烏司他丁聯(lián)合丙氨酰谷氨酰胺對(duì)體外循環(huán)瓣膜置換術(shù)患者的肺保護(hù)作用

于冬梅，劉海峰，陳克研，周　錦

沈陽(yáng)軍區(qū)總醫(yī)院麻醉科，沈陽(yáng) 110016

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*通信作者

烏司他丁聯(lián)合丙氨酰谷氨酰胺對(duì)體外循環(huán)瓣膜置換術(shù)患者的肺保護(hù)作用

于冬梅，劉海峰，陳克研，周錦*

沈陽(yáng)軍區(qū)總醫(yī)院麻醉科，沈陽(yáng) 110016

[摘要]目的探討烏司他丁聯(lián)合丙氨酰谷氨酰胺對(duì)體外循環(huán)瓣膜置換術(shù)患者肺泡毛細(xì)血管膜屏障功能的影響。方法擬在體外循環(huán)(Cardiopulmonary bypass，CPB)下行心臟瓣膜置換術(shù)患者40例，年齡40～60歲，ASAⅡ或Ⅲ級(jí)，采用隨機(jī)數(shù)字表法，將患者隨機(jī)分為烏司他丁組(U組)和烏司他丁聯(lián)合Ala-GLn組(UA組)，每組20例。麻醉誘導(dǎo)后，UA組泵注丙氨酰谷氨酰胺0.4 g/(kg·d)，U組泵注等量的復(fù)方氨基酸注射液，兩組持續(xù)輸注24 h，并均在轉(zhuǎn)流液內(nèi)加入烏司他丁2萬(wàn)U/kg。分別在麻醉后(T0)、CPB前(T1)、開放主動(dòng)脈30 min(T2)、閉合胸骨(T3)及術(shù)后5 h(T4)、24 h(T5)，經(jīng)頸內(nèi)靜脈采血3 mL，用于測(cè)定血漿TNF-α、IL-6和SP-A的含量；經(jīng)動(dòng)脈采血進(jìn)行血?dú)夥治?；觀察術(shù)后機(jī)械通氣時(shí)間。結(jié)果與T0時(shí)比較，兩組患者在T2～T5時(shí)的血清TNF-α、IL-6含量均升高(P<0.05)；UA組患者血漿TNF-α、IL-6含量低于U組(P<0.05)。與T0時(shí)比較，兩組患者在T2～T5時(shí)SP-A水平顯著升高(P<0.05)，UA組患者血漿SP-A含量低于U組(P<0.05)；與T0時(shí)比較，兩組患者在T2～T5時(shí)A-aDO2、RI值顯著升高(P<0.05)，UA組患者A-aDO2、RI值低于U組(P<0.05)；UA組術(shù)后機(jī)械通氣時(shí)間較U組縮短(P<0.05)。結(jié)論烏司他丁聯(lián)合丙氨酰谷氨酰胺能抑制體外循環(huán)瓣膜置換術(shù)患者的炎癥反應(yīng)，保護(hù)肺泡毛細(xì)血管膜屏障功能，具有一定的肺保護(hù)作用。

[關(guān)鍵詞]烏司他??；丙氨酰谷氨酰胺；瓣膜置換術(shù)；SP-A；肺保護(hù)

0引言

體外循環(huán)(Cardiopulmonary bypass，CPB)是開胸心血管手術(shù)的一項(xiàng)必備技術(shù)，其不但需要血液與人工管道直接接觸，而且需要在不同程度的低溫條件下，以平流方式進(jìn)行血液轉(zhuǎn)流，并不是一種生理過(guò)程。這些非生理因素會(huì)引發(fā)一系列炎性反應(yīng)過(guò)程，最終導(dǎo)致TNF-α、IL-6、IL-8等炎性因子的釋放，這些炎性因子的激活不但能導(dǎo)致術(shù)后肺功能障礙，還嚴(yán)重影響了患者的預(yù)后[1-4]。通過(guò)合理使用抗炎藥物，可調(diào)節(jié)CPB期間炎性因子和促炎因子的釋放，抑制炎癥反應(yīng)，有利于減輕體外循環(huán)相關(guān)性肺損傷和改善預(yù)后。

