馬　娟　李　雪　陳　龍　汪　麗　趙錦寧　唐仕芳　史　源

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·論著·

同步間歇指令通氣支持下吸入氦氧混合氣和空氧混合氣治療胎糞吸入綜合征的隨機(jī)對(duì)照試驗(yàn)

馬娟李雪陳龍汪麗趙錦寧唐仕芳史源

目的探討胎糞吸入綜合征(MAS)新生兒在同步間歇指令通氣(SIMV)支持下吸入氦氧混合氣(Heliox)和空氧混合氣的療效。方法2014年3月1日至2015年5月30日在第三軍醫(yī)大學(xué)大坪醫(yī)院NICU住院的MAS新生兒，以隨機(jī)數(shù)字表法分為Heliox組和對(duì)照組，全部患兒均給予SIMV作為呼吸支持模式；Heliox組吸入Heliox 70(He 70%，O230%)6 h后更換吸入空氧混合氣(O230%)；對(duì)照組吸入空氧混合氣。主要觀察指標(biāo)為治療期間氧合指數(shù)(OI)和拔管時(shí)間，次要觀察指標(biāo)為機(jī)械通氣并發(fā)癥發(fā)生率、NICU住院時(shí)間、血?dú)夥治?、炎癥反應(yīng)指標(biāo)、心肌損傷標(biāo)志物、生后28 d和100 d時(shí)振幅整合腦電圖(aEEG)結(jié)果。結(jié)果Heliox組和對(duì)照組分別納入33和31例。Heliox組OI顯著高于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(P=0.022), Heliox組拔管時(shí)間、機(jī)械通氣并發(fā)癥發(fā)生率及NICU住院時(shí)間均顯著低于對(duì)照組,差異均有統(tǒng)計(jì)學(xué)意義(P分別為0.037,0.013和0.010)；兩組呼吸支持后2、6、12、24、48 h時(shí)點(diǎn)血?dú)夥治鲋笜?biāo)(pH、HCO3-1、BE、PaO2、PaCO2)差異均有統(tǒng)計(jì)學(xué)意義(P均<0.05)； Heliox組6 h時(shí)點(diǎn)炎癥反應(yīng)指標(biāo)(IL-6、IL-8、TNF-α、CRP)和24 h時(shí)點(diǎn)心肌損傷標(biāo)志物(CK、 CK-MB)均較0 h時(shí)點(diǎn)降低，差異均有統(tǒng)計(jì)學(xué)意義(P均<0.05)。Heliox組生后28 d和100 d時(shí)aEEG檢查神經(jīng)發(fā)育重度異常發(fā)生率分別為9.1%和3.0%，顯著低于對(duì)照組的25.8%和9.6%(P<0.05)。結(jié)論在SIMV支持下吸入Heliox治療MAS新生兒較空氧混合氣具有良好的療效，安全性好，值得深入研究。

氦氧混合氣；胎糞吸入綜合征；新生兒；同步間歇指令通氣

胎糞吸入綜合征(MAS)是新生兒常見(jiàn)的呼吸系統(tǒng)疾病，以呼吸窘迫和持續(xù)肺動(dòng)脈高壓為主要臨床表現(xiàn)，病死率高[1～3]。重癥MAS患兒常需機(jī)械通氣治療[4～8]，同步間歇指令通氣(SIMV)是一種間歇正壓通氣(IPPV)與患兒自主呼吸有機(jī)結(jié)合的間歇按需通氣模式，根據(jù)患兒自主呼吸要求提供預(yù)設(shè)通氣，具有較少人機(jī)對(duì)抗產(chǎn)生、有效降低氣道壓力、減少撤機(jī)困難和防止呼吸肌萎縮的優(yōu)點(diǎn)，已成為MAS治療的重要手段[9～13]。近年來(lái)研究發(fā)現(xiàn)氦氧混合氣(Heliox)應(yīng)用于兒童呼吸系統(tǒng)疾病具有獨(dú)特的優(yōu)勢(shì)。新生兒肺發(fā)育不完全、呼吸道狹窄，Heliox低密度的物理特性使氧氣更易通過(guò)因炎癥所致更加狹窄的氣道管腔，從而可有效降低呼吸道阻力，增加血氧含量，改善呼吸系統(tǒng)癥狀[14～19]。本研究在SIMV呼吸支持下采用Heliox治療MAS新生兒以探討論其臨床療效。

