术前急性高容量血液稀释对维库溴铵量效关系的影响
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摘要
目的；研究术前急性高容量血液稀释状态(acute hypervolemic hemodilution，AHH)对常用非去极化类肌松药物维库溴铵量效关系的影响，以作为该类药物在急性高容量血液稀释状态下临床应用的参考。
方法：选择40例男性食管癌手术病人，ASAⅠ-Ⅱ级。术前各项常规检查及心肺肝肾功能检查均正常，无内分泌系统疾患，无神经-肌肉系统疾病史，术前1个月未用过影响神经肌肉传导的药物。凡有体重超过理想体重10％的肥胖患者及贫血患者(Hb＜120g／L)均被排除。将病人随机分为两组，每组20例。Ⅰ组为对照组，Ⅱ组为术前急性高容量血液稀释组。两组病人均于术前半小时肌注阿托品0.01mg／kg和安定0.2mg／kg。先以4％利多卡因2ml行环甲膜注射，吸氧去氮5分钟后，静注2.5％硫喷妥钠4-6mg／kg和芬太尼2-4μg／kg诱导麻醉，行气管内插管，接麻醉机机械控制呼吸。术中吸入异氟醚维持麻醉，异氟醚浓度为2.0％，总流量1L／min。必要时静注硫喷妥钠50-100mg，芬太尼50-100μg／kg调节麻醉深度，维持BIS指数在45±5左右。所有病人均于入室后，麻醉前补充前晚禁食水所失液体量(5％葡萄糖生理盐水8-10ml／kg)。麻醉平稳后，高容量血液稀释组于手术开始前输入羟乙基淀粉液(6％贺斯200／0.5，HES)15ml／kg，输液速
中文摘要
度为50ml／ndn。术中丢失的血液以等量HES代替，而尿
液与经创面蒸发的水分均用等量的林格液补充；对照组
仅给予常规补林格液81。所有病人均在入室后连
接黑龙江华翔科技开发有限公司生产的HXtr－－型多功
能组合监测仪，监测收缩压、舒张压、平均动脉压、血
氧饱和度、心电图、BIS指数；同时经右侧颈内静脉穿刺
置管，以测定中心静脉压（CVP）。术中采血监测稀释前
后的动脉血气、Hb、HCT、血钾、钠、氯和游离钙离子
浓度以及血浆总蛋白和白蛋白的浓度。用HXH－－型多
功能组合监测仪监测肌张力。将传感器固定于拇指掌侧
以测定拇指内收肌收缩时的肌张力，刺激电极置于腕部
尺神经径路表面，选择四个成串刺激（TOF）作为作为
刺激形式，将TOF的刺激间隔定为 14秒。采用累积给药
技术观察维库澳镣的量一效关系曲线，每次给药后，观
察TOF的刺激反应，当同等程度TI连续重复三次时，应
用下次剂量。每个患者应用四个剂量 （l，10，10，5 p
g／kg）。每次给药均通过静脉注入，给药的时间巧秒。
所有数据均于手术开始前测得。以药量的对数值为横坐
标，以 TI汀C的百分比的概率单位为纵坐标绘制曲线。以
log中robit法求出每个患者量效曲线的回归方程及相关系
数，并从该直线方程中计算出维库澳镀的50％的有效剂
量（ED。。）、90O有效齐量（ED。。）、和95O有效齐量（
ED。J，在此基础上分别求出两组患者的ED。卜ED。。和
ED。。的平均值，建立各组的平均量效关系曲线。
结果：门）血液稀释后，血红蛋白从135．gil 11．04
g／L下降到107＊2士10．sigh，HGt从41二6上3．85％下降至
2
中文摘要
29．70士4．37％，达中度血液稀释。总蛋白和白蛋白在稀
释后分别下降25．31％和 23．22％。与稀释前值相比，对照
组患者给药时的Hb，Hot，K＼Na＋，CI＼iCaZ＼ti，
lb及血气均无显著性差异。稀释组思者除血气及＊－，
iCaZ”外均有显著性差异。中心静脉压从 5．58士 0．87
ClllllZO增至门石7士0．82CInHZO，血容量明显增高。
＊）维库滇铰的第1，2，3次累计剂量的应用时间（ti，
tZ，t3）在稀释组分别为（7＊7士1．5 3）、（4＊5士0＊3）和（3．59
土0．48）分钟，在对照组分另为（6．66士0．61）、（．71士0．53）
和（2．98士0．73）分钟。两组间 无明显差异（．P＞0．05）。
门）血液稀释组于对照组相比其ED50，ED90，
E＊95分别增加23．42％，21．98％，24．72％（P＜0．05），两
组平均直线回归方程的斜率无明显差别，但乎均截距稀
释组明显低于对照组（P＜0．05），说明血液稀释平行右
移了量效关系曲线，对维库漠按的药效有降低作用。
结论：l、AHH可明显减弱维库涅铰的肌松作用，使
量效关系曲线右移。2、本文所采用的AHH方法安全有效
，稀释后血容量明显增高，Hot明显降低，达中度血液稀
释：无一例患者出现心力衰竭，肺水肿的临床征象，也
无一例发生过敏反应。3、HXDd型多功能监测仪可应
用于肌松药药效的定量监测中，结果准确可靠，但对于
传感器的固定要求较高。
Objective: This trial was designed to evaluate the influence of acute hypervolemic hemodilution (AHH) on the dose-response relationships of vecuronium, and to instruct the clinical application of the vecuronium during acute hypervolemic hemodilution.
