Study protocol: The effect of a low-carbohydrate enteral nutrition formula on postoperative hyperglycemia in non-diabetic patients with esophageal cancer: A randomized exploratory phase II trial (ENLICHE study)

Background Postoperative hyperglycemia in diabetic patients is a widely known risk factor for postoperative infectious complications (PICs) after esophagectomy; however, the significance of glycemic control in non-diabetic patients is less clear. In diabetic patients, early postoperative management of esophagectomy favors low-carbohydrate enteral nutrition (EN) over standard EN to suppress the risk of glycemic spike. Our single-center, randomized phase II trial seeks to test the hypothesis that low-carbohydrate EN can suppress hyperglycemia in non-diabetic patients who undergo esophagectomy. Herewith we present the study protocol. Methods A total of 50 patients will be enrolled and randomly assigned (1:1 ratio) to standard or low-carbohydrate EN. Randomization will be stratified by operation time (>= 560 vs. < 560 min) and HbA1c (6.0-6.4% vs. < 6.0%). Both EN formula will be fed according to the following protocol: 400 mL/24 h on postoperative day (POD)-1; 800 mL on POD-2; 1200 mL on POD-3 and 1600 mL from POD-4 to POD-8. On POD-9, oral food intake will be initiated. A continuous glucose monitoring (CGM) device will be used to monitor blood glucose levels from POD-1 to -8. The primary outcome is the mean time-in-range (TIR) across the 48 h from POD-1 to -2. TIR is defined as the percentage-time that blood glucose remains within the targeted range of 70-180 mg/dL. The primary analysis will calculate the least squares mean difference in TIR over the 48 h (POD-1 to -2) between the two groups, with p-values calculated to test the null hypothesis that the mean difference between the groups is zero. The secondary outcomes will be as follows: 1) the incidence of PICs and/or other adverse events within 30 days after esophagectomy or during the hospital stay; 2) the number of cases requiring any dose alteration in EN formula during monitoring; 3) the number of cases requiring interventions for hyperglycemia or hypoglycemia; 4) the rates in change of nutritional indicators, such as serum albumin, prealbumin, and total protein levels, during the post-surgical hospital stay (vs. those values on the day of admission); and 5) the following CGM indices in relation to the incidence rate of PICs within 30 days after esophagectomy: the mean values for time-above-range (TAR), area under the curve (AUC), and TIR for each POD or from POD-1 to -8. TAR is defined as the percentage of time of a patient is recorded as having hyperglycemia (>blood glucose level of 180 mg/dL), and is indicative of the frequency and duration of hyperglycemia. AUC, which identifies periods of hyperglycemia and provides a comprehensive picture of glucose variability and control in diabetes management, is defined as the area under the curve over blood glucose level of 180 mg/dL on CGM monitoring. Discussion This study is the first to investigate the impact of a low-carbohydrate EN formula on hyperglycemic control during perioperative nutritional management of esophageal cancer. These results will help to outline whether glycemic control should be also considered for non-diabetic patients during hospital care. Trial registration This trial has been registered in the Japanese Registry of Clinical Trials (jRCTs031240081).