Article, Cardiology

Epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest

Original Contribution

Epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest

Meng-Hua Chen MDa, Lu Xie DPharmb,*, Tang-Wei Liu MDa, Feng-Qing Song MDa,

Tao He MDa, Zhi-yu Zeng MDa, Shu-Rong Mo MDb

aInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Guangxi Medical University,

Nanning 530021, PR China

bDepartment of Physiology, School of Pre-Clinical Sciences, Guangxi Medical University, Nanning 530021, PR China

Received 15 August 2006; accepted 29 August 2006

Abstract Although vasopressin has been reported to be more effective than epinephrine for cardiopulmonary resuscitation in ventricular fibrillation animal models, its efficacy in asphyxia model remains controversy. The purpose of this study was to investigate the effectiveness of vasopressin vs epinephrine on restoration of spontaneous circulation (ROSC) in a rabbit model of asphyxia cardiac arrest. Cardiac arrest was induced by clamping endotracheal tube. After 5 minutes of basic life-support cardiopulmonary resuscitation, animals who had no ROSC were randomly assigned to receive either epinephrine alone (epinephrine group;

200 lg/kg) or vasopressin alone (vasopressin group; 0.8 U/kg). The coronary perfusion pressure was

calculated as the difference between the minimal diastolic aortic and simultaneously recorded right atrial pressure. Restoration of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of 60 mm Hg or higher for 5 minutes or longer. We induced arrest in 62 rabbits, 15 of whom had ROSC before drug administration and were excluded from analysis. The remaining 47 rabbits were randomized to epinephrine group (n = 24) and vasopressin group (n = 23). Before and after drug administration, CPP in epinephrine group increased significantly (from –4 F 4 to 36 F 9 mm Hg at peak value, P = .000), whereas CPP in vasopressin group increased only slightly (from 9 F 5 to 18 F 6 mm Hg at peak value, P = .20). After drug administration, 13 of 24 epinephrine rabbit had ROSC, and only 2 of 23 vasopressin rabbit had ROSC ( P b.01). Consequently, we conclude that epinephrine, but not vasopressin, increases survival rates in this adult rabbit asphyxia model.

D 2007

Introduction

Epinephrine has been well accepted as the drug of choice for cardiopulmonary resuscitation (CPR) in the clinical

This study was supported by the Guangxi Natural Science Foundation of China, Nanning, Guangxi, China (grant nos. 0135038 and 0640081).

* Corresponding author. Tel.: +86 771 5358282; fax: +86 771

5352775.

E-mail address: [email protected] (L. Xie).

settings for many years. Currently, however, the role of epinephrine during CPR has become controversial [1]. Animal CPR studies have shown that epinephrine is associated with ventricular arrhythmias [2] and severe postresuscitation myocardial dysfunction [3]. Searching for a better resuscitated drug remains a substantial challenge.

Recently, vasopressin has been reported to be more effective than epinephrine for CPR in animal models [4-10] and in human cases of CPR [11-13]. However, most of the

0735-6757/$ – see front matter D 2007 doi:10.1016/j.ajem.2006.08.022

previous investigations involved ventricular fibrillation (VF) models. Only a few studies have been reported using an asphyxia model [14-16]. Furthermore, the efficacy of vasopressin during CPR showed significant differences between porcine and rat asphyxia models. In a pediatric porcine asphyxia model, epinephrine is superior to vaso- pressin for CPR [14]. In a rat asphyxia model, vasopressin and epinephrine are equally effective for CPR [15]. In an adult porcine asphyxia model, either vasopressin alone or epinephrine alone showed almost no effect for CPR (none of

6 vasopressin and only 1 of 6 epinephrine pigs had restoration of spontaneous circulation) [16]. These conflicting reports lead us to suspect whether these discrepancies come from the result of species difference in addition to age.

The rabbit is one of the relatively less commonly used animals in CPR research. To verify whether the beneficial effects of vasopressin exist during CPR in animals other than rat and Porcine models, it was necessary to repeat the experiments in an adult rabbit asphyxia preparation. The purpose of this study, therefore, was to investigate the effectiveness of vasopressin vs epinephrine on restoration of spontaneous circulation in a rabbit model of asphyxia cardiac arrest. The hypothesis was that there would be no differences in study end points between both drugs regarding their effectiveness on the outcome of CPR.

Materials and methods

This study was approved by the animal investigation committee of our university and was performed in accor- dance with National Institutes of Health guidelines for ethical animal research.