1　方法

1.1倫理和知情同意本研究經(jīng)第三軍醫(yī)大學(xué)大坪醫(yī)院(我院)倫理委員會(huì)批準(zhǔn)，所有受試新生兒的監(jiān)護(hù)人均在試驗(yàn)前簽署書(shū)面知情同意書(shū)。

1.2納入標(biāo)準(zhǔn)①入院時(shí)符合第3版《實(shí)用新生兒學(xué)》臨床診斷MAS標(biāo)準(zhǔn)；②符合我院新生兒科SIMV上機(jī)標(biāo)準(zhǔn)(出生6 h內(nèi)應(yīng)用氣囊和面罩正壓通氣，胸部不抬起，或正壓通氣15～30 s,心率仍低于80～100·min-1，或1 min內(nèi)仍無(wú)自主呼吸，pH<7.2)；③胎齡≥37周且≤42周；④監(jiān)護(hù)人簽署書(shū)面知情同意書(shū)參與本研究。

1.3排除標(biāo)準(zhǔn)具備以下任意1項(xiàng)者：①患先天性或遺傳代謝性疾?。虎诎橥饪萍膊?，需行手術(shù)治療。

1.4分組方法和分配隱藏實(shí)施符合入組條件的新生兒在取得書(shū)面知情同意書(shū)后，按隨機(jī)數(shù)字表法分為Heliox組和對(duì)照組，分組序列號(hào)裝入密閉信封，在試驗(yàn)前由不產(chǎn)生隨機(jī)序列的試驗(yàn)人員抽取確定分組。

1.5干預(yù)措施①基礎(chǔ)干預(yù)措施：入組新生兒均在氣管插管下給予SIMV支持治療(美國(guó)鳥(niǎo)牌AVEA呼吸機(jī)，具有氦氧入口接頭)，根據(jù)胎齡調(diào)整呼吸機(jī)參數(shù)(吸氣峰壓、呼氣末正壓、吸氣時(shí)間、吸呼比、呼吸頻率)，到達(dá)目標(biāo)氧飽和度95%。 ②不同組別干預(yù)措施：Heliox組吸入Heliox 70(He 70%，O230%)，吸入6 h后更換為空氧混合氣(O230%)；對(duì)照組吸入空氧混合氣。③撤機(jī)指征:PIP≤15 cmH2O,有效自主呼吸逐漸增強(qiáng)，呼吸機(jī)呼吸頻率≤10·min-1，血?dú)夥治鼋Y(jié)果正常。

1.6療效指標(biāo)

1.6.1主要觀察指標(biāo)治療期間記錄并統(tǒng)計(jì)兩組患兒氧合指數(shù)(OI)和拔管時(shí)間。

1.6.2次要觀察指標(biāo)①血?dú)夥治觯河诤粑С?0、2、6、12、24、48 h時(shí)點(diǎn)采集患兒末梢血0.2 mL行血?dú)夥治?pH、HCO3-1、BE、PaO2、PaCO2)。②機(jī)械通氣并發(fā)癥發(fā)生率。③炎癥反應(yīng)指標(biāo)和心肌損傷標(biāo)志物： 采集靜脈血，于0和6 h時(shí)點(diǎn)測(cè)定IL-6、IL-8、CRP、TNF-α，0和24 h時(shí)點(diǎn)測(cè)定肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)。④NICU住院時(shí)間。⑤神經(jīng)發(fā)育情況：于生后28 d和100 d召回行振幅整合腦電圖(aEEG)檢查，aEEG最低電壓<5 μV，最高電壓<10 μV為神經(jīng)發(fā)育重度異常[20]。

