右美托咪啶對(duì)全麻下胃癌根治術(shù)老年病人免疫功能及認(rèn)知功能的影響

謝久東孫德軍

目的觀察右美托咪定對(duì)全麻下行胃癌根治術(shù)老年病人免疫功能和術(shù)后認(rèn)知功能的影響。方法48例擬行胃癌根治術(shù)的老年病人,年齡(68±5)歲,隨機(jī)分成對(duì)照組(C組)、0.5 μg/kg右美托咪定組(D1組)、0.75 μg/kg右美托咪定組(D2組)3組,每組16例。于麻醉誘導(dǎo)前10 min (T0), 手術(shù)結(jié)束時(shí) (T1),手術(shù)后24 h (T2), 手術(shù)后48 h (T3)抽取外周血,用流式細(xì)胞儀檢測(cè)T淋巴細(xì)胞(CD3+, CD4+,CD8+)、 NK細(xì)胞(CD16+CD56+)和瘤壞死因子(TNF)-α,白介素(IL)-2濃度,并采用簡(jiǎn)易智能狀態(tài)量表(MMSE)評(píng)估病人術(shù)前1 d和術(shù)后7 d認(rèn)知狀態(tài),評(píng)定術(shù)后認(rèn)知功能障礙(POCD)的發(fā)生率。結(jié)果與T0時(shí)點(diǎn)相比,3組T淋巴細(xì)胞(CD3+、CD4+、CD8+)、NK細(xì)胞(CD16+CD56+)在 T1～T3時(shí)點(diǎn)明顯降低,炎癥因子TNF-α、IL-2濃度增加(P<0.05)。與C組相比, D1、D2組的CD3+、CD4+、CD8+、CD16+CD56+及CD4/CD8在T1～T3時(shí)點(diǎn)明顯增加,TNF-α、IL-2濃度顯著降低(P<0.05);D1組與D2組間比較,各項(xiàng)指標(biāo)差異均無統(tǒng)計(jì)學(xué)意義 (P>0.05)。對(duì)照組6例(37.5%)發(fā)生POCD,D1組3例(18.8%)發(fā)生POCD,D2組2例(12.5%)發(fā)生POCD,3組比較差異有統(tǒng)計(jì)學(xué)意義。結(jié)論右美托咪定可改善全麻下行胃癌根治術(shù)老年病人術(shù)后免疫功能，降低術(shù)后認(rèn)知功能障礙的發(fā)生。

右美托咪定; 胃癌根治術(shù); 免疫功能; 認(rèn)知功能; 簡(jiǎn)易智能狀態(tài)量表

因創(chuàng)傷、出血、低溫等過度應(yīng)激反應(yīng)會(huì)導(dǎo)致T淋巴細(xì)胞、NK自然殺傷細(xì)胞免疫功能抑制,產(chǎn)生免疫功能抑制。術(shù)后認(rèn)知功能障礙(POCD)是老年病人麻醉手術(shù)后常見的中樞神經(jīng)并發(fā)癥之一[1];改善老年病人圍術(shù)期免疫功能,降低POCD,對(duì)改善預(yù)后具有重要意義。鹽酸右美托咪定(dexmedetomidine)是一種新型高選擇性α2腎上腺素能受體激動(dòng)劑,具有鎮(zhèn)靜、催眠、抗焦慮、鎮(zhèn)痛、抑制交感活性及改善圍術(shù)期心血管穩(wěn)定性等藥理作用[2],其在神經(jīng)保護(hù)方面的潛在作用亦逐漸被認(rèn)識(shí)[3]。本研究擬觀察不同劑量右美托咪定對(duì)全麻下行胃癌根治術(shù)老年病人免疫功能和術(shù)后認(rèn)知功能的影響。

1 材料與方法

1.1 一般資料 納入本院2014年8月至2015年3月胃腸科收治擬以全麻下行胃癌根治術(shù)的病人48例,ASAⅠ～Ⅲ級(jí),年齡(68±5)歲。排除標(biāo)準(zhǔn):肝腎功能障礙、凝血功能異常、術(shù)前存在呼吸道感染、放療、化療、近期使用激素或免疫抑制劑的病人。采用隨機(jī)數(shù)字表法分成生理鹽水組(C組)、0.5 μg/kg右美托咪定組(D1組)和0.75 μg/kg右美托咪定組(D2組),每組16例。本研究獲醫(yī)院倫理委員會(huì)審批,術(shù)前簽署知情同意書。

