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      腔鏡手術(shù)患者舒芬太尼靶控輸注的藥動(dòng)學(xué)研究*

      2016-12-22 10:19:51郭向陽翟所迪任宇鵬
      中國微創(chuàng)外科雜志 2016年12期
      關(guān)鍵詞:藥動(dòng)學(xué)腔鏡芬太尼

      劉 維 趙 艷 吳 瓊 郭向陽 翟所迪 盧 煒 任宇鵬 孫 誼

      (北京大學(xué)第三醫(yī)院麻醉科,北京 100083)

      ?

      ·實(shí)驗(yàn)研究·

      腔鏡手術(shù)患者舒芬太尼靶控輸注的藥動(dòng)學(xué)研究*

      劉 維①趙 艷**吳 瓊 郭向陽 翟所迪①盧 煒②任宇鵬②孫 誼②

      (北京大學(xué)第三醫(yī)院麻醉科,北京 100083)

      目的 探討腔鏡手術(shù)臨床常用濃度舒芬太尼靶控輸注(target-controlled infusion,TCI)的藥動(dòng)學(xué)特點(diǎn)。 方法2011年6~9月,擇期全麻下腔鏡手術(shù)30例(24~65歲,ASA Ⅰ級(jí)或Ⅱ級(jí)),應(yīng)用內(nèi)嵌Gepts藥動(dòng)學(xué)參數(shù)的TCI系統(tǒng)輸注舒芬太尼,效應(yīng)室靶濃度隨機(jī)采用0.2、0.3和0.4 μg/L各10例,復(fù)合吸入七氟烷維持麻醉。于不同時(shí)點(diǎn)經(jīng)橈動(dòng)脈取血至停止TCI后24小時(shí),以液相色譜-質(zhì)譜聯(lián)用法測定舒芬太尼的血藥濃度。運(yùn)用非線性混合效應(yīng)模型分析舒芬太尼群體藥動(dòng)學(xué)數(shù)據(jù)。結(jié)果 舒芬太尼TCI的藥動(dòng)學(xué)模型為三室模型,其藥動(dòng)學(xué)參數(shù)為:中央室容積(V1)=15.7 L,快速分布容積(V2)=50.4 L,慢速分布容積(V3)=213.0 L,穩(wěn)態(tài)分布容積(Vdss)=279.2 L;藥物總清除率(Cl1)=0.80 L/min,快速分布相清除率(Cl2)=1.09 L/min,慢速分布相清除率(Cl3)=0.27 L/min;快速分布半衰期(t1/2α)=4.6 min,慢速分布半衰期(t1/2β)=68.7 min,清除半衰期(t1/2γ)=739.5 min。年齡、性別和體重對(duì)藥動(dòng)學(xué)參數(shù)無顯著影響(P>0.05)。 結(jié)論 腔鏡手術(shù)患者臨床常用濃度舒芬太尼TCI的藥動(dòng)學(xué)可用三室模型描述。年齡、性別和體重對(duì)藥動(dòng)學(xué)參數(shù)無顯著影響。

      舒芬太尼; 靶控輸注; 藥動(dòng)學(xué); 非線性混合效應(yīng)模型; 液相色譜-質(zhì)譜聯(lián)用

      靶控輸注(target controlled infusion,TCI)使靜脈麻醉更精確、平穩(wěn)和可控[1~5],舒芬太尼是目前鎮(zhèn)痛作用最強(qiáng)的阿片類藥物,具有良好的血流動(dòng)力學(xué)穩(wěn)定性[6~10]。深入研究麻醉藥物的藥動(dòng)學(xué)規(guī)律,對(duì)于合理用藥、提高麻醉質(zhì)量和安全性、改善預(yù)后具有重要意義。我們前期初步探討了應(yīng)用Bovill等[11]的藥動(dòng)學(xué)模型進(jìn)行高濃度舒芬太尼TCI(復(fù)合異氟烷全麻)用于長時(shí)間手術(shù)患者的國人舒芬太尼藥動(dòng)學(xué)特點(diǎn)[12]。臨床麻醉中,Gepts等[13]的舒芬太尼藥動(dòng)學(xué)模型應(yīng)用廣泛。目前,對(duì)于應(yīng)用Gepts等[13]的藥動(dòng)學(xué)模型,采用臨床常用濃度舒芬太尼TCI(復(fù)合七氟烷全麻)用于成人腔鏡手術(shù)的藥動(dòng)學(xué)特點(diǎn),尚待進(jìn)一步研究[14,15]。本研究應(yīng)用內(nèi)嵌Gepts等[13]藥動(dòng)學(xué)模型的TCI系統(tǒng),采用臨床常用濃度舒芬太尼TCI用于腔鏡手術(shù)患者全麻,觀察舒芬太尼TCI的藥動(dòng)學(xué)特點(diǎn),為臨床麻醉提供參考。

