异丙酚单次剂量和恒速静脉注射在犬脑的摄取和分布
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摘要
静脉麻醉是临床不可或缺的重要手段,广泛应用于临床麻醉、ICU镇静催眠和门诊特殊诊疗等方方面面,但至今其麻醉机制尚未阐明。脑作为静脉麻醉药的效应器官,脑内药物浓度决定了药效,了解静脉麻醉药脑内药代动力学和药效学规律对于探索全麻作用机理、指导临床合理用药有重要的意义。目前,对人脑内静脉麻醉药浓度还无法直接测定,需要一种间接的测量手段,以满足对效应室药代动力学和药效学的探索,静脉麻醉药的脑摄取研究即由此发展而来。异丙酚作为目前临床广泛使用的全身麻醉药,成为静脉麻醉药脑摄取研究的主要对象。
Upton等首先提出和论述了脑摄取研究的基本设想—质量平衡法则(massbalance principles),并进行异丙酚脑摄取的研究:通过对出入脑循环的动、静脉血浆中异丙酚浓度的测定和计算,可间接反映异丙酚全脑摄取情况。由于实验方法的限制和脑功能的特殊性,此法则的异丙酚脑摄取研究不能反映脑组织对异丙酚的实际摄取和不同脑区的分布情况,也难以明确反映异丙酚脑摄取过程中某一时间点异丙酚实际摄取量。解剖异丙酚麻醉状态下的动物脑并直接测量脑组织中异丙酚浓度,此方案是对基于质量平衡法则的脑摄取间接研究的改进,但研究极少。Shyr和Larsson先后通过解剖异丙酚麻醉状态下的鼠脑,采用高效液相色谱紫外萃取法(HPLC-UV-萃取法)测定不同脑组织中异丙酚的浓度。实验结果揭示了异丙酚全麻状态下鼠脑组织中的异丙酚浓度及其分布情况,但Shyr的实验认为异丙酚在鼠脑内分布均衡,而Larsson的实验指出异丙酚在脑内分布情况与注射速度和鼠龄有关。二者的实验均采用SD大鼠为实验动物,由于其脑结构和功能与人脑差别较大,难以对实验结果进行推广,因此有必要对更高等的动物加以研究。另外,使用萃取法异丙酚提取量与异丙酚浓度之间的线性关系不够理想,使用内标物作为结构参照可降低对低浓度异丙酚的测量精度;而沉淀法结合使用外标物(异丙酚标准品)测量异丙酚,线性关系良好,可提高异丙酚提取率。本研究探索了HPLC-UV-沉淀法测量异丙酚脑组织浓度和血浆浓度的可行性。
临床上异丙酚通常与麻醉性镇痛药联合应用。尚无证据表明异丙酚脑摄取和脑分布是否受到这些药物的影响,而这一问题对指导异丙酚的临床应用有重要意义。研究表明,阿片类药物包括舒芬太尼影响异丙酚TCI效应室浓度,影响异丙酚的清除和分布;舒芬太尼在脑内分布不一致,在脑内的作用有区域选择性,舒芬太尼对脑代谢和脑血流有显著的影响;异丙酚脑摄取受区域脑血流等脑功能状况的影响。因此,有必要观察舒芬太尼对异丙酚脑摄取和脑分布的影响。
单次剂量静脉注射多用于全麻诱导和门诊小手术或腔镜检查等门诊检查或治疗,恒速静脉注射常用于全麻维持和ICU病人的镇静和催眠。本研究观察异丙酚上述两种不同全麻状态下,解剖并测量犬脑不同组织中异丙酚浓度,探索基于解剖和直接测量技术的异丙酚脑摄取研究的可行性,以了解不同脑组织对异丙酚的摄取和分布规律。同时,根据异丙酚脑分布特征结合其它相关研究成果探讨异丙酚可能的全麻作用机制。选择舒芬太尼为干扰药物,观察舒芬太尼作用下犬脑不同组织中异丙酚的浓度变化,对异丙酚脑摄取和脑分布受其它麻醉药物的影响程度作初步探索。
第一部分异丙酚单次剂量静脉注射在犬脑的摄取和分布
目的观察异丙酚7mg·kg~(-1)静脉注射和伍用舒芬太尼1μg·kg~(-1)在犬脑的摄取和分布。
材料和方法
实验动物准备与分组:12只年龄12-18个月、体重10-12kg雄性健康犬,随机分为A组(异丙酚组)和B组(异丙酚+舒芬太尼组)。实验均安排在白昼,实验前禁食、禁饮8小时,实验时由右后肢大隐静脉建立静脉通路并保持通畅。
麻醉实施:A组异丙酚7mg·kg~(-1)静脉注射;
B组舒芬太尼1μg·kg~(-1)静脉注射后,立即注入异丙酚7mg·kg~(-1)。
A、B组异丙酚注射时间均为15s,预定麻醉状态均为眼睑反射和踏板反射消失。
标本采集:达到预定麻醉状态后解剖犬右侧颈内动、静脉,各取血2ml快速注入抗凝管中,4℃冰箱中保存。断头法处死实验犬。无菌条件下去除颅盖等组织,专人解剖获取额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑和小脑组织,分别置于无菌干燥培养皿中,-17℃低温冰箱中保存。
标本处理:血标本在4℃低温离心机中离心30min(10000r·min~(-1))。取血浆200μl置于EP管中,加入乙腈400μl,涡旋器震荡2min后再离心10min(10000r·min~(-1)),取上清液于EP管中保存。脑组织样品精确称量后置于匀浆器中,加入乙腈(2ml·g~(-1))充分匀浆,匀浆液离心4min(10000r·min~(-1))后取上清液于EP管中保存。
异丙酚色谱分析:采用HPLC-UV-沉淀法测量异丙酚浓度,外标物为异丙酚标准品。色谱柱为Dikma Diamonsil C_(18)柱(200mm×4.6mm,5μm),柱温4℃。流动相A为乙酸胺(1mmol·L~(-1))和乙酸(1g·L~(-1)),流动相B为甲醇,A:B为25:75。自动进样量20μl,流速1ml·min~(-1),检测波长270nm。
数据分析:采用SPSS13.0软件进行统计处理,计量资料以均数±标准差((?)±s)表示。P＜0.05为差异有统计学意义。
结果
HPLC-UV-沉淀法:异丙酚在2.5～80μg·ml~(-1)间,异丙酚提取量与浓度之间的线性关系良好,R~2为0.999974,P＜0.0001;
血浆和脑组织样品异丙酚平均回收率分别为95.5%和92.3%。
异丙酚血浆浓度:A组颈内动脉和颈内静脉血浆异丙酚浓度分别为11.711±1.634、5.424±0.802μg·ml~(-1),二者差异有统计学意义(差值=6.287±0.878,t=17.545,P=0.000)。B组颈内动脉和颈内静脉血浆异丙酚浓度分别为11.700±1.585、5.444±0.780μg·ml~(-1),二者差异有统计学意义(差值=6.256±0.840,t=18.244,P=0.000)。
A组和B组颈内动脉血浆异丙酚浓度差异无统计学意义(t=0.012,P=0.991),两组颈内静脉血浆异丙酚浓度差异也无统计学意义(t=0.044,P=0.996)。统计表明异丙酚的剂量多少和颈内动静脉无交互效应(F=0.001,P=0.976)。
