Abstract
Postoperative euglycemic diabetic ketoacidosis (EDKA), a rare cause of acidosis, results from the metabolic derangement of diabetes and is not associated with a surgical complication requiring reoperation. Our acute care surgery service has managed several recent patients who developed postoperative EDKA. Our group was befuddled by the initial case but subsequently quickly recognized and managed the condition. The purpose of this report is to discuss the pathophysiology of EDKA, summarize 3 recent cases, and increase awareness about the condition to permit prompt recognition and treatment.
Keywords
Introduction
Postoperative acidosis is associated with poor outcomes, demands attentive assessment, and management and might require early reoperation. Euglycemic diabetic ketoacidosis (EDKA), a rare cause of acidosis, results from the metabolic derangement associated with diabetes and is not associated with a surgical complication requiring reoperation. Our acute care surgery service has managed several recent patients who developed postoperative EDKA. Our group was befuddled by the initial cases but subsequently quickly recognized and managed the condition. The purpose of this report is to discuss the pathophysiology of EDKA, summarize 3 recent cases, and increase awareness about the condition to permit prompt recognition and treatment.
Euglycemic diabetic ketoacidosis is defined as the presence of anion gap metabolic acidosis, ketonemia or ketonuria, and normoglycemia (serum glucose <200 mg/dL 1 Euglycemic diabetic ketoacidosis can be present in both type 1 and 2 diabetic patients. The underlying pathogenesis for the better known diabetic ketoacidosis (DKA) involves an imbalance between circulating insulin and counter-regulatory hormones, such as glucagon and catecholamines, and elevated serum glucose levels. 2 Euglycemic diabetic ketoacidosis occurs in the setting normally associated with DKA; however, it is mitigated by either decreased hepatic production of glucose or increased renal excretion of glucose, leading to ketosis and metabolic acidosis with lower glucose levels not traditionally associated with DKA. 2 Historically, EDKA has been associated with conditions that result in decreased hepatic glucose production such as pregnancy, alcohol abuse, cocaine abuse, pancreatitis, sepsis, cirrhosis, and states of decreased caloric intake. However, recently, the incidence of EDKA has risen sharply with the introduction of sodium glucose cotransporter-2 (SGLT-2) inhibitors to treat diabetes. 2 Sodium glucose cotransporter-2 inhibitors restrict renal glucose reabsorption. The resulting glycosuria lowers blood glucose without stimulating insulin release. Regardless of the underlying etiology, it is important to have a high clinical suspicion as the diagnosis can often be overlooked given the absence of high blood glucose levels and the absence of the usual symptoms associated with severe dehydration associated with hyperglycemia.1,2
In the surgical patient, aside from underlying SGLT-2 inhibitor use, a fasting state with dehydration can precipitate EDKA. The precipitating stressor of surgery or an underlying infection being treated surgically can induce the state of imbalance between insulin and counter-regulatory hormones that leads to metabolic acidosis and ketosis. However, in a diabetic patient who has decreased or no oral intake and who is being appropriately dosed with insulin to maintain euglycemia, EDKA may result.2,3 We present 3 cases to illustrate the pathophysiology and management strategies to address EDKA.
Case Series
Patient 1
The first patient we encountered was a 49-year-old woman with a medical history of poorly controlled diabetes (HbA1c of 9.4%) who presented to surgery clinic as a referral for cholelithiasis. She reported a 1-month history of right upper quadrant pain radiating to her back, along with postprandial pain, associated nausea, and vomiting. Abdominal ultrasound demonstrated gallstones. Her surgical history was significant for a laparoscopic appendectomy 1 year prior. She was scheduled for an elective laparoscopic cholecystectomy. The patient’s diabetes was being managed with metformin and canagliflozin (an SGLT-2 inhibitor).
The case was quickly converted from laparoscopic to open because of the extensive amounts of adhesions encountered upon entry into the abdomen. After converting to open, the remainder of the case was uncomplicated.