1.2 方法 無麻醉前用藥,常規(guī)禁食禁飲,入室后常規(guī)監(jiān)測(cè)心電圖、血壓、心率、動(dòng)脈血氧分壓(SPO2)、頸內(nèi)靜脈置管及行橈動(dòng)脈有創(chuàng)血壓監(jiān)測(cè),靜脈輸注乳酸鈉林格氏液6～8 ml/(kg·h)。麻醉誘導(dǎo)前10 min,經(jīng)靜脈泵注負(fù)荷劑量右美托咪定:D1、D2組分別靜脈輸注右美托咪定0.5 μg/kg、0.75 μg/kg的負(fù)荷劑量,隨后分別以0.5 (μg/kg·h)、0.75 μg/(kg·h)持續(xù)泵注,C組給予同等容量的生理鹽水泵入,手術(shù)結(jié)束前30 min停止。誘導(dǎo)期,3組均給予異丙酚2～2.5 mg/kg、舒芬太尼0.5 μg/kg、維庫溴銨0.15 mg/kg。誘導(dǎo)后行氣管插管,機(jī)械通氣,潮氣量8～10 ml/kg、頻率10～12次/min,保持術(shù)中PETCO235～45 mmHg。切皮前靜脈給予舒芬太尼0.3 μg/kg；維持期,給予異丙酚4～6 mg/(kg·h),阿曲庫銨0.3～0.5 mg/(kg·h)。根據(jù)麻醉深度指數(shù)和痛疼傷害敏感指數(shù)(腦電麻醉深度監(jiān)護(hù)儀,威浩康醫(yī)療公司)調(diào)節(jié)舒芬太尼和異丙酚的劑量;如遇術(shù)中高血壓或低血壓,使用血管活性藥調(diào)節(jié)。術(shù)中依據(jù)動(dòng)脈血?dú)夥治鲅a(bǔ)充生理鹽水需要量和失血量。術(shù)后帶氣管導(dǎo)管送麻醉后監(jiān)測(cè)治療室(PACU)觀察。記錄血壓、心率、SPO2,觀察術(shù)后清醒時(shí)間、氣管拔管時(shí)間、PACU停留時(shí)間。

1.3 標(biāo)本收集與處理 麻醉誘導(dǎo)前10 min (T0),手術(shù)結(jié)束時(shí) (T1),手術(shù)后24 h (T2),手術(shù)后48 h (T3)分別抽靜脈血5 ml,經(jīng)3000 r/min離心10 min后取血清,放置于-72 ℃冰箱保存。采用流式細(xì)胞儀(FACScaliber, BD公司)測(cè)定T淋巴細(xì)胞亞群(CD3+、CD4+、CD8+), NK細(xì)胞(CD16+,CD56+)水平(試劑盒BD公司,美國(guó));采用ELLSA法測(cè)定腫瘤壞死因子-α(TNF-α),白介素-2(IL-2)濃度(博士得,中國(guó));并采用簡(jiǎn)易智能狀態(tài)檢查量表(MMSE)評(píng)估病人術(shù)前1 d和術(shù)后7 d認(rèn)知狀態(tài)，評(píng)定POCD發(fā)生情況。評(píng)分標(biāo)準(zhǔn): MMSE 27～30分為正常;<27分為POCD,其中21～26分為輕度,10～20分為中度,0～9分為重度。

2 結(jié)果

2.1 3組病人一般情況比較 3組病人年齡、性別、體質(zhì)量、手術(shù)持續(xù)時(shí)間、術(shù)中失血量、血管活性藥使用、PACU停留時(shí)間差異均無統(tǒng)計(jì)學(xué)意義。D1、D2組清醒時(shí)間及拔管時(shí)間比C組延長(zhǎng);術(shù)中舒芬太尼總量比C組少(P<0.05)。見表1。所有病人在圍手術(shù)期均平穩(wěn)渡過,但是D2組的心動(dòng)過緩發(fā)生率較C組增高。見表1。

