Halothane-Epinephrine-induced Cardiac Arrhythmias and the Role of Heart Rate 氟烷-肾上腺素诱发的心律失常及心率的作用
J. Zink, B.Sc.,* B. I. Sasyniuk, Ph.D., † P. E. Dresel, Ph.D. ‡\ddagger J. Zink，B.S.，* B. I。Sasyniuk，博士，p. e。Dresel，博士。 ‡\ddagger
Abstract 摘要
The authors previously showed that cyclopro-pane-epinephrine-induced bigeminal anthythmias can best be explained by a re-entrant mechanism. They have now obtained evidence for reentry in bigeminal arrhythmias during infusions of epinephrine ( .5-3mug//kg//min.5-3 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} ) in dogs anesthetized with .8 per cent halothane. Both a critical level of blood pressure and a critical increase in heart rate were necessary for arhythmias to be induced in any given animal. Artificial elevation of the blood pressure during infusion of a subthreshold dose of epinephrine could induce bigeminy, and the anthythmia could be aborted by a sudden reduction of blood pressure. The heart rate accelerated approximately 40 beats/min prior to the onset of bigeminy, and atrial pacing at similarly increased rates during a subthreshold infusion of epinephrine could induce bigeminy. Stimulation of the peripheral end of the cut right cervical vagus reduced heart rate and converted bigeminy to sinus mythm. Bradycardia was not the sole mechanism of the vagal effect 作者先前表明，环丙烷-肾上腺素诱导的二联胸腺嘧啶可以用折返机制来解释。他们现在已经获得了证据，证明在用0.8%氟烷麻醉的狗输注肾上腺素（0#）时，二联律失常会折返。在任何给定的动物中，血压的临界水平和心率的临界增加都是诱导心律失常所必需的。在输注阈下剂量肾上腺素时人为升高血压可诱发二联律，突然降压可使心律失常终止。在二联律发作前，心率加速约40次/min，在阈下输注肾上腺素期间，以类似的加速速率进行心房起搏可诱导二联律。刺激切断的右颈迷走神经的外周端可降低心率，并将二联律转换为窦性心律。 心动过缓不是迷走神经效应的唯一机制
since conversion to sinus thythm could also be achieved with more rapid stimulation of the vagus when the heart rate was maintained constant by atrial pacing. Under these conditions further acceleration of the heart rate could reinstate a bigeminal anhythmia that was again sensitive to further increases in the frequency of vagal stimulation, and it is concluded that the vagus acts on the spread of the re-entrant impulse. This is best shown with cyclopropane anesthesia, because AV-nodal block occurs more easily with halothane. In addition, very brief periods of increased heart rate caused prolonged periods of bigeminy, which indicates that changes in heart rate may alter the electrophysiology of the halo-thane-sensitized myocardium to promote bigeminal 因为当通过心房起搏保持心率恒定时，通过更快地刺激迷走神经也可以实现向窦性心律的转换。在这些条件下，进一步加速的心率可以恢复二联性心律不齐，再次敏感的迷走神经刺激的频率进一步增加，它的结论是，迷走神经的行为上的折返脉冲的传播。这在环丙烷麻醉时表现得最好，因为氟烷更容易发生房室结阻滞。此外，非常短暂的心率增加导致二联律延长，这表明心率变化可能改变卤代乙烷致敏心肌的电生理学，以促进二联律。
arrhythmias by a re-entry mechanism. (Key words: Heart, arrhythmia; Anesthetics, volatile, halothane.) 心律失常的再进入机制。(Key心脏，心律失常;麻醉剂，挥发性，氟烷。）
Since the Early studies of Raventos, ^(1){ }^{1} 从Raventos的早期研究开始， ^(1){ }^{1}
