosis (neutrophil 84%, lymphocytes 7.4%, neutrophil-to-lymphocyte ratio 11), normal kidney function (Creatinine 1.1, BUN 20 mg/dL) and normal hepatic function Correspondence: Lorenzo Fornaciari, Graduate School of Emergency Medicine, Università degli Studi di Modena e Reggio Emilia, Italy. E-mail: lorenzo.fornaciari@ausl.re.it Key words: diabetic ketoacidosis, intestinal perforation, SGLT-2 protein. Contributions: LF, original case review and data collection, writing; LB, text editing; CSM final review. Funding: the authors declared that this study has received no finan- cial support. Ethics approval and consent to participate: no ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human partic- ipants or animals. Informed consent was obtained from the patient included in this study. Patient consent for publication: the patient gave her written consent to use her personal data for the publication of this case report and any accompanying images. Availability of data and materials: all data underlying the findings are fully available. Received: 8 April 2024. Accepted: 3 June 2024. Early view: 19 June 2024. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2024 Licensee PAGEPress, Italy Emergency Care Journal 2024; 20:12551 doi:10.4081/ecj.2024.12551 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Euglycemic diabetic ketoacidosis due to small bowel perforation: a case report Lorenzo Fornaciari,1 Lisa Bondavalli,1 Cesare Salvatore Mulas2 1Graduate School of Emergency Medicine, Università degli Studi di Modena e Reggio Emilia; 2Emergency Room and Emergency Medicine Department, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia, Italy Non -co mmerc ial us e o nly (ALT 15 U/L, total bilirubin 0.4 mg/dL, INR 1.09). There was severe hypokalemia (1.9 mmol/L) and a mild elevation of the C- reactive protein (7.45 mg/dL, nv <0.5 mg/dL). Later, the patient received 100 mEq of intravenous sodium bicarbonate 8,4% twice and 40 mEq of potassium chloride in normal saline. The patient was transferred to the observation unit of the emer- gency department and was then re-evaluated by another physician (the main author of this paper). The overall clinical picture was unchanged, as did the blood gas analysis. A point-of-care ketone fingerstick finally revealed ketonemia above the detection limit (>10 mmol/L) leading to the Diagnosis of Euglycemic Diabetic Ketoacidosis (eDKA). The patient received rapid volume expan- sion with 1000 ml of Lactated Ringer solution. Shortly after, rapid human insulin infusion was initiated at a dose of 0.1 UI/kg/hour. Alongside insulin therapy, intravenous potassium replacement was prescribed: the patient received 60 mEq of potassium chloride diluted in 500 mL of 10% dextrose and infused via a central venous catheter that was placed by the treating physician. A PoCUS (Point of Care Ultrasound) was performed by the authors and showed a normal diameter abdominal aorta with no signs of dissection and no free fluid in the abdominal recesses. There was no hydronephrosis bilaterally and no signs of cholecys- titis. Bowel-focused ultrasound was challenging due to copious subcutaneous fat tissue but showed dilated bowels (30 to 40 mm diameter) with nearly absent movement inside the hernia but with- out fluid around the bowel loops. For further diagnostic evaluation of the abdominal findings, the patient underwent a contrast CT scan, with raised concerns for bowel obstruction. She was diag- nosed with a small bowel perforation due to obstruction of the known incisional hernia, which likely triggered the DKA. The con- sultant surgeon was alerted and the patient was then admitted to the ICU for perioperative management. Discussion Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus. Risk factors for DKA include newly diag- nosed diabetes mellitus, omission of chronic insulin therapy, infec- tions, acute myocardial infarction, cocaine use, thyrotoxicosis, and many more, as any critical illness can induce DKA. This condition is characterized by an insulin deficit (absolute or relative associat- ed with insulin resistance) leading to hyperglycemia, osmotic diuresis (resulting in extracellular volume losses), elevated levels of blood ketones (also