2　結(jié)果

2.1一般情況2014年3月1日至2015年5月30日我院NICU中符合本文納入和排除標(biāo)準(zhǔn)檢驗(yàn)的 MAS新生兒64例，具體納入和排除流程見(jiàn)圖1。Heliox組33例，對(duì)照組31例。表1顯示，兩組0 h時(shí)點(diǎn)性別、胎齡、出生體重、分娩方式、炎癥反應(yīng)指標(biāo)和心肌損傷標(biāo)志物的差異均無(wú)統(tǒng)計(jì)學(xué)差異(P均>0.05)。

圖1　研究對(duì)象篩選流程

2.2主要觀察指標(biāo)Heliox組和對(duì)照組OI為(301±22)和(264±22) ，t=5.47,P=0.022；拔管時(shí)間為(78±30)和(115±50)h，t=12.32，P=0.037；兩組2個(gè)主要結(jié)局指標(biāo)差異均有統(tǒng)計(jì)學(xué)意義。

2.3次要觀察指標(biāo)

2.3.1血?dú)夥治霰?顯示，Heliox組和對(duì)照組在2、6、12、24、48 h時(shí)點(diǎn)pH、PaO2、BE、HCO3-較0 h時(shí)點(diǎn)均升高，PaCO2下降 ， 上述時(shí)點(diǎn)血?dú)夥治鲋笜?biāo)2組差異均有統(tǒng)計(jì)學(xué)意義。

Heliox(n=33)對(duì)照組(n=31)χ2/tP男/女20/1319/120.0030.08胎齡/周39.2±1.539.5±1.217.80.09體重/g3528±2513617±2495.710.12陰道產(chǎn)/剖腹產(chǎn)17/1616/15<0.0010.07IL-8/pg·mL-167.4±6.967.6±7.06.540.25IL-6/pg·mL-131.3±3.131.2±4.03.680.31TNF-α/ng·L-149.4±4.649.4±4.99.540.09CRP/mg·L-16.1±0.86.1±0.86.370.06CK/U·L-1176.1±18.3177.6±18.06.950.06CK-MB/U·L-127.3±8.127.4±8.04.390.07

2.3.2機(jī)械通氣并發(fā)癥發(fā)生率Heliox組和對(duì)照組機(jī)械通氣并發(fā)癥發(fā)生率為15.2%和29.0%，χ2=5.791，P=0.013，差異有統(tǒng)計(jì)學(xué)意義。

2.3.3炎癥反應(yīng)指標(biāo)Heliox組和對(duì)照組6 h時(shí)點(diǎn)IL-6分別為(15.2±1.8)和(20.0±2.6)pg·mL-1,差異有統(tǒng)計(jì)學(xué)意義(t=3.91，P=0.019)，Heliox組0 h與6 h時(shí)點(diǎn)IL-6差異有統(tǒng)計(jì)學(xué)意義(t=8.45,P=0.033)，對(duì)照組0 h與6 h時(shí)點(diǎn)IL-6差異無(wú)統(tǒng)計(jì)學(xué)意義(t=7.92，P=0.063)；Heliox組和對(duì)照組6 h時(shí)點(diǎn)IL-8分別為(31.7±4.4)和(36.7±4.3)pg·mL-1，差異有統(tǒng)計(jì)學(xué)意義(t=7.62，P=0.022)，Heliox組0 h與6 h時(shí)點(diǎn) IL-8差異有統(tǒng)計(jì)學(xué)意義(t=3.17,P=0.021)，對(duì)照組0 h與6 h時(shí)點(diǎn) IL-8差異無(wú)統(tǒng)計(jì)學(xué)意義(t=6.99，P=0.103)；Heliox組和對(duì)照組TNF-α分別為(38.5±3.9)和(43.0±4.2)ng·mL-1，差異有統(tǒng)計(jì)學(xué)意義(t=11.25，P=0.034)，Heliox組0 h與6 h時(shí)點(diǎn)TNF-α差異有統(tǒng)計(jì)學(xué)意義(t=13.35,P=0.010)，對(duì)照組0 h與6 h時(shí)點(diǎn)TNF-α差異無(wú)統(tǒng)計(jì)學(xué)意義(t=3.16，P=0.072)；Heliox組和對(duì)照組CRP分別為(5.6±0.5)和(5.9±0.7)mg·L-1，差異有統(tǒng)計(jì)學(xué)意義(t=9.35，P=0.039)，Heliox組0 h與6 h時(shí)點(diǎn)CRP差異有統(tǒng)計(jì)學(xué)意義(t=17.57,P=0.034)，對(duì)照組0 h與6 h時(shí)點(diǎn)CRP差異無(wú)統(tǒng)計(jì)學(xué)意義(t=6.77，P=0.088)。

