特异性磷酸二酯酶抑制剂在风湿性左心瓣膜病肺动脉高压患者围术期的应用研究
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摘要
一、目的
由于各种原因,体外循环可激发全身炎症反应综合征及肺缺血-再灌注损伤,导致急性炎性肺损伤,引起肺血管通透性增加、肺间质水肿、肺血管阻力增加,不仅影响患者呼吸功能,尚可加重或导致左心瓣膜病患者术后肺动脉高压,加重右心室后负荷甚至导致右心衰竭,影响患者术后早期的平稳过渡,显著增加术后并发症及死亡率。因此,如何最大限度减轻体外循环所致炎症反应及肺损伤,有效进行肺保护,防治体外循环肺损伤所致术后残余肺动脉高压,已成为降低重症心脏瓣膜病特别是合并严重肺动脉高压患者手术死亡率的关键。目前,磷酸二酯酶Ⅲ抑制剂米力农已被广泛应用于心衰及肺动脉高压的治疗,近年来,米力农的脏器保护作用日益受到重视。但静脉应用米力农由于其所导致的全身低血压等并发症限制了其临床疗效的发挥。作为一种新的局部给药途径,雾化吸入米力农开始受到关注。为了进一步探索米力农雾化吸入对体外循环炎性肺损伤的影响及其对左心瓣膜病术后残余肺动脉高压患者血流动力学的影响,我们设计了本课题。其主要内容如下：
1选取合并肺动脉高压的左心瓣膜病患者,系统的研究、比较静脉应用与雾化吸入米力农预处理对体外循环所致全身炎症反应及肺损伤可能的保护作用,以期寻求一种新的、安全有效的体外循环肺保护方法。
2选择术后仍残余显著肺动脉高压的左心瓣膜病患者,观察雾化吸入米力农对体外循环术后残余肺动脉高压患者血流动力学的影响,希望探索一种简单、安全、有效、便利的、选择性降低左心瓣膜病及体外循环所致术后残余肺动脉高压的方法。
二、方法
第一部分
1研究对象与干预措施
选择厦门大学附属中山医院心脏外科2010年4月至12月间收治的风湿性瓣膜病患者54例,术前无合并感染性疾病,无合并全身其他系统严重疾病,均未使用糖皮质激素及其他影响免疫功能的药物,并按Jones诊断标准排除风湿活动。由于瓣膜严重狭窄是米力农的禁忌症,同时为了尽量避免可能存在的较严重肺血管病变对研究可能造成的影响,瓣膜重度狭窄和(或)合并重度以上肺动脉高压(术前超声心动图提示肺动脉收缩压>70mmHg)患者不纳入本研究。为避免药物影响,所有患者除研究方案中所述米力农用法外,研究结束前均不额外使用米力农。为避免蛋白酶抑制剂对全身炎症反应的影响,研究结束前不使用抑肽酶及天普洛安。所选患者以随机数字表法随机分为对照组、静脉组和雾化吸入组,每组18例。雾化吸入组于术前48h以生理盐水5ml加入米力农注射液5mg经氧气压缩雾化器缓慢雾化吸入,每8h一次；静脉组于术前48h以微量泵自静脉泵入米力农注射液(15mg/24h,以生理盐水稀释成15mg/50ml,2ml/h持续泵入)。对照组术前不做米力农预处理。
2观察指标的选择、数据采集及统计学分析
既往研究已证实体外循环过程中白细胞在肺内的聚集与激活是体外循环炎性肺损伤的中心环节,白细胞在肺内的聚集与激活及肺缺血再灌注损伤,造成肺血管内皮损伤,通透性增加、肺水肿、肺组织过氧化损伤,最终引起肺血管阻力增加,加重或导致术后肺动脉高压,并影响患者氧合功能；同时也使得肺脏成为体外循环过程中炎性介质的主要来源。因此患者肺血管阻力及肺氧合指数是反应体外循环过程中炎性肺损伤的直接指标,而体循环中的细胞因子如肿瘤坏死因子(TNF-α)、白介素-6(IL-6)及人髓过氧化物酶(MPO)则是肺损伤的间接指标,因此本研究选择以上指标直接或间接的评价体外循环所致炎性肺损伤的严重程度及药物的影响,同时测定静脉血与动脉血白细胞比值(V/A值)以评估白细胞在肺内的滞留情况。
患者一般资料采集包括：姓名、性别、年龄、体重、身高、住院号、术前诊断、术前肺动脉压力、左心室射血分数、手术方式、手术时间、体外循环时间、主动脉阻断时间等。