Postoperatively, the patient was noted to have a CO2 of 15 mmol/L (ref, 23-29 mmol/L), and the following day, CO2 decreased to 8 mmol/L. There was no obvious clinical explanation for the acidosis as the patient was clinically doing well. Notably, during the first 48 hours of her postoperative stay, her glucose ranged from 142-192 mg/dL and she was started on a sliding scale insulin (SSI) regimen every 6 hours. Sliding scale insulin was chosen for management because we were concerned that a reoperation might be necessary. We considered type 4 renal tubular acidosis and EDKA to our possible explanations for acidosis. Euglycemic diabetic ketoacidosis was of high suspicion given the patient’s use of an SGLT-2 inhibitor for management of her diabetes. Laboratory work ultimately confirmed EDKA with a beta-hydroxybutyrate level of 4.8 mmol/L (ref, 0-.5 mmol/L) and positive urine ketones (3+). Of note, the patient’s lactic acid was normal at 1.1 mmol/L. An insulin drip was initiated, and volume resuscitation was started. The patient’s acidosis quickly resolved, and she was discharged 2 days later.
Patient 2
Our second patient in this series is a 61-year-old man with a history of hyperlipidemia, diabetes, and 2 previous episodes of pancreatitis attributed to hypertriglyceridemia who presented to the emergency department after 4 days of right upper quadrant abdominal pain. The pain was initially believed to be attributable to recurrent pancreatitis; however, the patient’s physical examination and imaging were consistent with acute cholecystitis, and he was taken to the operating room the following morning for a laparoscopic cholecystectomy. The patient was found to have gangrenous cholecystitis. The gallbladder was difficult to remove laparoscopically, but the procedure was ultimately completed successfully without apparent complication. Of note, the patient’s diabetes was being managed with metformin and insulin, and while he had previously trialed an SGLT-2 inhibitor, his last dose was 6 months prior.
Postoperatively, the patient was hemodynamically stable, without fever or leukocytosis. The patient was started on a moderate SSI regimen to manage his diabetes. However, the morning after the surgery, his CO2 was 9 mmol/L (ref, 23-29 mmol/L). There was no indication that his acidosis was the result of an infectious etiology or bleeding. We did not appreciate any evidence to support a diagnosis of profound dehydration to explain his acidosis. His highest glucose reading was 222 mg/dL, and the other readings were between 112 and 157 mg/dL.
Volume resuscitation initially improved his CO2 from 9 to 13 mmol/L; however, additional volume resuscitation failed to impact subsequent CO2 levels. On postoperative day 2, given no resolution of his acidosis, we began to consider the need for early postoperative imaging or reoperation. Less obvious and more esoteric causes of acidosis were also considered and discussed. The possibility of EDKA was raised, and a serum beta-hydroxybutyrate and urinalysis were ordered. The urine demonstrated elevated ketones. Plans to repeat computed tomography or reexploration were canceled. The patient was started on an insulin and 5% dextrose drip. During the ensuing 36 hours, his CO2 improved to 19 mmol/L. The following day, the diagnosis of EDKA was confirmed when the beta-hydroxybutyrate level returned markedly elevated at 5 mmol/L (ref, 0-.5 mmol/L).
The patient’s acidosis continued to resolve, and the insulin drip was discontinued. The patient was discharged on his home diabetes regimen. The patient was doing well without any notable postoperative complications at his 2-week surgery clinic visit.
Patient 3
Our third patient was a 65-year-old woman with a history of type 2 diabetes, hypertension, gastroesophageal reflux disease, and morbid obesity who had previously had a laparoscopic gastric band placed. She was having difficulty with nausea and vomiting due to a slipped band and was offered a lap band removal with conversion to a sleeve. Of note, preoperatively, the patient’s diabetes was managed with metformin, dulaglutide, and canagliflozin.
On postoperative day 1, after undergoing a laparoscopic band removal with conversion to sleeve gastrectomy, the patient was noted to be severely acidotic with a CO2 <5 mmol/L (ref, 23-29 mmol/L), while her glucose was 128 mg/dL. Her lactic acid was within normal limits at .9 mmol/L. The patient had been placed on low-dose SSI, but notably, her glucose level had not risen high enough to trigger the delivery of any doses. Ultimately, workup revealed the patient was in EDKA with a beta-hydroxybutyrate level of 5.1 mmol/L (ref, 0-.5 mmol/L) and a urinalysis showing 3+ urine ketones. An insulin drip and fluid resuscitation were initiated, with prompt resolution of her acidosis.