Methods: Forty male patients, ASA grade I - II , scheduled for elective esophageal carcinoma surgery were included in the study. Patients were excluded if they had cardiac, pulmonary, renal, hepatic, neurological, endocrine diseases. Those with a body weight more than 10% greater than the idea or with anemia (i.e, hemoglobin concentration 120g/l) were also excluded. Twenty patients, underwent acute hypervolemic hemodilution (group AHH, n=20), and twenty patients did not received hemodilution as controls(group C, n=20). All patients were premedicated with diazepam 0.2mg/kg, atropine 0.01mg/kg intramuscularly 0.5h before anesthesia. After topical anesthesia with 4% lidocaine, anesthesia was induced with IV thiopental 4-6mg/kg and fentanyl 2-4ug/kg. the trachea was intubated without the aid of a muscle relaxants, and general anestheia was maintained with 2% isoflurane (total flow of 0.51/min),
and further increments of thiopental 50-100mg or fentayl 50-lOOug/kg as required to keep BIS index at about 45 ?5. Immediately after anesthesia was stable, 5%G.S 8-10ml/kg was infused to supplement the fluid deficiency owing to an overnight fast, then 6% hydroxyethyl starch 15ml/kg was infused intravenously at a rate of 50ml/min in AHH group, and blood loss was replaced by an equal volume of HES solution, Ringer's solution was infused in a volume equal to urine output plus the fluids loss from the wound; the patients in group C was infused as usual. SP, DP, MAP, SPO2, ECG, BIS were monitered during the whole procedures. Blood sample was taken at time T0 and T,. Hb, Hct, K+, Na+, Cl-, iCa2+, TPP, ALB were measured at different time. Neuromuscular function was assessed by TOP stimulation of HXD-1 with the percentage depression of T, responsed as the study parameter. The dose-response relationship of vecuronium were determined with the cumulative dose-response technique. A total dose of 40ug/kg of vecuronium was given in four dose (15,10,10,5ug/kg) and administered cumulatively. Each dose of vecuronium was injected as an IV bolus over <5s into a rapidly running IV infusion. Each dose increment was given only after the effect of the previous dose had reached a stable response , defined as three equal. If 90% or more of twitch depression was achieved after the second increment dose , the third increment dose was not used. All data were gotten before the operation. The
individual dose-response relationship was examined by least squares linear regression of the logarithm of each dose against a probit transformation of the depression of T, response relative to Tc. The doses required for 50%, 90%, and 95% T\ depression (ED50, ED, and ED95 respectively) were calculated from the regression line. Then the mean dose-response relationships of two groups were compared.
Results: (l)In the hemodilution patients, the level of Hct and concentrations of hemoglobin decreased from 41.16 +3.85% to 29.70+4.37%and from 135.91+11.04 g/L to 107.6 +10.81g/L respectively; while the total plasma protein and albumin decreased by 25.31% and 23.22%. Compared with preoperative values, Hb, Hct, TP, Alb, all blood electrolytes (except for Cl" and iCa2+) decreased significantly in patients who had hemodilution but remained stable in the control group. There were no significant difference regarding blood gas data within and between the two groups.