术前置入Swan-Ganz飘浮导管,于麻醉诱导后切皮前(T0)、主动脉开放后30min(T1)、术毕(T2)、术后24h(T3)、72h(T4)及术后7d(T5)6个时点抽取动、静脉血(自凝血)各1m1分别送检血常规,检测其白细胞计数及红细胞压积(HCT)并计算V/A值；并于各时点抽取动脉血用酶联免疫吸附试验(ELISA)法测定样本中TNF-α、IL-6、MPO；于前5个时点抽取动脉血行动脉血气分析,并经Swan-Ganz导管连接Edwards vigilance血流动力学监测仪测量肺血管阻力(PVR)并计算氧合指数(OI)。其中OI=PaO2/FiO2,(Pa02为动脉血氧分压,Fi02为吸入氧浓度)。
各组患者基本临床资料的比较,计量资料采用单因素方差分析；计数资料采用χ2检验。所测得计量资料采用SPSS13.0统计软件进行数据分析,组间比较及组内不同时点比较采用重复测量的方差分析。P<0.05为差异有统计学意义。
第二部分
1研究对象与干预措施
选择厦门大学附属中山医院心脏外科2011年3月至7月间收治的风湿性二尖瓣狭窄合并重度肺动脉高压(术前心脏彩超提示肺动脉收缩压>70mmHg且平均肺动脉压力>50mmHg)患者23例,术前置入Swan-Ganz飘浮导管,术后返ICU且血流动力学平稳后复测肺动脉压,为便于观察术后肺动脉压力的变化,我们仅将术后平均肺动脉压力>30mmHg者纳入本研究。本研究共收集符合研究标准患者12例,术前无合并感染性疾病,无合并全身其他系统严重疾病,未使用糖皮质激素及其他影响免疫功能的药物,并按Jones诊断标准排除风湿活动。为避免药物影响,除研究方案中所述米力农用法外,所有患者研究结束前不额外使用米力农。为避免蛋白酶抑制剂对全身炎症反应、血流动力学指标的影响,研究结束前不使用抑肽酶及天普洛安。
2观察指标、数据采集及统计学分析
患者一般资料采集包括：姓名、性别、年龄、体重、身高、住院号、术前诊断、术前肺动脉压力、左心室射血分数、手术方式、手术时间、体外循环时间、主动脉阻断时间等。
所有患者在术毕返ICU后,待血流动力学参数稳定之后(T0)通过Edwards vigilance读取、记录全套用药前血流动力学参数(基线)：心率(HR)、主动脉平均压(MSAP)、肺动脉平均压(MPAP)、心脏指数(CI)、肺循环阻力(PVR)、体循环阻力(SVR)。记录后经呼吸机雾化装置吸入20mg米力农溶液20ml(约6-8ml/h),并分别在开始吸入药物后15分钟(T1)、30分钟(T2)、60分钟(T3)、120分钟(T4)、吸入结束后30分钟(T5)、60分钟(T6)、120分钟(T7)再次测量、记录上述全套血流动力学指标。
所测得计量资料采用SPSS13.0统计软件进行单因素重复测量方差分析,不同时点间采用Lsd法进行两两比较。P<0.05为差异有统计学意义。
三、结果
第一部分：
1全组无围术期死亡,各组患者术前性别结构、年龄、体重、术前肺动脉压力、左心室射血分数、手术时间、转流时间、主动脉阻断时间差异无统计学意义；
2手术前后不同时间之间患者肺血管阻力有显著差异(F=745.536,P<0.001),对照组、静脉组及雾化组均如此,F值分别为299.615、299.148及191.321,均为P<0.001。三组患者术前肺血管阻力无显著差异,主动脉开放后,各组患者肺血管阻力不同程度升高,并于手术结束时达到高峰,之后逐渐回落,围术期变化趋势基本一致；静脉组患者PVR除T1时间点低于对照组外,其余时间点与对照组间无显著差异；在体外循环后各时点,雾化组PVR显著低于对照组与静脉组,并于术后72小时即已恢复到术前水平。手术前后与预处理因素之间存在交互效应(F=17.426,P<0.001)；