异丙酚脑组织浓度:A组额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:8.007±0.987、8.015±1.010、8.182±1.051、5.593±0.747、8.232±1.029、10.644±1.660、8.558±1.052、8.389±1.070、7.836±0.964μg·g~(-1)。各脑组织异丙酚浓度差异有统计学意义(F=8.316,P=0.000),丘脑异丙酚浓度高于其它脑组织(P＜0.05),海马低于其它脑组织(P＜0.05)。
B组额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:8.154±1.542、8.125±1.572、8.340±1.544、5.605±0.729、8.351±1.738、11.240±2.111、8.434±1.586、8.567±1.687、7.968±1.323μg·g~(-1),各脑组织异丙酚浓度差异有统计学意义(F=4.873,P=0.000),丘脑异丙酚浓度高于其它脑组织,海马低于其它脑组织(P＜0.05)。
A组和B组各相应部位脑组织异丙酚浓度差异无统计学意义(P＞0.05)。
结论
1.异丙酚单次静脉注射达到犬眼睑反射和踏板反射消失即刻,异丙酚脑摄取尚未达到平衡状态。此时异丙酚在犬脑内的分布不均衡,丘脑最高,海马最低。
2.舒芬太尼(1μg·kg~(-1))对上述麻醉状态异丙酚脑摄取和分布的影响不明显。
3.HPLC-UV-沉淀法使用异丙酚标准品为外标物、纯乙腈为提取剂,测量的线性关系好,回收率高,适用于对脑组织和血浆异丙酚浓度的测定。
第二部分异丙酚恒速静脉注射在犬脑的摄取和分布
目的观察异丙酚恒速泵注至脑摄取平衡状态时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑的分布。
材料和方法
实验动物准备:6只年龄12-18个月、体重10-12kg雄性健康犬,实验前禁食、禁饮8小时。实验均安排在白昼,实验时由右后肢大隐静脉建立静脉通路并保持通畅。
麻醉实施:各犬以异丙酚7mg·kg~(-1)静脉注射,续以70mg·kg~(-1)·h~(-1)恒速静脉泵注。
标本采集:达到麻醉状态后解剖犬右侧颈内动、静脉,泵注30min(T30)、50min(T50)时分别取颈内动脉和颈内静脉血2ml,快速注入抗凝管中,4℃冰箱中保存。。T50时断头法处死实验犬,无菌条件下去除颅盖等组织,专人解剖取额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑组织。分别置于无菌干燥培养皿中,-17℃低温冰箱中保存。
标本处理:血标本在4℃低温离心机中离心30min(10000r·min~(-1))。取血浆200μl置于EP管中,加入乙腈400μl,涡旋器震荡2min后再离心10min(10000r·min~(-1)),取上清液于EP管中保存。脑组织样品精确称量后置于匀浆器中,加入乙腈(2ml·g~(-1))充分匀浆,匀浆液离心4min(10000r·min~(-1))后取上清液于EP管中保存。
异丙酚色谱分析:采用HPLC-UV-沉淀法测量异丙酚浓度,外标物为异丙酚标准品。色谱柱为Dikma Diamonsil C_(18)柱(200mm×4.6mm,5μm),柱温4℃。流动相A为乙酸胺(1mmol·L~(-1))和乙酸(1g·L~(-1)),流动相B为甲醇,A:B为25:75。自动进样量20μl,流速1ml·min~(-1),检测波长270nm。
数据分析:采用SPSS13.0软件进行统计处理,计量资料以均数±标准差((?)±s)表示。P＜0.05为差异有统计学意义。
结果
颈内动脉、静脉血浆异丙酚浓度在T30时分别为3.107±1.067、3.095±1.085μg·ml~(-1),两者差异无统计学意义(t=0.019,P=0.985);T50时分别为3.090±1.101、3.117±1.091μg·ml~(-1),两者差异无统计学意义(t=0.042,P=0.967)。T50时,额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:3.086±1.123、3.116±1.125、3.073±1.158、3.117±1.090、3.075±1.178、3.073±1.146、3.075±1.151、3.102±1.174、3.072±1.192μg·g~(-1),各脑组织异丙酚浓度差异无统计学意义(F=0.002,P=1.000)。
结论
1.犬脑对异丙酚的摄取在恒速泵注30、50min时均处于平衡状态;
2.脑摄取平衡时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑呈均衡分布。
通过对异丙酚单次剂量和恒速静脉注射在犬脑的摄取和分布的研究,我们得出如下结论:
1.异丙酚单次静脉注射达到犬眼睑反射和踏板反射消失即刻,异丙酚脑摄取尚未达到平衡状态。此时异丙酚在犬脑内的分布不均衡,丘脑最高,海马最低。
2.舒芬太尼(1μg·kg~(-1))对上述麻醉状态异丙酚脑摄取和分布的影响不明显。
3.犬脑对异丙酚的摄取在恒速泵注30、50min时均处于平衡状态;脑摄取平衡时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑呈均衡分布。
4.异丙酚恒速静脉注射至脑摄取达到平衡时的脑分布,与单次静脉注射达到眼睑反射和踏板反射消失即刻的分布特征不同(前者在犬脑组织呈均衡分布,后者分布不均衡)。
5.HPLC-UV-沉淀法使用异丙酚标准品为外标物、纯乙腈为提取剂,测量的线性关系好,回收率高,适用于对脑组织和血浆异丙酚浓度的测定。
Propofol (2,6-diisopropylphenol) has been the most common intravenous anesthetic as an induction and maintenance agent and is widely used as a sedative agent in the intensive care unit (ICU). Many researches have been done to investigate the anesthetic mechanism of propofol, but the mechanism has not been made out very clearly until today.