烏司他丁是一種廣譜的蛋白酶抑制劑，包括胰蛋白酶、糜蛋白酶、彈性蛋白酶和各種胰酶，并且能抑制炎性因子和促炎因子的釋放[5-7]。有研究表明，烏司他丁能減輕體外循環(huán)冠脈搭橋術(shù)患者圍術(shù)期炎癥反應(yīng)，減少術(shù)后并發(fā)癥[8]。丙氨酰谷氨酰胺(Alanyl glutamine，Ala-Gln)既具有抗氧化作用，也能抑制CPB相關(guān)炎癥反應(yīng)[9]，但是烏司他丁聯(lián)合Ala-Gln應(yīng)用于CPB下心臟手術(shù)的抗炎作用及對(duì)肺泡膜屏障功能和彌散功能的影響還未見報(bào)道。本研究擬通過(guò)觀察烏司他丁聯(lián)合Ala-Gln對(duì)CPB下心臟瓣膜置換術(shù)患者血清TNF-α、IL-6、肺表面活性蛋白A(Surfactant protein-A，SP-A)、肺泡-動(dòng)脈血氧分壓差(Aveolar-arterial gradient of oxygen，A-aDO2)和呼吸指數(shù)(Respiratory index，RI)值的影響，來(lái)探討烏司他丁和Ala-Gln聯(lián)合應(yīng)用對(duì)CPB引起的炎癥反應(yīng)和肺泡毛細(xì)血管膜屏障功能的影響。

1資料與方法

1.1臨床資料本研究經(jīng)本院醫(yī)學(xué)倫理委員會(huì)批準(zhǔn)，并與患者及家屬簽署知情同意書。隨機(jī)選取我院行體外循環(huán)心臟瓣膜置換術(shù)患者40例，ASAⅡ～Ⅲ級(jí)，年齡40～60歲，體重50～81 kg，均為初次心臟手術(shù)，無(wú)風(fēng)濕活動(dòng)、呼吸系統(tǒng)疾病和近期非甾體類抗炎鎮(zhèn)痛藥服用史。隨機(jī)分為烏司他丁組(U組)和烏司他丁聯(lián)合Ala-Gln組(UA組)，每組20例，兩組患者年齡、體重、CPB和手術(shù)時(shí)間等比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，具有可比性，見表1。

1.2方法所有患者均于麻醉前30 min肌肉注射嗎啡10 mg。入室后開放外周靜脈，在局麻下行橈動(dòng)脈穿刺置管，持續(xù)監(jiān)測(cè)心電圖(Electrocardiogram，ECG)、心率(Heart rate，HR)、脈搏血氧飽和度(Pulse oxygen saturation，SpO2)、體溫(Temperature，T)和有創(chuàng)動(dòng)脈壓。靜脈注射依托咪酯0.2 mg/kg、舒芬太尼1 μg/kg、哌庫(kù)溴銨 0.1 mg/kg、咪達(dá)唑侖0.05 mg/kg全麻誘導(dǎo)，氣管內(nèi)插管后連接麻醉機(jī)進(jìn)行機(jī)械通氣，潮氣量8～10 mL/kg、吸呼比(I∶E)1∶2、呼吸頻率12次/min、吸入氧濃度60%、機(jī)械通氣期間維持呼氣末二氧化碳分壓(End-tidal CO2pressure，PETCO2)在30～40 mmHg之間。行右頸內(nèi)靜脈穿刺置管，連續(xù)監(jiān)測(cè)中心靜脈壓(Central venous pressure，CVP)。吸入七氟烷，靜脈持續(xù)泵注丙泊酚，間斷靜脈注射舒芬太尼和哌庫(kù)溴銨維持麻醉。在麻醉誘導(dǎo)后，UA組持續(xù)泵注Ala-Gln 0.4 g/(kg·d)；U組以等量復(fù)方氨基酸注射液代替，輸注時(shí)間為24 h，兩組均在轉(zhuǎn)流液內(nèi)加入烏司他丁2×104U/kg。體外循環(huán)期間泵流量控制在2.2～2.6 L/(min·m2)，平均動(dòng)脈壓(Mean arterial pressure，MAP)維持在50～80 mmHg。