3手术前后不同时间之间患者肺氧合指数有显著差异(F=226.357,P<0.001),对照组、静脉组及雾化组均如此,F值分别为127.467、117.206及30.752,均为P<0.001。各组患者术前肺氧合指数无显著差异,主动脉开放后其氧合指数均不同程度降低,三组患者氧合指数均于手术结束时达到最低值,之后缓慢回升,其变化趋势基本一致；静脉组患者各时点肺氧合指数与对照组间比较无显著差异：在体外循环结束后各时点,雾化组患者肺氧合指数虽仍低于术前水平但显著高于同时点对照组与静脉组水平。手术前后与预处理因素之间存在交互效应(F=6.236,P<0.001)：
4手术前后不同时间之间患者血浆TNF-α水平有显著差异(F=996.009,P<0.001),对照组、静脉组及雾化组均如此,F值分别为483.915、302.079及253.260,均为P<0.001。三组患者术前血浆TNF-α水平无显著差异,体外循环开始后逐渐上升,主动脉开放后急剧升高,并于手术结束时达到高峰,之后逐渐回落,术后7d其水平仍显著高于术前,围术期变化趋势基本一致；除T3时点外,静脉组患者体外循环开始后TNF-α水平低于对照组；雾化组患者体外循环开始后各时点其TNF-α水平均显著低于对照组,除T4时点外其水平均显著低于同时点的静脉组患者。手术前后与预处理因素之间存在交互效应(F=17.285,P<0.001)；
5手术前后不同时点之间患者血浆IL-6水平有显著差异(F=517.324,P<0.001),对照组、静脉组及雾化组均如此,F值分别为236.136、176.066及115.221,均为P<0.001。三组患者术前血浆IL-6水平无显著差异,体外循环开始后逐渐上升,并于术后24h达到高峰,之后逐渐回落,术后7d其水平仍显著高于术前,围术期变化趋势基本一致；静脉组患者体外循环开始后直至术后24h其IL-6水平低于对照组；雾化组患者体外循环开始后各时点IL-6水平均显著低于对照组,且手术结束后各时点IL-6水平均显著低于静脉组。手术前后与预处理因素之间存在交互效应(F=13.644,P<0.001)；
6手术前后不同时点之间患者血浆MPO水平有显著差异(F=646.212,P<0.001),对照组、静脉组及雾化组均如此,F值分别为250.082、295.697及126.804,均为P<0.001。三组患者术前血浆MPO水平无显著差异,体外循环开始后逐渐上升,并于手术结束时达到高峰,之后逐渐回落,术后7d仍显著高于术前,其变化趋势基本一致；体外循环结束后各时点静脉组MPO水平均显著低于对照组；雾化组患者体外循环开始后各时点其MPO水平均显著低于对照组,且在主动脉开放后、术毕及术后24小时三个时点血浆MPO水平显著低于静脉组；手术前后与预处理因素之间存在交互效应(F=16.609,P<0.001)；
7手术前后不同时点之间患者静脉血与动脉血白细胞计数比值有显著差异(F=15.316,P<0.001),除雾化组外(F=0.964,P=0.444),对照组、静脉组均如此,F值分别为15.169和6.448,均为P<0.001。三组患者术前V/A无显著差异,对照组与静脉组体外循环开始后逐渐上升,并分别于手术结束时及术后24h达到高峰后逐渐回落,术后72h已基本回落到术前水平；围术期雾化组V/A值未见显著升高,体外循环开始后各时点V/A显著低于对照组与静脉组；手术前后与预处理因素之间存在交互效应(F=4.234,P<0.001)；
第二部分
1开始雾化吸入米力农后各时点与吸入前患者心率水平无显著差异(F=1.750,P=0.110),实验过程中患者心率波动较为平稳；
2开始雾化吸入米力农后各时点,患者平均动脉压力水平与吸入前相比无显著差异(F=1.009,P=0.432)；而开始吸入米力农后各时点,患者平均肺动脉压力水平与吸入前相比则存在显著差异(F=34.000,P<0.001)。吸入开始后,患者平均肺动脉压力逐渐下降,于吸入后120min时降至最低值；雾化结束后肺动脉压力逐渐回升,并于雾化结束后120min基本恢复到雾化前的基线水平；