In the past decade, a large body of experimental observations have accumulated that the central GABA_A receptors represent an important target in mediating the anesthetic mechanism of propofol. The central GABA_A receptors scatter in the brain, but it is more intensive in some cerebral tissues than the others. As we know, Positron emission tomography (PET) allows researchers to study brain function in vivo, and it has been applied to investigate the nature of the action of propofol in the brain. Using this technique, it has been found that the regional cerebral glucose metabolism and regional cerebral blood flow is depressed by propofol more significantly in some of the cerebral tissues. Based on these researches, it can be assumed that propofol concentrations are discordant in various cerebral tissues. Therefore, the cerebral uptake and regional distribution of propofol must be investigated to understand its anesthetic mechanism.
The research of cerebral uptake of propofol usually bases on mass balance principles. By determinations of propofol concentrations in arterial and venous blood of cerebral circulation using high-pressure liquid chromatrography(HPLC), we can evaluate indirectly the cerebral uptake of propofol by calculating the areas between the arterial and venous concentration-time curves. However, the concentrations of propofol at its site of action in the brain can't be accurately counted and the character of regional cerebral distribution of propofol can't be revealed by this method. To improve the research of cerebral uptake, the concentrations of propofol in different parts of the brain must be detected directly by anatomy.
Sufentanil has many advantages combining with propofol in clinical anesthesia,but no evidence can prove whether other anesthetics such as sufentanil can influence the cerebral uptake and regional distribution of propofol . Recently, it has been found that sufentanil has different effect on various cerebral tissues and can disturb the cerebral metabolism and cerebral blood flow. Because cerebral blood flow is involved in the cerebral uptake of propofol, it can be assumed that sufentanil may have effect on the cerebral uptake and regional distribution of propofol.
This study is firstly aimed to investigate the cerebral uptake and distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) after a single bolus or a constant rate intravenous infusion. Secondly, the aim of this study is to explore the effect of sufentanil on the cerebral uptake and regional distribution of propofol. Meanwhile, we improved the method of HPLC analysis for determination of propofol concentration of cerebral tissue and blood plasma.
Part One The cerebral uptake and distribution of propofol after a single bolus intravenous injection in dogs
Objective
To investigate the cerebral uptake and distribution of propofol in different cerebral tissues after a single bolus intravenous injection of propofol or combined with sufentanil in dogs.
Material and methods
Twelve male dogs aged 12-18 months weighing 10-12 kg were divided randomly into two groups (group A and B). The venous channel was established in the great saphenous vein of the right hind leg in every animal. Animals were anesthetized with propofol via the venous channel at a single bolus (7mg·kg~(-1)) in 15 sec in group A. After sufentanil (1μg·kg~(-1)) was intravenously injected, propofol (7mg·kg~(-1)) was infused in 15 sec in group B.
As the eyelid reflex disappeared,blood samples were collected by right internal carotid and internal jugular vein respectively for determination the plasma concentration of propofol in two groups. Then the animal was scarificed immediately by decapitation. The frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus were dissected for determination the concentration of propofol.
Propofol concentration was determined by modified HPLC-UV. External standard was a control article of propofol. The analysis was performed with a Dikma Diamonsil C_(18) reverse-phase column (200×4.6mm, 5μm) and a 2996 Waters ultraviolet detector (270nm). The solvent system was acidum aceticum-methanol-ammonium acetate at flow rate of 1ml·min~(-1). The brain tissue samples were extracted with acetonitrile (2ml·g~(-1)) and homogenized. The blood samples were extracted with acetonitrile (di-volume). After being centrifuged, the supernatant was submitted to HPLC analysis.
Measurement data were expressed as mean±standard deviation. All statistical calculations were performed using SPSS 13.0 for windows. The One-Way ANOVA ,factorial analysis and paired t-test were used to test the differences for measurement data. Multiple comparisons were analyzed by using Student-Newman-Keuls (SNK) test. Differences were considered statistically significant when P was less than 0.05.
Results
In group A and B, the blood plasma concentration of propofol in internal carotid artery (11.711±1.634,11.700±1.585μg·ml~(-1)) was higher than that in internal jugular vein (5.424±0.802,5.444±0.780μg·ml~(-1)) respectively (P<0.05).The propofol concentration in internal carotid artery of group A was the same as that of group B (P >0.05).
In group A, the propofol concentrations in frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 8. 007±0. 987,8. 015±1. 010,8.182±1. 051, 5. 593±0. 747, 8. 232±1. 029, 10. 644±1. 660,8. 558±1. 052, 8. 389±1. 070 and 7.836±0. 964μg·g~(-1) respectively. The propofol concentrations were highest in thalamus and lowest in hippocampus (P <0.05).
In group B, the propofol concentrations in the frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 8.154±1. 542,8.125±1. 572, 8. 340±1. 544, 5. 605±0. 729, 8. 351±1. 738, 11. 2 40±2.111, 8. 434±1. 586, 8. 567±1. 687 and 7.968±1.323μg·g~(-1) respectively. The propofol concentrations were highest in thalamus and lowest in hippocampus (P <0.05).
No differences were observed in propofol concentrations in brain tissues between group A and B (P >0.05).
Conclusions
As the eyelid reflex disappeared after a single bolus propofol intravenous injection in dogs,the cerebral uptake of propofol is unstable and the propofol concentrations are discordant in various cerebral tissues, highest in the thalamus, lowest in the hippocampus.
Under above condition, sufentanil(1μg·kg~(-1)) has no influence on the cerebral uptake and regional distribution of propofol.
Part Two The cerebral distribution of propofol when the cerebral uptake being in equilibrium in dogs
Objective
To investigate the cerebral distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) when the cerebral uptake being in equilibrium after a constant rate intravenous infusion in dogs.
Material and methods
Six male 12-18 months old dogs weighing 10-12kg were used in this study. Animals were anesthetized with propofol at a single bolus (7mg·kg~(-1)) in 15s and then was infused at a constant rate of 70 mg·kg~(_1)·h~(-1) using a microinfusion pump via the great saphenous vein of right hind leg.
Blood samples were collected by the right internal carotid and internal jugular vein at 30 min (T30) and 50 min (T50) after propofol was infused for measurement the blood plasma concentrations of propofol. Then the animal was scarificed immediately by decapitation. At T50, the frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus were dissected for determination the concentration of propofol.
Propofol concentration was determined by modified HPLC-UV. External standard was a control article of propofol. The analysis was performed with a Dikma Diamonsil C_(18) reverse-phase column (200×4.6mm, 5μm) and a 2996 Waters ultraviolet detector (270nm). The solvent system was acidum aceticum-methanol-ammonium acetate at flow rate of 1ml·min~(-1). The brain tissue samples were extracted with acetonitrile (2ml·g~(-1)) and homogenized. The blood samples were extracted with acetonitrile (di-volume). After being centrifuged, the supernatant was submitted to HPLC analysis.
