髖膝關(guān)節(jié)置換術(shù)加速康復(fù)中糖皮質(zhì)激素的作用*

徐彬 裴福興

（四川大學(xué)華西醫(yī)院骨科，成都610041）

·綜述·

髖膝關(guān)節(jié)置換術(shù)加速康復(fù)中糖皮質(zhì)激素的作用*

徐彬 裴福興**

（四川大學(xué)華西醫(yī)院骨科，成都610041）

隨著加速康復(fù)理念在髖膝關(guān)節(jié)置換術(shù)中逐步應(yīng)用，減輕術(shù)后炎癥、緩解疼痛、預(yù)防惡心嘔吐、改善患者精神、提高肌力等已成為圍術(shù)期管理的重要內(nèi)容。糖皮質(zhì)激素作為重要的抗炎藥物，已應(yīng)用在髖膝關(guān)節(jié)置換術(shù)圍術(shù)期治療中，并達(dá)到加速康復(fù)的目的。本文就糖皮質(zhì)激素在髖膝關(guān)節(jié)置換術(shù)加速康復(fù)中的應(yīng)用進行綜述，以期為進一步更科學(xué)有效地應(yīng)用糖皮質(zhì)激素提供理論基礎(chǔ)。

糖皮質(zhì)激素；髖膝關(guān)節(jié)置換術(shù)；加速康復(fù)；抗炎

加速康復(fù)外科（enhanced recovery after surgery, ERAS）是采用一系列有循證醫(yī)學(xué)證據(jù)證明有效的圍術(shù)期處理措施，以減少手術(shù)創(chuàng)傷應(yīng)激反應(yīng)，預(yù)防器官功能障礙，減少術(shù)后并發(fā)癥，縮短住院時間，減輕患者痛苦，從而提供高效率、高質(zhì)量的醫(yī)療服務(wù)[1,2]。ERAS在髖膝關(guān)節(jié)置換術(shù)（total hip/knee arthroplasty, THA/TKA）的應(yīng)用重點包括減輕術(shù)后應(yīng)激及炎癥反應(yīng)、優(yōu)化血液及營養(yǎng)管理、優(yōu)化疼痛和睡眠管理、預(yù)防靜脈血栓栓塞（venous thromboembolism,VTE）及感染、預(yù)防惡心嘔吐、優(yōu)化止血帶及引流管等[3]。

炎癥是手術(shù)創(chuàng)傷及應(yīng)激反應(yīng)的一個重要部分，炎癥反應(yīng)與術(shù)后疼痛、惡心嘔吐、疲倦、眩暈、肌力下降、睡眠障礙等密切相關(guān)，因此，降低術(shù)后炎癥反應(yīng)有助于減少術(shù)后并發(fā)癥、縮短住院時間，起到加速康復(fù)的作用。

糖皮質(zhì)激素作為常用而有效的抑制炎癥反應(yīng)藥物，已被廣泛應(yīng)用于髖膝關(guān)節(jié)置換術(shù)，通過降低術(shù)后炎癥反應(yīng)，從而達(dá)到緩解疼痛、預(yù)防惡心嘔吐等作用。本文圍繞加速康復(fù)外科這一理念，以降低炎癥反應(yīng)為中心，綜述髖膝關(guān)節(jié)置換術(shù)加速康復(fù)中糖皮質(zhì)激素的作用。

1 髖膝關(guān)節(jié)置換術(shù)的炎癥反應(yīng)

髖膝關(guān)節(jié)置換術(shù)是大型手術(shù)，手術(shù)部位深，需要進行分離和截骨等操作，手術(shù)失血多、創(chuàng)傷大，傷后的應(yīng)激反應(yīng)會導(dǎo)致全身及局部出現(xiàn)明顯的炎癥反應(yīng)，及包括C-反應(yīng)蛋白（C-reactionprotein,CRP）、白細(xì)胞介素（interleukin,IL）在內(nèi)的多種炎癥因子升高，同時引起局部疼痛、傷口腫脹、惡心嘔吐、精神食欲下降等術(shù)后并發(fā)癥。

1.1 疼痛與炎癥

疼痛的來源包括神經(jīng)刺激和炎癥反應(yīng)[4,5]，術(shù)后創(chuàng)傷可導(dǎo)致大量炎癥介質(zhì)釋放，從而降低痛覺感受器閾值，引起痛覺敏化[6]，導(dǎo)致患者接受輕微的刺激后，也會出現(xiàn)劇烈的疼痛。此外，炎癥反應(yīng)持續(xù)存在，也是術(shù)后慢性疼痛難以控制的重要原因[6]。髖膝關(guān)節(jié)置換術(shù)后包括IL-1β、IL-6、轉(zhuǎn)化生長因子α（transforming growth factor-α,TGF-α）在內(nèi)的多種炎癥因子均顯著升高。Zhang和An[7]的研究表明，IL-1β、IL-6、TGF-α等炎癥因子在疼痛的發(fā)生中扮演重要角色。

