山莨菪碱对心脏骤停复苏中心肌氧含量与复苏成功因素影响的研究
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摘要
心脏骤停的复苏是一个极其复杂的病理生理变化过程，其病理生理机制尚未完全清楚。心肺复苏实验研究的质量依赖于合理设计动物心脏骤停（cardiacarrest，CA）模型，制备CA动物模型是进行心肺复苏（cardiopulmonary resuscitation，CPR）动物实验研究的必要条件。理想的CA动物模型将尽可能反映出CA临床病理生理变化过程，即充分体现与临床状况的相似性，并具有良好的可操作性及可重复性，这对于保证CPR研究质量来讲有重要意义。
目前所用的心脏骤停模型并不统一。在国内的CPR实验研究中，模型动物以大鼠、家兔等较多见，而家猪的实验研究少见报道。家猪心脏从解剖学、血流动力学、组织病理学及血管侧枝循环分布等方面来讲与人类极其相似，与人类心脏不同点较少。因此，家猪是制作CA模型比较理想的实验动物。利用电刺激法制作CA模型，近年来国外研究较多，国内尚不多见。本研究即拟应用交流电刺激诱发建立家猪CA模型，意图寻找一种具有良好的可操作性并接近CPR临床实际的动物模型。
采用家猪9头，体质量（25.0±3.0）kg，麻醉后行气管插管，右侧颈外静脉插管（至右心房）及右侧股动脉插管（至胸主动脉）以备测压，经左侧颈外静脉插入临时起搏电极至右心室（接触心内膜）。另建立耳缘静脉通道以备静脉输液。将临时起搏电极与交流电调压变压器输出端相连，持续电刺激10s以诱发心室颤动。电压为20v，电流1mA，频率50Hz。达到心脏骤停标准后，维持9min未处理间期后开始常规心肺复苏。
所有动物均在持续电刺激10s后成功出现心室颤动并达心脏骤停标准，诱导成功率为100%。9头建模的动物中5头在经历9min未处理间期后采用常规心肺复苏方法成功恢复自主循环并复苏成功。
以交流电经心内膜刺激诱发家猪心室颤动模型，具有较好的可操作性、稳定性及与临床状况相似性，能够较好地满足心肺复苏实验研究的要求。
早在1906年，Crile和Dolley就已经注意到在心脏骤停复苏中足够的主动脉舒张压的重要性，并认为不使用肾上腺素（Epinephrine，Epi）则通常不可能达到足够的主动脉舒张压。主动脉舒张压是冠状动脉灌注压（coronary perfusionpressures，CPP）的主要构成因素。尔后的事实证明，不管是人类还是动物，心肺复苏期间，冠状动脉灌注压大于15mmHg与自主循环恢复（return ofspontaneous circulation，ROSC）率及生存率的提高明显相关。在CA复苏期间，肾上腺素的确可明显提高CPP和脑灌注压。但值得注意的是，CPP仅仅是心肌组织及细胞血液供应的一个替代指标，真正与ROSC率、复苏成功率及生存率有关的显然是CA复苏期间心肌等组织细胞的血液供应，而不是CPP。实际上在使用肾上腺素的情况下，CPP的增加并不能代表心肌组织及细胞血液供应的增加。肾上腺素至今存在最大的问题是在CPR期间虽可使CPP增加，但是冠状动脉血流、心肌组织及细胞的血液供应实际上并未因此而增加，相反由于肾上腺素使微循环血流灌注的减少或停止而显著降低，这显然不利于复苏的成功。文献报道山莨菪碱（anisodamine， Ani）可增加冠状动脉血流量，改善微循环，减轻脑组织和心肌的缺血/再灌注损伤。因此设想在复苏过程中将山莨菪碱与肾上腺素联合使用以减轻肾上腺素上述的对心肺复苏的负面作用，从而达到提高复苏成功率的目的。
本研究拟观察肾上腺素联合山莨菪碱对家猪血流动力学、呼气末二氧化碳分压（PETCO2）、电除颤次数、自主循环恢复率及复苏成功率的影响。
采用23头健康家猪随机分成3组，即对照组（control组，n=5，假手术，不经历交流电刺激致颤、心脏骤停及心肺复苏过程）、肾上腺素组（简称A组，n=9，心肺复苏过程中使用肾上腺素静脉推注）和肾上腺素联合山莨菪碱组（简称B组，n=9，心肺复苏过程中使用肾上腺素联合山莨菪碱静脉推注）。家猪麻醉固定后行心电监测，通过右侧股动脉（至胸主动脉）和右颈外静脉（至右心房）置管连续监测主动脉压（aortic pressure，AOP）和右房压（right atrial pressure，RAP），采用经左侧颈外静脉放置临时起搏电极至右心室内膜以交流电刺激致颤，建立家猪心室颤动（ventricular fibrillation，VF）模型。经过9min未干预间期后，同时给予呼吸机控制通气，胸外心脏按压及药物，2min后给予电除颤1次（150J），若失败则继续胸外心脏按压，每按压1min后电除颤1次，每3次电除颤后给药1次，30min无效则放弃复苏。复苏成功后观察1h将动物送入动物实验中心观察室，24h后安乐处死动物，取标本送检。整个复苏过程中连续监测记录心电图，AOP，RAP。比较A、B两组CPP、PETCO2、电除颤次数、ROSC率及复苏成功率。
A、B两组所有动物在持续电刺激10s后成功出现VF并达CA标准，模型建立成功率为100%。CPR期间，总除颤次数比较，A组较B组明显增多（p=0.007＜0.01）；首次除颤前A、B两组PETCO2值比较，A组（13.17±1.72mm Hg）明显小于B组（18.14±1.35mm Hg)（p＜0.01）；CPP的演变，A、B两组均呈现出先上升后下降的过程，在推药后5、20秒，B组均明显高于A组（p=0.033和0.012），但在55秒时，两组趋于相同无明显差别（p＞0.05）；两组首次除颤前平均CPP比较，A（13.93±9.98mm Hg）、B（12.65±5.50mm Hg）两组无明显差异（p=0.776＞0.05）。自主循环恢复率、复苏成功率及24小时存活率， B组（77.80%）高于A组（55.60%），但差异无显著性（p＞0.05）。
心脏骤停复苏期间，肾上腺素联合山莨菪碱能一过性提高冠状动脉灌注压、呼气末二氧化碳分压，有利于电除颤的成功、自主循环恢复及复苏的成功。
心肺复苏过程中的心肌血流灌注是否充分对于复苏成功与否起着至关重要的作用。微循环血流状况及其氧供是心脏骤停预后的终结决定因素。心脏骤停后微循环血流在0.5分钟内迅速下降到低于正常的1/4。心脏按压时，微循环血流部分恢复；而那些成功复苏的动物的微循环血流在心脏按压后1~5min内明显多于那些复苏失败的动物。早在1906年，Crile和Dolley就注意到在心脏复苏中足够的主动脉舒张压的重要性。肾上腺素可有效地提高主动脉舒张压，从而提高冠状动脉灌注压（CPP），这对于心肺复苏来讲至关重要。不管是人类还是动物，心肺复苏期间，CPP大于15mmHg与ROSC率及生存率的提高明显相关。但是，事实上，肾上腺素的最大的问题在于，CPR期间使用肾上腺素虽然可使CPP增加，但是心肌组织及细胞的血液供应并未因此而增加，反而由于肾上腺素导致微循环血流的减少或停止而显著降低。这种变化引起心肌毛细血管P02快速地降低，这显然不利于复苏。血流减少的直接后果和表现是局部组织尤其是心肌组织氧供的减少。为进一步证实这一论断和上述情况，本实验拟测定心室颤动（VF）前后心肌组织血氧饱和度（regional tissue oxygen saturation，rSO2）以及肾上腺素、山莨菪碱及肾上腺素联合山莨菪碱对rSO2的影响并探讨其机制。