Measurement data were expressed as mean±standard deviation. Statistical analysis was undertaken using SPSS 13.0 for windows. The One-Way ANOVA and paired t-test were used to test the differences for measurement data. Multiple comparisons were analyzed by using SNK test. Differences were considered statistically significant when P was less than 0.05.
Results
The propofol concentrations in internal carotid artery and internal jugular vein blood plasma were 3.107±1. 067, 3. 095±1. 085μg·ml~(-1) at T30 and 3. 090±1.101,3.117±1.091μg·ml~(-1) at T50 respectively. There were no significant differences between the propofol concentrations in internal carotid artery and internal jugular vein blood plasma at T30 and T50 (P>0.05).
The propofol concentrations in the frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 3. 086±1.123, 3.116±1. 125, 3. 073±1. 158, 3.117±1. 090, 3. 075±1. 178, 3. 073±1.146,3.075±1. 151,3.102±1.174 and 3. 072±1.192μg.g~(-1) respectively. Propofol were evenly distributed in these cerebral tissues at T50 (P>0.05).
Conclusions
1. At 30min and 50 min after a constant rate intravenous infusion , the cerebral uptake of propofol is in equilibrium.
2. When the cerebral uptake of propofol is in equilibrium , propofol is distributed evenly among regional cerebral tissues in dogs.
Summary
This study is to investigate the cerebral uptake and distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) after a single bolus or a constant rate propofol intravenous infusion. We can reach conclusions as follows:
1. As the eyelid reflex disappeared after a single bolus propofol intravenous injection in dogs, the cerebral uptake of propofol is unstable , and the propofol concentrations are discordant in various cerebral tissues, highest in the thalamus, lowest in the hippocampus.
2. With a single bolus propofol intravenous injection, sufentanil(1μg·kg~(-1)) has no influence on the cerebral uptake and regional distribution of propofol in dogs.
3. At 30min and 50 min after a constant rate intravenous injection , the cerebral uptake of propofol is in equilibrium and propofol is distributed evenly among regional cerebral tissues in dogs.
4. The HPLC- ultra-violet spectroscopy combining with precipitation method can be used appropriately to determinate the propofol concentration of blood plasma and brain tissue.
Upton等首先提出和论述了脑摄取研究的基本设想—质量平衡法则(massbalance principles),并进行异丙酚脑摄取的研究:通过对出入脑循环的动、静脉血浆中异丙酚浓度的测定和计算,可间接反映异丙酚全脑摄取情况。由于实验方法的限制和脑功能的特殊性,此法则的异丙酚脑摄取研究不能反映脑组织对异丙酚的实际摄取和不同脑区的分布情况,也难以明确反映异丙酚脑摄取过程中某一时间点异丙酚实际摄取量。解剖异丙酚麻醉状态下的动物脑并直接测量脑组织中异丙酚浓度,此方案是对基于质量平衡法则的脑摄取间接研究的改进,但研究极少。Shyr和Larsson先后通过解剖异丙酚麻醉状态下的鼠脑,采用高效液相色谱紫外萃取法(HPLC-UV-萃取法)测定不同脑组织中异丙酚的浓度。实验结果揭示了异丙酚全麻状态下鼠脑组织中的异丙酚浓度及其分布情况,但Shyr的实验认为异丙酚在鼠脑内分布均衡,而Larsson的实验指出异丙酚在脑内分布情况与注射速度和鼠龄有关。二者的实验均采用SD大鼠为实验动物,由于其脑结构和功能与人脑差别较大,难以对实验结果进行推广,因此有必要对更高等的动物加以研究。另外,使用萃取法异丙酚提取量与异丙酚浓度之间的线性关系不够理想,使用内标物作为结构参照可降低对低浓度异丙酚的测量精度;而沉淀法结合使用外标物(异丙酚标准品)测量异丙酚,线性关系良好,可提高异丙酚提取率。本研究探索了HPLC-UV-沉淀法测量异丙酚脑组织浓度和血浆浓度的可行性。
临床上异丙酚通常与麻醉性镇痛药联合应用。尚无证据表明异丙酚脑摄取和脑分布是否受到这些药物的影响,而这一问题对指导异丙酚的临床应用有重要意义。研究表明,阿片类药物包括舒芬太尼影响异丙酚TCI效应室浓度,影响异丙酚的清除和分布;舒芬太尼在脑内分布不一致,在脑内的作用有区域选择性,舒芬太尼对脑代谢和脑血流有显著的影响;异丙酚脑摄取受区域脑血流等脑功能状况的影响。因此,有必要观察舒芬太尼对异丙酚脑摄取和脑分布的影响。
单次剂量静脉注射多用于全麻诱导和门诊小手术或腔镜检查等门诊检查或治疗,恒速静脉注射常用于全麻维持和ICU病人的镇静和催眠。本研究观察异丙酚上述两种不同全麻状态下,解剖并测量犬脑不同组织中异丙酚浓度,探索基于解剖和直接测量技术的异丙酚脑摄取研究的可行性,以了解不同脑组织对异丙酚的摄取和分布规律。同时,根据异丙酚脑分布特征结合其它相关研究成果探讨异丙酚可能的全麻作用机制。选择舒芬太尼为干扰药物,观察舒芬太尼作用下犬脑不同组织中异丙酚的浓度变化,对异丙酚脑摄取和脑分布受其它麻醉药物的影响程度作初步探索。
第一部分异丙酚单次剂量静脉注射在犬脑的摄取和分布
目的观察异丙酚7mg·kg~(-1)静脉注射和伍用舒芬太尼1μg·kg~(-1)在犬脑的摄取和分布。
材料和方法
实验动物准备与分组:12只年龄12-18个月、体重10-12kg雄性健康犬,随机分为A组(异丙酚组)和B组(异丙酚+舒芬太尼组)。实验均安排在白昼,实验前禁食、禁饮8小时,实验时由右后肢大隐静脉建立静脉通路并保持通畅。
麻醉实施:A组异丙酚7mg·kg~(-1)静脉注射;
B组舒芬太尼1μg·kg~(-1)静脉注射后,立即注入异丙酚7mg·kg~(-1)。
A、B组异丙酚注射时间均为15s,预定麻醉状态均为眼睑反射和踏板反射消失。