1.3標(biāo)本采集及檢測(cè)分別于麻醉后(T0)、開胸后CPB前(T1)、主動(dòng)脈開放30 min(T2)、關(guān)胸(T3)、術(shù)后5 h(T4)、術(shù)后24 h(T5)靜脈采血3 mL，用酶聯(lián)免疫吸附(ELISA)方法測(cè)定SP-A、TNF-α、IL-6；動(dòng)脈采血進(jìn)行血?dú)夥治?，觀察肺泡氣-動(dòng)脈血氧分壓差(Aveolar-arterial gradient of oxygen，A-aDO2)和呼吸指數(shù)(Respiratory index，RI)的變化；記錄機(jī)械通氣時(shí)間。

2結(jié)果

2.1一般資料兩組患者性別、年齡、體重、CPB時(shí)間和手術(shù)時(shí)間比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，見表1。

表1　兩組患者一般情況比較

2.2兩組患者圍術(shù)期炎性因子和血清SP-A比較兩組患者血清TNF-α、IL-6含量、SP-A值在T2～T5時(shí)均高于T0時(shí)(P<0.05)，且UA組低于U組(P<0.05)。見表2。

表2　兩組患者血清TNF-α、IL-6、SP-A比較(ng/L)

注：*與T0時(shí)比較，P<0.05；#與U組比較，P<0.05

2.3兩組A-aDO2和RI值比較與組內(nèi)T0時(shí)比較，兩組動(dòng)脈血?dú)釧-aDO2值在T2～T5時(shí)均升高，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；與U組比較，UA組動(dòng)脈血?dú)釧-aDO2值在T2～T5時(shí)均降低(P<0.05)；與組內(nèi)T0時(shí)比較，兩組RI值在T2～T5時(shí)均顯著升高(P<0.05)，見表3。

表3　兩組患者動(dòng)脈血?dú)釧-aDO2、RI值的變化

注：*與T0時(shí)比較，P<0.05；#與U組比較，P<0.05

2.4兩組患者機(jī)械通氣時(shí)間比較U組機(jī)械通氣時(shí)間較UA組明顯延長(zhǎng)(14.3±0.6 vs.10.1±1.1)，兩組比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。

3討論

CPB相關(guān)肺功能障礙主要表現(xiàn)為肺換氣功能障礙，A-aDO2和RI是反映肺換氣功能、肺泡膜彌散功能和氧合功能的重要指標(biāo)，A-aDO2、RI值越高，肺換氣和氧合功能越差。本研究結(jié)果表明，兩組體外循環(huán)開始后、關(guān)胸、術(shù)后5 h及24 h各時(shí)間點(diǎn)的A-aDO2、RI值高于同組T0時(shí)，但烏司他丁聯(lián)合Ala-Gln組上述時(shí)間點(diǎn)的A-aDO2、RI值低于烏司他丁組，而且術(shù)后的機(jī)械通氣時(shí)間顯著縮短。說(shuō)明烏司他丁聯(lián)合Ala-Gln可改善體外循環(huán)患者術(shù)后的肺換氣和氧合功能。

SP-A是一種親水性肺表面活性物質(zhì)相關(guān)蛋白，不僅能降低肺泡表面張力，提高肺泡的穩(wěn)定性，還能促進(jìn)損傷的肺泡上皮細(xì)胞和毛細(xì)血管內(nèi)皮細(xì)胞修復(fù)，此外，還參與了免疫防御、控制炎癥反應(yīng)和調(diào)節(jié)其他肺表面活性蛋白的釋放等[10]。當(dāng)肺泡毛細(xì)血管屏障受損時(shí)，SP-A可外滲至血液中。因此，SP-A既是一種肺泡毛細(xì)血管屏障的保護(hù)性蛋白，也是一種評(píng)價(jià)肺泡毛細(xì)血管屏障損傷程度的標(biāo)志物[11-13]。本研究結(jié)果表明，各組T2～T5時(shí)血清SP-A顯著高于T0時(shí)，但是UA組上述時(shí)間點(diǎn)的血清SP-A含量低于U組，說(shuō)明烏司他丁聯(lián)合Ala-Gln能更好地保護(hù)肺泡毛細(xì)血管膜屏障的完整性。