健康成年新西兰兔32只，随机分为四组，即空白对照组（control）、肾上腺素组（简称Epi组）、山莨菪碱组（简称Ani组）及肾上腺素联合山莨菪碱组（简称Epi+Ani组）。麻醉完成后，予气管切开并插管连接呼吸机。分离左侧颈外静脉切开并置管以备静脉推药，分离右侧颈总动脉切开并置管以备测压。开胸暴露心脏。分别于致颤前后测定心脏rSO2，并观察肾上腺素、山莨菪碱及肾上腺素联合山莨菪碱对心脏rSO2的影响。
基础状态下测定心脏rSO2结果，各组间比较无明显差异（p＞0.05）。未致颤情况下静推药物后1min测定心脏组织血氧饱和度，（1）control组，心脏rSO2围绕77%上下波动，与基础状态比较无明显改变；（2）Epi组，心脏rSO2明显快速降低至64.47±4.36，与基础状态及control组对比差异均有统计学意义（p＜0.05），并持续于推药后0.5-2.5min，3.0min时才逐渐上升恢复到基础状态并与control组对比无明显差异（p＞0.05）；（3）Ani组，心脏rSO2先稍下降后明显回升；（4）Epi+Ani组，心脏rSO2先稍下降后明显回升，1.5min后明显高于基础状态及control组（p＜0.05）。
致颤前后各时间段测定心脏rSO2结果，致颤后各组心脏rSO2均快速下降，心脏按压后均部分恢复。心脏按压+静推药物后1min，各组表现不一，Epi组（33.73±7.13）明显较前单纯心脏按压未推药时（51.03±3.12）下降，差异有统计学意义（p＜0.05）；Epi+Ani组（66.79±8.43）却明显较前单纯心脏按压未推药时（50.81±1.97）上升，差异有统计学意义（p＜0.05）。Epi组中的心脏rSO2推药后表现为先明显降低后逐渐上升最后接近control组水平；而Epi+Ani组推药后表现无明显降低，反逐渐上升最后超过control组水平。
结论：1、自主循环存在（未致颤）和失去自主循环（心室颤动）情况下，肾上腺素的使用（静脉推注）均可使心脏组织血氧饱和度（氧含量）快速下降，反映了心肌局部血流灌注水平下降。2、肾上腺素联合山莨菪碱的使用（静脉推注）可提高心脏组织血氧饱和度，反映了心肌局部血流灌注水平的提高，肾上腺素和山莨菪碱对心脏组织血氧饱和度的提高有协同作用。
Cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) are extremelycomplex pathophysiological process which pathophysiological mechanism has notbeen clearly explained. Because of interference of many factors in the clinicalinvestigation, it is difficult to undertake a profound pathophysiologic study regardingCA and CPR. A variety of confounding factors can be strictly controlled in the animalexperiment, which makes the experimental results can be reproducible and providesan opportunity to testify different kinds of medications and treatments involved in CAand CPR. Experimental research about CPR depends on the use of animal models thatare designed to simulate cardiac arrest in humans. Such models are used to exploreimportant new treatments and to refne protocols used in standard interventions,including doses of drugs, chest compression techniques, defbrillation energies, andcerebral resuscitation, before they are applied to humans. The ideal CA animalmodels should reflect as far as possible the CPR clinical pathophysiological process,which fully embodies the "similarity" with the clinical status and has good operabilityto ensure the quality of CPR research. The heart of the domestic swine in anatomy,histopathology, hemodynamic and vascular collateral circulation distribution is verysimilar to human. Therefore, the domestic swine is ideal experimental animal for CA/CPR model. In this study, the domestic swine CA/CPR model was built by usingalternating current to stimulate the endocardium to find a CA/CPR model with agood operability and close to the clinical practice.