(2) The tl, t2 and t3 increment were 7.67 + 1.53, 4.15 + 0.63, and 3.59+0.48min, respectively, in the hemodilution group; and 6.66 + 0.61, 3.71 + 0.53, and 2.98 +0.73min in the control group. They did not differ significantly between the two groups.(P>0.05)
(3) Compared with those in the control patients, the ED50, ED90, and ED95 of vecuronium in the hemodilution patients were increased by 23.42%, 21.90% and 24.72%(P<0.05). The slope of the dose-response cur
方法：选择40例男性食管癌手术病人，ASAⅠ-Ⅱ级。术前各项常规检查及心肺肝肾功能检查均正常，无内分泌系统疾患，无神经-肌肉系统疾病史，术前1个月未用过影响神经肌肉传导的药物。凡有体重超过理想体重10％的肥胖患者及贫血患者(Hb＜120g／L)均被排除。将病人随机分为两组，每组20例。Ⅰ组为对照组，Ⅱ组为术前急性高容量血液稀释组。两组病人均于术前半小时肌注阿托品0.01mg／kg和安定0.2mg／kg。先以4％利多卡因2ml行环甲膜注射，吸氧去氮5分钟后，静注2.5％硫喷妥钠4-6mg／kg和芬太尼2-4μg／kg诱导麻醉，行气管内插管，接麻醉机机械控制呼吸。术中吸入异氟醚维持麻醉，异氟醚浓度为2.0％，总流量1L／min。必要时静注硫喷妥钠50-100mg，芬太尼50-100μg／kg调节麻醉深度，维持BIS指数在45±5左右。所有病人均于入室后，麻醉前补充前晚禁食水所失液体量(5％葡萄糖生理盐水8-10ml／kg)。麻醉平稳后，高容量血液稀释组于手术开始前输入羟乙基淀粉液(6％贺斯200／0.5，HES)15ml／kg，输液速
中文摘要
度为50ml／ndn。术中丢失的血液以等量HES代替，而尿
液与经创面蒸发的水分均用等量的林格液补充；对照组
仅给予常规补林格液81。所有病人均在入室后连
接黑龙江华翔科技开发有限公司生产的HXtr－－型多功
能组合监测仪，监测收缩压、舒张压、平均动脉压、血
氧饱和度、心电图、BIS指数；同时经右侧颈内静脉穿刺
置管，以测定中心静脉压（CVP）。术中采血监测稀释前
后的动脉血气、Hb、HCT、血钾、钠、氯和游离钙离子
浓度以及血浆总蛋白和白蛋白的浓度。用HXH－－型多
功能组合监测仪监测肌张力。将传感器固定于拇指掌侧
以测定拇指内收肌收缩时的肌张力，刺激电极置于腕部
尺神经径路表面，选择四个成串刺激（TOF）作为作为
刺激形式，将TOF的刺激间隔定为 14秒。采用累积给药
技术观察维库澳镣的量一效关系曲线，每次给药后，观
察TOF的刺激反应，当同等程度TI连续重复三次时，应
用下次剂量。每个患者应用四个剂量 （l，10，10，5 p
g／kg）。每次给药均通过静脉注入，给药的时间巧秒。
所有数据均于手术开始前测得。以药量的对数值为横坐
标，以 TI汀C的百分比的概率单位为纵坐标绘制曲线。以
log中robit法求出每个患者量效曲线的回归方程及相关系
数，并从该直线方程中计算出维库澳镀的50％的有效剂
量（ED。。）、90O有效齐量（ED。。）、和95O有效齐量（
ED。J，在此基础上分别求出两组患者的ED。卜ED。。和
ED。。的平均值，建立各组的平均量效关系曲线。
结果：门）血液稀释后，血红蛋白从135．gil 11．04
g／L下降到107＊2士10．sigh，HGt从41二6上3．85％下降至
2
中文摘要
29．70士4．37％，达中度血液稀释。总蛋白和白蛋白在稀
释后分别下降25．31％和 23．22％。与稀释前值相比，对照
组患者给药时的Hb，Hot，K＼Na＋，CI＼iCaZ＼ti，
lb及血气均无显著性差异。稀释组思者除血气及＊－，
iCaZ”外均有显著性差异。中心静脉压从 5．58士 0．87
ClllllZO增至门石7士0．82CInHZO，血容量明显增高。
＊）维库滇铰的第1，2，3次累计剂量的应用时间（ti，
tZ，t3）在稀释组分别为（7＊7士1．5 3）、（4＊5士0＊3）和（3．59
土0．48）分钟，在对照组分另为（6．66士0．61）、（．71士0．53）
和（2．98士0．73）分钟。两组间 无明显差异（．P＞0．05）。
门）血液稀释组于对照组相比其ED50，ED90，
E＊95分别增加23．42％，21．98％，24．72％（P＜0．05），两
组平均直线回归方程的斜率无明显差别，但乎均截距稀
释组明显低于对照组（P＜0．05），说明血液稀释平行右
移了量效关系曲线，对维库漠按的药效有降低作用。
结论：l、AHH可明显减弱维库涅铰的肌松作用，使
量效关系曲线右移。2、本文所采用的AHH方法安全有效
，稀释后血容量明显增高，Hot明显降低，达中度血液稀
释：无一例患者出现心力衰竭，肺水肿的临床征象，也
无一例发生过敏反应。3、HXDd型多功能监测仪可应
用于肌松药药效的定量监测中，结果准确可靠，但对于
传感器的固定要求较高。
Objective: This trial was designed to evaluate the influence of acute hypervolemic hemodilution (AHH) on the dose-response relationships of vecuronium, and to instruct the clinical application of the vecuronium during acute hypervolemic hemodilution.
