Effects Of Hypothermic Pulmonary Protective Solution On Lung Function In Congenital Heart Disease With Pulmonary Hypertension After Cardiopulmonary Bypass

Background Although technical refinement of cardiopulmonary bypass(CPB) has progressively improved the results of cardiac surgery, postoperative lung dysfunction remains as a most important complication that could lead to a life-threatening problem, particularly for children suffered from congenital heart disease(CHD) with pulmonary hypertension. The disturbance may be manifested as conditions ranging from subclinical functional changes in most patients to full-blown ARDS in 2% of cases after CPB. The mortality rate associated with ARDS is higher than 50%, not including the morbidity leading to prolonged postoperative recoveries and hospital stays.This study was to evaluate the protective effect of pulmonary perfusion with hypothermic protective solution on lung function after cardiopulmonary bypass.Subjects:Forty children who had CHD of left-to-right shunts with moderate-serious pulmonary hypertension were enrolled and had been performed the radical operation under CPB from Sep 2005 to Apr 2006 in the department of cardiovascular surgery, children's hospital of Zhejiang University in this study. Moderate-serious pulmonary hypertension was defined as pulmonary-to-systolic pressure ratio of greater than 0.45(Pp/Ps>0.45).All clinical materials were achieved via the clinical history, physical examinations, chest roentgenography, electrocardiography and ultrasound-doppler examination. There were twenty-four boys and sixteen girls in forty children, whose median age was 1.81±2.31 years old(ranged from 2 months to 11 years ) and medianweight was 9.45±4.64kg(ranged from 5kg to 13.5kg).There were 28 children with VSD,10 children with VSD+ASD,one child with VSD+PDA and the last with ASD. Forty children were allocated to the perfused group (n=20) and the control group (n=20) at random before operation.The two groups didn't differ significantly with regards to demographic or surgical data. The patients with leukocyte > 12000/ u 1, temperature>38 °C or CRP>8mg/L before the operation were excluded in this study.Methods:After inhalation and intravenous combined general anesthesia, all children were performed the radical operation under moderate hypothermia CPB. Children in the control group only received 4°C cardioplegia after aortic clamping, whereas children in the perfused group received 4 °C cardioplegia and 4 °C pulmonary protective solution after aortic clamping. The solution were sucked out of left atrium by a drain. The heart and/or pulmonary perfiisions were repeated when cross-clamp time was more than 20-30minutes. The ultrafiltration were routinely used in all childen. The protective solution involved ulinastatin (10,000KIU/kg) , anisodamine (1 mg/kg), methylprednisolone (30 mg/kg), L-arginine (0.2 g/kg), 5% sodium hydrogen carbonate (1 ml/kg) and dextran 40 (60ml/kg) . A series of arterial blood samples were analyzed with a blood gas analyzer at four different time points: pre-operation, 0 hours, 3 hours, 6 hours in the surgical intensive care unit (sICU). Pulmonary function indexes were collected from the respirator at the same time. Blood samples were collected for measuring the mean fluoresence intensity (MF I) of PMN CDllb and the concentration of tumor necrosis factor- a at five different time points: pre-operation, 0 hours, 3 hours, 6 hours and 24 hours in the sICU.The MFI of PMN CDllb were detected by flow cytometre. The tumor necrosis factor- a levels in plasma were measured in duplicate by using a commercial radioimmunoassay kit.. Lung biopsies were obtained after "weaning from CPB.Some pieces of the tissue were fixed in 10% buffered Formalin for light microscopy, other were immersed in universal fixative (2.5% glutaryl-aldehyde) immediately after biopsy for electron microscopy. Statitical analysis: All values were expressed as mean + standard error. Differences between groups were tested for significance by the Student's t test for unpaired samples or repeated measures ofanalysis of variance. All analyses were performed using SPSS 12.0 software for Windows (SPSS Inc, Chicago, IL) and differences were considered statistically significant at a probability level of less than 0.05.Results:1. Comparison of Clinical Measurements: There was no mortality in this study. Hospital stays had no statistical difference between the perfused group and the control group.The mean time of mechanical ventilation was shorter in the perfused group compared with the control group(17.60 hours versus 23.70 hours;t=2.564, PO.05).2. Assessment of Lung Function: Alveolar-arterial O2 gradient (A-aDC>2? mmHg) increased in both groups after operation, then came back gradually. A-aDO2 was lower in the perfused group than in the control group and the differences were significant at 3 hours and 6 hours in the sICU (F=5.14, PO.05;F = 7.99, PO.01). Dynamic compliance (Cdyn, mI/cmH2O/kg)descended in both groups after operation and touched bottom at 3 hours in the sICU.Then, the values increased by 6 hours,but stayed less than the prebypass . Cdyn was higher in the perfused group than in the control group and the differences were significant at 6 hours in the sICU(F = 5.14, PO.05).3. Analysis of Blood: The MFI of PMN CDllb increased in both groups after operations. The increasing extents of MFI were lower in the purfused group than in the control group at 3 and 6 hours in sICU, respectively (F = 5.204, PO.05;F=4.323, PO.05).The tumor necrosis factor- a levels increased in both groups after operations. The incresing extents of tumor necrosis factor- a levels were lower in the protective group and were significantly different at 0 and 3 hours in the sICU (F=5.39, PO.05;F=8.87, PO.01).4. Analysis of Tissue: Pathologic studies with a light microscope disclosed capillary hyperemia , hemorrhage and leukocytes accumulation in the control group. Electron microscopic studies revealed intra-alveolar edema, gas-blood barrierbroadening, and lung epithelium mitochondria swelling and vacuolation in the control group, whereas there were no significant changes in the perfused group.Conclusions:1. Our results suggested that lung perfusion with hypothermic protective solution during CPB relieved lung injury in some degree in children of CHD with pulmonary hypertension, ameliorated the early lung function and promoted recovery after operation.2. Lung perfusion with hypothermic protective solution during CPB retrained the release of inflammatory mediators and the action of PMN, impliedly relieved CPB-induced lung injury.