9domestic swines weighing (25.0±3.0) kg were employed in this experiment. The swines were anesthetized with sodium pentobarbital and ketamine. Endotrachealintubation were performed in all swines after anesthesia. Blunt dissection of bilateralexternal jugular vein and right femoral artery were performed and thencatheterizations were respectively inserted into the right atrium and thoracic aorta. Apacing electrode was inserted into the right ventricle. Ventricular fibrillation wasinduced by intraventricular stimulation with alternating current (20v,1mA,50Hz).Then, cardiopulmonary resuscitation (CPR) was initiated at the end of9min intervalsafter the cardiac arrest was indentified.
All swines were identified as cardiac arrest（ventricular fibrillation）after10sec byelectrical stimulation, and the success rate of model was100%.5swines returned thespontaneous circulation after CPR.
In conclusion, the cardiac arrest model induced by electrical stimulation in swinehas satisfactory similarity with those of clinical status, manipuility and stability,which can meet fundamental study on cardiopulmonary resuscitation.
As early as1906, Crile and Dolley noted the importance of an adequate aorticdiastolic pressure during attempted cardiac resuscitation. They stated that it often wasnot possible to achieve an adequate aortic diastolic pressure without the addition ofepinephrine. Coronary perfusion pressures (aortic diastolic minus right atrial diastolicpressure) above15mmHg during resuscitation are associated with improved return ofspontaneous circulation (ROSC) in both humans and animals and increased survivalin animals. During resuscitation from cardiac arrest, epinephrine improves coronary and cerebral perfusion. However, CPP is a surrogate for myocardial perfusion. In fact,microcirculatory blood fow is highly correlated with ROSC and survival.Administration of epinephrine resulted in a dramatic and signifcant decrease incapillary blood fow and might have compromised tissue blood fow and thereforeoxygenation and metabolism during CPR, although it increase CPP. The Anisodaminecan increase coronary blood flow and improve microcirculation myocardial perfusion.This study estimated whether the administration of anisodamine in combination withepinephrine during cardiopulmonary resuscitation would improve the hemodynamiclevel, the first defibrillation success rate, ROSC and resuscitation outcome in anestablished swine model of ventricular fibrillation.
Twenty-three domestic swines were randomized to three groups: the control group(n=5), the group A (n=9, epinephrine administration during CPR) and group B (n=9,administration of epinephrine with anisodamine during CPR). Cardiac arrest wasinduced by the electrical stimulation of the right ventricle endomembrane in the18domestic swines in A and B groups. These animals in A and B groups underwentstandard manual CPR and defibrillation with medicine after the duration of untreatedcardiac arrest for9min. CPP was calculated as the gradient of (AOP-RAP)simultaneously. The total number of defibrillation shocks, level of PETCO2, return ofspontaneous circulation rate and resuscitation rate were compared between thesegroups.