3开始雾化吸入米力农后各时点,患者SVR水平与吸入前不同(F=2.157,P=0.047)；但通过组内不同时点比较发现,米力农雾化吸入开始后除T4时点与基线(To)比较有统计学差异(P=0.039)外,其余各时点与基线比较差异无统计学意义；而开始吸入米力农后各时点,患者肺血管阻力(PVR)水平与吸入前水平存在显著差异(F=66.515,P<0.001),肺血管阻力在雾化开始后即显著下降并在雾化120min时达到最低值,雾化结束后肺血管阻力逐渐缓慢回升,在雾化结束120min后仍低于雾化前的基线水平；开始吸入米力农后各时点,患者CI水平与吸入前水平存在显著差异(F=36.054,P<0.001),雾化开始后早期(15min)患者心脏指数未见显著变化,雾化15mmin后逐渐升高并于雾化120min后达到最高值,雾化结束后缓慢下降,但雾化结束后各时点其心脏指数水平仍显著高于雾化前的基线水平；
四、结论
l体外循环激发了全身炎症反应及因脏器缺血-再灌注损伤所致的组织过氧化反应,表现为肿瘤坏死因子、白细胞介素等炎性因子及髓过氧化物酶水平显著升高；由于特殊的血液灌注模式,肺脏成为体外循环过程中白细胞聚集与激活的主要产所,使得肺脏成为体外循环炎性介质的主要来源及最易受到炎性损伤的内脏器官；
2体外循环后,患者的肺血管阻力不同程度升高,氧合指数不同程度下降,且术后恢复缓慢,呼吸功能受到显著影响。这一现象与体外循环所致的急性炎性肺损伤及肺缺血-再灌注损伤有关；
3术前用静脉注射及雾化吸入两种不同给药途径进行磷酸二酯酶III抑制剂米力农预处理均可明显抑制体外循环后炎性介质的产生,减轻全身炎症反应及组织脂质过氧化程度,减少白细胞在肺内的聚集；此外雾化吸入米力农尚可显著改善体外循环术后患者的肺氧合功能,减轻肺血管阻力升高程度,显示出良好的肺保护作用,而静脉应用米力农的肺保护作用并不明显,这可能与雾化吸入后的米力农主要在肺脏局部发挥作用、局部药物浓度较高有关；
4严重左心瓣膜病患者术后残余肺动脉高压的现象较为常见；雾化吸入米力农可显著降低该类患者肺动脉压力及肺血管阻力,增加其心脏指数；且对患者的心率、全身血管阻力并无显著影响,这说明了雾化吸入米力农在降低肺动脉压力及肺血管阻力的作用大大强于其对体循环的影响,反应出其良好的肺血管选择性；
5米力农雾化吸入为临床上应用米力农提供了新的安全、有效、便利的给药途径,有利于增强其局部作用,减少全身性副作用。
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:
PartⅠ
1、Cases collection and intervention approach
In 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 analyzed
General 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 Ⅱ
1、Cases collection and intervention approach
In 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 analyzed
General 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:
PartⅠ
1、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 Ⅱ
1、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.