标本采集:达到预定麻醉状态后解剖犬右侧颈内动、静脉,各取血2ml快速注入抗凝管中,4℃冰箱中保存。断头法处死实验犬。无菌条件下去除颅盖等组织,专人解剖获取额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑和小脑组织,分别置于无菌干燥培养皿中,-17℃低温冰箱中保存。
标本处理:血标本在4℃低温离心机中离心30min(10000r·min~(-1))。取血浆200μl置于EP管中,加入乙腈400μl,涡旋器震荡2min后再离心10min(10000r·min~(-1)),取上清液于EP管中保存。脑组织样品精确称量后置于匀浆器中,加入乙腈(2ml·g~(-1))充分匀浆,匀浆液离心4min(10000r·min~(-1))后取上清液于EP管中保存。
异丙酚色谱分析:采用HPLC-UV-沉淀法测量异丙酚浓度,外标物为异丙酚标准品。色谱柱为Dikma Diamonsil C_(18)柱(200mm×4.6mm,5μm),柱温4℃。流动相A为乙酸胺(1mmol·L~(-1))和乙酸(1g·L~(-1)),流动相B为甲醇,A:B为25:75。自动进样量20μl,流速1ml·min~(-1),检测波长270nm。
数据分析:采用SPSS13.0软件进行统计处理,计量资料以均数±标准差((?)±s)表示。P＜0.05为差异有统计学意义。
结果
HPLC-UV-沉淀法:异丙酚在2.5～80μg·ml~(-1)间,异丙酚提取量与浓度之间的线性关系良好,R~2为0.999974,P＜0.0001;
血浆和脑组织样品异丙酚平均回收率分别为95.5%和92.3%。
异丙酚血浆浓度:A组颈内动脉和颈内静脉血浆异丙酚浓度分别为11.711±1.634、5.424±0.802μg·ml~(-1),二者差异有统计学意义(差值=6.287±0.878,t=17.545,P=0.000)。B组颈内动脉和颈内静脉血浆异丙酚浓度分别为11.700±1.585、5.444±0.780μg·ml~(-1),二者差异有统计学意义(差值=6.256±0.840,t=18.244,P=0.000)。
A组和B组颈内动脉血浆异丙酚浓度差异无统计学意义(t=0.012,P=0.991),两组颈内静脉血浆异丙酚浓度差异也无统计学意义(t=0.044,P=0.996)。统计表明异丙酚的剂量多少和颈内动静脉无交互效应(F=0.001,P=0.976)。
异丙酚脑组织浓度:A组额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:8.007±0.987、8.015±1.010、8.182±1.051、5.593±0.747、8.232±1.029、10.644±1.660、8.558±1.052、8.389±1.070、7.836±0.964μg·g~(-1)。各脑组织异丙酚浓度差异有统计学意义(F=8.316,P=0.000),丘脑异丙酚浓度高于其它脑组织(P＜0.05),海马低于其它脑组织(P＜0.05)。
B组额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:8.154±1.542、8.125±1.572、8.340±1.544、5.605±0.729、8.351±1.738、11.240±2.111、8.434±1.586、8.567±1.687、7.968±1.323μg·g~(-1),各脑组织异丙酚浓度差异有统计学意义(F=4.873,P=0.000),丘脑异丙酚浓度高于其它脑组织,海马低于其它脑组织(P＜0.05)。
A组和B组各相应部位脑组织异丙酚浓度差异无统计学意义(P＞0.05)。
结论
1.异丙酚单次静脉注射达到犬眼睑反射和踏板反射消失即刻,异丙酚脑摄取尚未达到平衡状态。此时异丙酚在犬脑内的分布不均衡,丘脑最高,海马最低。
2.舒芬太尼(1μg·kg~(-1))对上述麻醉状态异丙酚脑摄取和分布的影响不明显。
3.HPLC-UV-沉淀法使用异丙酚标准品为外标物、纯乙腈为提取剂,测量的线性关系好,回收率高,适用于对脑组织和血浆异丙酚浓度的测定。
第二部分异丙酚恒速静脉注射在犬脑的摄取和分布
目的观察异丙酚恒速泵注至脑摄取平衡状态时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑的分布。
材料和方法
实验动物准备:6只年龄12-18个月、体重10-12kg雄性健康犬,实验前禁食、禁饮8小时。实验均安排在白昼,实验时由右后肢大隐静脉建立静脉通路并保持通畅。
麻醉实施:各犬以异丙酚7mg·kg~(-1)静脉注射,续以70mg·kg~(-1)·h~(-1)恒速静脉泵注。
标本采集:达到麻醉状态后解剖犬右侧颈内动、静脉,泵注30min(T30)、50min(T50)时分别取颈内动脉和颈内静脉血2ml,快速注入抗凝管中,4℃冰箱中保存。。T50时断头法处死实验犬,无菌条件下去除颅盖等组织,专人解剖取额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑组织。分别置于无菌干燥培养皿中,-17℃低温冰箱中保存。
标本处理:血标本在4℃低温离心机中离心30min(10000r·min~(-1))。取血浆200μl置于EP管中,加入乙腈400μl,涡旋器震荡2min后再离心10min(10000r·min~(-1)),取上清液于EP管中保存。脑组织样品精确称量后置于匀浆器中,加入乙腈(2ml·g~(-1))充分匀浆,匀浆液离心4min(10000r·min~(-1))后取上清液于EP管中保存。
异丙酚色谱分析:采用HPLC-UV-沉淀法测量异丙酚浓度,外标物为异丙酚标准品。色谱柱为Dikma Diamonsil C_(18)柱(200mm×4.6mm,5μm),柱温4℃。流动相A为乙酸胺(1mmol·L~(-1))和乙酸(1g·L~(-1)),流动相B为甲醇,A:B为25:75。自动进样量20μl,流速1ml·min~(-1),检测波长270nm。
数据分析:采用SPSS13.0软件进行统计处理,计量资料以均数±标准差((?)±s)表示。P＜0.05为差异有统计学意义。
结果
颈内动脉、静脉血浆异丙酚浓度在T30时分别为3.107±1.067、3.095±1.085μg·ml~(-1),两者差异无统计学意义(t=0.019,P=0.985);T50时分别为3.090±1.101、3.117±1.091μg·ml~(-1),两者差异无统计学意义(t=0.042,P=0.967)。T50时,额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑异丙酚浓度分别为:3.086±1.123、3.116±1.125、3.073±1.158、3.117±1.090、3.075±1.178、3.073±1.146、3.075±1.151、3.102±1.174、3.072±1.192μg·g~(-1),各脑组织异丙酚浓度差异无统计学意义(F=0.002,P=1.000)。
结论
1.犬脑对异丙酚的摄取在恒速泵注30、50min时均处于平衡状态;
2.脑摄取平衡时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑呈均衡分布。
通过对异丙酚单次剂量和恒速静脉注射在犬脑的摄取和分布的研究,我们得出如下结论:
1.异丙酚单次静脉注射达到犬眼睑反射和踏板反射消失即刻,异丙酚脑摄取尚未达到平衡状态。此时异丙酚在犬脑内的分布不均衡,丘脑最高,海马最低。
2.舒芬太尼(1μg·kg~(-1))对上述麻醉状态异丙酚脑摄取和分布的影响不明显。
3.犬脑对异丙酚的摄取在恒速泵注30、50min时均处于平衡状态;脑摄取平衡时,异丙酚在犬脑额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑呈均衡分布。
4.异丙酚恒速静脉注射至脑摄取达到平衡时的脑分布,与单次静脉注射达到眼睑反射和踏板反射消失即刻的分布特征不同(前者在犬脑组织呈均衡分布,后者分布不均衡)。
5.HPLC-UV-沉淀法使用异丙酚标准品为外标物、纯乙腈为提取剂,测量的线性关系好,回收率高,适用于对脑组织和血浆异丙酚浓度的测定。
Propofol (2,6-diisopropylphenol) has been the most common intravenous anesthetic as an induction and maintenance agent and is widely used as a sedative agent in the intensive care unit (ICU). Many researches have been done to investigate the anesthetic mechanism of propofol, but the mechanism has not been made out very clearly until today.
