| BackgroundFor patients under cardiac surgery, cardiopulmonary bypass(CPB), the trauma of cardiac surgery itself, ischemia-reperfusion, patients' dysporia, application of ventilator, operative pain, etc, provoke systemic inflammatory response and strong stress responses. Stress response leads to disturbance of general metabolism and endocrine functioning, including abnormal glucose tolerance and stressed hyperglycemia. In addition, hyperglycemia may also induce cell injuries and hydroelectric disturbance through increasing pro-inflammatory cytokine concentrations, hyperpermeability, weaken immunity, making patients more susceptible to infections, and all these will affect prognosis of cardiac operation . Recently, it has been proposed that intensive insulin therapy may markedly improve prognosis of serious patients with diabetes undergoing cardiac surgery. However, data is scarce that pertains to how intensive insulin therapy impacts prognosis of non-diabetes patients undergoing cardiac surgery with CPB,eapecially infants, in mixed surgical/medical ICU conditions. Objective1. To investigate the affects and mechanism of intensive insulin therapy on the systemic inflammatory response to patients including infants undergoing cardiac surgery with cardiopulmonary bypass (CPB).2. To observe the affects of intensive insulin therapy on plasma nitric oxide, endothelin-1 and ICAM-1levels in patients undergoing cardiac surgery with CPB.3. To observe the influences of intensive insulin therapy on the digestival organ functions and prognosis of patients undergoingcardiac surgery with CPB.Methods1. Between October 2006 and May 2007, 200 nondiabetic patients undergoing cardiac surgery in our department were enrolled in a randomized clinical controlled trial. The patients were randomized by using computerized randomization tables, with blinded envelopes opened sequentially by study personnel after participants signed the patient consent form, to receive routine therapy group (control group, n=100) or intensive insulin therapy group (IT group, n=100). Intensive therapy group (IT, n = 100) and received Intensive insulin therapy since the initiation of surgery. The blood glucose in Control group was maintained at 180 ~ 250 mg/dl, whereas the glucose in IT group was at 70 ~ 150 mg/dl. Changes in blood glucose were not controlled with insulin in the control group(Control group). Patients in the control group received the same institutional operative and postoperative care excluding insulin therapy.2. At 7 time points, blood samples were taken for each patient as: after anesthesia induction, at the initiation of CPB, after the termination of CPB, 6 hours after CPB, 12 hours after CPB, 24 hours after CPB and 48 hours after CPB (T1-T7). Plasma IL-1, 6, 10, TNF-αas well as intercellular adhesion molecule levels were determined using commercially available ELISA kits. Myocardium (about 1.0 g) was collected at auricle of right atrium at the initiation and termination of CPB, respectively. Peripheral blood mononuclear cell were also isolated from blood samples for each patient. Expression Nuclear factor-κBp65 and IκB in peripheral blood mononuclear cell, expression of InsRβin in cardiocytes were assayed by Western blot.3. Levels of plasma NO and ET-1 in both groups were respectively measured at the 7 time points. Gastric intramuco-sal pH(pHi), pH and red blood cell of gastric juice and gastrin in blood serum and liver and cardiac functions were measured 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.Results1. A total of 200 nondiabetic patients were enrolled in the present study. And there were no significant differences in general data between IT and control groups. There was a biphasic response of blood glucose levels and insulin levels. In control group, blood glucose level rapidly increased since the initiation of CPB and reached the peak at the termination of CPB. Then it began to decrease. However, blood glucose levels reached the peak once again 24 h after the termination of CPB and then decreased. And blood glucose levels in control group did not reach the preoperative level 48 h after CPB (P < 0.05). Blood glucose levels were reasonably controlled in the intensive insulin therapy group. Levels of blood glucose in IT group were always significantly higher than the corresponding values in control group during the period after the initiation of CPB (P < 0.05 or P < 0.01). An apparently similar biphasic response could be observed for plasma insulin levels in both groups. Plasma insulin levels in both groups rapidly increased since the initiation of CPB and reached the peak after 6h of 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. Contrary to blood glucose, levels of plasma insulin in IT group were always higher than the corresponding values in control 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 did not reach the preoperative level 48 h after CPB in either group (intergroup comparison, P < 0.05). The expressions of InsRβof controlgroup and intensive insulin therapy group 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 control group (P < 0.05), with no differences in InsRβexpression at the initiation of CPB between the two groups. Similarly, NF-κBp65 in PBMCs were increased significantly after the termination of CPB in both groups, with a peak at 6h after CPB, then they decreased, but did not reach the preoperative level 48 h after CPB in either group. NF-κBp65 expression was significantly lower in insulin therapy group than in the routine therapy group after the termination of CPB (p<0.05 or 0.01). IκB protein levels in PBMCs in the insulin therapy group increased significantly at the end of CPB, peaked at 6 h after CPB and declined at 12h after CPB, but did not reach the preoperative level 48 h after CPB. IκB expression was significantly higher in the insulin therapy group than in the routine therapy group at each time point after the termination of CPB (p<0.05 or 0.01).2. In both groups, plasma NO concentration was decreased since the initiation of CPB and reached the peak at the termination of CPB (P < 0.05 compared with that before anesthesia). Then it began to increase and didn't reach to the preoperational level 48 h after the termination of CPB(P < 0.05 compared with that before anesthesia). Plasma NO concentration was significantly higher in the IT group than in control group at each time point after the termination of CPB (p<0.05 or 0.01). In contrast, the plasma ET-1 concentration was increased since the initiation of CPB and reached the peak at the termination of CPB (P < 0.01 compared with that before anesthesia). Then it began to decrease and didin't reached the preoperational level 48 h after termination of CPB. ET concentration was significantly higher in the control group than in IT group at each time point after the termination of CPB (p<0.05 or 0.01).3. After initiation of CPB, pH and pHi in control group began to decrease and reach the wave hollow at 6h after the termination of CPB and then increased, but did not reach the preoperative level 48 h after CPB in either group. pH and pHi was significantly higher in the IT group than in the controlgroup at each time point after the termination of CPB; Red blood cell of gastric juice and plasma gastrin began to increase and reach the peak at 6h after the termination of CPB and then decreased, but did not reach the preoperative level 48 h after CPB in either group. Red blood cell of gastric juice and plasma gastrin was significantly higher in the control group than in the IT group at each time point after the termination of CPB;. 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 were decreased, and there were significant differences between the two groups (all P < 0.05). Compared with Control group, intensive insulin therapy 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.Conclusions 1. Intensive insulin therapy in patients undergoing cardiac surgery with CPB could control blood glucose levels, as well as attenuate the systemic inflammatory response by modifying the expression of pro-inflammatory and anti-inflammatory cytokines.2. Intensive insulin therapy may relieve the changes of CPB-induced NO,ET-1 and ICAM-1 levels during the cardiovascular surgery, which suggests its protective effects on organic function.3. Intesive insulin therapy may significantly improve the damaged liver and gastrointestinal organ function, and shorten the time on ventilator and length of postoperative hospital stay, thus leading to improved prognosis in the patients undergoing cardiac surgery with CPB. |