1.2 惡心嘔吐與炎癥

術(shù)后惡心嘔吐的重要因素包括手術(shù)創(chuàng)傷，患者個人體質(zhì)，麻醉、鎮(zhèn)痛藥物等引起的術(shù)后胃腸道反應(yīng)，而手術(shù)創(chuàng)傷可引起大量免疫細(xì)胞增殖和聚集，并釋放不同的炎癥介質(zhì)，這些免疫細(xì)胞及炎癥介質(zhì)是引起術(shù)后腸麻木甚至腸梗阻（postoperative ileus, POI）的重要原因[8]。POI常開始于術(shù)后3～4 h，并可持續(xù)數(shù)天。術(shù)后惡心嘔吐的原因很多，停用引起惡心嘔吐的藥物是重要的環(huán)節(jié)，但在麻醉后應(yīng)用糖皮質(zhì)激素?？深A(yù)防惡心嘔吐的發(fā)生，惡心嘔吐的發(fā)生率明顯下降。

1.3 疲倦與炎癥

Paddison等[9]發(fā)現(xiàn)，開放性結(jié)直腸術(shù)后患者疲倦評分與腹膜IL-6、IL-10、TNF-α水平相關(guān)。Maier等[10]的研究認(rèn)為，局部炎癥反應(yīng)可刺激迷走神經(jīng)引起疲倦，迷走神經(jīng)與孤束核直接相關(guān)，而孤束核可由外周免疫學(xué)刺激而激活[11,12]。因此，可以推測髖膝關(guān)節(jié)置換術(shù)后局部炎癥因子的升高也可刺激孤束核及迷走神經(jīng)系統(tǒng)，從而引起術(shù)后疲倦。

1.4 肌力下降與炎癥

已有充分的證據(jù)[13]表明，炎癥因子，如IL-6及TNF-α參與肌力下降及肌萎縮的發(fā)生過程。Bautmans等[14]的研究發(fā)現(xiàn)，急性感染時出現(xiàn)炎癥及IL-6升高的住院老年患者，與不伴有炎癥的患者比較，肌力及耐力更差。Bautmans等[15]以擇期腹部手術(shù)患者為研究對象，證明手術(shù)引起的炎癥反應(yīng)可引起CRP、IL-6、TNF-α升高，并與肌力下降相關(guān)。

2 糖皮質(zhì)激素在髖膝關(guān)節(jié)置換術(shù)中的應(yīng)用

糖皮質(zhì)激素因具有顯著的抗炎作用而被廣泛用于過敏、哮喘、自身免疫病、膿毒癥等。臨床上常用的糖皮質(zhì)激素有地塞米松、強的松、甲潑尼龍琥珀酸鈉、氫化可的松等,其中，0.75 mg地塞米松相當(dāng)于5 mg強的松、4 mg甲潑尼龍琥珀酸鈉、20 mg氫化可的松[16]。隨著圍術(shù)期加速康復(fù)的應(yīng)用，糖皮質(zhì)激素也逐漸應(yīng)用于圍術(shù)期治療。目前，糖皮質(zhì)激素已應(yīng)用于乳腺手術(shù)[17]、椎間盤手術(shù)[18]、腹腔鏡膽囊切除術(shù)[19]、結(jié)腸切除術(shù)[20]，關(guān)節(jié)置換術(shù)等[21,22]圍術(shù)期的處理中。（表1）

