劉明明,匡洪宇,姜曉艷,劉丹丹,于紀(jì)珠,潘宇
作者單位: 150001 哈爾濱醫(yī)科大學(xué)第一臨床醫(yī)學(xué)院內(nèi)分泌科
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嚴(yán)重腦外傷應(yīng)激性高血糖患者胰高血糖素樣肽-1水平與不良預(yù)后的相關(guān)性
劉明明,匡洪宇,姜曉艷,劉丹丹,于紀(jì)珠,潘宇
【摘要】目的探討腦外傷應(yīng)激性高血糖患者胰高血糖素樣肽-1(GLP-1) 水平變化及其對(duì)預(yù)后的影響。方法選取2013年1月—2014年9月ICU腦外傷患者64例,其中42例血糖升高為高血糖組,22例血糖正常為對(duì)照組。分別記錄創(chuàng)傷嚴(yán)重程度評(píng)分、病死率、ICU住院時(shí)間、總住院時(shí)間、GLP-1和血糖水平。隨訪(fǎng)3個(gè)月,終點(diǎn)為全因死亡。結(jié)果高血糖組GLP-1水平明顯低于對(duì)照組[(1.5±0.9)pmol/L vs. (0.8±0.4)pmol/L,t=3.828,P=0.001)]。高血糖組3個(gè)月病死率為42.9%,高于對(duì)照組13.6%(χ2=5.592,P<0.05)。GLP-1水平與血糖水平呈負(fù)相關(guān)(r=-0.58,P<0.01); 單變量、多變量分析均顯示創(chuàng)傷嚴(yán)重程度評(píng)分、GLP-1、血糖等3個(gè)指標(biāo)對(duì)終點(diǎn)事件的預(yù)測(cè)有顯著的意義(P<0.05),GLP-1為保護(hù)因素,創(chuàng)傷嚴(yán)重程度評(píng)分、血糖為危險(xiǎn)因素。結(jié)論GLP-1低水平與外傷后應(yīng)激性高血糖相關(guān),腦外傷應(yīng)激性高血糖患者的預(yù)后與低GLP-1和高血糖密切有關(guān)。
【關(guān)鍵詞】腦外傷;高血糖;胰高血糖素樣肽-1;重癥監(jiān)護(hù)病房
血糖穩(wěn)態(tài)的受損是在受傷及重大疾病之后常見(jiàn)的現(xiàn)象[1],常在無(wú)糖尿病史的患者中頻繁發(fā)生,維持<8.325 mmol/L(150 mg/dl)的葡萄糖水平成為重癥監(jiān)護(hù)病房(ICU)血糖控制的標(biāo)準(zhǔn)。胰高血糖素樣肽-1(glucagon-like peptide-1,GLP-1)受體在胰島α和β細(xì)胞及各種各樣的外圍組織中表達(dá),包括中樞和外周神經(jīng)系統(tǒng)、心臟、腎、肺、胃腸道。在正常生理狀態(tài), GLP-1通過(guò)導(dǎo)致葡萄糖調(diào)節(jié)的神經(jīng)機(jī)制來(lái)抑制胰高血糖素的分泌及促進(jìn)葡萄糖代謝。GLP-1的拮抗作用降低了胰島素分泌并導(dǎo)致血糖水平的上升[2]。注入外源的GLP-1促進(jìn)胰島素分泌并導(dǎo)致胰高血糖素抑制,而后導(dǎo)致血糖水平降低[3]。GLP-1受神經(jīng)機(jī)制調(diào)節(jié),繼發(fā)于腦外傷后,相關(guān)研究甚少,因此,筆者研究腦外傷對(duì)GLP-1循環(huán)水平的影響,探討是否嚴(yán)重外傷后GLP-1降低伴隨高血糖,是否與不良預(yù)后有關(guān)。
1資料與方法
1.1臨床資料選擇2013年1月—2014年9月我院ICU收治的嚴(yán)重腦外傷患者64例,入選標(biāo)準(zhǔn):(1)既往無(wú)糖尿病病史;(2)入院時(shí)糖化血紅蛋白正常;(3)年齡≥18歲;(4)嚴(yán)重腦外傷需ICU救治;(5)住院時(shí)間≥3 d。按隨機(jī)血糖分為2組,隨機(jī)血糖≥8.325 mmol/L(150 mg/dl)42例為高血糖組,其中男35例,女7例,年齡29~80(43.1±9.3)歲。隨機(jī)血糖<8.325 mmol/L 22例為對(duì)照組,其中男15例,女7例,年齡22~60(60.1±15.7)歲。