由于各种原因,体外循环可激发全身炎症反应综合征及肺缺血-再灌注损伤,导致急性炎性肺损伤,引起肺血管通透性增加、肺间质水肿、肺血管阻力增加,不仅影响患者呼吸功能,尚可加重或导致左心瓣膜病患者术后肺动脉高压,加重右心室后负荷甚至导致右心衰竭,影响患者术后早期的平稳过渡,显著增加术后并发症及死亡率。因此,如何最大限度减轻体外循环所致炎症反应及肺损伤,有效进行肺保护,防治体外循环肺损伤所致术后残余肺动脉高压,已成为降低重症心脏瓣膜病特别是合并严重肺动脉高压患者手术死亡率的关键。目前,磷酸二酯酶Ⅲ抑制剂米力农已被广泛应用于心衰及肺动脉高压的治疗,近年来,米力农的脏器保护作用日益受到重视。但静脉应用米力农由于其所导致的全身低血压等并发症限制了其临床疗效的发挥。作为一种新的局部给药途径,雾化吸入米力农开始受到关注。为了进一步探索米力农雾化吸入对体外循环炎性肺损伤的影响及其对左心瓣膜病术后残余肺动脉高压患者血流动力学的影响,我们设计了本课题。其主要内容如下：
1选取合并肺动脉高压的左心瓣膜病患者,系统的研究、比较静脉应用与雾化吸入米力农预处理对体外循环所致全身炎症反应及肺损伤可能的保护作用,以期寻求一种新的、安全有效的体外循环肺保护方法。
2选择术后仍残余显著肺动脉高压的左心瓣膜病患者,观察雾化吸入米力农对体外循环术后残余肺动脉高压患者血流动力学的影响,希望探索一种简单、安全、有效、便利的、选择性降低左心瓣膜病及体外循环所致术后残余肺动脉高压的方法。
二、方法
第一部分
1研究对象与干预措施
选择厦门大学附属中山医院心脏外科2010年4月至12月间收治的风湿性瓣膜病患者54例,术前无合并感染性疾病,无合并全身其他系统严重疾病,均未使用糖皮质激素及其他影响免疫功能的药物,并按Jones诊断标准排除风湿活动。由于瓣膜严重狭窄是米力农的禁忌症,同时为了尽量避免可能存在的较严重肺血管病变对研究可能造成的影响,瓣膜重度狭窄和(或)合并重度以上肺动脉高压(术前超声心动图提示肺动脉收缩压>70mmHg)患者不纳入本研究。为避免药物影响,所有患者除研究方案中所述米力农用法外,研究结束前均不额外使用米力农。为避免蛋白酶抑制剂对全身炎症反应的影响,研究结束前不使用抑肽酶及天普洛安。所选患者以随机数字表法随机分为对照组、静脉组和雾化吸入组,每组18例。雾化吸入组于术前48h以生理盐水5ml加入米力农注射液5mg经氧气压缩雾化器缓慢雾化吸入,每8h一次；静脉组于术前48h以微量泵自静脉泵入米力农注射液(15mg/24h,以生理盐水稀释成15mg/50ml,2ml/h持续泵入)。对照组术前不做米力农预处理。
2观察指标的选择、数据采集及统计学分析
既往研究已证实体外循环过程中白细胞在肺内的聚集与激活是体外循环炎性肺损伤的中心环节,白细胞在肺内的聚集与激活及肺缺血再灌注损伤,造成肺血管内皮损伤,通透性增加、肺水肿、肺组织过氧化损伤,最终引起肺血管阻力增加,加重或导致术后肺动脉高压,并影响患者氧合功能；同时也使得肺脏成为体外循环过程中炎性介质的主要来源。因此患者肺血管阻力及肺氧合指数是反应体外循环过程中炎性肺损伤的直接指标,而体循环中的细胞因子如肿瘤坏死因子(TNF-α)、白介素-6(IL-6)及人髓过氧化物酶(MPO)则是肺损伤的间接指标,因此本研究选择以上指标直接或间接的评价体外循环所致炎性肺损伤的严重程度及药物的影响,同时测定静脉血与动脉血白细胞比值(V/A值)以评估白细胞在肺内的滞留情况。
患者一般资料采集包括：姓名、性别、年龄、体重、身高、住院号、术前诊断、术前肺动脉压力、左心室射血分数、手术方式、手术时间、体外循环时间、主动脉阻断时间等。