2.2 3組病人檢測(cè)指標(biāo)比較 與T0時(shí)點(diǎn)相比,3組T淋巴細(xì)胞(CD3+、CD4+)、NK細(xì)胞(CD16+CD56+)在 T1～T3時(shí)點(diǎn)明顯降低,炎癥因子(TNF-α、IL-2)濃度增加(P<0.05)。與C組相比,D1、D2組的CD3+、CD4+、CD16+CD56+及CD4/CD8在T1～T3時(shí)明顯增加,TNF-α、IL-2濃度顯著降低(P<0.05);與D1組相比,D2組的CD3+、CD4+、CD8+、CD16+CD56+、CD4/CD8 、TNF-α和IL-2在T0、T1～T3時(shí)點(diǎn)差異無統(tǒng)計(jì)學(xué)意義 (P>0.05)。見表2。

2.3 3組POCD發(fā)生情況比較 通過MMSE評(píng)定,對(duì)照組6例(37.5%)發(fā)生POCD,D1組3例(18.8%)發(fā)生POCD,D2組 2例(12.5%)發(fā)生POCD,3組比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。

表1 各組病人一般資料(n=16)

注：與C組比較,*P<0.05

表2 各組不同時(shí)段各個(gè)指標(biāo)檢測(cè)結(jié)果

注：與T0比較,*P<0.05;與C組比較△P<0.05

3 討論

圍術(shù)期的麻醉方式及藥物、手術(shù)創(chuàng)傷、出血、低溫、疼痛、輸血等因素均可影響機(jī)體的免疫狀態(tài)[4],其中麻醉因素和手術(shù)因素起著重要作用。免疫功能中,T淋巴細(xì)胞、NK淋巴細(xì)胞數(shù)量或比值是反映機(jī)體免疫紊亂的敏感指標(biāo);T淋巴細(xì)胞亞群水平可評(píng)估機(jī)體細(xì)胞免疫功能,T淋巴細(xì)胞亞群中,CD3+反映細(xì)胞免疫總體水平[5];CD4+是輔助性T淋巴細(xì)胞,輔助其他細(xì)胞參與免疫應(yīng)答;CD8+為免疫抑制細(xì)胞,對(duì)免疫應(yīng)答有負(fù)性調(diào)節(jié)功能; CD4+/CD8+<1.4稱為免疫抑制狀態(tài),提示病人免疫功能減低。TNF-α是全身炎性反應(yīng)中較早出現(xiàn)的細(xì)胞因子,IL-2等細(xì)胞因子主要由Th1型細(xì)胞分泌[6],參與細(xì)胞免疫和遲發(fā)型超敏反應(yīng)性炎性反應(yīng)。本研究結(jié)果發(fā)現(xiàn)給予一定劑量的右美托咪定可減輕胃癌根治術(shù)老年病人的免疫抑制狀態(tài)。

右美托咪定改善胃癌根治術(shù)老年病人免疫功能的機(jī)制可能為:一方面,右美托咪定是選擇性α2腎上腺素能受體激動(dòng)劑,可作用于交感神經(jīng),調(diào)控兒茶酚胺等的釋放和降低交感神經(jīng)張力,減輕機(jī)體的應(yīng)激反應(yīng)[7],降低機(jī)體自主神經(jīng)系統(tǒng)和下丘腦-垂體-腎上腺素軸活化程度,從而使單核巨噬細(xì)胞和T細(xì)胞表面的腎上腺素受體和糖皮質(zhì)激素受體的兒茶酚胺和糖皮質(zhì)激素減少,減少細(xì)胞內(nèi)炎癥因子的產(chǎn)生,從而緩解機(jī)體的免疫反應(yīng)抑制狀態(tài)。同時(shí),其他的研究也證實(shí)右美托咪定可抑制炎癥反應(yīng)。Bekker等[8]研究提示,圍術(shù)期間持續(xù)使用右美托咪定可有效降低手術(shù)病人的TNF-α、IL-6等炎性因子的表達(dá),抑制圍術(shù)期炎癥反應(yīng)。研究也證實(shí)右美托咪定可降低胃癌根治術(shù)病人IL-6的釋放[9-10],降低炎癥反應(yīng)。這與本研究結(jié)果一致。另一方面,右美托咪定可減少圍術(shù)期阿片類藥物的應(yīng)用[11],提示具有一定鎮(zhèn)痛作用。Pestieau 等[12]研究發(fā)現(xiàn)一定劑量的右美托咪定可減少小兒行扁桃體切除術(shù)的阿片類藥物需求量。阿片類藥物與機(jī)體免疫功能密切相關(guān);研究證實(shí)阿片類藥物可通過介導(dǎo)Th1型細(xì)胞向Th2型細(xì)胞分化,使Th1/Th2的平衡向Th2偏移,抑制免疫功能[13]。本研究中C組術(shù)中應(yīng)用舒芬太尼總量為(53±7) μg,明顯高于D1組(42±5) μg及D2組(45±4) μg。故推測(cè)右美托咪定具有的鎮(zhèn)痛作用可減少阿片類藥物使用,從而間接改善病人細(xì)胞免疫功能。

