Effects And The Mechanisms Of Methylprednisolone On Pulmonary Endothelial Function, Alveolar-capillary Permeability And Clinical Outcomes After Hypothermic Cardiopulmonary Bypass

Objectives To investigate if Methylprednisolone (MP) could attenuate inflammatory responses to hypothermic cardiopulmonary bypass (CPB) and improve pulmonary endothelial function and alveolar-capillary permeability. Methods Fifteen dogs were randomly divided into three groups. Group A acted as the control group without CPB; Group B and Group C were subjected to cardiopulmonary bypass and crossclamping the aorta for 90 minutes. After weaning from cardiopulmonary bypass, they were allowed to survive till 90 min. after aortic declamping. MP (Group C) or saline (Group B) was injected intravenously before surgery. Intraoperative and postoperative hemodynamic studies and lung parameters were recorded. Plasma levels of IL-1 β, TNF-α, IL-6, IL-8, IL-10, MMP-9 and Hct, colloid osmotic pressure (COP) and blood glucose (BG) were measured at the following time points: before MP or saline was administered, aortic declamping, 30 min. and 90 min. after aortic declamping. Immediately after the animals were killed, pulmonary arterial rings and the left lungs were obtained from 15 dogs. Pulmonary vascular rings were mounted in organ chamber for assessment of endothelial function with endothelium-dependent (acetylcholine) or non-endothelium-dependent (nitroglycerin) studies. The left lungs were mounted in isolated perfused lung chambers for filtration coefficient (Kf) assessment. Results After cardiopulmonary bypass, MPAP was significantly increased related to pre-CPB measures in Group B. Pulmonary vascular resistance (PVR) had a rising trend in two groups but had no statistical significance. Compared with Group B, there was a lower PVR in Group C after aortic declamping. Cardiac output (CO) was also increased in two groups after CPB (P<0.05 and 0.01, respectively). Related to preoperative measures, there was a statistically significant increase in alveolar-arterial oxygen difference (P_A-aDO₂) at 90 min. after declamping in two groups, but no differences were found between groups. Compared with Group B, there was a higher oxygenation index (PaO₂/FiO₂) in GroupC after aortic declamping. After CPB there was a significant elevation in plasma levels of IL-ip, TNF-oc, IL-6, IL-8 and IL-10. Compared with those in Group B, MP treatments were associated with lower plasma IL-ip, TNF-cc, IL-6, IL-8 and increased IL-10. The concentrations of MMP-9 and BG were also significantly increased after CPB, but there were a lower MMP-9 and a higher BG levels in Group C. Similar maximal contraction to norepinephrine was observed in three groups of vascular rings. Maximal relaxation response to acetylcholine was reduced after bypass to 50% of control values (P<0.01). Treatments with MP significantly improved the relaxation from 31% to 48% (P<0.01). Maximal relaxation response to nitroglycerin was similar in three groups. From isolated lung study, we found statistically significant changes in Kf between groups. In addition, statistically significant positive correlation was found between postbypass peak MMP-9 levels and lung Kf (P<0.05), and statistically significant negative correlation was found between MMP-9 and postbypass oxygenation indices. Conclusions (1) Hypothermic CPB could induce a systemic inflammatory response syndrome, increase blood levels of various cytokines and neutrophil proteases, cause pulmonary endothelial dysfunction, and increase alveolar-capillary permeability. (2) lOmg/kg MP could effectively attenuate inflammatory responses to CPB, alter the balance of proinflammatory and anti-inflammatory mediators, reduce the release of cytokines and neutrophil proteases, improve pulmonary endothelial function and alveolar-capillary permeability. (3) The protective effects of MP maybe partially attribute to the reducing of MMP-9 release induced by MP treatments.PartHEffects of Methylprednisolone on Fluid Balance and Clinical Outcomes after Hypothermic Cardiopulmonary BypassObjectives To investigate whether lOmg/kg MP could effectively attenuate inflammatory responses to hypothermic CPB, improve perioperative fluid balances, enhance postoperative cardiovascular stability, and beneficially affect clinicaloutcomes. Methods Thirty-two adult patients undergoing elective single or dual valves repair or replacement with moderate hypothermic cardiopulmonary bypass were included in this study. Patients of the treatment group (Group MP) received lOmg/kg MP after induction of anesthesia, and patients of the control group (Group NS) were administered 10ml normal saline at the same time. Anesthetic managements, extracorporeal circulation techniques and postoperative treatments were standardized according to our clinical routines. In addition to various hemodynamic and pulmonary measurements, tracheal extubation time, length of ICU stay and hospital stay, postoperative complications and treatments were recorded. Plasma levels of IL-lp, TNF-a, IL-6, IL-8, NE, MMP-9 and Hct, COP, BG were measured at the following time points: before the induction of anesthesia, 10 minutes after sternotomy, aortic declamping, 10 minutes after protamine injection and 1, 6, 20 hours after the end of surgery. Responses of pulmonary vascular to acetylcholine (Ach) were measured after induction of anesthesia and at the end of surgery, respectively. The reactivity was calculated from PVRI measured before the start of an infusion of Ach and PVRI measured after the infusion. Detailed assessments of the net balance of crystalloids, colloids and total fluid were performed during the study. Results One patient in Group NS was omitted from statistical analysis because of reoperation 2 hours after surgery, so results were presented for 15 patients in Group NS and 16 patients in Group MP. There were no differences between groups regarding demographic characteristics, cross-clamp times, duration of CPB and intraoperative blood loss. Related to patients in Group NS, patients receiving MP exhibited significantly increased CO and CI, significantly decreased MAP and SVR during the immediate postbypass period. Both groups exhibited significant increases in P(A-a)DO2 (PO.05) after CPB, with no differences between groups. Compared with Group NS, there was a higher PaO2/FiO2 in Group MP after aortic declamping. After bypass there was a significant elevation in plasma levels of IL-ip, TNF-a, IL-6, and IL-8. Compared with those in Group NS, MP treatments were associated with lower plasma cytokines. The concentrations of MMP-9 and NE were also significantly increased after CPB. The levels of MMP-9 increased by threefold and twofold, respectively, in two groups when cross-clamp releasing, and both returned within normal limits within 6 hours after surgery. Plasma concentrations of NE increased by more than sixfold and threefold, respectively, in two groups, and maintained a high level until 20 hours after surgery. MP treatment could reduce the release of MMP-9...