2.3.4心肌損傷標(biāo)志物Heliox組和對(duì)照組24 h時(shí)點(diǎn)CK分別為(131.7±13.7)和(156.6±14.4)U·L-1，差異有統(tǒng)計(jì)學(xué)意義(t=6.73，P=0.045)，Heliox組0 h與24 h時(shí)點(diǎn)CK差異有統(tǒng)計(jì)學(xué)意義(t=8.39,P=0.043)，對(duì)照組0 h與24 h時(shí)點(diǎn)CK差異無(wú)統(tǒng)計(jì)學(xué)意義(t=4.33，P=0.076)；Heliox組和對(duì)照組24 h時(shí)點(diǎn)CK-MB分別為(23.2±7.2)和(26.0±7.9)U·L-1，差異有統(tǒng)計(jì)學(xué)意義(t=3.67，P=0.039)，Heliox組0 h與24 h時(shí)點(diǎn)CK-MB差異有統(tǒng)計(jì)學(xué)意義(t=7.77,P=0.008)，對(duì)照組0 h與24 h時(shí)點(diǎn)CK-MB差異無(wú)統(tǒng)計(jì)學(xué)意義(t=7.90，P=0.055)。

時(shí)點(diǎn)/hpHHeliox組對(duì)照組HCO3-1/mmol·L-1Heliox組對(duì)照組BE/mmol·L-1Heliox組對(duì)照組PaO2/kPaHeliox組對(duì)照組PaCO2/kPaHeliox組對(duì)照組a/APO2/kPaHeliox組對(duì)照組07.1±0.07.1±0.118.2±1.318.2±1.3-5.8±1.3-5.8±1.45.2±0.95.2±0.87.8±1.57.8±1.50.1±0.10.12±0.0727.2±0.11)7.2±0.019.6±1.41)18.4±1.3-5.2±1.21)-5.4±1.25.7±1.01)5.6±1.07.6±1.41)7.7±1.30.2±0.11)0.15±0.07t8.897.8110.016.517.914.51P0.0120.0320.0270.0160.0010.02367.3±0.11)7.2±0.120.1±1.41)18.9±1.2-4.1±1.01)-4.3±1.17.9±1.51)6.6±1.47.2±1.31)7.5±1.40.2±0.11)0.17±0.08t2)13.013.986.739.5416.8719.96P2)0.0120.0250.0470.0450.0160.31127.3±0.11)7.18±0.120.3±1.51)19.1±1.2-3.9±1.01)-4.1±1.18.9±1.61)8.0±1.57.0±1.21)7.3±1.30.4±0.21)0.20±0.09t2)11.213.676.989.573.579.67P2)0.0370.0120.0350.0660.0240.038247.4±0.11)7.3±0.122.8±1.71)19.4±1.5-3.0±1.01)-3.8±1.19.4±1.61)8.2±1.76.9±1.11)7.2±1.00.4±0.21)0.22±0.09t2)16.2113.959.3119.5416.9312.68P2)0.0240.0170.0010.0040.0020.023487.4±0.11)7.3±0.123.2±1.81)21.0±1.6-2.5±1.01)-3.4±1.210.0±1.81)8.5±1.36.7±1.31)7.0±1.00.4±0.21)0.29±0.12t2)31.5127.1518.4211.5415.4919.17P2)0.0160.0140.0290.0170.0280.019

注1)Heliox組與對(duì)照組相比P<0.05;2) 與0 h時(shí)點(diǎn)相比

2.3.5NICU住院時(shí)間Heliox組和對(duì)照組NICU住院時(shí)間為(15.3±4.2)和(19.5±5.0)d，t=7.98，P=0.010，差異有統(tǒng)計(jì)學(xué)意義。