炎癥反應(yīng)以及免疫反應(yīng)被認(rèn)為參與了POCD的發(fā)生發(fā)展。Zhao等[14]研究發(fā)現(xiàn)手術(shù)后的老年大鼠認(rèn)知功能下降與下丘腦周圍炎癥反應(yīng)呈正相關(guān)。右美托咪啶作為新型的α2腎上腺素能受體激動(dòng)劑在預(yù)防POCD方面有較好的作用。其機(jī)制可能一方面通過調(diào)控免疫功能,另一方面抑制炎癥反應(yīng),從而降低對(duì)中樞神經(jīng)系統(tǒng)的損害,從而降低POCD的發(fā)生。MMSE是評(píng)價(jià)認(rèn)知功能常用工具,以敏感度高、操作簡(jiǎn)單方便在臨床應(yīng)用較多[15]。本研究所有病人術(shù)前評(píng)分均在正常范圍,排除了術(shù)前合并認(rèn)知功能障礙。本研究結(jié)果證實(shí)右美托咪定有助于預(yù)防全麻老年病人POCD的發(fā)生。

綜上所述,對(duì)全麻下行胃癌根治術(shù)的老年病人,右美托咪定可改善免疫功能和炎癥反應(yīng),從而降低POCD的發(fā)生。

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Effectsofdexmedetomidineonpost-operativeimmunefunctionandcognitivedysfunctionaftertheradicalgastrectomyinelderlypatientswithgeneralanesthesia

XIEJiu-dong,SUNDe-jun.

DepartmentofIntensiveCareUnit(ICU),ZhongshanHospitalAffiliatedtoXiamenUniversity,Xiamen361004,China

ObjectiveTo investigate the effects of dexmedetomidine on post-operative immune function and cognitive dysfunction after radical gastrectomy in elderly patients.MethodsForty-eight elderly patients were randomized divided into control group (group C), 0.5 μg/kg dexmedetomidine group (group D1) and 0.75 μg/kg dexmedetomidine group (group D2), with 16 cases in each group. Blood sample of all patients 10 min before the starting of operation (T0), at the end of the operation (T1), 24 h after the operation (T2) and 48 h after the operation(T3) were collected to detect T lymphocytes(CD3+, CD4+,CD8+), NK cell(CD16+CD56+),the concentration of TNF-α,IL-2. Cognition state was evaluated by mini-mental state examination (MMSE)1 day before operation and 7 days after operation. And the incidence rate of POCD in the three groups was recorded and compared.ResultsCompared to T0time, the levels of CD3+, CD4+,CD8+,CD4/CD8,CD16+CD56+ were significantly decreased, and the levels of TNF-α,IL-2 were significantly increased at T1-T3in the three groups. Compared to group C, the levels of CD3+, CD4+,CD8+,CD4/CD8,CD16+CD56+ in group D1 and D2 were significantly increased, and the levels of TNF-α,IL-2 were significantly decreased at T0, T1-T3time. The incidence rate of POCD in group C (6 cases) was significantly higher than that in group D1 (3 cases) and group D2 (2 cases) (P<0.05).ConclusionsThe dexmedetomidine can decrease the incidence of POCD in elderly patients at a dose-dependent manmer; The possible mechanism is that dexmedetomidine can alleviate the immune function and inhibit the inflammation reaction.

dexmedetomidine; radical gastrectomy; immune function; cognitive function; mini-mental state examination

361004 福建省廈門市，廈門大學(xué)附屬中山醫(yī)院重癥醫(yī)學(xué)科

孫德軍，Email：sundejin6788@163.com

R 641.2; R 749.1

A

10.3969/j.issn.1003-9198.2017.10.013

2016-11-09)