Intensive vs Intermediate Glucose Control in SICU Patients
Participants were recruited and had follow-up during the period from August 2008 through August 2012; 502 were randomly assigned to one of the two treatment groups: 252 to intermediate glucose control and 250 to intensive glucose control (Figure 1). Study treatment was discontinued prematurely in 27 of 252 patients (10.7%) in the intermediate IT group and 28 of 250 patients (11.2%) in the intensive IT group. There were five in-hospital deaths in the intermediate IT group (mortality rate 1%). Four patients underwent hepatectomy for hepatocellular carcinoma. Two of four hepatectomized patients, who were suffering from severe liver cirrhosis, fell into hepatic failure owing to limited liver function of the remnant liver and died after surgery (42 days and 47 days after liver resection for hepatocellular carcinoma). One patient of hepatectomized patients, who had a gastrointestinal bleeding after liver resection, developed sequential hepatic failure and died 63 days after surgery. Another hepatectomized patient, who had an accidentally dissecting aneurysm of aorta, died 2 days after surgery. The remaining patient, who had a 4-cm-sized adenocarcinoma located in the head of the pancreas, with insufficiency of pancreato-enteric anastomosis, was relaparotomized for diffuse peritonitis 27 days after the initial pancreatico-duodenectomy, ran a fatal course due to subsequent intra-abdominal septic complications, and died on the 91st postoperative day. Reasons for discontinuation were withdrawal because of five in-hospital deaths in the intermediate IT group or closed-loop glycemic control system errors in patients who underwent IT during the surgical ICU for 22 of the 252 patients (8.7%) assigned to intermediate IT and 28 of the 250 patients (11.2%) assigned to intensive IT; thus, study data were available for 225 and 222 patients, respectively. Of the 50 patients for whom study data were unavailable, we could recognize 42 cases (8.5%) of an insufficiency for blood sampling from peripheral vessels and 8 cases (1.6%) of trouble with the glucose sensor of the closed-loop glycemic control system itself.
(Enlarge Image)
Figure 1.
Assessment, randomization, and follow-up of the study patients. Patient excluded for a number of medical reasons, including 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. Study treatment was discontinued prematurely in 27 of 252 patients in the intermediate IT group and 28 of 250 patients in the intensive IT group. Study data were available for 225 in the intermediate IT group and 222 patients in the intensive IT group, respectively. BS, target levels of blood glucose concentration.
The baseline characteristics of the treatment groups were similar ( Table 1 ). The mean ± SD age was 66.4 ± 10.4 and 66.7 ± 10.1 years in the intermediate IT group and the intensive IT group, respectively; the percentage of male patients 67.1% and 64.0%; and the mean BMI score, 23.1 ± 3.4 and 23.3 ± 3.6. Also, both preoperative liver and renal function were similar in the two groups. Furthermore, the presence of a previous medical history for DM was equally distributed between the two groups. In the current study, because all of the surgeries were scheduled procedures, DM status in patients who were recruited in our study was preoperatively well controlled by the diabetologist; the mean HbA1c levels were 5.6 ± 1.1% in the intermediate IT group and 5.6 ± 0.9% in the intensive IT group, respectively.
All patients underwent either hepatectomy or pancreatectomy consisting of curative resection of both hepatic and pancreatic tissue for the removal of a tumor. There was no significant predisposition to these operative procedures between the two groups; liver surgery for 142 cases in intermediate IT group and 148 cases in intensive IT group and pancreatic surgery for 83 cases in intermediate IT group and 74 cases in intensive IT group, respectively ( Table 2 ). The operation time and estimated volume of blood loss did not differ significantly between the two groups (operation time 36.2 ± 144.2 min in intermediate IT group and 337.2 ± 142.1 min in intensive IT group; estimated blood loss volume 768.7 ± 764.5 mL in intermediate IT group and 762.1 ± 720.0 mL in intensive IT group) ( Table 2 ).
