| Objectives:Acute lung injury are induced by systemic inflammatory reaction and lung ischemia-reperfusion injury during cardiopulmonary bypass. Vascular permeability and pulmonary vascular resistance increase, pulmonary interstitial edema happen during this procedure.It not only affect the respiratory function,but also aggratate or lead to residuary pulmonary hypertension and even right heart failure after operation of valve disease.So how to prevention and cure residuary pulmonary hypertension induced by acute lung injury in cardiopulmonary bypass is important in decreasing operative mortality of severe left heart disease with severe pulmonary hypertension.Now, as phosphodiesteraselll inhibitor,milrinone has been widely used in the therapy of pulmonary hypertension and heart failure. For the past few years, scientists paid more and more attention to the organ protective effect of milrinone.However,because of the systemic hypotension, intravenous injection of milrinone is restricted.As a new topical drug administration,inhaling milrinone shows its advantage.The purpose of our research is to evaluate the effect of inhaling milrinone on inflammatory lung injury induced by cardiopulmonary bypass and on residuary pulmonary hypertension induced by acute lung injury in patients with severe left heart valve diseases.In the first part of our research,we choose patients with left heart valve disease, and then compare the affections of inhaling or injecting milrinone pretreatment on systemic inflammatorome and acute lung injury after cardiopulmonary bypass, aiming to explore a new,safe and effective lung protection approach during cardiopulmonary bypass. In the second part,we choose patients with significant residuary pulmonary hypertension after heart valve disease operation,then observe the hemodynamic affection of inhaling milrinone,aiming to explore a new,safe,effective and convenient approach to reduce residuary pulmonary hypertension induced by cardiopulmonary bypass.Methods:PartⅠ1、Cases collection and intervention approachIn this part,we adopted54patients with rheumatic valvular diseases hospitalized in Xiamen Heart Center from April,2010to December,2010for study group.All patients’ heart function grade Ⅱ～Ⅲ (NYHA),without infectious diseases,without other severe system diseases, without active stage of rheumatism also without glucocorticoid therapy and proteinase inhibitors therapy.Patients with severe valve stenosis and severe pulmonary hypertension(PASP>70mmHg, according to the echocardiogram) were excluded.All patients were separate to three groups according to random digits table with eighteen patients in each group.In inhalation group,patients received milrinone inhalation48h before operation(5mg q8h,5mg/10ml); In intravenous injection group,milrinone were administrated continuously through intravenous injection48h before operation(15mg/24h,15mg/50ml,2ml/h);And in control group,none were administrated before operation.2、Parameter collected and analyzedGeneral parameters:every patients’ name,sex,weight,height,ID number,diagnosis, pulmonary pressure, left ventricular ejection fraction,operation method, operation time, CPB time and aorta obstruct time.Swan-Ganz was inserted before operation.At the following time points:beforeoperation (T0)、30min after aorta open (T1)、end of operation (T2)、24h after operation (T3)、72h after operation (T4) and7d after operation (T5),patients were collected artery blood and vein blood for routine blood test. White blood cell count and haematocrit were noted,and the ratio of white blood for vein and artery blood were calculated. TNF-α,IL-6and MPO were detected with ELISA at all the time points.At the first5time points, arterial blood were collected for blood gas analysis,pulmonary vascular resistance(PVR) and oxygenation index(OI) were detected by Swan-Ganz.Analysis of variance was used in the comparison of measurement data when variance was homogenetic,otherwise Kruskal-Wallis nonparameter test was used. χ2test was used in the comparison of enumeration data. Analysis of variance in repeat measurement date was used in the comparison of test date or different groups or different time points. And P<0.05was consider as statistical significance.Part Ⅱ1、Cases collection and intervention approachIn this part,we adopted23patients with rheumatic mitral stenosis(PASP>70mmHg,and MPAP>50mmHg) hospitalized in Xiamen Heart Center from March,2011to July,2011for study. Swan-Ganz was inserted before operation.Pulmonary pressure were redetected after operation,12patients whose MPAP>30mmHg were include in our study group.All patients’heart function grade Ⅱ～Ⅲ (NYHA),without infectious diseases,without other severe system diseases, without active stage of rheumatism also without glucocorticoid therapy,milrinone therapy and proteinase inhibitors therapy.2、Parameter collected and analyzedGeneral parameters:every patients’ name,sex,weight,height,ID number,diagnosis, pulmonary pressure, left ventricular ejection fraction,operation method, operation time, CPB time and aorta obstruct time.Hemodynamic parameters including heart rate(HR), mean systemic arterial pressure(MSAP), mean pulmonary arterial pressure (MPAP),cardiac index(CI), pulmonary vascular resistance(PVR) and systemic vascular resistance(SVR) were collected when the patients returned to ICU after operation(To).Then the patients received milrinone inhalation continuously(20mg,about6-8ml/h) through breathing machine.at the following time points:15min (T1)、30min (T2)、60min (T3)120min (T4) after beginning of milrinone inhalation and30min (T5)、60min (T6)、120min (T7) after the end of milrinone inhalation,all the hemodynamic parameters mentioned above were redetected.Analysis of variance in repeat measurement date with single factor was used in the comparison of measurement data.And P<0.05was consider as statistical significance. Results:PartⅠ1、All patients received operations without any death,and there were no significant difference among three groups with regard to the patients’ sex ratio,age,weight,pulmonary artery pressure,LVEF,operation time,CPB time and aorta block time.2、There was significant difference with PVR among different time points after operation (F=745.536,P<0.001).The same results was seen in all the three group. The PVR showed no significant diference among the three groups before operation.However their PVR rised in different degree after aorta opening and reached its peak at the end of the operation.There were no significant difference between intravenous group and control group except T1time point,in which the PVR of intravenous group was lower than control group.The PVR of inhalation group was significantly lower than both intravenous and control group after the beginning of CPB.,and it recovered to its