Research Design and Methods
Study Design
We conducted a parallel-group, randomized, controlled trial involving adult surgical patients admitted to the ICU of our hospital. Patients were randomized at the time of the starting operation. Also, blood glucose control of recruited patients was begun from the start of surgery. All eligible patients were those surgically treated for hepato-biliary-pancreatic diseases and admitted to the surgical ICU overnight until postoperative day 1 after hepatic and/or pancreatic resection to control postoperative blood glucose concentration levels by using closed-loop glycemic control system. Patient exclusion criteria included a body weight loss >10% during the 6 months prior to surgery, the presence of distant metastases, or seriously impaired function of vital organs due to respiratory, renal, or heart disease. Patients were informed of the purpose and details of the study, and written consent was obtained from them prior to enrolment. The study was approved by the local ethics committee at the Kochi Medical School and carried out in accordance with the Declaration of Helsinki. All studies were performed at the Kochi Medical School between August 2008 and August 2012.
A complete physical examination was undertaken and clinical histories were obtained from all patients. Laboratory tests included the measurement of serum levels of albumin, total bilirubin, total cholesterol, and alanine and aspartate aminotransferases, as well as peripheral blood cell counts and prothrombin time. The patients' clinical history included details of glucose metabolism, including medication for the treatment of diabetes, fasting blood glucose level, and the monitoring of hemoglobin A1c (HbA1c) levels in plasma. Of all patients included in this study, diabetes mellitus (DM) status was checked by diabetologist, and DM were all type 2. Operation-related parameters of liver and pancreatic surgery were also evaluated.
Postoperative Nutrition in Surgical ICU and Glycemic Control
In our study, all patients were given parenteral nutrition (PN) postsurgery just after bring admitted to the surgical ICU. The total caloric requirement was calculated according to the Harris-Benedict equation. All of the patients who were assigned to this study received intravenous PN and 20% intravenous fat emulsions and 25% glucose solution, which included an adequate amount of protein, glucose, vitamins, minerals, and trace element such as zinc, iron, copper, manganese, and iodine (rate of glucose administration <5 mg/kg/min). Enteral feeding was attempted as soon as possible when the patients were hemodynamically stable. The amount of PN was calculated daily as the difference between the total energy intake that was effectively delivered by enteral nutrition and the calculated caloric goal when postoperative oral intake would be restarted.
The Nikkiso Company (Tokyo, Japan) developed the closed-loop glycemic control system in 1984. The closed-loop glycemic control system is a reliable and accurate device that measures blood glucose concentration compared with the ABL 800FLEX machine (Radiometer Medical ApS, Brønshøj, Denmark) recommended by the National Committee for Clinical Laboratory. The closed-loop glycemic control system is composed of a glucose sensor, which performs glucose detection/monitoring, and pumps for infusing the appropriate amount of insulin or glucose. The insulin and glucose pumps are computer regulated based on a target blood glucose value predefined prior to the system initiation. Peripheral blood for glucose monitoring was sampled continuously at 2 mL/h during at least the first postoperative 18 h in the surgical ICU. Furthermore, the closed-loop artificial pancreas system was used to evaluate the patient's insulin requirements.
Study participants were randomly assigned to glucose control with one of two target ranges: the intensive (i.e., tight) control target of 4.4–6.1 mmol/L (intensive IT group), based on that used in previous studies, or an intermediate control target of 7.7–10.0 mmol/L (intermediate IT group), based on that used in a previous study. Blood glucose concentration (intermediate vs. intensive) was controlled by a closed-loop glycemic control system from the start of surgery, and either intermediate or intensive IT was performed during the operation. After patients were removed from the closed-loop glycemic control system at postoperative day 1, blood glucose levels were routinely checked by nursing staff and were controlled by the subcutaneous injection of regular human insulin every 2 h: the dose was determined by the commonly used sliding scale, and the target blood glucose level to avoid hypoglycemia was 8.3–11.1 mmol/L.
Data Collection
Baseline demographic and clinical characteristics of the patients were well matched between the two study groups ( Table 1 ). Local study coordinators at our institution collected the data; source data were verified by study monitors from our coordinating center at the department of biostatistics. Daily records were kept regarding all intensive care treatments and surgical procedures, new bacterial or fungal infections, the results of blood and urine chemical analyses and hematologic studies, and markers of inflammation. Also recorded were the total energy intake delivered daily by means of enteral and PN, interruptions of delivery of enteral nutrition, and feeding-related complications. In addition, whenever practically feasible, the functional status of patients before hospital discharge was quantified.
Outcome Measures
Safety End Points. Safety end points included vital status (the rates of death in the ICU and the hospital) and especially the rates of hypoglycemia. Hypoglycemia that was resistant to parenteral glucose administration during the intervention window was considered to be a serious adverse event. And a blood glucose level of ≤40 mg/dL was considered a serious adverse event.
Primary Efficacy End Point. The primary end point of this study was to determine whether the incidence of SSI is reduced by perioperative intensive IT. The Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance has developed standardized surveillance criteria for defining SSI. According to these criteria, the infection control team evaluated whether postoperative SSI in patients who underwent liver and pancreatic resection had occurred.
Secondary Efficacy End Point. The secondary end point was to evaluate the duration of hospital stay in each patient group. To reduce bias that might result from variability in the availability of beds on regular wards, we defined the time to discharge from our institute as the time by which patients were ready for hospital discharge, according to the suggestion by trained expert staff of the Department of Diagnostic Medicine at our institute and nutritional support team blindly.
Statistical Analysis
Given that the primary outcome of the study is SSI, we aim to detect a clinically relevant difference in 5% of SSI incidence concretely from 10 to 5% of patients during hospitalization. This difference is in accordance with previous reports and is considered clinically significant. Consequently, the required number to detect this difference with 80% is 219 patients per group. Allowing for attrition of 10% of cases with SSI, we have to recruit 438 patients and randomly assign 219 patients into the intensive IT group and 219 patients into the intermediate IT group (Fisher exact test, two-sided, intention-to-treat basis). Because of the probably rate of dropout that is estimated, ~10% of the patients initially enrolled into the study, additional patients were randomized, resulting in a total subject number of 482 across the two groups. Continuous variables are presented as the mean ± SD. Dichotomous variables are presented as both number and percentage values. P < 0.05 was considered significant. Data were analyzed using the Student t test (two-tailed), with dichotomous variables analyzed by the χ test (two-tailed) or Fisher exact test (two-tailed), as appropriate.
Subgroup analyses on intent to treat for the primary outcome were based on an unadjusted test of interaction in a logistic model to evaluate which patients would benefit from intensive IT during the surgical ICU to reduce the incidence of postoperative SSI. All analyses were performed using SPSS (SPSS, Chicago, IL). The data were analyzed by an independent statistician of the Department of Biostatistics (Kochi University). The analyses were reviewed by the independent data and safety-monitoring committee, which was charged with recommending that the trial be stopped if there was evidence beyond a reasonable doubt of a difference in the rate of postoperative complications, such as hypoglycemia, hospital death, bile leakage from liver stump after hepatic resection, and pancreatic fistula after pancreatic resection, from any cause between the two treatment groups.