it has been recognized that halothane resembles other hydrocarbons in its ability to sensitize the heart to the arrhythmogenic effects of epinephrine. Although in-citro evidence indicates that this anesthetic depresses ventricular automaticity, ^(2.3){ }^{2.3} in-cico experiments by Hashimoto and Hashimoto suggest that the sensitizing action of halothane is due primarily to slowing of the heart rate by halothane, which in turn allows emergence of a ventricular pacemaker in response to epinephrine. Their suggestion reopened the discussion concerning the mechanism of hy-drocarbon-epinephrine-induced arrhythmias, in that it stands in opposition to the evidence from this laboratory that these arrhythmias are due to a re-entry phenomenon. ^("s-7 "){ }^{\text {s-7 }} Our conclusions, based on studies with cyclopropane in vico, are supported to some extent by the studies with both cyclopropane and halothane in isolated tissues, where in addition to depression of automaticity, changes in conduction velocity, in refractory period and in duration of action potential have been reported. ^(3,8){ }^{3,8} These are consistent with the combination of slowed conduction and unidirectional block now genemally accepted to be necessary for re-entry to occur. 人们已经认识到，氟烷与其他碳氢化合物类似，能够使心脏对肾上腺素的致心律失常作用敏感。尽管体内证据表明，这种麻醉剂可抑制心室自律性，但Hashimoto和Hashimoto的 ^(2.3){ }^{2.3} 体内实验表明，氟烷的致敏作用主要是由于氟烷减慢心率，进而使心室起搏器对肾上腺素产生反应。他们的建议重新开启了关于碳氢化合物-肾上腺素诱发心律失常的机制的讨论，因为它与本实验室的证据相反，这些心律失常是由于折返现象。 ^("s-7 "){ }^{\text {s-7 }} 我们的结论基于vico中环丙烷的研究，在一定程度上得到了离体组织中环丙烷和氟烷研究的支持，其中除了自律性抑制外，还报告了传导速度、不应期和动作电位持续时间的变化。 ^(3,8){ }^{3,8} 这些与现在普遍接受的传导减慢和单向阻滞的组合是一致的，这是折返发生所必需的。
Subsequent to the completion of the present study, Hashimoto et al. described experiments that led them to revise their conclusions and to support re-entry as the mechanism of these arrhythmias. ^(9){ }^{9} There remains, however, a key issue which has not been dealt with adequately. This is the role of heart rate in the induction of ventricular arrhythmias. Although it is obvious that a slow atrial mate will predispose to the appearance of a ventricular pacemaker, it is also known that changes in heart rate affect re-entry. ^(10-12){ }^{10-12} 在完成本研究之后，Hashimoto等人描述了导致他们修改其结论并支持折返作为这些心律失常机制的实验。 ^(9){ }^{9} 然而，还有一个关键问题没有得到充分处理。这是心率在诱发室性心律失常中的作用。虽然很明显，缓慢的心房匹配将倾向于出现心室起搏器，但也知道心率的变化会影响再进入。 ^(10-12){ }^{10-12}
The present study was designed to investigate the characteristics of bigeminy produced by epinephrine during anesthesia with halothane and to compare the features of these arrhythmias with those that occur under identical conditions with cyclopropane anesthesia. In addition, detailed consideration was given to the role of heart rate in the generation of these arrhythmias. 本研究旨在探讨氟烷麻醉期间肾上腺素产生的二联律的特点，并将这些心律失常的特点与环丙烷麻醉相同条件下发生的心律失常进行比较。此外，还详细考虑了心率在这些心律失常发生中的作用。
Methods 方法
Experiments were performed on 24 mongrel dogs of either sex weighing 10-16kg10-16 \mathrm{~kg}. Anesthesia was induced with sodium thiopental ( 20mg//kg20 \mathrm{mg} / \mathrm{kg}, iv), and a tracheal cannula was inserted for mechanical rentilation at a frequence of 18//min18 / \mathrm{min} with a tidal volume of 20-25mL//kg20-25 \mathrm{~mL} / \mathrm{kg}. Anesthesia was maintained in five animals with 20 per cent cyclopropane as described previously or with 0.8 per cent halothane in oxygen delivered in a nonrebreathing system through