2.1 糖皮質(zhì)激素的應(yīng)用途徑及劑量

關(guān)節(jié)置換術(shù)圍術(shù)期中可應(yīng)用的糖皮質(zhì)激素包括地塞米松、甲潑尼龍琥珀酸鈉、氫化可的松、氟羥氫化潑尼松，應(yīng)用方式包括全身（靜脈應(yīng)用或口服）及局部應(yīng)用（關(guān)節(jié)內(nèi)或關(guān)節(jié)周圍），應(yīng)用時機包括術(shù)前、術(shù)中、術(shù)后[37]。全身應(yīng)用包括高劑量[21-25]（地塞米松40 mg、甲潑尼龍琥珀酸鈉125 mg）及低劑量應(yīng)用[26-28]（地塞米松10 mg/8 mg、氫化可的松100 mg），目前大部分研究均為單次應(yīng)用，多于術(shù)前靜脈注射，僅Jules-Elyee等[28]在術(shù)前及術(shù)后8 h兩次應(yīng)用100 mg氫化可的松，Romundstad等[23]在術(shù)后第1天予甲潑尼龍琥珀酸鈉125 mg靜脈注射。局部注射多為雞尾酒鎮(zhèn)痛方案中加用糖皮質(zhì)激素，于術(shù)中行關(guān)節(jié)周圍浸潤注射，藥物包括地塞米松6.6 mg[30]、甲潑尼龍琥珀酸鈉40 mg[29]、去炎松40/80 mg[31-35]、倍他米松1 mg[36]，多為低劑量應(yīng)用，僅Chia等[35]的研究中包含低劑量組去炎松40 mg及高劑量組去炎松80 mg。

2.2 髖膝關(guān)節(jié)置換術(shù)圍術(shù)期糖皮質(zhì)激素應(yīng)用的臨床效果

2.2.1 抗炎作用：Lunn等[21,22]在TKA及THA術(shù)前靜脈應(yīng)用甲潑尼龍琥珀酸鈉125 mg發(fā)現(xiàn)，24 h時CRP較對照組下降，Kardash等[25]在THA術(shù)前靜脈應(yīng)用地塞米松40 mg發(fā)現(xiàn)，48 h時CRP較對照組下降。Jules-Elyee等[28]在雙側(cè)TKA術(shù)前及8 h后靜脈應(yīng)用氫化可的松100 mg發(fā)現(xiàn)，術(shù)后6 h及10 h時IL-6下降，24 h時IL-6無明顯下降。Ng等[32]在膝關(guān)節(jié)單髁置換術(shù)中發(fā)現(xiàn)，布比卡因及腎上腺素中加用40 mg去炎松行關(guān)節(jié)周圍注射術(shù)后前3 d CRP及ESR較不加去炎松下降。Ikeuchi等[30]在TKA術(shù)中應(yīng)用6.6 mg地塞米松也發(fā)現(xiàn)，術(shù)后CRP及IL-6下降。

2.2.2 鎮(zhèn)痛作用：術(shù)前甲潑尼龍琥珀酸鈉高劑量靜脈應(yīng)用發(fā)現(xiàn)，患者整體疼痛下降，包括靜息痛及活動痛，并減少羥考酮的使用劑量[21,22]。同樣，術(shù)前地塞米松高劑量或低劑量靜脈應(yīng)用均可緩解術(shù)后疼痛，并可減少阿片類藥物的應(yīng)用[26-28]。在關(guān)節(jié)腔周圍行雞尾酒浸潤注射時加用地塞米松6.6 mg、去炎松40 mg可緩解術(shù)后疼痛，減少嗎啡等藥物的應(yīng)用[30-35]，而加用1 mg倍他米松可縮短塞來昔布的應(yīng)用時間[36]。

2.2.3 預(yù)防惡心嘔吐：在髖膝關(guān)節(jié)置換術(shù)前，靜脈應(yīng)用高劑量甲潑尼龍琥珀酸鈉及地塞米松或低劑量地塞米松均發(fā)現(xiàn)，可預(yù)防術(shù)后惡心嘔吐，并可減少昂丹司瓊等鎮(zhèn)吐藥物的應(yīng)用[25-27]。而術(shù)中行糖皮質(zhì)激素關(guān)節(jié)周圍浸潤注射并無相關(guān)作用。國際公認(rèn)的預(yù)防術(shù)后惡心嘔吐的指南[38]也推薦，靜脈應(yīng)用低劑量地塞米松及甲潑尼龍琥珀酸鈉具有預(yù)防術(shù)后惡心嘔吐的作用。

2.2.4 改善術(shù)后疲倦：Lunn等[21]在TKA術(shù)前靜脈應(yīng)用高劑量甲潑尼龍琥珀酸鈉后發(fā)現(xiàn)，患者手術(shù)當(dāng)天疲倦感減輕，之后并無相關(guān)作用。其評估疲倦的方法為10分制數(shù)字評分法（1分為舒適，10分為疲倦）[39]。2.2.5改善肌力及關(guān)節(jié)功能：在單髁置換術(shù)（unicompartmental knee arthroplasty,UKA）及TKA術(shù)中，行關(guān)節(jié)周圍雞尾酒注射時加用地塞米松6.6 mg或去炎松40 mg可使患者術(shù)后直腿抬高時間提前，并改善術(shù)后關(guān)節(jié)活動度[30-34]，這表明糖皮質(zhì)激素局部應(yīng)用可加速術(shù)后肌力恢復(fù)，有改善術(shù)后關(guān)節(jié)功能的作用。術(shù)后全身應(yīng)用糖皮質(zhì)激素是否也可增強肌力，改善關(guān)節(jié)功能仍需進一步研究。