术前置入Swan-Ganz飘浮导管,于麻醉诱导后切皮前(T0)、主动脉开放后30min(T1)、术毕(T2)、术后24h(T3)、72h(T4)及术后7d(T5)6个时点抽取动、静脉血(自凝血)各1m1分别送检血常规,检测其白细胞计数及红细胞压积(HCT)并计算V/A值；并于各时点抽取动脉血用酶联免疫吸附试验(ELISA)法测定样本中TNF-α、IL-6、MPO；于前5个时点抽取动脉血行动脉血气分析,并经Swan-Ganz导管连接Edwards vigilance血流动力学监测仪测量肺血管阻力(PVR)并计算氧合指数(OI)。其中OI=PaO2/FiO2,(Pa02为动脉血氧分压,Fi02为吸入氧浓度)。
各组患者基本临床资料的比较,计量资料采用单因素方差分析；计数资料采用χ2检验。所测得计量资料采用SPSS13.0统计软件进行数据分析,组间比较及组内不同时点比较采用重复测量的方差分析。P<0.05为差异有统计学意义。
第二部分
1研究对象与干预措施
选择厦门大学附属中山医院心脏外科2011年3月至7月间收治的风湿性二尖瓣狭窄合并重度肺动脉高压(术前心脏彩超提示肺动脉收缩压>70mmHg且平均肺动脉压力>50mmHg)患者23例,术前置入Swan-Ganz飘浮导管,术后返ICU且血流动力学平稳后复测肺动脉压,为便于观察术后肺动脉压力的变化,我们仅将术后平均肺动脉压力>30mmHg者纳入本研究。本研究共收集符合研究标准患者12例,术前无合并感染性疾病,无合并全身其他系统严重疾病,未使用糖皮质激素及其他影响免疫功能的药物,并按Jones诊断标准排除风湿活动。为避免药物影响,除研究方案中所述米力农用法外,所有患者研究结束前不额外使用米力农。为避免蛋白酶抑制剂对全身炎症反应、血流动力学指标的影响,研究结束前不使用抑肽酶及天普洛安。
2观察指标、数据采集及统计学分析
患者一般资料采集包括：姓名、性别、年龄、体重、身高、住院号、术前诊断、术前肺动脉压力、左心室射血分数、手术方式、手术时间、体外循环时间、主动脉阻断时间等。
所有患者在术毕返ICU后,待血流动力学参数稳定之后(T0)通过Edwards vigilance读取、记录全套用药前血流动力学参数(基线)：心率(HR)、主动脉平均压(MSAP)、肺动脉平均压(MPAP)、心脏指数(CI)、肺循环阻力(PVR)、体循环阻力(SVR)。记录后经呼吸机雾化装置吸入20mg米力农溶液20ml(约6-8ml/h),并分别在开始吸入药物后15分钟(T1)、30分钟(T2)、60分钟(T3)、120分钟(T4)、吸入结束后30分钟(T5)、60分钟(T6)、120分钟(T7)再次测量、记录上述全套血流动力学指标。
所测得计量资料采用SPSS13.0统计软件进行单因素重复测量方差分析,不同时点间采用Lsd法进行两两比较。P<0.05为差异有统计学意义。
三、结果
第一部分：
1全组无围术期死亡,各组患者术前性别结构、年龄、体重、术前肺动脉压力、左心室射血分数、手术时间、转流时间、主动脉阻断时间差异无统计学意义；
2手术前后不同时间之间患者肺血管阻力有显著差异(F=745.536,P<0.001),对照组、静脉组及雾化组均如此,F值分别为299.615、299.148及191.321,均为P<0.001。三组患者术前肺血管阻力无显著差异,主动脉开放后,各组患者肺血管阻力不同程度升高,并于手术结束时达到高峰,之后逐渐回落,围术期变化趋势基本一致；静脉组患者PVR除T1时间点低于对照组外,其余时间点与对照组间无显著差异；在体外循环后各时点,雾化组PVR显著低于对照组与静脉组,并于术后72小时即已恢复到术前水平。手术前后与预处理因素之间存在交互效应(F=17.426,P<0.001)；