a Foregger Copper Kettle vaporizer. The use of a Beckman Medical Gas Analyzer (Model LB-1) in studies of three dogs showed that inspiratory and expiratory anesthetic concentrations equilibrated within 17-20 minutes. During this interal no recordings were taken, but bilateral vagotomy was performed and the left carotid artery was cannulated for measurement of arterial blood pressure with a Statham P23-A transducer. The chest was entered either through the midline or through the right fourth intercostal space and the pericardium was incised. Two pairs of platinum electrodes were sewn to the right atrium to permit pacing and to record the atrial electrogram. A lead II electrocardiogram was recorded from the peripher: In some animals a soft ligature was placed around the thoracic aorta to allow manipulation of the blood pressure by partial compression. 实验在24只体重为0#的杂种狗上进行。用硫喷妥钠（ 20mg//kg20 \mathrm{mg} / \mathrm{kg} ，iv）诱导麻醉，插入气管插管进行机械通气，频率为 18//min18 / \mathrm{min} ，潮气量为 20-25mL//kg20-25 \mathrm{~mL} / \mathrm{kg} 。如前所述，用20%环丙烷或通过Foregger Copper Kettle蒸发器在非再呼吸系统中输送的含0.8%氟烷的氧气维持5只动物的麻醉。在三只犬的研究中使用Beckman Medical气体分析仪（LB-1型）显示，吸气和呼气麻醉剂浓度在17-20分钟内达到平衡。在此期间不进行记录，但进行双侧迷走神经切断术，左颈动脉插管，用斯坦森P23-A传感器测量动脉血压。通过中线或右侧第四肋间隙进入胸腔，切开心包。 将两对铂电极缝在右心房上，以允许起搏并记录心房电图。从外周记录II导联心电图：在一些动物中，在胸主动脉周围放置软结扎线，以允许通过部分压迫来操纵血压。
Tektronix stimulators with isolation transformers were used to pace the right atrium (twice threshold voltage; 5 msec pulse duration) and to stimulate the peripheral end of the cut right vagus nerve ( 1-20Hz1-20 \mathrm{~Hz} ). Epinephrine bitartrate (doses expressed as the free base) was infused by a Harvard pump into a femoral vein. A minimum of 15 minutes was allowed for recovery following each 使用带有隔离变压器的Tektronix刺激器起搏右心房（两倍阈值电压; 5 msec脉冲持续时间）并刺激切割的右迷走神经（ 1-20Hz1-20 \mathrm{~Hz} ）的外周端。通过哈佛泵将重酒石酸依匹林（剂量以游离碱表示）输注至股静脉。在每次注射后，允许至少15分钟的恢复时间
infusion. All variables were recorded on a Grass model P-5 polygraph. Experiments were terminated within 3 hours of the first exposure to the anesthetic. 输液所有变量均记录在Grass型P-5测谎仪上。实验在第一次暴露于麻醉剂的3小时内终止。
Results 结果
Characteristics of Thiopental-Halothane-EplnephrineindUCED ARrhythMlas 硫喷妥钠-氟烷-肾上腺素诱发心律失常的特点
Bigeminal arrhythmias were repeatedly produced in all animals anesthetized with halothane by intravenous infusions of epinephrine (0.5-3.0 mug//kg//min)(0.5-3.0 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min}). The rate of epinephrine infusion necessary for bigeminy to occur remained relatively constant throughout the period of recording. Bigeminy was induced a minimum of four times in each experiment. The mean dose of epinephrine effective in producing bigeminy was 1.3+-0.1 mug//kg//min1.3 \pm 0.1 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} in 19 animals. More rapid rates of infusion led to the development of multifocal ventricular arrhythmias. Ventricular fibrillation did not occur at the doses tested. 通过静脉输注肾上腺素 (0.5-3.0 mug//kg//min)(0.5-3.0 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min}) ，在用氟烷麻醉的所有动物中反复产生二联性心律失常。在整个记录期间，发生二联律所需的肾上腺素输注速率保持相对恒定。在每个实验中诱导二联律至少四次。在19只动物中，有效产生二联律的肾上腺素平均剂量为 1.3+-0.1 mug//kg//min1.3 \pm 0.1 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} 。更快的输注速率导致多灶性室性心律失常的发展。在试验剂量下未发生室颤。