All swines in the A and B groups, were successfully induced into venturicularfibrillation by electrical stimulation for10s. The total number of defibrillation shocksdelivered to achieve successful defibrillation was less in the group B (p=0.007). Thelevel of PETCO2in the group B (n=9, anisodamine+epinephrine,18.14±1.35mm Hg)was higher than the group A (n=9, epinephrine alone,13.17±1.72mm Hg) beforefirst-shock defibrillation (after9minutes of untreated prolonged VF with1minute of CPR)(t=5.735, p＜0.01) vs. epinephrine alone. Mean CPP (mean±SD)fluctuation for animals receiving1minutes of CPR after intravenous drugadministration in time in the two groups. p=0.033at5seconds after intravenous drugadministration; p=0.012at20seconds after intravenous drug administration; At55seconds, p＞0.05; at60seconds, p＞0.05. Mean CPP (mean±SD,12.65±5.50in thegroup B versus13.93±9.98mm Hg in the group A) at60sec after intravenous drugadministration (chest compression pause before first defibrillation) p=0.776vs.group A (epinephrine alone).
In conclusion, adminstration of anisodamine in combination with epinephrine atthe beginning of cardiac arrest could improve CPP (transiently), level of PETCO2,contributing to decrease total number of defibrillation shocks to facilitatedefibrillation, ROSC rate and resuscitation.
The microcirculation, and more specifcally, the capillary exchange bed is likely tobe the ultimate determinant of circulatory function. A study investigated thatmicrovascular blood fow during cardiopulmonary resuscitation was predictive ofoutcome. Microcirculatory blood fow decreased to less than one-fourth within0.5min after inducing ventricular fbrillation. Precordial compression partiallyrestored microvascular fow in each animal. In animals that were successfullyresuscitated, microvascular fow was signifcantly greater after1~5min of chestcompression than in animals with failed resuscitation attempts. Microvascular bloodfow was highly correlated with coronary perfusion pressure. Microvascular blood flow in the sublingual mucosa is therefore closely related to coronary perfusionpressure during cardiopulmonary resuscitation and both are predictive of outcome.
As early as1906, Crile and Dolley noted the importance of an adequate aorticdiastolic pressure during attempted cardiac resuscitation. They stated that it often wasnot possible to achieve an adequate aortic diastolic pressure without the addition ofepinephrine. Coronary perfusion pressures (aortic diastolic minus right atrial diastolicpressure) above15mmHg during resuscitation are associated with improved return ofspontaneous circulation (ROSC) in both humans and animals and increased survivalin animals. During resuscitation from cardiac arrest, epinephrine improves coronaryand cerebral perfusion.
However, CPP is a surrogate for myocardial perfusion. In fact, microcirculatoryblood fow is highly correlated with ROSC and survival. Administration ofepinephrine resulted in a dramatic and signifcant decrease in capillary blood fow andmight have compromised tissue blood fow and therefore oxygenation andmetabolism during CPR, although it increase CPP. The reduction of microcirculatoryblood flow reduces directly oxygen supply of the myocardial tissue. This studyestimated whether the administration of epinephrine during cardiopulmonaryresuscitation would reduce （regional tissue oxygen saturation, rSO2）and theadministration of anisodamine in combination with epinephrine duringcardiopulmonary resuscitation would improve rSO2in an established rabbit’s modelof ventricular fibrillation.
32rabbits were randomized to four groups: the control, epinephrine, anisodamineand epinephrine plus anisodamine group. After the completion of anesthesia,tracheotomy and intubation were performed connecting a ventilator. The left externaljugular vein,left common carotid artery were surgically isolated. A catheter wasinserted into the left external jugular vein for medicine. Another catheter was inserted into the left common carotid artery in order to prepare manometry. Thoracotomy wasperformed to expose the heart. Cardiac arrest was induced by intravenous injectionof potassium chloride. Respectively, rSO2was measured before and after VF.
There were no significant difference in the heart rSO2among the these groupsunder the baseline（p＞0.05）. However, there occurred different phenomenon in theheart rSO2among the these groups1min after administration of drugs. The heartrSO2in the control group was not significantly different compared with the baseline（p＞0.05）. In the group Epi, the heart rSO2decreased quickly and sustained from0.5to2.5min after administration of drug, and lower than the baseline and controlgroup（p＜0.05）. In the group Ani, the heart rSO2decreased and then increased. Inthe group Epi+Ani, the heart rSO2decreased and then increased to surpass thebaseline and control group（p＜0.05）.
The heart rSO2in all the these groups was declining rapidly after ventricularfibrillation (VF) and recovered partly after cardiac compression. There occurreddifferent phenomenon in the heart rSO2among the these groups1min afteradministration of drugs. The heart rSO2in the control group was not significantlydifferent compared with the cardiac compression alone（p＞0.05）. In the group Epi（33.73±7.13）, the heart rSO2was lower than the cardiac compression alone（p＜0.05）. In the group Epi+Ani（66.79±8.43）, the heart rSO2was higher than thecardiac compression alone（50.81±1.97）（p＜0.05）decreased and then increased tosurpass the baseline and control group（p＜0.05）.