2.3 糖皮質(zhì)激素應(yīng)用的安全性

雖然長期應(yīng)用糖皮質(zhì)激素有增加感染、消化道出血等風(fēng)險[40,41]，但圍術(shù)期單次應(yīng)用糖皮質(zhì)激素并無相關(guān)風(fēng)險[16,39,42-45]。一項涉及51個研究的meta分析也證實，心臟手術(shù)及創(chuàng)傷手術(shù)術(shù)前單次應(yīng)用高劑量甲潑尼龍琥珀酸鈉15～30 mg/kg不會增加術(shù)后并發(fā)癥風(fēng)險[44]。Lunn等[21]的研究發(fā)現(xiàn)，在TKA術(shù)前全身應(yīng)用糖皮質(zhì)激素可導(dǎo)致術(shù)后第1晚睡眠不良。此外，術(shù)前應(yīng)用糖皮質(zhì)激素會導(dǎo)致術(shù)后在PACU內(nèi)血糖升高[28]。有研究[24,34]發(fā)現(xiàn)，局部應(yīng)用糖皮質(zhì)激素可能增加術(shù)后感染，雖然與對照組比較，發(fā)生率差異無統(tǒng)計學(xué)意義，但仍需重視。目前，髖膝關(guān)節(jié)置換術(shù)圍術(shù)期應(yīng)用糖皮質(zhì)激素出現(xiàn)感染及消化道出血等風(fēng)險的相關(guān)研究限于患者數(shù)量、隨訪時限等因素，仍需進一步研究以確證。

表 1 糖皮質(zhì)激素在髖膝關(guān)節(jié)置換術(shù)圍術(shù)期中的應(yīng)用方案及臨床療效

應(yīng)用糖皮質(zhì)激素有引起骨壞死的風(fēng)險，而使用時間及劑量均與骨壞死發(fā)生率呈正相關(guān)。梅奧診所報道的77例激素引起的骨壞死患者中，最早出現(xiàn)骨壞死是在口服甲潑尼龍琥珀酸鈉16 mg/d第36天（累積劑量達(dá)576 mg）[46]。Wong等[47]報道的1352例接受短期高劑量激素治療的患者中，僅4例出現(xiàn)股骨頭壞死，平均激素使用總劑量為102 mg（以地塞米松為當(dāng)量）（59～150 mg），平均激素使用時間20 d（15～27 d）。Powell等[48]的研究報道，在短期內(nèi)口服1000 mg強的松可增加骨壞死發(fā)生率。目前，文獻報道，在髖膝關(guān)節(jié)置換術(shù)圍術(shù)期全身應(yīng)用糖皮質(zhì)激素，地塞米松每日使用劑量為8～40 mg，或甲潑尼龍琥珀酸鈉125 mg，或氫化可的松100 mg，使用時間不超過48 h，累計量地塞米松不超過40 mg，甲潑尼龍琥珀酸鈉不超過125 mg，氫化可的松不超過200 mg，文獻并未發(fā)現(xiàn)骨壞死相關(guān)并發(fā)癥。因此，控制使用劑量非常重要，在髖膝關(guān)節(jié)置換術(shù)圍術(shù)期短期、低劑量應(yīng)用糖皮質(zhì)激素并不會引起骨壞死相關(guān)并發(fā)癥。目前，對糖皮質(zhì)激素引起骨壞死的研究多為長期應(yīng)用及短期大劑量應(yīng)用，圍術(shù)期單次應(yīng)用或短期數(shù)次應(yīng)用糖皮質(zhì)激素引起骨壞死風(fēng)險的研究仍非常有限，需要進一步研究。

3 小結(jié)