In the past decade, a large body of experimental observations have accumulated that the central GABA_A receptors represent an important target in mediating the anesthetic mechanism of propofol. The central GABA_A receptors scatter in the brain, but it is more intensive in some cerebral tissues than the others. As we know, Positron emission tomography (PET) allows researchers to study brain function in vivo, and it has been applied to investigate the nature of the action of propofol in the brain. Using this technique, it has been found that the regional cerebral glucose metabolism and regional cerebral blood flow is depressed by propofol more significantly in some of the cerebral tissues. Based on these researches, it can be assumed that propofol concentrations are discordant in various cerebral tissues. Therefore, the cerebral uptake and regional distribution of propofol must be investigated to understand its anesthetic mechanism.
The research of cerebral uptake of propofol usually bases on mass balance principles. By determinations of propofol concentrations in arterial and venous blood of cerebral circulation using high-pressure liquid chromatrography(HPLC), we can evaluate indirectly the cerebral uptake of propofol by calculating the areas between the arterial and venous concentration-time curves. However, the concentrations of propofol at its site of action in the brain can't be accurately counted and the character of regional cerebral distribution of propofol can't be revealed by this method. To improve the research of cerebral uptake, the concentrations of propofol in different parts of the brain must be detected directly by anatomy.
Sufentanil has many advantages combining with propofol in clinical anesthesia,but no evidence can prove whether other anesthetics such as sufentanil can influence the cerebral uptake and regional distribution of propofol . Recently, it has been found that sufentanil has different effect on various cerebral tissues and can disturb the cerebral metabolism and cerebral blood flow. Because cerebral blood flow is involved in the cerebral uptake of propofol, it can be assumed that sufentanil may have effect on the cerebral uptake and regional distribution of propofol.
This study is firstly aimed to investigate the cerebral uptake and distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) after a single bolus or a constant rate intravenous infusion. Secondly, the aim of this study is to explore the effect of sufentanil on the cerebral uptake and regional distribution of propofol. Meanwhile, we improved the method of HPLC analysis for determination of propofol concentration of cerebral tissue and blood plasma.
Part One The cerebral uptake and distribution of propofol after a single bolus intravenous injection in dogs
Objective
To investigate the cerebral uptake and distribution of propofol in different cerebral tissues after a single bolus intravenous injection of propofol or combined with sufentanil in dogs.
Material and methods
Twelve male dogs aged 12-18 months weighing 10-12 kg were divided randomly into two groups (group A and B). The venous channel was established in the great saphenous vein of the right hind leg in every animal. Animals were anesthetized with propofol via the venous channel at a single bolus (7mg·kg~(-1)) in 15 sec in group A. After sufentanil (1μg·kg~(-1)) was intravenously injected, propofol (7mg·kg~(-1)) was infused in 15 sec in group B.
As the eyelid reflex disappeared,blood samples were collected by right internal carotid and internal jugular vein respectively for determination the plasma concentration of propofol in two groups. Then the animal was scarificed immediately by decapitation. The frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus were dissected for determination the concentration of propofol.
Propofol concentration was determined by modified HPLC-UV. External standard was a control article of propofol. The analysis was performed with a Dikma Diamonsil C_(18) reverse-phase column (200×4.6mm, 5μm) and a 2996 Waters ultraviolet detector (270nm). The solvent system was acidum aceticum-methanol-ammonium acetate at flow rate of 1ml·min~(-1). The brain tissue samples were extracted with acetonitrile (2ml·g~(-1)) and homogenized. The blood samples were extracted with acetonitrile (di-volume). After being centrifuged, the supernatant was submitted to HPLC analysis.
Measurement data were expressed as mean±standard deviation. All statistical calculations were performed using SPSS 13.0 for windows. The One-Way ANOVA ,factorial analysis and paired t-test were used to test the differences for measurement data. Multiple comparisons were analyzed by using Student-Newman-Keuls (SNK) test. Differences were considered statistically significant when P was less than 0.05.
Results
In group A and B, the blood plasma concentration of propofol in internal carotid artery (11.711±1.634,11.700±1.585μg·ml~(-1)) was higher than that in internal jugular vein (5.424±0.802,5.444±0.780μg·ml~(-1)) respectively (P<0.05).The propofol concentration in internal carotid artery of group A was the same as that of group B (P >0.05).
In group A, the propofol concentrations in frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 8. 007±0. 987,8. 015±1. 010,8.182±1. 051, 5. 593±0. 747, 8. 232±1. 029, 10. 644±1. 660,8. 558±1. 052, 8. 389±1. 070 and 7.836±0. 964μg·g~(-1) respectively. The propofol concentrations were highest in thalamus and lowest in hippocampus (P <0.05).
In group B, the propofol concentrations in the frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 8.154±1. 542,8.125±1. 572, 8. 340±1. 544, 5. 605±0. 729, 8. 351±1. 738, 11. 2 40±2.111, 8. 434±1. 586, 8. 567±1. 687 and 7.968±1.323μg·g~(-1) respectively. The propofol concentrations were highest in thalamus and lowest in hippocampus (P <0.05).