3手术前后不同时间之间患者肺氧合指数有显著差异(F=226.357,P<0.001),对照组、静脉组及雾化组均如此,F值分别为127.467、117.206及30.752,均为P<0.001。各组患者术前肺氧合指数无显著差异,主动脉开放后其氧合指数均不同程度降低,三组患者氧合指数均于手术结束时达到最低值,之后缓慢回升,其变化趋势基本一致；静脉组患者各时点肺氧合指数与对照组间比较无显著差异：在体外循环结束后各时点,雾化组患者肺氧合指数虽仍低于术前水平但显著高于同时点对照组与静脉组水平。手术前后与预处理因素之间存在交互效应(F=6.236,P<0.001)：
4手术前后不同时间之间患者血浆TNF-α水平有显著差异(F=996.009,P<0.001),对照组、静脉组及雾化组均如此,F值分别为483.915、302.079及253.260,均为P<0.001。三组患者术前血浆TNF-α水平无显著差异,体外循环开始后逐渐上升,主动脉开放后急剧升高,并于手术结束时达到高峰,之后逐渐回落,术后7d其水平仍显著高于术前,围术期变化趋势基本一致；除T3时点外,静脉组患者体外循环开始后TNF-α水平低于对照组；雾化组患者体外循环开始后各时点其TNF-α水平均显著低于对照组,除T4时点外其水平均显著低于同时点的静脉组患者。手术前后与预处理因素之间存在交互效应(F=17.285,P<0.001)；
5手术前后不同时点之间患者血浆IL-6水平有显著差异(F=517.324,P<0.001),对照组、静脉组及雾化组均如此,F值分别为236.136、176.066及115.221,均为P<0.001。三组患者术前血浆IL-6水平无显著差异,体外循环开始后逐渐上升,并于术后24h达到高峰,之后逐渐回落,术后7d其水平仍显著高于术前,围术期变化趋势基本一致；静脉组患者体外循环开始后直至术后24h其IL-6水平低于对照组；雾化组患者体外循环开始后各时点IL-6水平均显著低于对照组,且手术结束后各时点IL-6水平均显著低于静脉组。手术前后与预处理因素之间存在交互效应(F=13.644,P<0.001)；
6手术前后不同时点之间患者血浆MPO水平有显著差异(F=646.212,P<0.001),对照组、静脉组及雾化组均如此,F值分别为250.082、295.697及126.804,均为P<0.001。三组患者术前血浆MPO水平无显著差异,体外循环开始后逐渐上升,并于手术结束时达到高峰,之后逐渐回落,术后7d仍显著高于术前,其变化趋势基本一致；体外循环结束后各时点静脉组MPO水平均显著低于对照组；雾化组患者体外循环开始后各时点其MPO水平均显著低于对照组,且在主动脉开放后、术毕及术后24小时三个时点血浆MPO水平显著低于静脉组；手术前后与预处理因素之间存在交互效应(F=16.609,P<0.001)；
7手术前后不同时点之间患者静脉血与动脉血白细胞计数比值有显著差异(F=15.316,P<0.001),除雾化组外(F=0.964,P=0.444),对照组、静脉组均如此,F值分别为15.169和6.448,均为P<0.001。三组患者术前V/A无显著差异,对照组与静脉组体外循环开始后逐渐上升,并分别于手术结束时及术后24h达到高峰后逐渐回落,术后72h已基本回落到术前水平；围术期雾化组V/A值未见显著升高,体外循环开始后各时点V/A显著低于对照组与静脉组；手术前后与预处理因素之间存在交互效应(F=4.234,P<0.001)；
第二部分
1开始雾化吸入米力农后各时点与吸入前患者心率水平无显著差异(F=1.750,P=0.110),实验过程中患者心率波动较为平稳；
2开始雾化吸入米力农后各时点,患者平均动脉压力水平与吸入前相比无显著差异(F=1.009,P=0.432)；而开始吸入米力农后各时点,患者平均肺动脉压力水平与吸入前相比则存在显著差异(F=34.000,P<0.001)。吸入开始后,患者平均肺动脉压力逐渐下降,于吸入后120min时降至最低值；雾化结束后肺动脉压力逐渐回升,并于雾化结束后120min基本恢复到雾化前的基线水平；