All patients received PN just after being admitted to the surgical ICU. The mean daily amount of calories administered was 1,479 ± 207 kcal in the intermediate IT group and 1,465 ± 216 kcal in the intensive IT group, respectively. Enteral feeding was attempted as soon as possible when the patients were hemodynamically stable. Postoperative blood glucose levels in the intermediate and intensive IT groups during the first 18 h after surgery are shown in Figure 2A. The average blood glucose levels in patients from the intermediate IT group were controlled to the target zone (7.7–10.0 mmol/L). The percentage in blood glucose target at intermediate glucose control by a closed-loop system during surgical ICU was 96.8% (Figure 2A), although blood glucose levels gradually increased during the first 6 h after the hepatectomy and pancreatectomy and reached a plateau of ~13.8 mmol/L between 4 and 8 h by the ordinary blood glucose control methods by using sliding scale and then the concentrations gradually decreased toward 8.3 mmol/L by 18 h after surgery in our previous studies. Also, the average blood glucose levels in patients from the intensive IT group were well controlled to the target zone (4.4–6.1 mmol/L) but did not decrease to hypoglycemic levels, and the percentage within the blood glucose target for intensive glucose control by a closed-loop system during surgical ICU was 85.8% (Figure 2A). Patients undergoing intensive glucose control received a larger mean insulin dose (101 ± 88 units [range 8–390] in the surgical ICU vs. 77 ± 72 units [range 0–355] for the intermediate IT group) for 18 h after the hepatic resection (Figure 2B). This represents a significant difference in total insulin consumption between the two groups (P = 0.015).
(Enlarge Image)
Figure 2.
Postoperative blood glucose levels and total insulin requirement. A: Postoperative blood glucose levels using the closed-loop glycemic control system in the intermediate IT (solid line) and intensive IT (dashed line) groups. The percentage of subjects within the blood glucose target range for intermediate glucose control by a closed-loop system during surgical ICU was 96.8%, and also, the average blood glucose levels in patients from the intensive IT group were well controlled to the target zone (80–110 mg/dL) but did not decrease to hypoglycemic levels, and the percentage within the blood glucose target range for intensive glucose control by a closed-loop system during surgical ICU was 85.8%. B: Total insulin usage with the closed-loop glycemic control system in the intermediate and intensive IT groups. Patients undergoing intensive glucose control received a larger mean insulin dose (101 ± 88 units [range 8–390] in the surgical ICU vs. 77 ± 72 [0–355] with the intermediate IT group) for 18 h after the hepatic resection (P = 0.015).
The study groups had similar rates of death in the ICU and the hospital. However, mortality occurred solely in the intermediate IT group, although postoperative complications occurred in these patients after surgery. This included four patients in postoperative liver failure after hepatic surgery and one patient in postoperative acute respiratory distress syndrome after pancreatic surgery. No patients in either group became hypoglycemic (<2.2 mmol/L) during their stay in the surgical ICU or during the hospitalization.
The short-term outcomes of patients who underwent hepatic and pancreatic resection are detailed in Table 2 . With respect to postoperative characteristics, when blood glucose levels were tightly controlled using the closed-loop glycemic control system, the incidence of SSI in the intensive IT group was significantly lower than that in the intermediate IT group (P = 0.028). There was no readmission of patients who had postoperative SSI in the current study.
Postoperative morbidities were examined by abdominal ultrasonography or computed tomography. There was no significant difference between the two groups in the incidence of bile leakage after liver resection. Interestingly, the incidence of postoperative pancreatic fistula formation after pancreatic surgery in the intensive IT group was significantly lower than that in the intermediate IT group (P = 0.040). It is of note that patients in the intensive IT group required a significantly shorter hospitalization than patients in the intermediate IT group (P = 0.017). There was one operation-related readmission of patients in the intensive IT group due to the abdominal abscess formation for delayed pancreatic fistula in the current study.
In postsubgroup intent-to-treat analyses, we evaluated association between the incidence of postoperative SSI and perioperative predictable factors. Three parameters were identified as independent markers for the occurrence of postoperative SSI by the Spearman correlation analysis: 1) elderly patients (>65 years old) (P = 0.039), preoperative predictable factor; 2) patients with DM (P = 0.036), preoperative predictable factor; and 3) the presence of pancreatic fistula formation after pancreatic resection (P = 0.047), postoperative factor after the surgical management. Considering DM status, which was a preoperatively predictable factor, the rate of SSI was lower in patients without DM (3.7%) than in patients with DM (19.0%, P < 0.001).