1.2觀察指標(biāo)收集研究對(duì)象的一般資料,包括性別、年齡、創(chuàng)傷嚴(yán)重程度評(píng)分(injury severity score,ISS<16分為輕傷,≥16分為重傷,ISS≥25分嚴(yán)重傷)、死亡時(shí)間、ICU觀察時(shí)間、總住院時(shí)間。
1.3血清血糖、 GLP-1測(cè)定(1)血糖測(cè)定:入院即刻、入院后72 h每2 h測(cè)1次,并計(jì)算平均血糖值。采用葡萄糖氧化酶法,儀器使用日立7600生化分析儀,試劑盒由寧波美康生物科技有限公司提供(正常參考值范圍3.9~6.1 mmol/L)。(2)GLP-1測(cè)定:入院即刻、入院后72 h每8 h測(cè)1次,并計(jì)算平均GLP-1值。GLP-1采用酶聯(lián)免疫吸附試驗(yàn)(ELISA),試劑盒購(gòu)自上海陽(yáng)光試劑有限公司(正常參考值范圍1.9~38 pmol/L)。檢驗(yàn)均嚴(yán)格按說(shuō)明書(shū)操作。
1.4隨訪(fǎng)采用門(mén)診、電話(huà)進(jìn)行隨訪(fǎng),隨訪(fǎng)期限為出院后3個(gè)月,終點(diǎn)事件是全因死亡。
2結(jié)果
2.12組臨床資料比較與對(duì)照組比較高血糖組血GLP-1明顯降低,差異有統(tǒng)計(jì)學(xué)意義(P<0.05),高血糖組年齡明顯升高,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。2組性別、損傷嚴(yán)重程度評(píng)分、ICU停留時(shí)間及總體住院時(shí)間比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。見(jiàn)表1。
表1 對(duì)照組與高血糖組患者臨床資料比較 ±s)
2.22組預(yù)后比較隨訪(fǎng)3個(gè)月,高血糖組患者死亡18例(42.9%),對(duì)照組死亡3例(13.6%),2組差異有統(tǒng)計(jì)學(xué)意義(χ2=5.592,P<0.05)
2.3GLP-1與血糖相關(guān)性分析對(duì)照組GLP-1與血糖無(wú)明顯相關(guān)性(r=-0.08,P=0.693);高血糖組GLP-1與血糖呈明顯負(fù)相關(guān)(r=-0.58,P<0.01)。見(jiàn)圖1、2。
圖1 對(duì)照組GLP-1與血糖相關(guān)性分析
圖2 高血糖組GLP-1與血糖相關(guān)性分析
2.4各項(xiàng)指標(biāo)對(duì)腦外傷應(yīng)激性高血糖患者死亡的預(yù)測(cè)價(jià)值單變量分析中,年齡、ISS評(píng)分、ICU住院時(shí)間、總住院時(shí)間、GLP-1、血糖等6個(gè)變量依次單獨(dú)進(jìn)入Cox回歸方程,結(jié)果顯示:ISS評(píng)分、GLP-1、血糖及住院時(shí)間等4個(gè)指標(biāo)對(duì)終點(diǎn)事件的預(yù)測(cè)有統(tǒng)計(jì)學(xué)意義(P<0.05),GLP-1為保護(hù)因素。多變量分析中:上述6個(gè)變量依次進(jìn)入Cox回歸方程,結(jié)果也顯示ISS評(píng)分、GLP-1、血糖等3個(gè)指標(biāo)對(duì)終點(diǎn)事件的預(yù)測(cè)有統(tǒng)計(jì)學(xué)意義(P<0.05),而其他變量對(duì)終點(diǎn)事件的預(yù)測(cè)無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05),GLP-1為保護(hù)因素。見(jiàn)表2。
表2 各項(xiàng)指標(biāo)對(duì)腦外傷應(yīng)激性高血糖患者死亡的預(yù)測(cè)價(jià)值
3討論