      1 臨床資料與方法

      本研究經(jīng)北京大學(xué)生物醫(yī)學(xué)倫理委員會(huì)審核批準(zhǔn)(倫理批件號(hào):IRB00001052-10051),所有受試者均在術(shù)前簽署知情同意書。

      1.1 一般資料

      入選標(biāo)準(zhǔn):ASA Ⅰ級(jí)或Ⅱ級(jí),年齡18~65歲,擇期在全麻下施行腔鏡手術(shù)。

      排除標(biāo)準(zhǔn):既往有精神、神經(jīng)肌肉疾病史,有未經(jīng)控制的高血壓病史,嚴(yán)重心、肺疾病,肝、腎功能異常,長期服用阿片類或鎮(zhèn)靜催眠類藥物史,對(duì)阿片類藥物有不良反應(yīng)史,6個(gè)月內(nèi)參加過類似研究,有藥物及酒精依賴,或術(shù)中失血量>500 ml者。

      2011年6~9月入選30例,男12例,女18例。年齡24~65歲,(43.8±12.5)歲。身高147~180 cm,(165.9±8.3)cm。體重45~85 kg,(66.7±10.8)kg。體重指數(shù)17.6~35.8,24.2±3.6。手術(shù)類型:婦科手術(shù)15例(腹腔鏡卵巢囊腫剔除術(shù)6例,腹腔鏡子宮肌瘤剔除術(shù)5例,腹腔鏡子宮切除術(shù)4例),泌尿科手術(shù)6例(后腹腔鏡手術(shù)4例,腹腔鏡手術(shù)1例,經(jīng)皮腎鏡手術(shù)1例),普通外科手術(shù)9例(腹腔鏡膽囊切除術(shù)4例,腹腔鏡肝囊腫切除術(shù)3例,腹腔鏡闌尾切除術(shù)2例)。手術(shù)時(shí)間33~305 min,中位數(shù)104 min。靶控輸注時(shí)間27~194 min,中位數(shù)87 min。舒芬太尼用量24.4~129.0 μg,中位數(shù)52.2 μg。

      1.2 麻醉及監(jiān)測方法

      術(shù)前禁食禁飲8 h。入室后開放上肢靜脈,以8~10 ml/(kg·h)的速度輸注乳酸林格氏液。對(duì)側(cè)橈動(dòng)脈穿刺置管,用于直接測定動(dòng)脈壓和采血。持續(xù)監(jiān)測平均動(dòng)脈壓(mean arterial pressure,MAP)、心電圖、心率(heart rate,HR)、脈搏血氧飽和度和腦電雙頻指數(shù)(bispectral index,BIS)。