3开始雾化吸入米力农后各时点,患者SVR水平与吸入前不同(F=2.157,P=0.047)；但通过组内不同时点比较发现,米力农雾化吸入开始后除T4时点与基线(To)比较有统计学差异(P=0.039)外,其余各时点与基线比较差异无统计学意义；而开始吸入米力农后各时点,患者肺血管阻力(PVR)水平与吸入前水平存在显著差异(F=66.515,P<0.001),肺血管阻力在雾化开始后即显著下降并在雾化120min时达到最低值,雾化结束后肺血管阻力逐渐缓慢回升,在雾化结束120min后仍低于雾化前的基线水平；开始吸入米力农后各时点,患者CI水平与吸入前水平存在显著差异(F=36.054,P<0.001),雾化开始后早期(15min)患者心脏指数未见显著变化,雾化15mmin后逐渐升高并于雾化120min后达到最高值,雾化结束后缓慢下降,但雾化结束后各时点其心脏指数水平仍显著高于雾化前的基线水平；
四、结论
l体外循环激发了全身炎症反应及因脏器缺血-再灌注损伤所致的组织过氧化反应,表现为肿瘤坏死因子、白细胞介素等炎性因子及髓过氧化物酶水平显著升高；由于特殊的血液灌注模式,肺脏成为体外循环过程中白细胞聚集与激活的主要产所,使得肺脏成为体外循环炎性介质的主要来源及最易受到炎性损伤的内脏器官；
2体外循环后,患者的肺血管阻力不同程度升高,氧合指数不同程度下降,且术后恢复缓慢,呼吸功能受到显著影响。这一现象与体外循环所致的急性炎性肺损伤及肺缺血-再灌注损伤有关；
3术前用静脉注射及雾化吸入两种不同给药途径进行磷酸二酯酶III抑制剂米力农预处理均可明显抑制体外循环后炎性介质的产生,减轻全身炎症反应及组织脂质过氧化程度,减少白细胞在肺内的聚集；此外雾化吸入米力农尚可显著改善体外循环术后患者的肺氧合功能,减轻肺血管阻力升高程度,显示出良好的肺保护作用,而静脉应用米力农的肺保护作用并不明显,这可能与雾化吸入后的米力农主要在肺脏局部发挥作用、局部药物浓度较高有关；
4严重左心瓣膜病患者术后残余肺动脉高压的现象较为常见；雾化吸入米力农可显著降低该类患者肺动脉压力及肺血管阻力,增加其心脏指数；且对患者的心率、全身血管阻力并无显著影响,这说明了雾化吸入米力农在降低肺动脉压力及肺血管阻力的作用大大强于其对体循环的影响,反应出其良好的肺血管选择性；
5米力农雾化吸入为临床上应用米力农提供了新的安全、有效、便利的给药途径,有利于增强其局部作用,减少全身性副作用。
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:
PartⅠ
1、Cases collection and intervention approach
In 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 analyzed
General 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 Ⅱ
1、Cases collection and intervention approach
In 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 analyzed
General 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:
PartⅠ
1、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 Ⅱ
1、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.
引文
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