In conclusion, administration of epinephrine can decrease the heart rSO2withrelation to decrease of myocardialblood flow. Epinephrine with anisodamine canincrease the heart rSO2with relation to increase of myocardial blood flow.
目前所用的心脏骤停模型并不统一。在国内的CPR实验研究中，模型动物以大鼠、家兔等较多见，而家猪的实验研究少见报道。家猪心脏从解剖学、血流动力学、组织病理学及血管侧枝循环分布等方面来讲与人类极其相似，与人类心脏不同点较少。因此，家猪是制作CA模型比较理想的实验动物。利用电刺激法制作CA模型，近年来国外研究较多，国内尚不多见。本研究即拟应用交流电刺激诱发建立家猪CA模型，意图寻找一种具有良好的可操作性并接近CPR临床实际的动物模型。
采用家猪9头，体质量（25.0±3.0）kg，麻醉后行气管插管，右侧颈外静脉插管（至右心房）及右侧股动脉插管（至胸主动脉）以备测压，经左侧颈外静脉插入临时起搏电极至右心室（接触心内膜）。另建立耳缘静脉通道以备静脉输液。将临时起搏电极与交流电调压变压器输出端相连，持续电刺激10s以诱发心室颤动。电压为20v，电流1mA，频率50Hz。达到心脏骤停标准后，维持9min未处理间期后开始常规心肺复苏。
所有动物均在持续电刺激10s后成功出现心室颤动并达心脏骤停标准，诱导成功率为100%。9头建模的动物中5头在经历9min未处理间期后采用常规心肺复苏方法成功恢复自主循环并复苏成功。
以交流电经心内膜刺激诱发家猪心室颤动模型，具有较好的可操作性、稳定性及与临床状况相似性，能够较好地满足心肺复苏实验研究的要求。
早在1906年，Crile和Dolley就已经注意到在心脏骤停复苏中足够的主动脉舒张压的重要性，并认为不使用肾上腺素（Epinephrine，Epi）则通常不可能达到足够的主动脉舒张压。主动脉舒张压是冠状动脉灌注压（coronary perfusionpressures，CPP）的主要构成因素。尔后的事实证明，不管是人类还是动物，心肺复苏期间，冠状动脉灌注压大于15mmHg与自主循环恢复（return ofspontaneous circulation，ROSC）率及生存率的提高明显相关。在CA复苏期间，肾上腺素的确可明显提高CPP和脑灌注压。但值得注意的是，CPP仅仅是心肌组织及细胞血液供应的一个替代指标，真正与ROSC率、复苏成功率及生存率有关的显然是CA复苏期间心肌等组织细胞的血液供应，而不是CPP。实际上在使用肾上腺素的情况下，CPP的增加并不能代表心肌组织及细胞血液供应的增加。肾上腺素至今存在最大的问题是在CPR期间虽可使CPP增加，但是冠状动脉血流、心肌组织及细胞的血液供应实际上并未因此而增加，相反由于肾上腺素使微循环血流灌注的减少或停止而显著降低，这显然不利于复苏的成功。文献报道山莨菪碱（anisodamine， Ani）可增加冠状动脉血流量，改善微循环，减轻脑组织和心肌的缺血/再灌注损伤。因此设想在复苏过程中将山莨菪碱与肾上腺素联合使用以减轻肾上腺素上述的对心肺复苏的负面作用，从而达到提高复苏成功率的目的。
本研究拟观察肾上腺素联合山莨菪碱对家猪血流动力学、呼气末二氧化碳分压（PETCO2）、电除颤次数、自主循环恢复率及复苏成功率的影响。
采用23头健康家猪随机分成3组，即对照组（control组，n=5，假手术，不经历交流电刺激致颤、心脏骤停及心肺复苏过程）、肾上腺素组（简称A组，n=9，心肺复苏过程中使用肾上腺素静脉推注）和肾上腺素联合山莨菪碱组（简称B组，n=9，心肺复苏过程中使用肾上腺素联合山莨菪碱静脉推注）。家猪麻醉固定后行心电监测，通过右侧股动脉（至胸主动脉）和右颈外静脉（至右心房）置管连续监测主动脉压（aortic pressure，AOP）和右房压（right atrial pressure，RAP），采用经左侧颈外静脉放置临时起搏电极至右心室内膜以交流电刺激致颤，建立家猪心室颤动（ventricular fibrillation，VF）模型。经过9min未干预间期后，同时给予呼吸机控制通气，胸外心脏按压及药物，2min后给予电除颤1次（150J），若失败则继续胸外心脏按压，每按压1min后电除颤1次，每3次电除颤后给药1次，30min无效则放弃复苏。复苏成功后观察1h将动物送入动物实验中心观察室，24h后安乐处死动物，取标本送检。整个复苏过程中连续监测记录心电图，AOP，RAP。比较A、B两组CPP、PETCO2、电除颤次数、ROSC率及复苏成功率。
A、B两组所有动物在持续电刺激10s后成功出现VF并达CA标准，模型建立成功率为100%。CPR期间，总除颤次数比较，A组较B组明显增多（p=0.007＜0.01）；首次除颤前A、B两组PETCO2值比较，A组（13.17±1.72mm Hg）明显小于B组（18.14±1.35mm Hg)（p＜0.01）；CPP的演变，A、B两组均呈现出先上升后下降的过程，在推药后5、20秒，B组均明显高于A组（p=0.033和0.012），但在55秒时，两组趋于相同无明显差别（p＞0.05）；两组首次除颤前平均CPP比较，A（13.93±9.98mm Hg）、B（12.65±5.50mm Hg）两组无明显差异（p=0.776＞0.05）。自主循环恢复率、复苏成功率及24小时存活率， B组（77.80%）高于A组（55.60%），但差异无显著性（p＞0.05）。
心脏骤停复苏期间，肾上腺素联合山莨菪碱能一过性提高冠状动脉灌注压、呼气末二氧化碳分压，有利于电除颤的成功、自主循环恢复及复苏的成功。
心肺复苏过程中的心肌血流灌注是否充分对于复苏成功与否起着至关重要的作用。微循环血流状况及其氧供是心脏骤停预后的终结决定因素。心脏骤停后微循环血流在0.5分钟内迅速下降到低于正常的1/4。心脏按压时，微循环血流部分恢复；而那些成功复苏的动物的微循环血流在心脏按压后1~5min内明显多于那些复苏失败的动物。早在1906年，Crile和Dolley就注意到在心脏复苏中足够的主动脉舒张压的重要性。肾上腺素可有效地提高主动脉舒张压，从而提高冠状动脉灌注压（CPP），这对于心肺复苏来讲至关重要。不管是人类还是动物，心肺复苏期间，CPP大于15mmHg与ROSC率及生存率的提高明显相关。但是，事实上，肾上腺素的最大的问题在于，CPR期间使用肾上腺素虽然可使CPP增加，但是心肌组织及细胞的血液供应并未因此而增加，反而由于肾上腺素导致微循环血流的减少或停止而显著降低。这种变化引起心肌毛细血管P02快速地降低，这显然不利于复苏。血流减少的直接后果和表现是局部组织尤其是心肌组织氧供的减少。为进一步证实这一论断和上述情况，本实验拟测定心室颤动（VF）前后心肌组织血氧饱和度（regional tissue oxygen saturation，rSO2）以及肾上腺素、山莨菪碱及肾上腺素联合山莨菪碱对rSO2的影响并探讨其机制。