      麻醉誘導(dǎo)前靜脈注射東莨菪堿0.3 mg。麻醉誘導(dǎo):靜脈注射丙泊酚2.0~2.5 mg/kg,患者意識(shí)消失(呼之不應(yīng)和睫毛反射消失)后,靜脈注射羅庫溴銨0.6 mg/kg,應(yīng)用內(nèi)嵌Gepts等[13]藥動(dòng)學(xué)參數(shù)的TCI系統(tǒng)(協(xié)奏曲工作站,F(xiàn)resenius公司,法國),按照隨機(jī)數(shù)字表維持舒芬太尼(Impfstoffwerk Dessau-Tornau公司,德國,批號(hào):100877)的效應(yīng)室靶濃度(target effect-site concentration,Ce)分別為0.2、0.3和0.4 μg/L(臨床常用濃度)各10例。給予羅庫溴銨2 min后行氣管插管,機(jī)械通氣,氧流量2 L/min,維持呼氣末CO2分壓30~35 mm Hg。麻醉維持:術(shù)中舒芬太尼TCI的Ce恒定,復(fù)合吸入七氟烷(Baxter healthcare公司,美國)維持麻醉,通過觀察BIS(術(shù)中維持40~60)、MAP及HR(變化幅度不超過基礎(chǔ)值的20%)等情況調(diào)整七氟烷的濃度以維持適當(dāng)?shù)穆樽砩疃?。術(shù)中根據(jù)手術(shù)需要間斷靜脈注射肌松藥羅庫溴銨。注意保溫,監(jiān)測鼻咽溫(維持36~37 ℃)。根據(jù)手術(shù)進(jìn)程及TCI系統(tǒng)預(yù)計(jì)的患者蘇醒時(shí)間適時(shí)停止舒芬太尼TCI,術(shù)畢停止吸入七氟烷。

      1.3 舒芬太尼血藥濃度的測定方法

      分別于麻醉誘導(dǎo)前,舒芬太尼TCI開始后1、3、10 min,停止TCI前,停止TCI后20 min、1 h、4 h、12 h及24 h共10個(gè)時(shí)點(diǎn)經(jīng)橈動(dòng)脈取血,每次約1.5 ml,置于肝素抗凝管中,4000 r/min離心10 min,分離血漿,-80 ℃冰凍保存。采用液相色譜-質(zhì)譜聯(lián)用技術(shù)(liquid chromatography-mass spectrometry/mass spectrometry,LC-MS/MS)[16,17]測定舒芬太尼血藥濃度。測定血漿舒芬太尼濃度的線性范圍為2~5000 ng/L。

      1.4 統(tǒng)計(jì)學(xué)和藥動(dòng)學(xué)分析

      協(xié)變量分析采用逐步回歸法進(jìn)行正向模型化和逆向剔除。首先將所有協(xié)變量依次逐個(gè)加入基礎(chǔ)模型中,如果使目標(biāo)函數(shù)值(objective function value,OFV)降低大于3.84(P<0.05),則保留該協(xié)變量再進(jìn)行逆向剔除;在逆向剔除過程中,如果使OFV升高大于6.63(P<0.01),則該協(xié)變量對(duì)藥動(dòng)學(xué)參數(shù)有顯著性影響,并得到最終模型。

      最終模型的驗(yàn)證:自舉法(bootstrap method)[20]用于評(píng)價(jià)模型的精確性和穩(wěn)定性。將自舉法計(jì)算得出的中位數(shù)和95%置信區(qū)間(confidential interval,CI)與NONMEM軟件分析得出的藥動(dòng)學(xué)參數(shù)估計(jì)值和相對(duì)標(biāo)準(zhǔn)誤(relative standard error,RSE)進(jìn)行比較。可視化預(yù)測檢驗(yàn)(visual predictive check,VPC)用于評(píng)價(jià)模型的準(zhǔn)確性及預(yù)測能力。通過最終模型對(duì)原數(shù)據(jù)文件的1000次仿真,建立模型的2.5%、50%和97.5%預(yù)測分位數(shù)線及其95%預(yù)測區(qū)間,并與觀測數(shù)據(jù)進(jìn)行比對(duì),檢測數(shù)據(jù)在此范圍內(nèi)的分布情況。

      2 結(jié)果

      腔鏡手術(shù)患者臨床常用濃度舒芬太尼TCI的藥動(dòng)學(xué)可用三室模型描述,藥動(dòng)學(xué)參數(shù)見表1。年齡、性別、身高、體重、體重指數(shù)、手術(shù)時(shí)間、麻醉時(shí)間、TCI時(shí)間和舒芬太尼總用量等協(xié)變量對(duì)藥動(dòng)學(xué)參數(shù)無顯著性影響。