糖皮質(zhì)激素因其有顯著的抗炎作用，已被廣泛應(yīng)用于圍術(shù)期處理中，以降低術(shù)后炎癥反應(yīng)、緩解疼痛、降低惡心嘔吐發(fā)生、增強肌力、緩解疲勞、改善關(guān)節(jié)功能等，加速患者術(shù)后康復(fù)。全身應(yīng)用糖皮質(zhì)激素，不管是高劑量應(yīng)用還是低劑量應(yīng)用，均有明確的預(yù)防術(shù)后惡心嘔吐的作用[29,37]，而局部應(yīng)用糖皮質(zhì)激素也有相關(guān)臨床優(yōu)勢。介于糖皮質(zhì)激素可預(yù)防術(shù)后惡心嘔吐并改善患者精神，從而改善患者術(shù)后營養(yǎng)狀況，是否減少術(shù)后血紅蛋白及白蛋白下降尚需進一步研究。全身應(yīng)用高劑量糖皮質(zhì)激素可緩解髖膝關(guān)節(jié)置換術(shù)后的疼痛[21-25]，但全身應(yīng)用低劑量糖皮質(zhì)激素疼痛并無明顯緩解[26-28]。因此，Lunn等[37]贊同Oliveira等[40]的觀點：與全身應(yīng)用低劑量地塞米松0.1 mg/kg比較，全身應(yīng)用高劑量地塞米松≥0.11 mg/kg可減少阿片類藥物的應(yīng)用，并可更有效地緩解關(guān)節(jié)活動痛。但地塞米松更高劑量≥0.21 mg/kg的鎮(zhèn)痛效果可能并不比中等劑量更好[40]。此外，研究報道，局部應(yīng)用糖皮質(zhì)激素也可降低局部炎癥反應(yīng)，緩解局部疼痛，但由于各研究樣本有限、研究設(shè)計欠科學(xué)、偏移較大等原因，局部應(yīng)用糖皮質(zhì)激素是否有鎮(zhèn)痛效果仍需進一步設(shè)計更為科學(xué)的研究進行探索。在降低術(shù)后炎癥反應(yīng)、緩解疼痛、改善體力、增強肌力等前提下，患者一般情況，如精神食欲，得到明顯改善，從而加速術(shù)后恢復(fù)并縮短住院時間。雖然目前無論糖皮質(zhì)激素是全身應(yīng)用還是局部應(yīng)用均未發(fā)現(xiàn)可增加包括感染及消化道出血在內(nèi)的嚴(yán)重并發(fā)癥，但可能會影響術(shù)后第1天的睡眠質(zhì)量[21]，因此，圍術(shù)期糖皮質(zhì)激素應(yīng)用可考慮在術(shù)后予安定等藥物改善睡眠。此外，由于糖皮質(zhì)激素有升高血糖的作用，加上手術(shù)應(yīng)激等影響，圍術(shù)期應(yīng)用糖皮質(zhì)激素時，應(yīng)檢測血糖水平，并進行控制，尤其對于糖尿病患者。雖然目前認(rèn)為，圍術(shù)期單次應(yīng)用糖皮質(zhì)激素有較高的安全性，但由于各研究樣本量較小、隨訪時間較短、缺少嚴(yán)謹(jǐn)?shù)姆椒ㄔu估感染及其他一些并發(fā)癥，圍術(shù)期應(yīng)用糖皮質(zhì)激素的安全性仍需要隨訪時間長、設(shè)計嚴(yán)格的大樣本研究進一步驗證[49]。目前，臨床中應(yīng)用糖皮質(zhì)激素方法眾多，藥物類別、劑量及應(yīng)用途徑不同，各應(yīng)用方案之間的比較也值得進一步研究，以期尋找最有效且安全的應(yīng)用方案，為臨床提供統(tǒng)一的應(yīng)用流程。

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f Effect of glucocorticoid in the enhanced recovery after surgery program of total hip/knee arthroplasty*

XU Bin,PEI Fuxing**

(Department of Orthopedic Surgery,West China Hospital,Sichuan University,Chengdu 610041,China)

As the enhanced recovery after surgery(ERAS)program is being applied in total hip/knee arthroplasty(THA/ TKA),alleviating postoperative inflammation,relieving pain,preventing nausea and vomiting,improving psychological status and enhancing muscle strengthen have become important in perioperative management.Glucocorticoid,a kind of important anti-inflammatory drug,has been applied in the perioperative management of THA/TKA to achieve the effect of ERAS. In this paper,we reviewed the application of glucocorticoid in the ERAS program of THA/TKA,to provide more evidences for a scientific and effective use of glucocorticoid.

Glucocorticoid;Total Hip/KneeArthroplasty;Enhanced RecoveryAfter Surgery;Anti-inflammation

2095-9958（2017）06-0 259-06

10.3969/j.issn.2095-9958.2017.03-20

國家衛(wèi)計委行業(yè)科研專項（201302007）

**通信作者：裴福興，E-mail：peifuxing@vip.163.com