Animal preparation

Sixty-two rabbits of both sexes, weighing 1.8 to 2.3 kg, were fasted overnight with the exception of free access to water. The animals were anesthetized with urethane (1 g/kg) given via an ear vein, placed in a supine position on a surgical board, and the extremities immobilized. The proximal trachea was surgically exposed in the animals, and a cannula was inserted through a tracheostomy 10 mm caudal to the larynx during spontaneous respiration. The

cannula was advanced for a distance of 1.5 cm into the trachea and secured by ligature, which was also anchored to the skin.

Through the right external jugular vein, a 16-gauge polyethylene catheter was advanced through the superior vena cava into the right atrium. Right atrial pressure was measured with reference to the midchest with a high sensitivity pressure transducer. Another 16-gauge polyeth- ylene catheter was advanced from the left carotid artery into the thoracic aorta for measurement of aortic pressure with the high sensitivity pressure transducer. The void space of the catheters was filled with a physiologic salt solution containing 5 IU/mL of bovine heparin, and heparin 200 IU/kg IV was administered to prevent intracardiac clot formation. The core temperature was measured through a rectal temperature probe. Conventional lead II electrocardio- grams were recorded with subcutaneous needles.

The electrocardiogram (lead II) and aortic and right atrial pressures were continuously recorded on a desktop com- puter via 4-channel physiologic recorder (BL-420 E Bio- systems, The Chengdu Technology and Market Co Ltd, Chengdu, China) for subsequent analyses. The Coronary perfusion pressure was calculated as the difference between the minimal diastolic aortic and simultaneously recorded right atrial pressure [17,18].

Experimental protocol

After a 10- to 15-minute equilibration period after surgery, asphyxia cardiac arrest was then induced by clamping of the endotracheal tube until immediately before CPR. Cardiac arrest was determined by loss of aortic pulsa- tions and mean aortic pressure (MAP) below 10 mm Hg, together with asystole or pulseless electrical activity [18], which then marked time zero. After 3 minutes of untreated cardiac arrest (following time zero), endotracheal tube was unclamped, and a basic life support CPR was initiated. Ventilation was performed by a volume-controlled small animal ventilator (DH-150, the medical instrument of Zhejiang University, Hangzhou, China), with room air at 50 breaths per minute and tidal volume adjusted to 20 mL/kg. This ventilation was consistently maintained until spontane- ous breathing started. Manual chest compression was performed by the same investigator in all animals at a rate of 180 compressions per minute with equal compression- relaxation duration guided by acoustical audio tone. The

Fig. 1 The flow chart of the experimental protocol. Timeline expressed in minutes. The line indicates elapsed mean intervals until the start of each intervention. CA, cardiac arrest. BLS, base life support. ACLS, advanced cardiac life support.

investigator was blinded to hemodynamic monitor tracings throughout the experiment. Compression depth was approx- imately 30% of anterioposterior chest diameter at maximal compression. Restoration of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of 60 mm Hg or higher for 5 minutes or longer.

After 5 minutes of basic life-support CPR, the animals who had ROSC were excluded from the study, whereas those who failed to return automatic circulation were randomly assigned to receive either epinephrine alone(epi-

nephrine group; 200 lg/kg) or vasopressin alone(vasopres-

sin group; 0.8 U/kg). The drugs were diluted to 2 mL with normal saline and intravenously injected separately, fol- lowed by a 3-mL saline flush (all investigators were blinded to the drugs). After the administration of the study drug, CPR was continued. For rabbits with ROSC, they were monitored for 1 hour. For those without ROSC, within 10 minutes, the experiment was terminated. The flow chart of the experimental protocol is shown in Fig. 1.

Primary outcome measures were rate of ROSC, second- ary outcomes were Hemodynamic variables (CPP). An independent observer, blinded to the drug injections, observed the animal and determined ROSC.

When the experimental protocol was finished, the animals were euthanized with an overdose of potassium chloride. Necropsy was routinely performed after death, including resuscitated and unResuscitated animals. Thoracic and abdominal organs were examined for gross evidence of traumatic injures that followed airway management, vascu- lar cannulation, or precordial compression. The position of catheters was documented.

Statistical analysis

Data were presented as mean F SEM. Student t test was used to determine statistical significance between 2 groups. Comparisons between time-based measurements within each group were performed with analysis of variance repeated measurements. Using Fisher exact test, we tested

Fig. 2 Changes in CPP during 15 minutes of resuscitation phase. Variables expressed as mean F SEM.