mediated by glucagon effect), and elec- trolyte imbalances (with hypokalemia and hyperkalemia being the most concerning). Unfortunately, there are no definite criteria for diagnosing DKA. Typically, the pH is below 7.30, sodium bicar- bonate is less than 15 mmol/L, and anion gap (AG) is above 12 mmol/L, associated with positive urine or serum ketones (> 3 mmol/L).1 Euglycemic DKA (eDKA) was first described in 1973 by Munro et al.2 The available literature reports that 2.6 to 7% of DKA admissions are euglycemic. Furthermore, SGTL-2 inhibitors (such as empagliflozin, canagliflozin, and dapagliflozin) increase the risk of eDKA by a factor of 7.3 The mechanism by which SGTL-2 inhibitors cause eDKA is complex: they enhance glucose excretion by the kidney and promote reabsorption of ketone bod- ies. These drugs also appear to inhibit beta-cells and stimulate alpha-cells, ultimately increasing lipolysis and ketone body pro- duction, and causing an overall imbalance between glucagon and insulin levels.4 In the context of eDKA, the hyperglycemia is mod- erate (below 300 mg/dL). The management of these variants of DKA differs slightly from the classic DKA approach. Reversal of concomitant shock and hypoperfusion is paramount, as well as aggressive correction of electrolyte imbalances (i.e., hypokalemia). Many protocols have been published, but they all agree on holding the insulin infusion until a potassium level of at least 3.5 mEq/L is reached. Potassium levels between 3.5 and 5.5 mEq/L require intravenous supplementation with 10 mEq per liter of infused crystalloid. Potassium infusion is held above 5.5 mEq/L. In the context of eDKA, the intravenous insulin infusion must be paired with dextrose infusion to prevent hypoglycemia. Sodium bicarbonate in DKA is generally unnecessary, although it can be considered in the presence of profound acidosis (pH <7.0), hemo- dynamic instability, or life-threatening hyperkalemia.3 In our case, the patient did well overnight and by continuing the above-men- tioned treatment, the anion gap was reduced, the potassium returned to baseline values, and the pH began to rise (Table 1). Case Report [Emergency Care Journal 2024; 20:12551] [page 60] Table 1. Changes in arterial blood gas parameters. Location ICU ICU ICU ICU ICU ICU ICU ICU ICU ICU ICU OR ICU ICU ICU ED ED ED Date and time Day 5 Day 4 Day 4 Day 4 Day 3 Day 3 Day 3 Day 3 Day 2 Day 2 Day 2 Day 2 Day 2 Day 2 Day 2 Day 1 Day 1 Day 1 5.36 22.14 15.43 9.11 21.28 14.01 09.54 03.55 23.50 15.45 12.14 11.11 09.02 04.48 02.47 23.08 16.43 15.27 pH 7.53 7.54 7.54 7.53 7.45 7.42 7.36 7.34 7.29 7.18 7.05 7.2 7.27 7.19 7.26 7.32 7.21 pCO2 (mmHg) 44 41 40 34.3 29 24 25 25 28 34 35 19 18 13 14 16 12 pO2 (mmHg) 85 82 80 77 103 103 97 103 106 106 93 110 106 117 122 109 124 P/F 304 293 286 308 412 343 323 343 353 265 233 524 505 557 581 519 590 FiO2 (%) 28 28 28 25 25 30 30 30 30 40 40 21 21 21 21 21 21 HCO3 (mmol/L) 37 35 35 29 20 17 14 13 13 12 9 7 8 5 6 8 5 Sodium (mmol/L) 146 148 150 153 149 147 146 143 144 147 135 144 141 140 136 135 132 Potassium (mmol/L) 2.9 3.3 3 3.1 2.7 2.7 2.8 2.7 2.7 3 3.1 3.1 2.9 2.6 2 2 2 Chloride (mmol/L) 108 110 115 118 122 122 122 121 120 123 121 118 117 115 106 106 105 Ionized calcium (mmol/L) 1.15 1.17 1.18 1.21 1.16 1.23 1.22 1.17 1.18 1.2 1.25 1.27 1.19 1.12 1.18 1.19 1.27 Anion Gap (mmol/L) 1 3 0 6 7 8 10 9 11 12 5 19 16 20 24 21 22 Serum osmolarity (mosm/L) 300 305 311 317 310 308 N/A 286 300 302 282 297 289 289 279 279 272 Glucose (mg/dL) 145 163 187 200 208 236 267 225 226 165 210 160 112 178 148 154 161 Lactate (mmol/L) 1.4 2 2.1 1.3 1.1 1 1 1.2 1.2 0.8 0.6 0.7 0.6 0.8 1.4 1.5 1 Non -co mmerc ial us e o nly Unfortunately, a quantitative trend of ketone clearance is not avail- able, since finger-stick β-hydroxybutyrate (β-OHB) test results were charted only in the emergency department; although a urine dipstick was probably performed during the first evaluation in the ED, it was not reported in the charts and we could not find it when we reviewed the case. The patient underwent an urgent surgical operation the following morning. The surgeons were able to iden- tify the source of perforation and performed a terminal-terminal resection of the bowel. From