The bigeminal electrocardiogram (EKG) recorded in the present study with halothane showed the characteristic features of bigeminy previously found with eyclopropane. ^(3){ }^{3} The coupling interal ( Q-Q\mathrm{Q}-\mathrm{Q} ) was constant or varied within very narrow limits ( 10-15msec10-15 \mathrm{msec} ). The QRS complexes of the bigeminal beats were prolonged in duration, although their polarity was only rarely inverted. The P-R interal of the bigeminal beat was invariably shorter than that of the preceding normal beat, and in many cases the configuration of the bigeminal QRS complex obscured the P-wave entirely or in part. Nevertheless, inspection of the atrial electrogram showed that the P-P interval remained constant. 在本研究中记录的二联心电图（EKG）与氟烷显示的特征性特点，二联以往发现的环丙烷。 ^(3){ }^{3} 耦合区间（ Q-Q\mathrm{Q}-\mathrm{Q} ）是恒定的或在非常窄的范围内变化（ 10-15msec10-15 \mathrm{msec} ）。二联心搏的QRS波群持续时间延长，尽管它们的极性很少反转。二联心搏的P-R间期总是短于前一个正常心搏的P-R间期，并且在许多情况下，二联QRS波群的构型完全或部分掩盖了P波。然而，检查心房电描记图显示P-P间期保持恒定。
Role of the Blood Pressure 血压的作用
Previous experiments with animals anesthetized with cyclopropane had shown that the arterial blood pressure is a critical factor influencing the development of both bigeminal and multifocal arthythmias. ^(5.6){ }^{5.6} This was also found to be true of halothane. Independent of variations in the rate of infusion of epinephrine, bigeminy occurred 之前对环丙烷麻醉动物进行的实验表明，动脉血压是影响二联性和多灶性心律失常发展的关键因素。 ^(5.6){ }^{5.6} 氟烷也是如此。二联律的发生与肾上腺素输注速率的变化无关
only when a critical level of blood pressure was reached. This level was constant in any given dog but varied among animals. The coefficient of variation of the systolic arterial pressure at the onset of bigeminal arrhythmia did not exceed 6 per cent in any dog. In 19 animals, the systolic and diastolic blood pressures at the onset of arrhythmia were 161+-6161 \pm 6 and 132+-5mmHg132 \pm 5 \mathrm{~mm} \mathrm{Hg}, compared with control values of 104+-3104 \pm 3 and 84+-384 \pm 3 mm Hg . The onset of bigeminy was in virtually all cases accompanied by a complete pulse deficit, such that systolic pressure was considerably increased whereas diastolic pressure was decreased. 只有在血压达到临界水平时才能进行。该水平在任何给定的犬中是恒定的，但在动物之间变化。在任何犬中，二联性心律失常发作时收缩期动脉压的变异系数均不超过6%。在19只动物中，心律失常发作时的收缩压和舒张压为 161+-6161 \pm 6 和 132+-5mmHg132 \pm 5 \mathrm{~mm} \mathrm{Hg} ，而对照值为 104+-3104 \pm 3 和 84+-384 \pm 3 mm Hg。二联律的发作几乎在所有情况下都伴随着完全的脉搏缺损，这样收缩压显著升高，而舒张压降低。
As shown in figure 1 A , bigeminal arrhythmias could be initiated by aortic compression during infusion of a subthreshold dose of epinephrine. This maneuver artificially elevated the thoracic arterial pressure to levels comparable to those occurring after effective doses of epinephrine without altering the intrinsic cardiac rate. In each case the arrhythmia subsided within 10 seconds after the release of aortic compression. The induction of arnhthmias in this manner was demonstrated on 19 occasions in eight of nine 如图1A所示，在输注亚阈值剂量的肾上腺素期间，主动脉压迫可引发二联性心律失常。这一操作人为地将胸动脉压升高到与有效剂量肾上腺素后发生的水平相当，而不改变固有心率。在每种情况下，心律失常在主动脉压迫解除后10秒内消退。以这种方式诱导arnhthastrin在9个中的8个中的19个场合中得到了证明