Methods: Forty male patients, ASA grade I - II , scheduled for elective esophageal carcinoma surgery were included in the study. Patients were excluded if they had cardiac, pulmonary, renal, hepatic, neurological, endocrine diseases. Those with a body weight more than 10% greater than the idea or with anemia (i.e, hemoglobin concentration 120g/l) were also excluded. Twenty patients, underwent acute hypervolemic hemodilution (group AHH, n=20), and twenty patients did not received hemodilution as controls(group C, n=20). All patients were premedicated with diazepam 0.2mg/kg, atropine 0.01mg/kg intramuscularly 0.5h before anesthesia. After topical anesthesia with 4% lidocaine, anesthesia was induced with IV thiopental 4-6mg/kg and fentanyl 2-4ug/kg. the trachea was intubated without the aid of a muscle relaxants, and general anestheia was maintained with 2% isoflurane (total flow of 0.51/min),
and further increments of thiopental 50-100mg or fentayl 50-lOOug/kg as required to keep BIS index at about 45 ?5. Immediately after anesthesia was stable, 5%G.S 8-10ml/kg was infused to supplement the fluid deficiency owing to an overnight fast, then 6% hydroxyethyl starch 15ml/kg was infused intravenously at a rate of 50ml/min in AHH group, and blood loss was replaced by an equal volume of HES solution, Ringer's solution was infused in a volume equal to urine output plus the fluids loss from the wound; the patients in group C was infused as usual. SP, DP, MAP, SPO2, ECG, BIS were monitered during the whole procedures. Blood sample was taken at time T0 and T,. Hb, Hct, K+, Na+, Cl-, iCa2+, TPP, ALB were measured at different time. Neuromuscular function was assessed by TOP stimulation of HXD-1 with the percentage depression of T, responsed as the study parameter. The dose-response relationship of vecuronium were determined with the cumulative dose-response technique. A total dose of 40ug/kg of vecuronium was given in four dose (15,10,10,5ug/kg) and administered cumulatively. Each dose of vecuronium was injected as an IV bolus over <5s into a rapidly running IV infusion. Each dose increment was given only after the effect of the previous dose had reached a stable response , defined as three equal. If 90% or more of twitch depression was achieved after the second increment dose , the third increment dose was not used. All data were gotten before the operation. The
individual dose-response relationship was examined by least squares linear regression of the logarithm of each dose against a probit transformation of the depression of T, response relative to Tc. The doses required for 50%, 90%, and 95% T\ depression (ED50, ED, and ED95 respectively) were calculated from the regression line. Then the mean dose-response relationships of two groups were compared.
Results: (l)In the hemodilution patients, the level of Hct and concentrations of hemoglobin decreased from 41.16 +3.85% to 29.70+4.37%and from 135.91+11.04 g/L to 107.6 +10.81g/L respectively; while the total plasma protein and albumin decreased by 25.31% and 23.22%. Compared with preoperative values, Hb, Hct, TP, Alb, all blood electrolytes (except for Cl" and iCa2+) decreased significantly in patients who had hemodilution but remained stable in the control group. There were no significant difference regarding blood gas data within and between the two groups.