2.3.6神經(jīng)發(fā)育情況生后28 d時(shí)aEEG檢查顯示Heliox組和對(duì)照組神經(jīng)發(fā)育重度異常發(fā)生率分別為9.1%(3/33)和25.8%(8/31)，差異有統(tǒng)計(jì)學(xué)意義(χ2=3.138，P=0.047)。生后100 d時(shí)aEEG檢查顯示Heliox組和對(duì)照組重度異常發(fā)生率分別為3.0%(1/33)和9.6%(3/31)，差異有統(tǒng)計(jì)學(xué)意義(χ2=3.38，P=0.027)。

3　討論

氦氣是無(wú)色無(wú)味且無(wú)毒的非易燃惰性單原子氣體，在體內(nèi)與其他氣體不發(fā)生反應(yīng)，無(wú)藥理活性，具有極好的生物安全性。MAS的主要發(fā)病原因?yàn)樘号懦鎏ゼS污染羊水，隨后將其吸入呼吸道而引起機(jī)械性阻塞，使氣道狹窄、阻力變大。氦氣低密度、高黏滯度和運(yùn)動(dòng)時(shí)受到阻力更小的物理特性，使其在MAS的治療中可顯著增加每分鐘通氣量，增大呼氣流速，減輕呼吸功耗，促進(jìn)氧氣向肺泡彌散及CO2排除，有效改善肺順應(yīng)性[21,22]，因此亟需開(kāi)發(fā)更有效的機(jī)械通氣方案和模式改善新生兒預(yù)后，提高嚴(yán)重低氧的新生兒MAS治療水平, SIMV較少產(chǎn)生人機(jī)對(duì)抗，同時(shí)心血管并發(fā)癥少[7]，而Heliox低密度的物理特性更適用于新生兒狹窄的呼吸道，有效提高血氧含量[23～25]，因此在SIMV支持下予Heliox治療MAS有可能具有重要的潛在臨床應(yīng)用價(jià)值。

MAS可致肺損傷、呼吸衰竭、氣漏及持續(xù)肺動(dòng)脈高壓，如未及時(shí)發(fā)現(xiàn)并處理，可能導(dǎo)致新生兒死亡。研究顯示氦氣可減輕肺損害的炎癥反應(yīng)，且具備有效的抗炎作用，動(dòng)物實(shí)驗(yàn)顯示氦氣可降低小鼠肺泡出血，肺組織中性粒細(xì)胞侵潤(rùn)、水腫和肺透明膜的發(fā)生[26]，針對(duì)MAS患兒的全身化學(xué)性炎癥反應(yīng)，采用Heliox聯(lián)合SIMV治療MAS可有效發(fā)揮抗炎作用，本研究Heliox組較對(duì)照組炎癥反應(yīng)指標(biāo)得到顯著改善。Heinen等[27]的動(dòng)物研究表明氦氣在缺血再灌注中具有保護(hù)心臟的作用，臨床上顯示MAS患兒常并發(fā)心肌損害，心肌損害的嚴(yán)重程度進(jìn)一步增加了MAS患兒心力衰竭發(fā)生率，本研究顯示與對(duì)照組相比，Heliox組缺氧狀況得到了顯著改善，驗(yàn)證了動(dòng)物實(shí)驗(yàn)結(jié)果[26,27]，Heliox治療可有效減輕肺損害的炎癥反應(yīng)，且具備一定的抗炎作用，同時(shí)在缺血再灌注中具有保護(hù)心臟的作用。