there, the patient had a positive intra- hospital course and was first transferred to the surgical ward, and then to the medicine ward for optimization of her diabetes treat- ment. She was discharged home 14 days later without complica- tions. Usually, metabolic acidosis and ketosis are not the primary goals of care for DKA patients. This case was different because the profound metabolic derangement precluded safe induction of gen- eral anesthesia, which was required to treat the underlying cause of the overall clinical picture and sustain the DKA itself. The patient was also profoundly hypokalemic, so insulin was delayed until safe levels of serum potassium were obtained. Typically, metabolic acidosis due to DKA presents with hyperkalemia due to insulin deficiency,5 however, this patient was hypokalemic likely due to renal excretion of potassium promoted by SGLT-2 inhibitor thera- py. The patient stayed too little time in the emergency department, but the intensive care unit team reported polyuria, which likely was caused by the osmotic effect of glucose.6 Glucose was not highly elevated because of multiple factors: the patient continued to comply with her prescription and SGLT-2 inhibitors can promote ketoacidosis with normal to slightly elevat- ed glucose levels, as described above. She was also eating very lit- tle in the days before the presentation (due to nausea, vomiting, and abdominal pain) which probably contributed to the euglycemia observed. The patient was on empagliflozin for more than six months before this presentation, so it is unlikely that empagliflozin alone triggered the EDKA. The obstruction and subsequent perfo- ration of a bowel loop likely acted as the triggering event of the DKA; while her anti-diabetes therapy and poor food intake favored near-normal glucose levels. She was not even brought to the operating room in perfect metabolic balance because, after fourteen hours of medical man- agement, the metabolic acidosis was still ongoing. However, she required definitive treatment of her bowel perforation. She was not induced into general anesthesia but kept awake with a loco-region- al block. Conclusions Euglycemic DKA is a challenging diagnosis to make during an emergency evaluation because its presentation pattern is different from classic hyperglycemic DKA: it lacks hyperglycemia by defi- nition. Emergency physicians often rely on pre-existing mental maps and cognitive shortcuts (which can generate biases), and eDKA differs from the classic high anion gap metabolic acidosis with hyperglycemia. This diagnosis requires an extra cognitive step, which can be challenging to make if simultaneously caring for other life-threatening conditions (i.e., severe hyperkalemia, shock, severe respiratory failure). This specific patient tricked an experienced emergency doctor. For this reason, it is important to be aware that eDKA exists and to know who is the most at risk of developing it. With the spread of SGLT-2 inhibitors, this relatively rare condition is expected to increase in overall number of cases annually. Delay in recognition and, consequently, in treatment can be life-threatening. These patients require the same expedited ther- apy as those with hyperglycemic DKA. References 1. Diabetes Canada Clinical Practice Guidelines Expert Committee; Goguen J, Gilbert J. Hyperglycemic emergencies in adults. Can J Diabetes 2018;42:S109-S114. 2. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycemic diabetic ketoacidosis. Br Med J 1973;2:578-80. 3. Long B, Lentz S, Koyfman A, Gottlieb M. Euglycemic diabet- ic ketoacidosis: Etiologies, evaluation, and management. Am J Emerg Med 2021;44:157-60. 4. Somagutta MR, Agadi K, Hange N, et al. Euglycemic diabetic ketoacidosis and sodium-glucose cotransporter-2 inhibitors: a focused review of pathophysiology, risk factors, and triggers. Cureus 2021;13:e13665. 5. Wiederseiner JM, Muser J, Lutz T, et al. Acute metabolic aci- dosis: characterization and diagnosis of the disorder and the plasma potassium response. J Am Soc Nephrol 2004:15:1589- 96. 6. Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2014;16:875-82. Case Report [page 61] [Emergency Care Journal 2024; 20:12551] Non -co mmerc ial us e o nly