      最終模型的驗(yàn)證:自舉法得到的參數(shù)中位數(shù)及其95%CI見表1??梢娮耘e法得出的中位數(shù)與最終NONMEM法模型估計(jì)值基本一致,說明最終模型穩(wěn)定可靠。數(shù)據(jù)的VPC結(jié)果見圖1,模型1000次仿真得到的95%預(yù)測區(qū)間能夠覆蓋大部分觀測數(shù)據(jù),仿真結(jié)果與觀測值一致,表明最終模型準(zhǔn)確性和預(yù)測性良好。

      表1 舒芬太尼靶控輸注藥動(dòng)學(xué)模型參數(shù)

      NONMEM:非線性混合效應(yīng)模型(nonlinear mixed-effect model);RSE:相對(duì)標(biāo)準(zhǔn)誤(relative standard error);CI:置信區(qū)間(confidential interval)

      圖1 可視化預(yù)測檢驗(yàn)圖(半自然對(duì)數(shù)坐標(biāo)圖) LNDV:ln of dependent variable,因變量的自然對(duì)數(shù)值,即血藥濃度(ng/L)的自然對(duì)數(shù)值;Time:給藥后時(shí)間注:圖中藍(lán)色空心圓圈為觀測數(shù)據(jù),紅色虛線和紅色實(shí)線分別為觀測數(shù)據(jù)(即實(shí)測舒芬太尼血藥濃度)和預(yù)測數(shù)據(jù)(最終模型預(yù)計(jì)的血藥濃度)的2.5%、97.5%以及50%分位數(shù)線,藍(lán)色陰影和紅色陰影分別為2.5%、97.5%以及50%預(yù)測分位數(shù)線的95%置信區(qū)間。由圖可知,最終模型的準(zhǔn)確性和預(yù)測性良好

      3 討論

      臨床常用濃度舒芬太尼TCI的靶濃度為0.2~1 μg/L[21],本研究選擇臨床常用濃度舒芬太尼TCI(Ce=0.2~0.4 μg/L),復(fù)合吸入七氟烷,用于腔鏡手術(shù)的全身麻醉。TCI以效應(yīng)室藥物濃度為靶濃度(Ce),與以血漿濃度為靶濃度相比,可以更快地達(dá)到血漿與效應(yīng)室藥物濃度的平衡(即穩(wěn)態(tài)濃度),而且舒芬太尼具有良好的血流動(dòng)力學(xué)穩(wěn)定性,故本研究選擇以舒芬太尼效應(yīng)室濃度為靶濃度。

      研究證實(shí)[16,17],LC-MS/MS精確度和靈敏度高,可用于臨床血藥濃度的測定及藥動(dòng)學(xué)研究。本研究測定舒芬太尼血藥濃度的最低檢測限為2 ng/L(線性范圍內(nèi))。關(guān)于藥動(dòng)學(xué)研究取血樣的持續(xù)時(shí)間,Gepts等[13]提出,為準(zhǔn)確計(jì)算舒芬太尼終末消除相,取血樣應(yīng)至少至停藥后24 h。因此,本研究取動(dòng)脈血樣至停藥后24 h。

      群體藥動(dòng)學(xué)[22,23]將經(jīng)典的藥動(dòng)學(xué)基本原理與統(tǒng)計(jì)學(xué)模型結(jié)合,分析藥動(dòng)學(xué)特征中存在的變異性,研究藥物體內(nèi)的群體規(guī)律、藥動(dòng)學(xué)參數(shù)的統(tǒng)計(jì)分布及影響因素。由于群體各受試對(duì)象的遺傳、環(huán)境及個(gè)體特征等的差異,使群體藥動(dòng)學(xué)參數(shù)具有很大的個(gè)體間變異及個(gè)體自身變異。與經(jīng)典方法相比,群體藥動(dòng)學(xué)只需要每個(gè)個(gè)體提供稀疏血樣即可分析,提高了臨床研究的可行性。

      NONMEM法將所有患者個(gè)體間的變異(隨機(jī)效應(yīng))與患者自身影響因素(固定效應(yīng)),如年齡、性別和體重等因素統(tǒng)一考察,構(gòu)建群體藥動(dòng)學(xué)模型,可排除因樣本量小和個(gè)別樣本測量準(zhǔn)確性差造成的誤差[18,19,24,25]。