健康成年新西兰兔32只，随机分为四组，即空白对照组（control）、肾上腺素组（简称Epi组）、山莨菪碱组（简称Ani组）及肾上腺素联合山莨菪碱组（简称Epi+Ani组）。麻醉完成后，予气管切开并插管连接呼吸机。分离左侧颈外静脉切开并置管以备静脉推药，分离右侧颈总动脉切开并置管以备测压。开胸暴露心脏。分别于致颤前后测定心脏rSO2，并观察肾上腺素、山莨菪碱及肾上腺素联合山莨菪碱对心脏rSO2的影响。
基础状态下测定心脏rSO2结果，各组间比较无明显差异（p＞0.05）。未致颤情况下静推药物后1min测定心脏组织血氧饱和度，（1）control组，心脏rSO2围绕77%上下波动，与基础状态比较无明显改变；（2）Epi组，心脏rSO2明显快速降低至64.47±4.36，与基础状态及control组对比差异均有统计学意义（p＜0.05），并持续于推药后0.5-2.5min，3.0min时才逐渐上升恢复到基础状态并与control组对比无明显差异（p＞0.05）；（3）Ani组，心脏rSO2先稍下降后明显回升；（4）Epi+Ani组，心脏rSO2先稍下降后明显回升，1.5min后明显高于基础状态及control组（p＜0.05）。
致颤前后各时间段测定心脏rSO2结果，致颤后各组心脏rSO2均快速下降，心脏按压后均部分恢复。心脏按压+静推药物后1min，各组表现不一，Epi组（33.73±7.13）明显较前单纯心脏按压未推药时（51.03±3.12）下降，差异有统计学意义（p＜0.05）；Epi+Ani组（66.79±8.43）却明显较前单纯心脏按压未推药时（50.81±1.97）上升，差异有统计学意义（p＜0.05）。Epi组中的心脏rSO2推药后表现为先明显降低后逐渐上升最后接近control组水平；而Epi+Ani组推药后表现无明显降低，反逐渐上升最后超过control组水平。
结论：1、自主循环存在（未致颤）和失去自主循环（心室颤动）情况下，肾上腺素的使用（静脉推注）均可使心脏组织血氧饱和度（氧含量）快速下降，反映了心肌局部血流灌注水平下降。2、肾上腺素联合山莨菪碱的使用（静脉推注）可提高心脏组织血氧饱和度，反映了心肌局部血流灌注水平的提高，肾上腺素和山莨菪碱对心脏组织血氧饱和度的提高有协同作用。
Cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) are extremelycomplex pathophysiological process which pathophysiological mechanism has notbeen clearly explained. Because of interference of many factors in the clinicalinvestigation, it is difficult to undertake a profound pathophysiologic study regardingCA and CPR. A variety of confounding factors can be strictly controlled in the animalexperiment, which makes the experimental results can be reproducible and providesan opportunity to testify different kinds of medications and treatments involved in CAand CPR. Experimental research about CPR depends on the use of animal models thatare designed to simulate cardiac arrest in humans. Such models are used to exploreimportant new treatments and to refne protocols used in standard interventions,including doses of drugs, chest compression techniques, defbrillation energies, andcerebral resuscitation, before they are applied to humans. The ideal CA animalmodels should reflect as far as possible the CPR clinical pathophysiological process,which fully embodies the "similarity" with the clinical status and has good operabilityto ensure the quality of CPR research. The heart of the domestic swine in anatomy,histopathology, hemodynamic and vascular collateral circulation distribution is verysimilar to human. Therefore, the domestic swine is ideal experimental animal for CA/CPR model. In this study, the domestic swine CA/CPR model was built by usingalternating current to stimulate the endocardium to find a CA/CPR model with agood operability and close to the clinical practice.