animals. On four occasions the identical maneuver was performed in the absence of epinephrine infusion and arrhythmias did not occur. 动物在没有肾上腺素输注的情况下进行了4次相同的操作，未发生心律失常。
The importance of blood pressure elevation to the development of bigeminy was further demonstrated by the effects of hypotension during ongoing bigeminal arrhythmias. In four dogs the arterial pressure was fixed to an artificially high level by compression of the thoracic aorta and arrhythmias were produced by the necessary infusions of epinephrine. Subsequently, the aortic compression was released, and in each case a normal sinus rhythm was restored (fig. 1B). 血压升高对二联律发展的重要性通过持续性二联律心律失常期间低血压的影响得到进一步证实。在四只狗中，通过压迫胸主动脉将动脉压固定在一个人为的高水平，并通过必要的肾上腺素输注产生心律失常。随后，主动脉压迫被释放，在每种情况下恢复了正常的窦性心律（图1B）。
Effects of Atrial Rate 心房率的影响
In addition to the necessary elevation of arterial pressure, the ability of epinephrine to induce bigeminy was dependent upon the attainment of a critical cardiac rate. For any given dog the heart rate at the onset of bigeminy was remarkably constant, and in no case did the coefficient of variation exceed 4 per cent. An increase of approximately 40 beats //min/ \mathrm{min} was necessary for the induction of bigeminy with an epinephrine infusion. For 除了必要的动脉压升高外，肾上腺素诱导二联律的能力取决于达到临界心率。对于任何给定的犬，二联律开始时的心率明显恒定，并且在任何情况下变异系数均不超过4%。增加约40次心跳 //min/ \mathrm{min} 是用肾上腺素输注诱导二联律所必需的。为
FIC. 1. Influence of arterial blood pressure on cardiac arrhythmias during halothane anesthesia. A, induction of bigeminal arrhythmia by compression of the thoracic aorta during a subthreshold ( 1mug//kg//min1 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} ) infusion of epinephrine. B, conversion of bigeminy to sinus rhythm by hypotension produced by the withdrawal of aortic compression during a 2mug//kg//min2 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} infusion of epinephrine. Upper traces: lead II electrocardiogram. Middle traces: atrial electrogram (atrial potentials marked “P”), Lower traces: carotid arterial blood pressure. FIC。1.氟烷麻醉时动脉血压对心律失常的影响。A，在阈下（ 1mug//kg//min1 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} ）输注肾上腺素期间通过压迫胸主动脉诱导二联性心律失常。B，在 2mug//kg//min2 \mu \mathrm{~g} / \mathrm{kg} / \mathrm{min} 肾上腺素输注过程中，由于主动脉压迫解除而产生的低血压导致二联律转为窦性心律。上迹线：导联II心电图。中间轨迹：心房电图（心房电位标记为“P”），下部轨迹：颈动脉血压。
Predoctoral Fellow. 博士前研究员。 †\dagger Assistant Professor. Present address: Department of Pharmacology and Therapeutics, MeGill University, McIntyre Medical Sciences Building, Montreal, P.Q., Canada. †\dagger 助理教授。现住址：MeGill大学药理学和治疗学系，McIntyre医学科学大楼，蒙特利尔，P.Q.，加拿大 ‡\ddagger Professor. 教授。
Received from the Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine, Winnipeg, R3E OW3, Manitoba, Canada. Accepted for publication July: 8, 1975. Aided by Accepted from the Medical Researeh Council of Canada. Address reprint requests to Dr. Dresel. 接收自马尼托巴大学药学院药理学和治疗学系，温尼伯，R3E OW3，马尼托巴，加拿大。接受出版：1975年7月8日。由加拿大医学研究理事会资助。将重印请求发送给Dr. Dresel。