      本研究與Gepts等[13]研究得出的舒芬太尼藥動(dòng)學(xué)主要參數(shù)值近似:本研究中,V1=15.7 L,t1/2γ=739.5 min;Gepts等[13]研究中V1=14.3 L,t1/2γ=769 min。本研究中,30例患者平均年齡43.8歲,平均體重66.7 kg;Gepts等[13]研究中,23例患者平均年齡47歲,平均體重67.8 kg。兩研究對(duì)象的年齡和體重相似。

      我們既往的研究[12]應(yīng)用Bovill等[11]舒芬太尼藥動(dòng)學(xué)參數(shù)的TCI系統(tǒng),探討高濃度舒芬太尼TCI的藥動(dòng)學(xué)。入選12例患者,平均年齡56歲,平均體重53.8 kg,施行長時(shí)間手術(shù)(平均手術(shù)時(shí)間6.7 h),平均舒芬太尼用量7.2 μg/kg。得出藥動(dòng)學(xué)參數(shù)為:V1= 5.4 L,t1/2γ=271.8 min。本研究采用Gepts等模型得出的舒芬太尼藥動(dòng)學(xué)參數(shù)與之前[12]應(yīng)用Bovill等模型的研究結(jié)果有一定差異,可能由于TCI系統(tǒng)、藥動(dòng)學(xué)模型、靶濃度、手術(shù)類型以及受試者人群的不同,會(huì)對(duì)研究結(jié)果產(chǎn)生影響。

      不同腹腔鏡手術(shù)的手術(shù)時(shí)間和麻醉時(shí)間不同,這對(duì)藥動(dòng)學(xué)參數(shù)有無影響是值得關(guān)注的問題。本研究30例手術(shù)時(shí)間0.55~5.08 h。在Gepts等[13]的研究中,手術(shù)時(shí)間0.5~14 h,結(jié)果表明年齡和體重對(duì)藥動(dòng)學(xué)參數(shù)無影響,但未提及手術(shù)時(shí)間和麻醉時(shí)間對(duì)藥動(dòng)學(xué)參數(shù)有無影響。在Hudson等[26]的研究中,手術(shù)時(shí)間(227±70)min,結(jié)果顯示,手術(shù)時(shí)間對(duì)藥動(dòng)學(xué)參數(shù)無顯著影響。本研究組[12]曾經(jīng)探討采用高濃度舒芬太尼TCI用于長時(shí)間手術(shù)[3.5~12.7 h,(6.7±2.6) h]的藥動(dòng)學(xué),隨后的分析[27]結(jié)果表明,手術(shù)時(shí)間對(duì)藥動(dòng)學(xué)參數(shù)無顯著影響,與Hudson等[26]的結(jié)果一致。

      本研究的臨床意義在于,初步分析了臨床常用濃度舒芬太尼TCI用于國人腔鏡手術(shù)全麻的藥動(dòng)學(xué)規(guī)律,為臨床麻醉提供參考。腹腔鏡手術(shù)多數(shù)需要CO2氣腹,有增加應(yīng)激反應(yīng)和導(dǎo)致高碳酸血癥的可能性。強(qiáng)效鎮(zhèn)痛藥舒芬太尼在抑制應(yīng)激反應(yīng)方面有一定優(yōu)勢,但其兼具中長效阿片類藥的特點(diǎn)。因而,在采用臨床常用濃度舒芬太尼TCI時(shí),應(yīng)提前停藥(根據(jù)手術(shù)進(jìn)程、靶濃度和TCI系統(tǒng)預(yù)計(jì)患者蘇醒時(shí)間等);同時(shí)術(shù)中應(yīng)密切監(jiān)護(hù),適當(dāng)調(diào)整呼吸參數(shù),防治高碳酸血癥,維持內(nèi)環(huán)境穩(wěn)定,以免影響舒芬太尼和其他麻醉藥的代謝和消除,使患者平穩(wěn)、迅速地蘇醒。