9domestic swines weighing (25.0±3.0) kg were employed in this experiment. The swines were anesthetized with sodium pentobarbital and ketamine. Endotrachealintubation were performed in all swines after anesthesia. Blunt dissection of bilateralexternal jugular vein and right femoral artery were performed and thencatheterizations were respectively inserted into the right atrium and thoracic aorta. Apacing electrode was inserted into the right ventricle. Ventricular fibrillation wasinduced by intraventricular stimulation with alternating current (20v,1mA,50Hz).Then, cardiopulmonary resuscitation (CPR) was initiated at the end of9min intervalsafter the cardiac arrest was indentified.
All swines were identified as cardiac arrest（ventricular fibrillation）after10sec byelectrical stimulation, and the success rate of model was100%.5swines returned thespontaneous circulation after CPR.
In conclusion, the cardiac arrest model induced by electrical stimulation in swinehas satisfactory similarity with those of clinical status, manipuility and stability,which can meet fundamental study on cardiopulmonary resuscitation.
As early as1906, Crile and Dolley noted the importance of an adequate aorticdiastolic pressure during attempted cardiac resuscitation. They stated that it often wasnot possible to achieve an adequate aortic diastolic pressure without the addition ofepinephrine. Coronary perfusion pressures (aortic diastolic minus right atrial diastolicpressure) above15mmHg during resuscitation are associated with improved return ofspontaneous circulation (ROSC) in both humans and animals and increased survivalin animals. During resuscitation from cardiac arrest, epinephrine improves coronary and cerebral perfusion. However, CPP is a surrogate for myocardial perfusion. In fact,microcirculatory blood fow is highly correlated with ROSC and survival.Administration of epinephrine resulted in a dramatic and signifcant decrease incapillary blood fow and might have compromised tissue blood fow and thereforeoxygenation and metabolism during CPR, although it increase CPP. The Anisodaminecan increase coronary blood flow and improve microcirculation myocardial perfusion.This study estimated whether the administration of anisodamine in combination withepinephrine during cardiopulmonary resuscitation would improve the hemodynamiclevel, the first defibrillation success rate, ROSC and resuscitation outcome in anestablished swine model of ventricular fibrillation.
Twenty-three domestic swines were randomized to three groups: the control group(n=5), the group A (n=9, epinephrine administration during CPR) and group B (n=9,administration of epinephrine with anisodamine during CPR). Cardiac arrest wasinduced by the electrical stimulation of the right ventricle endomembrane in the18domestic swines in A and B groups. These animals in A and B groups underwentstandard manual CPR and defibrillation with medicine after the duration of untreatedcardiac arrest for9min. CPP was calculated as the gradient of (AOP-RAP)simultaneously. The total number of defibrillation shocks, level of PETCO2, return ofspontaneous circulation rate and resuscitation rate were compared between thesegroups.