preoperative level72h after operation. Interaction existed between pretreatment factor and time factor (F=17.426,P<0.001)3、There was significant difference with OI among different time points after operation (F=226.357,P<0.001).The same results was seen in all the three group. The OI showed no significant diference among the three groups before operation.However their OI decreased in different degree after aorta opening and reached its nadir at the end of operation.There were no significant difference between intravenous group and control group in any time point.The01of inhalation group was significantly higher than that of intravenous group and control group,although significantly lower than the preoperative level after the end of CPB. Interaction existed between pretreatment factor and time factor (F=6.236,P<0.001)4、There was significant difference with TNF-αlevel among different time points after operation(F=996.009,P<0.001).The same results was seen in all the three group. The TNF-αlevel showed no significant diference among the three groups before operation.However they all rised in different degree after the beginning of CPB and reached their peak at the end of the operation until7d after operation. The TNF-α level of intravenous group was significantly lower than control group after the beginning of CPB except T5time point. After the beginning of CPB,the TNF-a level of inhalation group was significantly lower than control group and significantly lower than intravenous group except T4time point. Interaction existed between pretreatment factor and time factor (F=17.285,P<0.001)5、There was significant difference with IL-6level among different time points after operation(F=517.324,P<0.001).The same results was seen in all the three group. The IL-6level showed no significant diference among the three groups before operation.However they all rised in different degree after the beginning of CPB and reached their peak24h after operation. The IL-6level of intravenous group was significantly lower than control group until24h after operation. The IL-6level of inhalation group was significantly lower than control group after the beginning of CPB and significantly lower than intravenous group after operation. Interaction existed between pretreatment factor and time factor (F=13.644,P<0.001)6、There was significant difference with MPO level among different time points after operation(F=646.212,P<0.001).The same results was seen in all the three group. The MPO level showed no significant diference among the three groups before operation.However they all rised in different degree after the beginning of CPB and reached their peak at the end of the operation. The MPO level of intravenous group was significantly lower than control group after the end of CPB. The MPO level of inhalation group was significantly lower than control group after the beginning of CPB and significantly lower than intravenous group until24h after operation. Interaction existed between pretreatment factor and time factor (F=16.609,P<0.001).7、There was significant difference with V/A level among different time points after operation (F=15.316,P<0.001).The same results was also seen in control group and intravenous group. The V/A level showed no significant diference among the three groups before operation.However that of intravenous group and control group rised in different degree after the beginning of CPB. The V/A level of inhalation group showed no significant change surround operation,and it was lower than that of intravenous group and control group after the beginning of CPB. Interaction existed between pretreatment factor and time factor (F=4.234,P<0.001)Part Ⅱ1、There were no significant change of heart rate after the beginning of milrinone inhalation (F=1.750,P=0.110)2、There were no significant change of MSAP after the beginning of milrinone inhalation (F=1.009,P=0.432)3、The patients’MPAP decreased after milrinone inhalation and reach its nadir120min after milrinone inhalation.It began to rise at the end of milrinone inhalation and recover to its preoperative level120min after the end of inhalation.4、The patients’ VR decreased in different degree after the beginning of milrinone inhalation but showed no significant difference comparing to the preoperative level except T4time point.However,the PVR level decreased significantly after the beginning of milrinone inhalation and reach its nadir120min later. Then it began to rise slowly at the end of inhalation,but still significantly lower than its preoperative level120min after the end of inhalation.The cardiac index began to increase15min after the beginning of milrinone inhalation and reach its peak120min after the beginning of inhalation.Then it began to decrease slowly at the end of inhalation, but still significantly higher than its preoperative level at any time point after the end of inhalation. Conclusions:1、Systemic inflammatory reaction and tissue peroxidatic reaction due to ischemia-reperfusion injury are induced by cardiopulmonary bypass.Which leading to the significantly increasion of tumor necrosis factor, interleukin and myeloperoxidase,etc.Due to the specific hemoperfusion model,lung become a significant source of inflammatory mediators and also become the sufferer of inflammatory injury because of the aggregation and activation of leucocytes.2、Pulmonary vascular resistance step up and oxygenation index descends after cardiopulmonary bypass,which significantly affect the respiratory function of the patients.This phenomenon is correlate to the inflammatory injury and ischemia-reperfusion injury of lung during cardiopulmonary bypass.3、Pretreatment of milrinone by intravenous injection or inhalation can alleviate systemic inflammatory reaction and tissue peroxidatic reaction after cardiopulmonary by inhibitting the production of inflammatory mediators and the aggregation of leucocytes in lung.Inhaling but not injecting milrinone can also protect pulmonary function by improving oxygenation function and alleviating the increasion of pulmonary vascular resistance.This maybe due to its local effect in lung.4、Residuary pulmonary hypertension is common after operation of severe valvular disease of left heart.Inhaling milrinone can significantly reduce the pulmonary pressure and pulmonary vascular resistance,at the same time, increase the cardiac index without significant affection to the heart rate and systemic vascular resistance in these patients.This demonstrates that the effect of milrinone to pulmonary circulation is strongger than to systemic circulation.5、Inhaling milrinone is safe, effective and convenient, this strategy might be useful in enhancing the local effect and decreasing systemic side effect of milrinone. |
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