      分析本研究與既往研究舒芬太尼藥動(dòng)學(xué)的結(jié)果,可見影響舒芬太尼藥動(dòng)學(xué)的因素復(fù)雜多樣,尚需綜合考慮,不斷探索,深入研究,以期為臨床合理用藥提供可靠的依據(jù)。

      1 Struys MM,De Smet T,Glen JI,et al.The history of target-controlled infusion.Anesth Analg,2016,122(1):56-69.

      2 Short TG,Hannam JA,Laurent S,et al.Refining target-controlled infusion:an assessment of pharmacodynamic target-controlled infusion of propofol and remifentanil using a response surface model of their combined effects on bispectral index.Anesth Analg,2016,122(1):90-97.

      3 Kawano S,Okada H,Iwamuro M,et al.An effective and safe sedation technique combining target-controlled infusion pump with propofol,intravenous pentazocine,and bispectral index monitoring for peroral double-balloon endoscopy.Digestion,2015,91(2):112-116.

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      6 Bhavsar R,Sloth E,Folkersen L,et al.Sufentanil preserves hemodynamics and left ventricular function in patients with ischemic heart disease.Acta Anaesthesiol Scand,2011,55(8):1002-1009.

      7 Ji M,Tao J,Cheng M,et al.Endotracheal administration of sufentanil and tetracaine during awake fiberoptic intubation.Am J Ther,2016,23(1):e92-e97.

      8 Abdollahpour A,Azadi R,Bandari R,et al.Effects of adding midazolam and sufentanil to intrathecal bupivacaine on analgesia quality and postoperative complications in elective cesarean section.Anesth Pain Med,2015,5(4):e23565.

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      10 Jove M,Griffin DW,Minkowitz HS,et al.Sufentanil sublingual tablet system for the management of postoperative pain after knee or hip arthroplasty:a randomized,placebo-controlled study.Anesthesiology,2015,123(2):434-443.

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      13 Gepts E,Shafer SL,Camu F,et al.Linearity of pharmacokinetics and model estimation of sufentanil.Anesthesiology,1995,83(6):1194-1204.

      14 吳 瓊,趙 艷,郭向陽.舒芬太尼及其靶控輸注的藥代動(dòng)力學(xué)研究進(jìn)展.中國微創(chuàng)外科雜志,2013,13(10):941-943.

      15 王 靖,楊承祥,王漢兵,等.舒芬太尼TCI系統(tǒng)用于心臟手術(shù)患者CPB結(jié)束至術(shù)畢的準(zhǔn)確性.中華麻醉學(xué)雜志,2014,34(10):1231-1233.

      16 Manfio JL,Santos VJ,Lanchote VL,et al.Development and validation of an HPLC/MS/MS method for the determination of sufentanil and morphine in human plasma.J AOAC Int,2011,94(1):136-142.

      17 Nosseir NS,Michels G,Binder P,et al.Simultaneous detection of ketamine,lorazepam,midazolam and sufentanil in human serum with liquid chromatography-tandem mass spectrometry for monitoring of analgosedation in critically ill patients.J Chromatogr B Analyt Technol Biomed Life Sci,2014,12,973C:133-141.

      18 Choi L,Ferrell BA,Vasilevskis EE,et al.Population pharmacokinetics of fentanyl in the critically ill.Crit Care Med,2016,44(1):64-72.

      19 Bi SS,Deng CH,Zhou TY,et al.Remifentanil-sevoflurane interaction models of circulatory response to laryngoscopy and circulatory depression.Br J Anaesth,2013,110(5):729-740.

      20 Wesley MC,Pereira LM,Scharp LA,et al.Pharmacokinetics of tranexamic acid in neonates,infants,and children undergoing cardiac surgery with cardiopulmonary bypass.Anesthesiology,2015,122(4):746-758.

      21 Pandin PC,Cantraine F,Ewalenko P,et al.Predictive accuracy of target-controlled propofol and sufentanil coinfusion in long-lasting surgery.Anesthesiology,2000,93(3):653-661.

      22 Sherwin CM,Kiang TK,Spigarelli MG,et al.Fundamentals of population pharmacokinetic modelling:validation methods.Clin Pharmacokinet,2012,51(9):573-590.