No differences were observed in propofol concentrations in brain tissues between group A and B (P >0.05).
Conclusions
As the eyelid reflex disappeared after a single bolus propofol intravenous injection in dogs,the cerebral uptake of propofol is unstable and the propofol concentrations are discordant in various cerebral tissues, highest in the thalamus, lowest in the hippocampus.
Under above condition, sufentanil(1μg·kg~(-1)) has no influence on the cerebral uptake and regional distribution of propofol.
Part Two The cerebral distribution of propofol when the cerebral uptake being in equilibrium in dogs
Objective
To investigate the cerebral distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) when the cerebral uptake being in equilibrium after a constant rate intravenous infusion in dogs.
Material and methods
Six male 12-18 months old dogs weighing 10-12kg were used in this study. Animals were anesthetized with propofol at a single bolus (7mg·kg~(-1)) in 15s and then was infused at a constant rate of 70 mg·kg~(_1)·h~(-1) using a microinfusion pump via the great saphenous vein of right hind leg.
Blood samples were collected by the right internal carotid and internal jugular vein at 30 min (T30) and 50 min (T50) after propofol was infused for measurement the blood plasma concentrations of propofol. Then the animal was scarificed immediately by decapitation. At T50, the frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus were dissected for determination the concentration of propofol.
Propofol concentration was determined by modified HPLC-UV. External standard was a control article of propofol. The analysis was performed with a Dikma Diamonsil C_(18) reverse-phase column (200×4.6mm, 5μm) and a 2996 Waters ultraviolet detector (270nm). The solvent system was acidum aceticum-methanol-ammonium acetate at flow rate of 1ml·min~(-1). The brain tissue samples were extracted with acetonitrile (2ml·g~(-1)) and homogenized. The blood samples were extracted with acetonitrile (di-volume). After being centrifuged, the supernatant was submitted to HPLC analysis.
Measurement data were expressed as mean±standard deviation. Statistical analysis was undertaken using SPSS 13.0 for windows. The One-Way ANOVA and paired t-test were used to test the differences for measurement data. Multiple comparisons were analyzed by using SNK test. Differences were considered statistically significant when P was less than 0.05.
Results
The propofol concentrations in internal carotid artery and internal jugular vein blood plasma were 3.107±1. 067, 3. 095±1. 085μg·ml~(-1) at T30 and 3. 090±1.101,3.117±1.091μg·ml~(-1) at T50 respectively. There were no significant differences between the propofol concentrations in internal carotid artery and internal jugular vein blood plasma at T30 and T50 (P>0.05).
The propofol concentrations in the frontal lobe, parietal lobe, temporal lobe, hippocampus, cingulate gyrus, thalamus, midbrain, pons, cerebellum were 3. 086±1.123, 3.116±1. 125, 3. 073±1. 158, 3.117±1. 090, 3. 075±1. 178, 3. 073±1.146,3.075±1. 151,3.102±1.174 and 3. 072±1.192μg.g~(-1) respectively. Propofol were evenly distributed in these cerebral tissues at T50 (P>0.05).
Conclusions
1. At 30min and 50 min after a constant rate intravenous infusion , the cerebral uptake of propofol is in equilibrium.
2. When the cerebral uptake of propofol is in equilibrium , propofol is distributed evenly among regional cerebral tissues in dogs.
Summary
This study is to investigate the cerebral uptake and distribution of propofol in different cerebral tissues (frontal lobe, parietal lobe, temporal lobe, cingulated gyrus, midbrain, pons, cerebellum, thalamus and hippocampus) after a single bolus or a constant rate propofol intravenous infusion. We can reach conclusions as follows:
1. As the eyelid reflex disappeared after a single bolus propofol intravenous injection in dogs, the cerebral uptake of propofol is unstable , and the propofol concentrations are discordant in various cerebral tissues, highest in the thalamus, lowest in the hippocampus.
2. With a single bolus propofol intravenous injection, sufentanil(1μg·kg~(-1)) has no influence on the cerebral uptake and regional distribution of propofol in dogs.
3. At 30min and 50 min after a constant rate intravenous injection , the cerebral uptake of propofol is in equilibrium and propofol is distributed evenly among regional cerebral tissues in dogs.
4. The HPLC- ultra-violet spectroscopy combining with precipitation method can be used appropriately to determinate the propofol concentration of blood plasma and brain tissue.
引文
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1.Sneyd JR.Recent advances in intravenous anaesthesia.Br J Anaesth.2004Nov;93(5):725-36..
2.Giuseppe Trapani,Cosimo Altomare,Enrico Sanna,et al.Propofol in anesthesia.Mechanism of action,structure-activity relationships,and drug delivery.Current medicinal chemistry.2000,7:249-271.
3.Short CE,Bufalari A.Propofol anesthesia.Vet Clin North Am Small Anim Pract.1999May;29(3):747-78.
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5.Sheiner LB,Stanske DR,Vozeh S,et al.Simultaneous modeling of pharmacokinetics and pharmacodynamics:application to d-tubocurarine.Clin Pharmacol Ther,1979,25(3):358-71.
6.Upton RN,Mather LE,Runciman WB,et al.The use of mass balance principles to describe regional drug distribution and elimination[J].J Pharmacokinet Biopharm.1988,16(1):13-29.
7.Shyr MH,Tsai TH,Tan PP,et al.Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat[J].Neurosci Lett,1995,30;184(3):212-5.
8.Larsson JE,Wahlstron G.The influence of age and administration rate on the brain sensitivity to propofol in rats[J].Acta Anaesthesiol Scand,1998,42:987-94.
9.Franks NP,Lieb WR.Molecular and cellar mechanisms of general anaesthesia[J].Nature,1994,367:607-13.
10.Sigel E.Mapping of the benzodiazepine recognition site on GABA(A) receptors[J].Curr Top Med Chem.2002 Aug;2(8):833-839.
11.Xu LX,Jia YS,Qiu JY,et al.Expression and distribution of C-fos oncogene wthin central nerous system of the rat following halothane anesthesia[J].J Med Coll PLA,1997,12:273-8.
12.Trapani G,Altomare C,Liso G,et al.Propofol in anesthesia.Mechanism of action,structure-activity relationships,and drug delivery[J].Curr med chem,2000,7:249-71.
13.Alkire MT,Haier RJ,Barker SJ,et al.Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography[J].Anesthesiology,1995,82:393-403.