All swines in the A and B groups, were successfully induced into venturicularfibrillation by electrical stimulation for10s. The total number of defibrillation shocksdelivered to achieve successful defibrillation was less in the group B (p=0.007). Thelevel of PETCO2in the group B (n=9, anisodamine+epinephrine,18.14±1.35mm Hg)was higher than the group A (n=9, epinephrine alone,13.17±1.72mm Hg) beforefirst-shock defibrillation (after9minutes of untreated prolonged VF with1minute of CPR)(t=5.735, p＜0.01) vs. epinephrine alone. Mean CPP (mean±SD)fluctuation for animals receiving1minutes of CPR after intravenous drugadministration in time in the two groups. p=0.033at5seconds after intravenous drugadministration; p=0.012at20seconds after intravenous drug administration; At55seconds, p＞0.05; at60seconds, p＞0.05. Mean CPP (mean±SD,12.65±5.50in thegroup B versus13.93±9.98mm Hg in the group A) at60sec after intravenous drugadministration (chest compression pause before first defibrillation) p=0.776vs.group A (epinephrine alone).
In conclusion, adminstration of anisodamine in combination with epinephrine atthe beginning of cardiac arrest could improve CPP (transiently), level of PETCO2,contributing to decrease total number of defibrillation shocks to facilitatedefibrillation, ROSC rate and resuscitation.
The microcirculation, and more specifcally, the capillary exchange bed is likely tobe the ultimate determinant of circulatory function. A study investigated thatmicrovascular blood fow during cardiopulmonary resuscitation was predictive ofoutcome. Microcirculatory blood fow decreased to less than one-fourth within0.5min after inducing ventricular fbrillation. Precordial compression partiallyrestored microvascular fow in each animal. In animals that were successfullyresuscitated, microvascular fow was signifcantly greater after1~5min of chestcompression than in animals with failed resuscitation attempts. Microvascular bloodfow was highly correlated with coronary perfusion pressure. Microvascular blood flow in the sublingual mucosa is therefore closely related to coronary perfusionpressure during cardiopulmonary resuscitation and both are predictive of outcome.
As early as1906, Crile and Dolley noted the importance of an adequate aorticdiastolic pressure during attempted cardiac resuscitation. They stated that it often wasnot possible to achieve an adequate aortic diastolic pressure without the addition ofepinephrine. Coronary perfusion pressures (aortic diastolic minus right atrial diastolicpressure) above15mmHg during resuscitation are associated with improved return ofspontaneous circulation (ROSC) in both humans and animals and increased survivalin animals. During resuscitation from cardiac arrest, epinephrine improves coronaryand cerebral perfusion.
However, CPP is a surrogate for myocardial perfusion. In fact, microcirculatoryblood fow is highly correlated with ROSC and survival. Administration ofepinephrine resulted in a dramatic and signifcant decrease in capillary blood fow andmight have compromised tissue blood fow and therefore oxygenation andmetabolism during CPR, although it increase CPP. The reduction of microcirculatoryblood flow reduces directly oxygen supply of the myocardial tissue. This studyestimated whether the administration of epinephrine during cardiopulmonaryresuscitation would reduce （regional tissue oxygen saturation, rSO2）and theadministration of anisodamine in combination with epinephrine duringcardiopulmonary resuscitation would improve rSO2in an established rabbit’s modelof ventricular fibrillation.
32rabbits were randomized to four groups: the control, epinephrine, anisodamineand epinephrine plus anisodamine group. After the completion of anesthesia,tracheotomy and intubation were performed connecting a ventilator. The left externaljugular vein,left common carotid artery were surgically isolated. A catheter wasinserted into the left external jugular vein for medicine. Another catheter was inserted into the left common carotid artery in order to prepare manometry. Thoracotomy wasperformed to expose the heart. Cardiac arrest was induced by intravenous injectionof potassium chloride. Respectively, rSO2was measured before and after VF.
There were no significant difference in the heart rSO2among the these groupsunder the baseline（p＞0.05）. However, there occurred different phenomenon in theheart rSO2among the these groups1min after administration of drugs. The heartrSO2in the control group was not significantly different compared with the baseline（p＞0.05）. In the group Epi, the heart rSO2decreased quickly and sustained from0.5to2.5min after administration of drug, and lower than the baseline and controlgroup（p＜0.05）. In the group Ani, the heart rSO2decreased and then increased. Inthe group Epi+Ani, the heart rSO2decreased and then increased to surpass thebaseline and control group（p＜0.05）.
The heart rSO2in all the these groups was declining rapidly after ventricularfibrillation (VF) and recovered partly after cardiac compression. There occurreddifferent phenomenon in the heart rSO2among the these groups1min afteradministration of drugs. The heart rSO2in the control group was not significantlydifferent compared with the cardiac compression alone（p＞0.05）. In the group Epi（33.73±7.13）, the heart rSO2was lower than the cardiac compression alone（p＜0.05）. In the group Epi+Ani（66.79±8.43）, the heart rSO2was higher than thecardiac compression alone（50.81±1.97）（p＜0.05）decreased and then increased tosurpass the baseline and control group（p＜0.05）.
In conclusion, administration of epinephrine can decrease the heart rSO2withrelation to decrease of myocardialblood flow. Epinephrine with anisodamine canincrease the heart rSO2with relation to increase of myocardial blood flow.
引文
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