Results
Study Participants
Participants were recruited and had follow-up during the period from August 2008 through August 2012; 502 were randomly assigned to one of the two treatment groups: 252 to intermediate glucose control and 250 to intensive glucose control (Figure 1). Study treatment was discontinued prematurely in 27 of 252 patients (10.7%) in the intermediate IT group and 28 of 250 patients (11.2%) in the intensive IT group. There were five in-hospital deaths in the intermediate IT group (mortality rate 1%). Four patients underwent hepatectomy for hepatocellular carcinoma. Two of four hepatectomized patients, who were suffering from severe liver cirrhosis, fell into hepatic failure owing to limited liver function of the remnant liver and died after surgery (42 days and 47 days after liver resection for hepatocellular carcinoma). One patient of hepatectomized patients, who had a gastrointestinal bleeding after liver resection, developed sequential hepatic failure and died 63 days after surgery. Another hepatectomized patient, who had an accidentally dissecting aneurysm of aorta, died 2 days after surgery. The remaining patient, who had a 4-cm-sized adenocarcinoma located in the head of the pancreas, with insufficiency of pancreato-enteric anastomosis, was relaparotomized for diffuse peritonitis 27 days after the initial pancreatico-duodenectomy, ran a fatal course due to subsequent intra-abdominal septic complications, and died on the 91st postoperative day. Reasons for discontinuation were withdrawal because of five in-hospital deaths in the intermediate IT group or closed-loop glycemic control system errors in patients who underwent IT during the surgical ICU for 22 of the 252 patients (8.7%) assigned to intermediate IT and 28 of the 250 patients (11.2%) assigned to intensive IT; thus, study data were available for 225 and 222 patients, respectively. Of the 50 patients for whom study data were unavailable, we could recognize 42 cases (8.5%) of an insufficiency for blood sampling from peripheral vessels and 8 cases (1.6%) of trouble with the glucose sensor of the closed-loop glycemic control system itself.
(Enlarge Image)
Figure 1.
Assessment, randomization, and follow-up of the study patients. Patient excluded for a number of medical reasons, including 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. Study treatment was discontinued prematurely in 27 of 252 patients in the intermediate IT group and 28 of 250 patients in the intensive IT group. Study data were available for 225 in the intermediate IT group and 222 patients in the intensive IT group, respectively. BS, target levels of blood glucose concentration.
The baseline characteristics of the treatment groups were similar ( Table 1 ). The mean ± SD age was 66.4 ± 10.4 and 66.7 ± 10.1 years in the intermediate IT group and the intensive IT group, respectively; the percentage of male patients 67.1% and 64.0%; and the mean BMI score, 23.1 ± 3.4 and 23.3 ± 3.6. Also, both preoperative liver and renal function were similar in the two groups. Furthermore, the presence of a previous medical history for DM was equally distributed between the two groups. In the current study, because all of the surgeries were scheduled procedures, DM status in patients who were recruited in our study was preoperatively well controlled by the diabetologist; the mean HbA1c levels were 5.6 ± 1.1% in the intermediate IT group and 5.6 ± 0.9% in the intensive IT group, respectively.
All patients underwent either hepatectomy or pancreatectomy consisting of curative resection of both hepatic and pancreatic tissue for the removal of a tumor. There was no significant predisposition to these operative procedures between the two groups; liver surgery for 142 cases in intermediate IT group and 148 cases in intensive IT group and pancreatic surgery for 83 cases in intermediate IT group and 74 cases in intensive IT group, respectively ( Table 2 ). The operation time and estimated volume of blood loss did not differ significantly between the two groups (operation time 36.2 ± 144.2 min in intermediate IT group and 337.2 ± 142.1 min in intensive IT group; estimated blood loss volume 768.7 ± 764.5 mL in intermediate IT group and 762.1 ± 720.0 mL in intensive IT group) ( Table 2 ).