14.林春水,于冬男,古妙宁,等.异丙酚靶控输注对健康志愿者脑葡萄糖代谢的影响[J].中华麻醉学杂志,2004,24(9):645-8.
15.Fiset P,Paus T,Dalozer T,et al.Brain mechanisms of propofol-induced loss of consciousness in humans:a positron emission tomographic study[J].J Neurosci,1999,19:5506-5513.
16.Paus T.Functional anatomy of arousal and attention systems in the human brain[J].Prog Brain Res.2000,126:65-77.
17.Concas A,Santoro G.Mascia MP,et al.The general anesthetic propofol enhances the function of gamma-aminobutyric acid-coupled chloride channel in the rat cerebral cortex[J].J Neurochem,1990,55(6):2135-8.
18.Huq CC Jr.Pharmacokinetics of drugs administered intravenously[J].Anesth Analg,1978, 57:704-723.
19.Kaile K Kaisti,Jaakko W Langsj(O|¨),Sargo Aalto,et al.Effects of sevoflurane,propofol,and adjunct nitrous oxide on regional cerebral blood flow,oxygen consumption,and blood volume in humans[J].Anesthesiology,2003,99:603-13.
20.Fiset P.Functional brain imaging and propofol mechanisms of action[J].Adv Exp Med Biol,2003,523:115-21.
21.Peacock JE,Blackburn A,Sherry KM,et al.Arterial jugular venous bulb blood propofol concentrations during induction of anesthesia[J].Anesth Analg,1995,80:1002-6.
22.欧阳铭文,盖成林,林春水,等.异丙酚脑摄取研究[J].《国外医学》麻醉学与复苏分册,2002,23:333-5.
23.Ludbrook GL,Upton RN.A physiological model of induction of anaesthesia with propofol in sheep.2.Model analysis and implications for dose requirements[J].Br J Anaesth.1997,79(4):505-13.
24.Ludbrook GL,Upton RN,Grant C,et al.The effect of rate of administration on brain concentrations of propofol in sheep[J].Anesth Analg,1998,86(6):1301-6.
25.古妙宁,盖成林,林春水,等.恒速静脉输注异丙酚时脑摄取的研究[J].中华麻醉学杂志,2001,21(3):133-5.
26.欧阳铭文,古妙宁,林春水,等.效应室浓度作为目标浓度靶控输注异丙酚的脑摄取研究[J].第一军医大学学报,2002,22(1):642-6.
27.Dowrie RH,Ebling WF,Mandema JW,et al.High-performance liquid chromatographic assay of propofol in human and rat plasma and fourteen rat tissues using electrochemical detection[J].J Chromatogr B Biomed Appl,1996,678(2):279-88.
28.Riu PL,et al.Disposition of propofol between red blood cell,plasma,brain and cerebrospinal fluid in rabbits.Eur J Anaesthesiol 2000 Jan;;17(1):18-22.
29.林春水,卢刚,古妙宁,等.犬静脉注射异丙酚后脑的摄取和分布.中华麻醉学杂志,2007,27(11)969-71.
30.林春水,卢刚,古妙宁,等.脑摄取平衡时异丙酚在犬脑不同区域分布的实验研究.南方医科大学学报,2007,27(6):836-8.
2.Sneyd JR.Recent advances in intravenous anaesthesia[J].Br J Anaesth,2004,93:725-36.
3.Sheiner LB,Staski DR,Vozeh S,et al.Simultaneous modeling of pharmacokinetics and pharmacodynamics:application to d-tubocurarine[J].clin pharmacol ther,1979,25(3):358-71.
4.Wakeling HG,Zimmerman JB,Howell S,et al.Targeting effect compartment or central compartment concentration of propofol:what predicts loss of consciousness?[J]Anesthesiology,1999,90(1):92-7.
5.Upton RN,Mather LE,Runciman WB,et al.The use of mass balance principles to describe regional drug distribution and elimination[J].J Pharmacokinet Biopharm.1988,16(1):13-29.
6.欧阳铭文,盖成林,林春水,等.异丙酚脑摄取研究[J].《国外医学》麻醉学与复苏分册,2002,23:333-5.
7.Ludbrook GL,Upton RN.A physiological model of induction of anaesthesia with propofol in sheep.2.Model analysis and implications for dose requirements[J].Br J Anaesth.1997,79(4):505-13.
8.Dutta S,Matsumoto Y,Muramatsu A,et al.Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibration paradox[J].Br J Anaesth.1998 Sep;81(3):422-4.
9.欧阳铭文,古妙宁,林春水等.效应室浓度作为目标浓度靶控输注异丙酚的脑摄取研究[J].第一军医大学学报,2002,1.
10.Shyr MH,Tsai TH,Tan PP,et al.Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat[J].Neurosci Lett,1995,30;184(3):212-5.
11.Larsson JE,Wahlstron G.The influence of age and administration rate on the brain sensitivity to propofol in rats[J].Acta Anaesthesiol Scand,1998,42:987-94.
12.申屠建中,吴丽花,章霞,等.高效液相色谱-荧光检测法测定异丙酚的血药浓度J].药物分析杂志,2002,22(1):65-7.
13. Trapani G, Altomare C, Liso G, et al. Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery[J]. Curr med chem, 2000, 7: 249-71.
14. Franks NP, Lieb WR. Molecular and cellar mechanisms of general anaesthesia [J]. Nature,1994,367:607-13.
15. Sigel E. Mapping of the benzodiazepine recognition site on GABA(A) receptors[J]. Curr Top Med Chem. 2002 Aug;2(8):833-839.
16. Mantz J, Lecharny JB, Laudenbach V, et al. Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes[J]. Anesthesiology, 1995, 82(2):502-11.
17. Sanna E, Mascia MP, Klein RL, et al. Actions of the general anesthetic propofol on recombinant human GABAA receptors: influence of receptor subunits[J]. J Pharmacol Exp Ther, 1995, 274(1):353-60.
18. Wooltorton JR, Moss SJ, Smart TG. Pharmacological and physiological characterization of murine homomeric beta3 GABA(A)receptors[J].Eur J Neurosci, 1997, 9(11):2225-35.
19. Fiset P. Functional brain imaging and propofol mechanisms of action [J]. Adv Exp Med Biol, 2003,523:115-21.
20. Alkire MT, Haier RJ, Barker SJ, et al. Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography[J]. Anesthesiology, 1995,82:393-403.
21. Fiset P, Paus T, Dalozer T, et al. Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study [J]. J Neurosci, 1999,19:5506-13.
22. Paus T. Functional anatomy of arousal and attention systems in the human brain[J]. Prog Brain Res. 2000,126:65-77.
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