      23 Bonate PL,Strougo A,Desai A,et al.Guidelines for the quality control of population pharmacokinetic-pharmacodynamic analyses:an industry perspective.AAPS J,2012,14(4):749-758.

      24 Mallaysamy S,Johnson MG,Rao PG,et al.Population pharmacokinetics of lamotrigine in Indian epileptic patients.Eur J Clin Pharmacol,2013,69(1):43-52.

      25 Wiczling P,Bienert A,Sobczyński P,et al.Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery.Pharmacol Rep,2012,64(1):113-122.

      26 Hudson RJ,Bergstrom RG,Thomson IR,et al.Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery.Anesthesiology,1989,70(3):426-431.

      27 Zhao Y,Duan JL,Wu XM,et al.Two-stage analysis of pharmacokinetics of sufentanil administered by target-controlled infusion in Chinese patients. Chin Med J,2009,122(17):1979-1984.

      (修回日期:2016-09-26)

      (責(zé)任編輯:王惠群)

      Pharmacokinetic Study of Sufentanil Administered by Target-controlled Infusion in Patients Undergoing Endoscopic Surgery

      LiuWei,ZhaoYan*,WuQiong*,etal.

      *DepartmentofAnesthesiology,PekingUniversityThirdHospital,Beijing100083,China

      ZhaoYan,E-mail:zhaoyan2004@263.net

      Objective To study the pharmacokinetics of sufentanil administered by target-controlled infusion (TCI) at commonly used concentrations in patients undergoing endoscopic surgery. Methods The pharmacokinetic parameters of sufentanil TCI were investigated in 30 patients (ASA Ⅰ or Ⅱ), aged 24-65 years old, scheduled for elective endoscopic surgery under general anesthesia. Induction of anesthesia was started with sufentanil TCI, and target effect-site concentrations of sufentanil were randomly set at 0.2, 0.3 or 0.4 μg/L in each 10 cases, respectively. Anesthesia was maintained with sufentanil TCI, inhalation of sevoflurane and intermittent injection of rocuronium as needed to maintain muscle relaxation. Arterial blood samples were gathered at specific intervals from the beginning of TCI to 24 h after TCI. Plasma concentrations of sufentanil were measured by liquid chromatography-mass spectrometry/mass spectrometry (limit of quantitation was 2 ng/L). The population pharmacokinetic data of sufentanil were analyzed with the nonlinear mixed-effect model. Results The pharmacokinetic pattern of sufentanil TCI was described as a three-compartment model with the following parameters: volume of the central compartment (V1)=15.7 L, volume of the rapidly equilibrating compartment (V2) = 50.4 L, volume of the slowly equilibrating compartment (V3)=213.0 L, volume of distribution at steady state (Vdss) = 279.2 L, total drug clearance (Cl1) = 0.80 L/min, rapid intercompartmental clearance (Cl2) = 1.09 L/min, slow intercompartmental clearance (Cl3) = 0.27 L/min, rapid distribution half-time (t1/2α) = 4.6 min, slow distribution half-time (t1/2β) = 68.7 min, and elimination half-time (t1/2γ) = 739.5 min. No significant relations to age, gender, or body weight were found for any of the pharmacokinetic parameters (P>0.05). Conclusions The pharmacokinetics of sufentanil TCI at commonly used concentrations in patients undergoing endoscopic surgery can be optimally described by a three-compartment model. No significant relations to age, gender, or body weight are found for any of the pharmacokinetic parameters.

      Sufentanil; Target-controlled infusion; Pharmacokinetics; Nonlinear mixed-effect model; Liquid chromatography-mass spectrometry/mass spectrometry

      北京大學(xué)第三醫(yī)院中青年骨干基金項(xiàng)目(65476-01)

      A

      1009-6604(2016)12-1131-05

      10.3969/j.issn.1009-6604.2016.12.018

      2016-07-23)

      **通訊作者,E-mail:zhaoyan2004@263.net

      ①(北京大學(xué)第三醫(yī)院藥劑科,北京 100083)

      ②(北京大學(xué)藥學(xué)院,北京 100083)

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