Surgical dilemma

A woman in her 60s with non-insulin-dependent diabetes was found to have a CDH1 mutation from genetic workup after colectomy for sigmoid colon cancer discovered on diagnostic colonoscopy for rectal bleeding 6 years earlier. She pursued annual endoscopic surveillance until several foci of intramucosal, poorly differentiated, signet ring adenocarcinoma were found a month prior to her operation. Notably, her glucose levels were normal on outpatient checks, but her last hemoglobin A1c within the 3 months leading up to her operation was 7.4%. Her diabetes had been managed with sitagliptin-metformin 50 mg to 1000 mg two times per day, glipizide 15 mg daily, and empagliflozin 25 mg daily. She underwent an uncomplicated total gastrectomy, D2 lymphadenectomy, and Roux-en-Y esophagojejunostomy reconstruction. She progressed well postoperatively. She had no leak on an esophagogram performed with water-soluble contrast on postoperative day 2. By postoperative day 3, she was passing gas, had weaned to only oral pain medications, and advanced to her intended discharge diet of full liquids. Her diabetic medications had been held and an insulin sliding scale had been ordered with fewer than 4 units needed daily. Her point-of-care glucose levels ranged from 79 mg/dL to 201 mg/dL during this time.

Despite meeting these discharge criteria by postoperative day 3, her bicarbonate declined from 26 mmol/L preoperatively to 9 mmol/L, with a widening anion gap from 14 preoperatively to 23. She otherwise remained afebrile, hemodynamically stable, and asymptomatic without nausea, vomiting, diarrhea, or tachypnea. She felt fatigue, thirst, and had high-volume urine output of 5.7 L during the last day despite weaned intravenous fluids. Her abdominal examination was as expected, with minimal tenderness and no distension. Her lactate level returned to normal at 0.9 mmol/L and creatinine remained normal at 0.42 mg/dL.

What would you do?

1. Discharge the patient home.

2. Consult nephrology to aid in the workup of her anion gap acidosis.

3. Trend her bicarbonate and anion gap during the next 24 to 48 hours.

4. Order CT of the abdomen and pelvis with intravenous contrast to rule out infection.

What we did and why

B. Consult nephrology to aid in the workup of her anion gap acidosis.

The nephrology service was consulted and requested a urinalysis, discovering 3+ glucose and 2+ ketones. The patient had no prior episodes of diabetic ketoacidosis (DKA). With no history of renal failure, starvation, or alcoholism, the patient was diagnosed with euglycemic DKA from empagliflozin use, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. This, combined with starvation, stress from surgery, and altered nutrient absorption, contributed to euglycemic DKA.

Her ketoacidosis was corrected by resuscitation with 5% dextrose and normal saline at 125 mL/hour, starting an insulin drip between 0.7 and 1 unit/hour, with a glucose goal of 120 mg/dL to 160 mg/dL, and potassium replenishment. She transitioned off the insulin drip on postoperative day 5 after her anion gap closed. Since the empagliflozin had contributed to euglycemic DKA, the endocrinology service was consulted to re-evaluate her outpatient diabetic regimen. She was recommended to continue sitagliptin-metformin, stop empagliflozin, and start using 6 units of glargine. She was discharged home on postoperative day 6. She unfortunately developed shortness of breath and palpitations 3 days later, prompting her to present to the emergency department where her glucose was 196 mg/dL, her anion gap was 18, and her urinary ketones were 1+ and glucose 3+. She was admitted for euglycemic DKA and discharged home 48 hours later on 16 units of glargine nightly and metformin 500 mg two times per day.

Her course illustrates the need for surgeons to understand the complications of common antihyperglycemic medications and their pharmacokinetics. There are eight classes of oral medications that mediate glycemic homeostasis (table 1).

Metformin suppresses liver gluconeogenesis and is the first-line treatment for type 2 diabetes. SGLT-2 inhibitors block glucose reabsorption from renal proximal tubules. In a randomized trial comparing SGLT-2 inhibitors with placebo, experimental arm patients had lower risk of cardiovascular and renal complications. If a second agent is needed beyond metformin, an SGLT-2 inhibitor should be considered especially for patients at high risk of cardiovascular disease or diabetic nephropathy. The combination of metformin+SGLT-2 inhibitors reduces hemoglobin A1c and controls systolic blood pressure better than other combinations, thus SGLT-2 inhibitor use has increased. Unfortunately, as noted in this case, SGLT-2 inhibitors can lead to euglycemic DKA through carbohydrate depletion while inhibiting glucose reabsorption in the kidneys due to its long half-life (~12 hours) during early postoperative diet restriction. This contributes to an overall insulin-deficient state instigating lipolysis and ketoacidosis. During this period of limited oral intake, intravenous carbohydrate supplementation should be considered.

Awareness of complications from common antihyperglycemic medications is essential in the management of surgical patients. Especially in the perioperative period when substantial changes to the antihyperglycemic regimen occur in the setting of diet restriction and the physiological response to an operation (especially a total gastrectomy where nutrient absorption is additionally impaired), consideration of preoperative medications should inform interpretation of postoperative patient progression.