Fig. 3 The results of resuscitation between epinephrine group and vasopressin group. *P b .05 vs vasopressin.

discrete variables such as ROSC; a 2-tailed value of P b .05 was considered statistically significant.

Results

During the initial 5 minutes of basic life-support CPR, 15 of a total of 62 rabbits had ROSC and were excluded from the study. Of the remaining, 47 were entered into the study and were randomized to epinephrine group (n = 24) and vasopressin group (n = 23), respectively.

Before asphyxia, no significant differences were observed between both groups in regard to body weight, heart rate (HR), systolic blood pressure, diastolic blood pressure, MAP, central venous pressure, and body temperature. The interval between clamping the tube and loss of aortic pulsations was 5.8 F 0.9 minutes in the epinephrine group and 6.1 F 0.6 minutes in the vasopressin group rabbits ( P = NS between groups). During the subsequent 3 minutes of the nonintervention interval, spontaneous VF occurred in 1 of 47 animals and pulseless electrical activity in 46 of 47 ( P = NS between groups). Only in 5 of the 47 animals (including the animal with VF) cardiac rhythms subsequently

Fig. 4 Changes in MAP during 60 minutes of monitoring after CPR. Variables expressed as mean F SEM.

Fig. 5 Changes in HR during 60 minutes of monitoring after CPR. Variables expressed as mean F SEM.

developed into asystole, whereas 42 of 47 animals remained on pulseless electrical activity until the initiation of CPR ( P = NS between groups).

During the initial 5 minutes of basic life-support CPR, CPP in both groups did not exhibit significant differences. However, after drug administration, CPP in the epinephrine group increased significantly (from –4 F 4 to 36 F 9 mm Hg at peak value, P = .000), whereas CPP in vasopressin group increased only slightly (from 9 F 5 to 18 F 6 mm Hg at peak value, P = .20), compared to that before drug administration (Fig. 2).

Only 2 of 23 vasopressin rabbits had ROSC, whereas

13 of 24 epinephrine rabbits had ROSC after drug administration ( P b .01 vasopressin vs epinephrine, Fig. 3).

There was no significant difference between the groups in regard to the changes of MAP and HR after ROSC (Figs. 4 and 5).

Necropsy confirmed appropriate catheter positions in all of the animals. No adverse effects of invasive procedures or other traumatic injures were found.

Discussion

During CPR, CPP correlates positively with ROSC and survival [19]. A vasopressor is given during cardiac arrest to increase this perfusion pressure and thereby enhance both myocardial and cerebral blood flow in the hopes that this will improve survival. Epinephrine 0.2 mg/kg during CPR was the maximum effective dose to enhance vital organ blood flow in pigs [20], which improved resuscitation of asystole and electromechanical dissociation in patients [21]. Furthermore, the vasopressin doses 0.8 U/kg provide maximal vital organ perfusion during CPR [22]. This epinephrine dose was chosen to be compared with the maximum effective vasopressin dose [22]. In this model of adult rabbit asphyxia CPR, both epinephrine and vasopres- sin groups exhibited a relatively low CPP during the initial 5 minutes of basic life support CPR. After drug adminis- tration, the increase of CPP in the epinephrine group was

significantly higher than that in the vasopressin group. Of 24 epinephrine rabbits, 13 had ROSC, whereas only 2 of 23 vasopressin rabbits had ROSC ( P b .05). The present research results demonstrated that epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest.

In successfully resuscitated patients during CPR, levels of vasopressin are higher, and epinephrine and norepinephrine (noradrenaline) levels are lower compared with concentra- tions in those patients who die [23,24]. This may indicate that the human body discharges vasopressin as an adjunct vasopressor to epinephrine to preserve homeostasis in life- threatening situations such as cardiac arrest. Thus, vasopres- sin may have a more important effect on CPR outcome than previously thought. These findings, along with the disadvan- tages of epinephrine, have encouraged extensive investiga- tion of vasopressin as a therapy during CPR [25,26].

It is well known that vasopressin appears to work during CPR by acutely increasing systemic vascular resistance [27] via the V1 receptor [28] and by potentiating the vasocon- strictor effects of endogenous catecholamines [29,30]. It produces vasoconstriction in bnonvitalQ circulations, such as the skin, skeletal muscle, and small bowel, thereby diverting blood to the brain, heart, and kidneys, which helps to increase the survival rate.