Postoperative Blood Glucose Levels
All patients received PN just after being admitted to the surgical ICU. The mean daily amount of calories administered was 1,479 ± 207 kcal in the intermediate IT group and 1,465 ± 216 kcal in the intensive IT group, respectively. Enteral feeding was attempted as soon as possible when the patients were hemodynamically stable. Postoperative blood glucose levels in the intermediate and intensive IT groups during the first 18 h after surgery are shown in Figure 2A. The average blood glucose levels in patients from the intermediate IT group were controlled to the target zone (7.7–10.0 mmol/L). The percentage in blood glucose target at intermediate glucose control by a closed-loop system during surgical ICU was 96.8% (Figure 2A), although blood glucose levels gradually increased during the first 6 h after the hepatectomy and pancreatectomy and reached a plateau of ~13.8 mmol/L between 4 and 8 h by the ordinary blood glucose control methods by using sliding scale and then the concentrations gradually decreased toward 8.3 mmol/L by 18 h after surgery in our previous studies. Also, the average blood glucose levels in patients from the intensive IT group were well controlled to the target zone (4.4–6.1 mmol/L) but did not decrease to hypoglycemic levels, and the percentage within the blood glucose target for intensive glucose control by a closed-loop system during surgical ICU was 85.8% (Figure 2A). Patients undergoing intensive glucose control received a larger mean insulin dose (101 ± 88 units [range 8–390] in the surgical ICU vs. 77 ± 72 units [range 0–355] for the intermediate IT group) for 18 h after the hepatic resection (Figure 2B). This represents a significant difference in total insulin consumption between the two groups (P = 0.015).
(Enlarge Image)
Figure 2.
Postoperative blood glucose levels and total insulin requirement. A: Postoperative blood glucose levels using the closed-loop glycemic control system in the intermediate IT (solid line) and intensive IT (dashed line) groups. The percentage of subjects within the blood glucose target range for intermediate glucose control by a closed-loop system during surgical ICU was 96.8%, and also, the average blood glucose levels in patients from the intensive IT group were well controlled to the target zone (80–110 mg/dL) but did not decrease to hypoglycemic levels, and the percentage within the blood glucose target range for intensive glucose control by a closed-loop system during surgical ICU was 85.8%. B: Total insulin usage with the closed-loop glycemic control system in the intermediate and intensive IT groups. Patients undergoing intensive glucose control received a larger mean insulin dose (101 ± 88 units [range 8–390] in the surgical ICU vs. 77 ± 72 [0–355] with the intermediate IT group) for 18 h after the hepatic resection (P = 0.015).
Safety Outcomes
The study groups had similar rates of death in the ICU and the hospital. However, mortality occurred solely in the intermediate IT group, although postoperative complications occurred in these patients after surgery. This included four patients in postoperative liver failure after hepatic surgery and one patient in postoperative acute respiratory distress syndrome after pancreatic surgery. No patients in either group became hypoglycemic (<2.2 mmol/L) during their stay in the surgical ICU or during the hospitalization.
Primary Outcome
The short-term outcomes of patients who underwent hepatic and pancreatic resection are detailed in Table 2 . With respect to postoperative characteristics, when blood glucose levels were tightly controlled using the closed-loop glycemic control system, the incidence of SSI in the intensive IT group was significantly lower than that in the intermediate IT group (P = 0.028). There was no readmission of patients who had postoperative SSI in the current study.
Secondary Outcome
Postoperative morbidities were examined by abdominal ultrasonography or computed tomography. There was no significant difference between the two groups in the incidence of bile leakage after liver resection. Interestingly, the incidence of postoperative pancreatic fistula formation after pancreatic surgery in the intensive IT group was significantly lower than that in the intermediate IT group (P = 0.040). It is of note that patients in the intensive IT group required a significantly shorter hospitalization than patients in the intermediate IT group (P = 0.017). There was one operation-related readmission of patients in the intensive IT group due to the abdominal abscess formation for delayed pancreatic fistula in the current study.
Subgroup Analysis
In postsubgroup intent-to-treat analyses, we evaluated association between the incidence of postoperative SSI and perioperative predictable factors. Three parameters were identified as independent markers for the occurrence of postoperative SSI by the Spearman correlation analysis: 1) elderly patients (>65 years old) (P = 0.039), preoperative predictable factor; 2) patients with DM (P = 0.036), preoperative predictable factor; and 3) the presence of pancreatic fistula formation after pancreatic resection (P = 0.047), postoperative factor after the surgical management. Considering DM status, which was a preoperatively predictable factor, the rate of SSI was lower in patients without DM (3.7%) than in patients with DM (19.0%, P < 0.001).
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