| BackgroundHyperglycemia is a common phenomenon in patients undergoing cardiac surgery, which was previously thought to be beneficial and thus not treated. However, recent studies have demonstrated that tight glycemic control (TGC) may be effective to prevent the morbidity and reduce the mortality in critically ill patients, especially diabetic patients. Unfortunately, there are few reports on the effects of TGC on the prognosis of nondiabetic patients undergoing valve replacement under cardiopulmonary bypass (CPB). Moreover, the mechanism responsible for the improved prognosis by TGC is not well established.Objective1. To observe the effects of tight glycemic control (TGC) on the organ function and prognosis of patients undergoing valve replacement under cardiopulmonary bypass (CPB).2. To investigate the effects of intensive insulin therapy on plasma nitric oxide (NO) and endothelin-1 (ET-1) levels in patients undergoing valve replacement under CPB.3. To study the effects of intensive insulin therapy on the expression or activation of proteins such as InsRβ, PI3Kp85, Akt and pAkt in myocardium at the initiation and termination of CPB, respectively.Methods1. The nondiabetic patients undergoing valve replacement in our department between October 2006 and May 2007 were selected and assigned to intensive therapy group (IT, n = 245) and received tight glycemic control (TGC) since the initiation of surgery. And those nondiabetic patients undergoing valve replacement but without tight glycemic control between December 2005 and September 2006 were assigned to routine therapy group (RT, n = 265) as the controls. The blood glucose in RT group was maintained at 180 ~ 250 mg/dl, whereas the glucose in IT group was at 70 ~ 150 mg/dl. Liver and renal functions were measured and heart function assessment was performed after the surgery. Moreover, the time on ventilator, length of stay in ICU, length of postoperative hospital stay, in-hospital infection rate and mortality were recorded.2. A total of 36 patients were randomly assigned to routine therapy (RT) group and intensive insulin therapy (IT) group, with 18 patients in each group. The blood glucose levels during surgery were maintained at 70 to 180 mg/dl and those after surgery at 70 to 110 mg/dl in IT group, whereas the patients in RT group didn't receive the manipulation of controlling glucose levels during surgery and maintained below 250 mg/dl after surgery. Levels of plasma NO and ET-1 in both groups were respectively measured before surgical anesthesia, at the initiation of CPB, and 0 h, 4 h, 12 h, 24 h and 48 h after the termination of CPB.3. Sixteen patients were randomly assigned to routine therapy (RT) group and intensive insulin therapy (IT) group, with eight in each group. The intensive insulin therapy program and the targeted glycose levels were similar to those in Trial 2. Levels of plasma insulin in both groups were measured before surgical anesthesia, at the initiation of CPB, and 0 h, 4 h, 12 h, 24 h and 48 h after the termination of CPB, respectively. Myocardium (about 0.5 g) was collected at auricle of right atrium at the initiation and termination of CPB, respectively; and the expression or activation of InsRβ, PI3K-p85, Akt and pAkt were measured by Western blot.Results1. A total of 510 nondiabetic patients were enrolled into the present study and there were no significant differences in general data between IT and RT groups. After valve replacement, the numbers of patients with the peak ALT higher than 80 IU/L, peak AST higher than 80 IU/L, peak creatinine higher than 221μmol/L and peak urea nitrogen higher than 19.3 mmol/L were decreased, and there were significant differences between the two groups (all P < 0.05). Compared with RT group, tight glycemic control markedly shorten the time on ventilator and length of postoperative hospital stay (both P < 0.05). Although the length of stay in ICU, in-hospital infection rate and mortality were decreased, the differences in these measures between the two groups didn't reach the significance.2. In RT group, plasma NO concentration was decreased since the initiation of CPB (from 68.2±16.3μmol/L to 67.9±8.4μmol/L) and reached the trough at the termination of CPB (60.0±10.2μmol/L, P < 0.05 compared with that before anesthesia). Then it began to increase and neared to the preoperational level 48 h after the termination of CPB. In contrast, the plasma ET-1 concentration was increased since the initiation of CPB (from 62.2±10.2 ng/L to 68.3±10.8 ng/L) and reached the peak at the termination of CPB (112.5±18.6 ng/L, P < 0.01 compared with that before anesthesia). Then it began to decrease and reached the preoperational level 24 h after termination of CPB. In IT group, however, the changes of NO and ET-1 levels at different time points during CPB and thereafter didn′t reach the significance compared to those before anesthesia.3. Plasma insulin levels in both groups changed smoothly during the induction of anesthesia, rapidly increased since the initiation of CPB and reached the peak at the termination of CPB. Then it began to decrease. However, plasma insulin levels reached the peak once again 12 h after the termination of CPB and then decreased. Levels of plasma insulin in IT group were always higher than the corresponding values in RT group during the period between the initiation and termination of CPB (P < 0.05 or P < 0.01). And plasma insulin levels in both groups neared to preoperational level 24 h after termination of CPB (intergroup comparison, P > 0.05). The expressions of InsRβof routine therapy (RT) and intensive insulin therapy (IT) at the initiation of CPB were significantly higher than those at termination of CPB (P < 0.05 or P < 0.01, respectively), and InsRβexpression of IT group at termination of CPB was significantly higher than that of RT group (P < 0.05) , with no differences in InsRβexpression at the initiation of CPB between the two groups. Similarly, the expressions of PI3K-p85 of both groups at the initiation of CPB were significantly higher than those at the termination of CPB (P < 0.01), and the PI3K-p85 expression of IT group at the termination of CPB was significantly higher than that of RT group (P < 0.05), with no differences in PI3K-p85 expression at the initiation of CPB between the two groups. The expressions of Akt of both groups at the termination of CPB were significantly higher than those at the initiation of CPB (P < 0.05 or P < 0.01, respectively), and Akt expression of IT group at the termination of CPB was significantly higher than that of RT group (P < 0.05). In contrast, the expressions of pAkt of the two groups at the termination of CPB were significantly lower than those at the initiation of CPB (P < 0.05 or P < 0.01, respectively), however, the pAkt expression of IT group at the termination of CPB was significantly higher than that of RT group at the same time point (P < 0.05).Conclusions1. Tight glycemic control may significantly improve the damaged liver and renal function, and shorten the time on ventilator and length of postoperative hospital stay, thus leading to improved prognosis in the patients undergoing valve replacement under CPB.2. Intensive insulin therapy may relieve the changes of CPB-induced NO and ET-1 levels during the cardiovascular surgery, which suggests its protective effects on cardiovascular function.3. Intesive insulin therapy may elevate the expression or activation of proteins including InsRβ, PI3K-p85, Akt and pAkt, thus leading to improved prognosis for patients undergoing cardiac surgery via the activation of PI3K-Akt/PKB pathway. |
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