Most of the previous investigations involved VF models [4-10]. Vasopressin improved vital organ blood flow during CPR [22], cerebral oxygen delivery [31], resuscitability [32], and Neurologic recovery [10] better than did epinephrine.

However, asphyxia cardiac arrest differs pathophysiolog- ically from VF because the progression to complete ischemia is sudden in VF and gradual in asphyxia. The beneficial effects of vasopressin in a model of VF could not be extrapolated to a model of asphyxia cardiac arrest. Even in the same animal model of asphyxia cardiac arrest, the beneficial effects of vasopressor in newborn infants could not be extrapolated to mature animals. It has been reported that in a pediatric porcine model of asphyxia cardiac arrest, epinephrine was clearly superior to vasopressin with respect to improving vital-organ blood flow and ROSC (1 of 6 vasopressin- but 6 of 6 epinephrine-treated animals had ROSC) [14]. But in an adult pig model of asphyxia cardiac arrest, both epinephrine alone and vasopressin alone had almost no effects on ROSC. None of 6 vasopressin and only 1 of 6 epinephrine pigs had ROSC in the asphyxia cardiac arrest model [16].

These data indicate different efficiencies of vasopressors in pediatric vs adult preparations and in dysrhythmic vs asphyxia cardiac arrest, which may be of significant importance for vasopressor efficiency. This could help us to choose a rational CPR strategy according to different subjects and different Experimental models or clinical settings, so as to achieve an optimal resuscitation outcome. In the present study, the efficacy of epinephrine was clearly superior to that of vasopressin in regard to the increase of CPP and the rate of ROSC after drug administration during CPR. These research results derived

from an adult rabbit asphyxia model differed considerably from the results derived from an adult pig asphyxia model [16]. They also differed from the results coming from an adult rat asphyxia model [15], in which vasopressin and epinephrine were equally effective for CPR (7 of 7 rats were resuscitated with vasopressin and 6 of 7 rats were resuscitated with epinephrine).

A proposed explanation for this phenomenon could be the result of species differences. Because different species hold different biologic characters, metabolic status, and endoge- nous stress hormone levels, the vasopressor response of the vasculature may be fundamentally different during cardiac arrest and CPR. Even in an asphyxia cardiac arrest rat model, numerous resuscitation-related variables may appear differ- ent between Sprague-Dawley and Wistar rats [33].

Another explanation for the discrepancies may be the diversity of nonintervention interval in different studies, which can greatly affect the results during CPR researches. Consequently, all the results of experimental investigations could not be extrapolated immediately to clinical settings.

Some limitations of the present study should be noted. As a preliminary investigation, we did not make an effort to determine and use equipressor doses of the vasopressor agent in the present study. In other words, whether epinephrine and vasopressin dosing chosen in the present study is an equipressor, doses or optimal dose for rabbit cardiac arrest model remains to be established. This study also did not consider a combination of both drugs as a separate arm. Whether the combination of 2 drugs can achieve better outcome than epinephrine alone during CPR remains unclear as well. In addition, the animals were not paralyzed with pancuronium in this study. This gives the animal an opportunity to gasp and produces a state of stress when the endotracheal tube is clamped. Meanwhile, a great deal of endogenous epinephrine were immediately discharged dur- ing the induction of cardiac arrest in an effort to maintain cardiocirculatory homeostasis until cardiac arrest finally occurred, which may have depleted the endogenous epineph- rine of the animals and affected the efficacy of vasopressin during CPR. Furthermore, a period of 3 minutes without intervention in the present study, just as mentioned above, appeared to be an inadequate nonintervention interval. Because 15 of the total of 62 rabbits had been resuscitated with ventilation and chest compressions alone, this prevented our studying the effects of vasopressor drugs. Although the animals who had ROSC during basic life support CPR had to be excluded from the study, a relatively short nonintervention interval may result in a different vasopressor response of the vasculature, compared with a relatively longer noninterven- tion interval in an asphyxia cardiac arrest model.

Conclusion

The present study shows that epinephrine alone, but not vasopressin alone, increases CPP during advanced cardiac

life support and resulted in higher survival rates in this model of an adult rabbit asphyxia model.

Acknowledgments

The authors thank the staff of the Department of Physiology for excellent technical help and constructive criticism. The authors also thank Mr Harry Baume for language editing of the manuscript.

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