GLP-1是一種內(nèi)源性的腸促胰島素,它由小腸的L細(xì)胞分泌入血液循環(huán),并繼而增強(qiáng)葡萄糖依賴(lài)性的胰島素分泌,當(dāng)血糖濃度接近正常水平時(shí)該作用即消失[4]。GLP-1也會(huì)抑制餐后胰高血糖素的分泌,但其并不阻礙作為低血糖應(yīng)答的激素反向調(diào)節(jié)[5]。研究已經(jīng)證實(shí)了GLP-1主要分布于中樞神經(jīng)系統(tǒng)的孤束、背側(cè)和腹側(cè)髓質(zhì)以及嗅球神經(jīng)元細(xì)胞的核周體內(nèi)[6],它們的纖維投射到大腦各種結(jié)構(gòu)中,而這些部位也存在GLP-1受體的mRNA。因此筆者考慮腦外傷患者直接是中樞受累,可能更易出現(xiàn)GLP-1水平變化,從而影響血糖隨之變化。伴隨受傷后高血糖的發(fā)展機(jī)制較復(fù)雜。在本研究中,筆者嘗試確定GLP-1代謝的改變是否導(dǎo)致了葡萄糖穩(wěn)態(tài)受損,研究結(jié)果證實(shí)了筆者的假設(shè),所有腦外傷患者中對(duì)照組和高血糖組GLP-1水平傾向于比正常人群GLP-1范圍要低。高血糖組GLP-1明顯低于對(duì)照組,2組差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。且GLP-1水平降低伴隨血糖水平增高。因此,筆者在創(chuàng)傷后GLP-1水平和高血糖癥之間建立了明確的關(guān)系。
創(chuàng)傷后發(fā)生高血糖影響很多生理系統(tǒng),包括免疫功能、切口愈合及其他部位的新陳代謝[7~9]。通常高血糖癥的患者預(yù)后較差[10,11],另外,血糖升高的優(yōu)化管理在這些人群中異常困難和復(fù)雜。有報(bào)道在有或沒(méi)有糖尿病的嚴(yán)重疾病患者中外源性GLP-1的實(shí)施有利于控制血糖水平[12~14]。研究發(fā)現(xiàn)GLP-1能使得2型糖尿病患者的空腹血糖和餐后血糖水平恢復(fù)正常,此作用機(jī)制具有有益的促胰島素和胰高血糖素分泌作用[15,16]。因此,GLP-1似乎是維持正常胰腺內(nèi)分泌功能所不可缺少的。甚至在長(zhǎng)期的多肽輸液過(guò)程中,給予GLP-1治療的患者并未發(fā)生低血糖事件[17]。當(dāng)葡萄糖濃度低于生理水平時(shí)并未出現(xiàn)GLP-1誘發(fā)的胰島素釋放,可能是缺乏GLP-1降糖作用的原因[18]。這說(shuō)明GLP-1相對(duì)安全,不宜出現(xiàn)低血糖反應(yīng)。本研究發(fā)現(xiàn)42例高血糖患者有18例死亡(42.9%),22例血糖正常者僅3例死亡(13.6%),2組差異有統(tǒng)計(jì)學(xué)意義(P<0.05),GLP-1、血糖都能預(yù)測(cè)病死率,病死率在低GLP-1和高血糖患者中更高。
另外,本研究發(fā)現(xiàn)高血糖組年齡較大,2組年齡差異有統(tǒng)計(jì)學(xué)意義(P<0.01),這可能與高齡更容易血糖穩(wěn)態(tài)受損有關(guān)。
GLP-1的前景被廣泛看好,一項(xiàng)研究中[19],81例受試者接受了GLP-1治療,另有82例受試者則被給予胰島素或安慰劑,結(jié)果有7例患者發(fā)生了無(wú)癥狀性低血糖(<60 mg/dl),其中接受GLP-1輸注4例(4.9%),給予胰島素或安慰劑3例(3.7%)。所有繼發(fā)于GLP-1治療的低血糖情況在暫停輸注后均可緩解。需要注意的是,GLP-1輸注效果最佳且耐受性最好的劑量約為1~1.2 pmol·kg-1·min-1。大多數(shù)與GLP-1輸注相關(guān)的低血糖發(fā)生于用藥劑量大于1.2 pmol·kg-1·min-1時(shí)[20]。在大多數(shù)試驗(yàn)中,輸注GLP-1均能被患者良好耐受,且并無(wú)發(fā)生惡心或嘔吐的相關(guān)報(bào)告[21~24]。然而,Nikolaidis等[20]發(fā)現(xiàn),在GLP-1輸注劑量達(dá)1.5 pmol·kg-1·min-1時(shí),10例患者中發(fā)生惡心4例,嘔吐2例。所有試驗(yàn)均未報(bào)告嚴(yán)重的不良事件及與GLP-1治療相關(guān)的死亡病例,無(wú)論危重患者是否患有糖尿病,GLP-1在治療其高血糖癥方面都將會(huì)是一種有前途的藥物。
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論著·臨床