本研究Heliox組血?dú)夥治鲋笜?biāo)顯著優(yōu)于對(duì)照組，表明采用Heliox治療MAS有效改善了患兒通氣效果，可有效緩解新生兒癥狀；Heliox組OI、拔管時(shí)間、住院時(shí)間、機(jī)械通氣并發(fā)癥發(fā)生率均優(yōu)于對(duì)照組，顯示出良好的近期療效；新生兒窒息的本質(zhì)是缺氧，多為胎兒窒息(宮內(nèi)窘迫)的延續(xù)，早期可直接導(dǎo)致死亡，遠(yuǎn)期可導(dǎo)致多種神經(jīng)系統(tǒng)并發(fā)癥及后遺癥。重癥MAS常合并新生兒窒息，所以早期診斷新生兒窒息所造成的腦損傷并積極進(jìn)行臨床干預(yù)，對(duì)降低患兒病死率及致殘率具有重要意義。

aEEG能簡(jiǎn)便有效的評(píng)價(jià)神經(jīng)功能，對(duì)神經(jīng)系統(tǒng)損傷預(yù)后有較高的預(yù)測(cè)價(jià)值[28,29]；本研究于患兒生后28 d及100 d時(shí)行aEEG檢查評(píng)估神經(jīng)發(fā)育情況，Heliox組28 d及100 d時(shí)aEEG重度異常發(fā)生率分別為9.1%和3.0%，顯著低于對(duì)照組的25.8%和9.6%，有較好的近期療效。

本文為SIMV支持下予Heliox治療MAS療效的初步結(jié)果，樣本量不足可能會(huì)影響結(jié)果的可靠性；MAS新生兒生后28 d及100 d時(shí)aEEG僅可反映近期神經(jīng)發(fā)育情況，并不反映遠(yuǎn)期神經(jīng)發(fā)育結(jié)局。

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(本文編輯：張崇凡)

Randomized controlled trial of inhaling heliox and air oxygen mixture in meconium aspiration syndrom under the support of synchronized intermittent mandatory ventilation

MAJuan，LIXue，CHENLong,WANGLi,ZHAOJin-ning,TANGShi-fang,SHIYuan

(DepartmentofPediatrics，DapingHospital，ThirdMilitaryMedicalUniversity，Chongqing400042，China)

SHI Yuan，E-mail:petshi530@ vip.163.com

Objective To investigate the curative effect of inhaling heliox and air oxygen mixture in meconium aspiration syndrome under the support of synchronized intermittent mandatory ventilation (SIMV).MethodsSixty-four children with MAS in NICU of the DaPing Hospital, Third Military Medical University from March 1st, 2014 to May 30th, 2015 were taken as samples. The children, who were treated with SIMV as respiratory support mode, were divided into Helio group (n=33) and control group (n=31) in accordance with the random number table. Heliox group inhaled Heliox 70 (He 70% O230%) for 6 h after replacement of inhaling air oxygen mixture (30% O2); Control group inhaled air oxygen mixed gas. Main outcome measures: oxygenation index (OI) during treatment and extubation time; Secondary outcome measures: incidence of the complications of mechanical ventilation, hospital stays in NICU, bood gas analysis, inflammation index and myocardial injury markers, amplitude integrated electroencephalography (aEEG) results.ResultsOI in the heliox group was significantly higher than that in the control group; the difference was statistically significant (P=0.022), and the extubation time, incidence of the complications of mechanical ventilation and hospital stays in NICU of heliox group were significantly lower than those of control group; the differences were statistically significant (P=0.037, 0.013 and 0.010). Blood gas analysis index (pH, HCO3-, BE, PaO2, PaCO2) in two groups (2, 6, 12, 24, 48 h) presented some discrepancy; the differences were statistically significant (P<0.05). The inflammation index (IL-6, IL-8, TNF-a CRP) at 6 h and myocardial injury markers (CK, CK-MB) at 24 h of the two groups were decreased compared with those at 0 h, and heliox group decreased more significantly compared with the control group; the differences were statistically significant (P<0.05). The aEEG abnormal checking rate of children born after 28 and 100 days of heliox group was 9.1% and 3.0%, significantly lower than 25.8% and 9.6% of the control group (P< 0.05).ConclusionInhaling heliox has better curative effect and high security than inhaling air oxygen mixture for MAS under the support of SIMV, and it is worthy of further study.

Heliox; Meconium aspiration syndrome; Neonate; Synchronized intermittent mandatory ventilation

10.3969/j.issn.1673-5501.2016.02.003

第三軍醫(yī)大學(xué)大坪醫(yī)院兒科重慶，400042

史源，E-mail:petshi530@ vip.163.com

2015-12-30

2016-03-07)