Discussion
Surgery is a known physiologic stressor and can lead to ketoacidosis. The increased postoperative production of counter-regulatory hormones such as glucagon, growth hormone, and cortisol leads to increased insulin resistance. 4 In DKA, insulin deficiency leads to a decrease in glucose utilization and upregulation of lipolysis. With the breakdown of adipose tissue comes a massive influx of free fatty acids (FFAs) into the liver, the primary site for conversion of FFA to ketones. 5 Increased FFA in the liver in concert with elevated glucagon levels promotes oxidation of FFA and production of ketone bodies. 6 Diabetic ketoacidosis typically presents with significant hyperglycemia (glucose >250 mg/dL), glycosuria, and hyperketonemia (plasma beta-hydroxybutyrate 4.2-11.0 mmol/L).7,8 However, patients taking SGLT-2 inhibitors exhibit euglycemia or mild hyperglycemia.
Before the availability of SGLT-2 inhibitors, EDKA was first described as DKA with glucose levels <300 mg/dL in young female type 1 diabetic patients. 1 The pathophysiology of EDKA was reduced carbohydrate availability in conjunction with reduced insulin dose. The mechanism of EDKA in type 2 diabetics taking SGLT-2 inhibitors is different. Sodium glucose cotransporter-2 inhibition induces glucose excretion in the urine of 50-100 mg/day. 6 With the significant decline in blood glucose levels (by 20-25 mg/dL), comes a concomitant decrease in plasma insulin levels and a compensatory increase in glucagon levels. 9 The prehepatic insulin to glucagon ratio drops, the inhibition of gluconeogenesis in the liver is released, and endogenous glucose production is augmented. 6 In EDKA, insulin deficiency and resistance are minor. Glucose overproduction and underutilization exist to a lesser extent than in classic DKA. In patients taking SGLT-2 inhibitors, renal glucose clearance (ie, the ratio of glycosuria to prevailing glycemia) doubles in EDKA in comparison to DKA. 6 Furthermore, patients in DKA often have concomitant renal impairment (decreased glycosuria), whereas those with EDKA on SGLT-2 inhibitors will have significantly elevated glycosuria. With the increase in glycosuria, plasma glucose levels are decreased, predisposing to ketogenesis.
Patients subjected to stressors such as surgical intervention often have increased insulin requirements due to the increase in counter-regulatory hormones. Further, patients on SGLT-2 inhibitors have an increased renal threshold for glucose which, in turn, reduces plasma glucose concentrations. This may mask true insulin requirements postoperatively and therefore predispose to DKA. 10 Because the half-life of SGLT-2 inhibitors is 12.5 hours, surgical patients on these medications are especially prone to EDKA. 11 The American Association of Clinical Endocrinologists and the American College of Endocrinology acknowledge the risk of EDKA in surgical patients and recommend holding SGLT-2 inhibitors 24 hours prior to surgery. 12 However, the SGLT-2 inhibitor half-life might demand more time for the drug to be eliminated.
In conclusion, we present 3 surgical patients with type 2 diabetes (2 of whom were on SGLT-2 inhibitors) who were subjected to surgical stress and subsequently developed EDKA, resulting most commonly, from the persistent action of the drug in the perioperative period. Euglycemic diabetic ketoacidosis is as a result of preoperative fasting in combination with the physiologic stress of surgery. It is important to retain a high index of suspicion if acidosis of unknown etiology arises in the postoperative period. Surgeons should be aware that SGLT-2 inhibitors predispose patients to EDKA and that patients may require increased monitoring and warrant further investigation. Because of the prolonged half-life, patients may require earlier cessation of SGLT-2 than 24 hours. In the case of urgent or emergent procedures and the inability to discontinue the medication for longer than 24 hours, patients may require more intense monitoring and increased insulin doses in the perioperative period.
The diagnosis of EDKA should be considered when severe acidosis develops in euglycemic diabetic surgical patients, once perioperative complications have been excluded. A quick evaluation for urine ketones and a confirmatory test to check the patient’s beta-hydroxybutyrate level can confirm the diagnosis of EDKA. If EDKA is discovered, prompt administration of insulin infusion in combination with aggressive fluid resuscitation should be initiated.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.