The correlation of the level of glucagon like peptide 1 to predict the poor outcome after brain injuryLIUMingming,KUANGHongyu,JIANGXiaoyan,LIUDandan,YUJizhu,PANYu.DepartmentofEndocrinology,FirstAffiliatedHospitalofHarbinMedicalUniversity,HeilongjiangProvince,Harbin150001,China
Correspondingauthor:KUANGHongyu,E-mail:panyu0203@163.com
【Abstract】ObjectiveTo investigate the hyperglycemia of glucagon like peptide 1 (GLP-1) level in brain trauma patients with stress and its effect on prognosis.MethodsSixty-four patients with cerebral trauma were selected, including 42 patients with hyperglycemia, 22 patients with normal blood glucose. The injury severity score, the mortality rate, hospitalization time, blood glucose and GLP-1 were recorded. Follow up for 3 months, the end point was the all cause mortality.ResultsHyperglycemia group's GLP-1 levels was significantly lower than that in normal blood glucose group [(1.5±0.9) pmol/L vs. (0.8±0.4)pmol/L,t=3.828,P=0.001].The mortality rate in hyperglycemia group was higher the normal blood glucose group(42.9% vs. 13.6%,χ2=5.592,P<0.05);GLP-1 levels and blood glucose levels were negatively correlated(r=-0.58,P<0.01); single variable and multivariable analysis showed that injury severity score (ISS), GLP-1, blood glucose has significant prediction for endpoint (P<0.05), GLP-1 was protective factor,injury severity score, blood glucose were risk factors.ConclusionThe lower level of the GLP-1 and post-traumatic stress hyperglycemia were correlated, prognosis of the traumatic brain injuries patients with stress hyperglycemia and low GLP 1 and hyperglycemia were closely related.
【Keywords】Brain injury; Hyperglycemia; Glucagon like peptide 1; Intensive care unit
收稿日期:(2015-10-09)
【DOI】10.3969 / j.issn.1671-6450.2015.12.013
通信作者:匡洪宇,E-mail:panyu0203@163.com
作者單位: 150001哈爾濱醫(yī)科大學(xué)第一臨床醫(yī)學(xué)院內(nèi)分泌科