(2) The tl, t2 and t3 increment were 7.67 + 1.53, 4.15 + 0.63, and 3.59+0.48min, respectively, in the hemodilution group; and 6.66 + 0.61, 3.71 + 0.53, and 2.98 +0.73min in the control group. They did not differ significantly between the two groups.(P>0.05)
(3) Compared with those in the control patients, the ED50, ED90, and ED95 of vecuronium in the hemodilution patients were increased by 23.42%, 21.90% and 24.72%(P<0.05). The slope of the dose-response cur
引文
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2． Lars L, Mielke, Elmar K et al. Preoperative acute hypervolemic hemodilution with hydroxyethylstarch: an alter-native to acute normovolemic hemodilution? Anesth Analg, 1997, 84: 26-30
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15． Thomberry EA, Schleinzer W, Singbartl G et al. The effect of changes in arm temperature on neuromuscular montioring in the presence of atracuronium blocked. Anathesia 1988,43:447-451
16． Xue FS,Tong SY,Liao X,et al. Dose-response and time course of effct of rocuronium in male and female anethesized patients. Anesth Analg, 1997,85: 667-671
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18． Shanks CA. Pharmacokinetics of the nondeepolarizing neuromuscular relaxants applied to calculating of bolus and infusion dosage regimens. Anesthesiology, 1986, 64:72-86．
19．杨克勤，叶铁虎，段赫，等。国产维库溴铵量效关系的多中心研究。中华麻醉学杂志，2000，20：693
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24. Duvaldestin P, Henzel D. Binding of tubocurarine, fazadinium, pancuronium and ORG NC 45 to serum protein in normal man and in patients with cirrhosis. Br J Anaesth, 1982, 54, 513-516.
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6. Singbartl K, Schleinzer W, Smgbartl G. Related Articles Hypervolemic hemodilution: an alternative to acute normovolemic hemodilution? A mathematical analysis. J Surg Res. 1999, 86: 206-218
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8．贾慧群，宋子贤，褚海辰，等。术前急性高容量血液稀释应用于肿瘤病人手术的可行性。中华麻醉学杂志，2000，20：661-663。
9．彭云水，褚海辰，贾慧群。术前急性高容量血液稀释对肿瘤病人围术期T淋巴细胞免疫功能的影响。中华麻醉学杂志，2000，20：326-327。
10．张欢，许幸，张京范。加速度法和肌力法在肌松监测中的比较。中华麻醉学杂志，1997，17：523-528。
11. Smith CE, Donati F, Bevan DR. Cumulative dose- response with infusion: A technique to determine
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12, 陈锡明，杭燕南，孙大金，罗库溴铵量效关系两种测 定方法的比较。中华麻醉学杂志， 1998, 18:292-294．
13． Xue FS,Liu Jian H,Liao X,et al. The influence of acute normovolemic hemodilution on the dose-response and time course of action of vecuronium. Anesth Analg, 1998,86: 861-867
14． Ham J,Stanske DR,Miller RD,et al.pharmacokinetics and dynamica of d-tubocuraine during hypothermia. Anesthesiolgy 1981,55:631-635
15． Thomberry EA, Schleinzer W, Singbartl G et al. The effect of changes in arm temperature on neuromuscular montioring in the presence of atracuronium blocked. Anathesia 1988,43:447-451
16． Xue FS,Tong SY,Liao X,et al. Dose-response and time course of effct of rocuronium in male and female anethesized patients. Anesth Analg, 1997,85: 667-671
17． Donti F, Bevan DR. The influence of patients' sex, age and weight on pancuronium onset time. Can Anaesth J, 1986,33:86-89．
18． Shanks CA. Pharmacokinetics of the nondeepolarizing neuromuscular relaxants applied to calculating of bolus and infusion dosage regimens. Anesthesiology, 1986, 64:72-86．
19．杨克勤，叶铁虎，段赫，等。国产维库溴铵量效关系的多中心研究。中华麻醉学杂志，2000，20：693
20．薛富善，刘清华，邹勤，等。急性等容血液稀释对维库溴胺药代动力学的影响。中国医学科学院学报，1997，19：456-460．
21．张利平，顾振华。急性中度等容血液稀释下潘库溴胺药代动力学的研究。中华麻醉学杂志，1995，15：486-488
22．秦任甲，主编。血液流变学。第一版。北京：人民卫生出版社。1999，247。
23．叶平安，朱银南主编。实用麻醉药理学。西安：陕西科学技术出版社，1995，506。
24. Duvaldestin P, Henzel D. Binding of tubocurarine, fazadinium, pancuronium and ORG NC 45 to serum protein in normal man and in patients with cirrhosis. Br J Anaesth, 1982, 54, 513-516.