应用响应曲面研究丙泊酚与瑞芬太尼在腹腔镜胆囊切除术麻醉中最佳配伍剂量

目的应用响应曲面分析法,观察丙泊酚与瑞芬太尼在镇静作用上的药效学相互作用规律,探讨腹腔镜胆囊切除术(laparoscopic cholecystectomy,LC)靶控输注丙泊酚与瑞芬太尼的最佳配伍剂量。方法选择2014~2016年北京大学第三医院择期LC 100例,5例因手术方式改变、1例因术中出现过敏性休克退出研究,94例完成临床观察和随访。选择丙泊酚与瑞芬太尼靶控输注起始配伍浓度,观察靶控输注至警醒/镇静(Observer’s Assessment of Alertness/Sedation,OAA/S)评分≤1分的意识消失时间(time to loss of consciousenss,T LOC),术中根据脑电双频谱指数(bispectral index,BIS)、有创动脉血压和心率(heart rate,HR)调整丙泊酚和瑞芬太尼的靶控输注浓度,维持BIS 40~60、平均动脉压≥60 mm Hg、HR≥50次/min且平均动脉压和HR波动不超过基础值30%。记录停止输注瑞芬太尼与丙泊酚至OAA/S评分≥3分的意识恢复时间(time to recovery of consciousness,T ROC)。以受试者T LOC≤5 min、T ROC≤10 min、术中95%患者药效指标满意为目标,计算丙泊酚与瑞芬太尼在LC术中靶控浓度的最佳配伍范围。结果丙泊酚(2~9μg/ml)与瑞芬太尼(1~10 ng/ml)在T LOC和T ROC的药效上呈协同作用。LC药物靶控浓度的最佳配伍范围:丙泊酚2μg/ml(推荐监测BIS)伍用瑞芬太尼6~10 ng/ml,丙泊酚3μg/ml伍用瑞芬太尼3~5 ng/ml,丙泊酚4μg/ml伍用瑞芬太尼3 ng/ml,丙泊酚4.5μg/ml伍用瑞芬太尼2.6 ng/ml。丙泊酚浓度≥5μg/ml复合小剂量瑞芬太尼,45例中43例BIS<40;靶控输注丙泊酚2μg/ml复合瑞芬太尼6~10 ng/ml,给予气管插管刺激时,25例中2例BIS值呈一过性上升,术中BIS均维持在40~60。3例(3.2%)意识消失前出现呼吸暂停;7例(7.4%)麻醉诱导期间出现循环抑制,其中4例使用血管活性药物;21例(22.3%)主诉注射痛;7例(7.4%)出现多语和不自主活动。术后随访无知晓发生。结论丙泊酚(2~9μg/ml)与瑞芬太尼(1~10 ng/ml)在镇静药效反应呈协同作用;不同的药效反应相结合创建出的丙泊酚与瑞芬太尼最佳配伍剂量范围,可以为LC提供满意的麻醉,并且麻醉诱导和麻醉恢复快速。

Use of Response Surface to Study Optimal Combination Dose of Propofol and Remifentanil in Patients Undergoing Laparoscopic Cholecystectomy

Objective To apply response surface models to investigate the pharmacodynamic interaction in sedation between propofol and remifentanil,and to analyze the optimal combination dose of propofol and remifentanil in patients undergoing laparoscopic cholecystectomy(LC).Methods A total of 100 patients were scheduled for LC from 2014 to 2016.Withdrawal from the study occurred in 5 cases due to the change of operation mode and in 1 case due to anaphylactic shock during operation,and the clinical observations and follow-ups were completed in other 94 patients.The patients were assigned to receive target-controlled infusion(TCI)of propofol and remifentanil.The Observer’s Assessment of Alertness/Sedation(OAA/S)score,bispectral index(BIS),invasive blood pressure(IBP)and heart rate(HR)were monitored.The target concentrations of these two drugs were adjusted to maintain BIS 40-60,mean arterial pressure(MAP)≥60 mm Hg and HR≥50 beats/min,with the mean arterial pressure and HR fluctuation less than 30%of the basic value.The time to regain of consciousness(T ROC)from remifentanil and propofol to OAA/S≥3 points was recrded.The optimal combination dose range of propofol and remifentanil in the target control concentration of LC was calculated with the goal of time to loss of consciousness(T LOC)≤5 min,T ROC≤10 min and satisfactory pharmacodynamic parameters in more than 95%patients.Results The parameters of response surfaces model showed synergistic interaction in T LOC and T ROC.The range of optimal combination dose for LC were propofol 2μg/ml(BIS monitor was recommended)combined with remifentanil 6-10 ng/ml,propofol 3μg/ml combined with remifentanil 3-5 ng/ml,propofol 4μg/ml combined with remifentanil 3 ng/ml,and propofol 4.5μg/ml combined with remifentanil 2.6 ng/ml,respectively.Using the combination of propofol(concentration≥5μg/ml)and low-dose remifentanil,43 out of 45 cases recorded BIS<40.When TCI of propofol 2μg/ml combined with remifentanil 6-10 ng/ml,we observed transient increase of BIS value for 2 out of 25 cases during tracheal intubation stimulation,and BIS values were maintained between 40 and 60 intra-operatively.Three cases(3.2%)developed apnea before losing consciousness;7 cases(7.4%)had circulatory depression during induction,and vasoactive drugs were used in 4 of these cases;21(22.3%)complained of injection pain;7 cases(7.4%)experienced logorrhea and involuntary movements.During postoperative follow-ups,none reported occurrence of intraoperative awareness.Conclusions Response surface models in the LC reveals significant synergy between propofol(2-9μg/ml)and remifentanil(1-10 ng/ml)for T LOC and T ROC.The range of optimal combination dose of propofol and remifentanil which is established by combining different pharmacodynamic reactions can be used for LC anesthesia successfully with rapid anesthetic induction and recovery.