眾所周知，CPB導(dǎo)致的全身炎癥反應(yīng)是術(shù)后肺功能障礙的重要機(jī)制之一[14]。TNF-α是炎癥反應(yīng)的始發(fā)和促發(fā)因子，在CPB肺損傷早期起著重要作用[15]。IL-6是由激活的T細(xì)胞、巨噬細(xì)胞和上皮細(xì)胞分泌，并可被TNF-α誘導(dǎo)。有研究表明，IL-6能進(jìn)一步促進(jìn)白細(xì)胞聚集，導(dǎo)致細(xì)胞腫脹和蛋白酶的釋放，進(jìn)而破壞肺泡膜屏障并導(dǎo)致血漿和蛋白滲出，最終導(dǎo)致肺泡壁充血、水腫和低氧血癥[16-17]。本研究結(jié)果表明，各組在體外循環(huán)后T2～T5時(shí)血清TNF-α、IL-6含量均高于T0時(shí)，在體外循環(huán)期間最高，隨后在T3～T5時(shí)皆有所下降。血清SP-A含量、A-aDO2、RI值與血清TNF-α、IL-6含量的變化趨勢(shì)相一致，隨著TNF-α、IL-6含量增高而增加，隨其降低而下降，說(shuō)明血清SP-A含量、A-aDO2、RI值與血清TNF-α、IL-6含量具有一定的相關(guān)性。UA組血清TNF-α、IL-6含量在T2～T5時(shí)顯著低于U組，說(shuō)明烏司他丁聯(lián)合Ala-Gln能更好地抑制CPB導(dǎo)致的全身炎癥反應(yīng)。

綜上所述，烏司他丁聯(lián)合Ala-Gln通過(guò)抑制TNF-α、IL-6的釋放，保護(hù)了肺泡毛細(xì)血管屏障的完整性，從而減少SP-A向血液外漏，因而改善了體外循環(huán)心臟瓣膜置換手術(shù)患者的肺換氣和氧合功能，從而具有更好的保護(hù)作用。

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Effect of ulinastatin combined with alanyl glutamine on lung protection in patients undergoing valve replacement operation through cardiopulmonary bypass

YU Dong-mei,LIU Hai-feng,CHEN Ke-yan,ZHOU Jin*

(Department of Anesthesiology,General Hospital of Shenyang Military Region,Shenyang 110016,China)

[Abstract]ObjectiveTo investigate the effect of ulinastatin combined with alanyl glutamine on alveolar barrier function in patients undergoing valve replacement operation through cardiopulmonary bypass(CPB).MethodsForty ASA Ⅱ or Ⅲ patients aged 40～60 years undergoing valve replacement operation through cardiopulmonary bypass were randomly divided into 2 groups (20 cases in each group):ulinastatin group(group U) and ulinastatin combined with alanyl glutamine group(group UA).After anesthesia induction,alanyl glutamine 0.4 g/(kg·d)was infused in group UA,and the same volume of compound amino acid injection was given in group U,the drugs being infused for 24 h.Ulinastatin 20 000 U/kg was added to the priming solution in both groups.Three mL venous blood was taken for IL-6,TNF-α and SP-A detection accompanied by arterial blood gas analysis after anesthesia preoperatively (T0),before CPB (T1),at 30 min after aorta unclamping(T2),at the end of operation(T3),at 5 h (T4) and 24 h after operation (T5).The mechanical ventilation time was observed in ICU.ResultsCompared with T0,the levels of plasma TNF-α and IL-6 in both groups at T2～T5 increased (P<0.05),and there were significant differences between the two groups (P<0.05).Compared with T0,the SP-A level in both groups at T2～T5increased (P<0.05),and there was significant difference between the two groups (P<0.05).Compared with T0,the A-aDO2 and RI values in both groups increased at T2～T5(P<0.05),and there were significant differences between the two groups (P<0.05).The time of mechanical ventilation in group UA was significantly shorter than that of group U (P<0.05).ConclusionUlinastatin combined with alanyl glutamine can decrease the inflammatory response,protect alveolar barrier function,and thus protecting the lung from injury.

Key words：Ulinastatin;Alanyl glutamine;Valve replacement;SP-A;Lung protection

收稿日期：2015-08-06

DOI:10.14053/j.cnki.ppcr.201604010