Original Contribution

Atenolol in combination with epinephrine improves the initial outcome of cardiopulmonary resuscitation in a swine model of ventricular fibrillation^?

Eleni Bassiakou MD, Theodoros Xanthos PhD?, Eleni Koudouna MD, Sotirios Goulas MD, Vassiliki Prapa MD, Dimitrios Papadimitriou MD, George Rokas MD, Lila Papadimitriou PhD

Department of Experimental Surgery and Surgical Research <>, Athens School of Medicine, Athens 11527, Greece

Received 25 July 2007; revised 14 September 2007; accepted 15 September 2007

Abstract

Study objectives: The aim of the present study was to assess whether a ?-adrenergic blocking agent such as atenolol, administered during cardiopulmonary resuscitation, would improve Initial resuscitation success.

Methods: Ventricular fibrillation was induced in 20 Landrace/Large White piglets, which were left untreated for 8 minutes before attempted resuscitation with precordial compression, mechanical ventilation, and electrical defibrillation. Animals were randomized into 2 groups (10 animals each) to receive saline as placebo (20 mL dilution, bolus) + epinephrine (0.02 mg/kg) (group A) or atenolol (0.05 mg/kg per 20 mL dilution, bolus) + epinephrine (0.02 mg/kg) (group B) during cardiopulmonary resuscitation. Electrical defibrillation was attempted after 10 minutes of ventricular fibrillation.

Results: Nine animals in group B restored spontaneous circulation in comparison to only 4 in group A. Aortic systolic and diastolic pressures as well as coronary perfusion pressure were significantly increased during cardiopulmonary resuscitation in group B. Furthermore, postresusci- tation heart rate of the atenolol-treated group was significantly decreased.

Conclusions: A ?-adrenergic blocking agent, when administered during cardiopulmonary resuscitation, significantly improves initial Resuscitation success and increases blood and coronary perfusion pressures during cardiopulmonary resuscitation.

(C) 2008

Introduction

^? This project is cofinanced with Op. Education by European Social Fund and National Resources EPEAK II-Pythagoras I.

* Corresponding author.

E-mail address: [email protected] (T. Xanthos).

Sudden cardiac arrest is a leading cause of death in the United States, affecting about 700 000 individuals a year [1]. At the time of the first heart Rhythm analysis, about 40% of arrest victims have ventricular fibrillation (VF) [2-5]. The optimum treatment of VF cardiac arrest is immediate

0735-6757/$ - see front matter (C) 2008 doi:10.1016/j.ajem.2007.09.010

bystander cardiopulmonary resuscitation (CPR) plus elec- trical defibrillation [6].

Epinephrine has been preferred for almost 40 years as the adrenergic amine for increasing coronary perfusion pressure during CPR in humans experiencing cardiac arrest [7,8]. Currently, the role of epinephrine during CPR is controversial [9].

The main clinical benefit from the administration of epinephrine is the restoration and maintenance of threshold levels of CPP [10]. Evidence suggests that epinephrine’s efficacy is because of the ?-adrenergic peripheral vasocon- striction effect [11]. On the other hand, the action of epinephrine on myocardium has been associated with adverse Cardiac effects, which are attributed to adrenergically induced increase of the already excessive myocardial oxygen requirements of the fibrillating heart [12].

It was therefore logical to assume that the coadministration of a ?-blocker such as atenolol, during CPR but before defibrillation, would improve initial resuscitation success. The aim of the present study was to assess whether the combination of epinephrine and atenolol would improve initial resuscitation success in an established model of VF and CPR.

Materials and methods

The experimental protocol was approved by the General Directorate of Veterinary Services (permit no. K/2262/27-3- 2006), according to Greek legislation regarding ethical and experimental procedures (Presidential Decree 160/1991 [in compliance to the European Economic Community (EEC) Directive 86/609] and Law 2015/1992, and in conformance with the European Convention “for the protection of vertebrate animals used for experimental or other scientific purposes, 123/1986”). Twenty male and female Landrace/ Large White piglets, all coming from the same breeder, aged 10 to 15 weeks and with an average weight of 19 +- 2 kg were included in the study. The animals were fasted overnight, but access to water was ad libitum.

The animals were premedicated with the use of Intramuscular injection of 10 mg/kg ketamine hydrochloride,

0.5 mg/kg midazolam, and 0.05 mg/kg atropine sulfate. The marginal auricular vein was then catheterized. Anesthesia was induced with an Intravenous bolus dose of propofol (2.0 mg/kg). While spontaneously breathing, but anesthetized, the pigs were intubated with a 4.5-mm endotracheal tube (Portex, 4.5 mm ID, Mallinckrodt Medical, Athlone, Ireland). The tracheal tube was secured on the upper jaw; hair was clipped from the ventral thorax to facilitate the use of self-adhesive electrodes.

The animals were then immobilized in supine position on the operating table. Additional propofol 1 mg/kg, cis- atracurium 0.15 mg/kg, and fentanyl 4 ug/kg were administered immediately before connecting the animals to the automatic ventilator (ventiPac, Sims pneuPac, Luton, UK) with oxygen (fraction of inspired oxygen, 21%).

Propofol infusion (0.1 mg/kg per minute) and additional doses of cis-atracurium followed to maintain adequate anesthetic depth. Fentanyl was administered as required. The animals were ventilated with the aid of a volume- controlled ventilator and with a total tidal volume of 15 ml/kg. End-tidal PCO2 was monitored (Nihon Kohden Corp, Bergamo, Italy) and the respiratory frequency was adjusted to maintain end-tidal PCO2 of 35 to 40 mmHg.

electrocardiographic monitoring (Mennen Med- ical, Envoy, Papapostolou, Athens, Greece) was performed using leads I, II, and III with the use of self-adhesive electrodes to assess the cardiac rhythm.

Pulse oximeter (Vet/Ox Plus 4700, Heska, USA) was placed on the tongue of the animal for continuous monitoring of peripheral oxygen saturation.

For measurement of the aortic pressure, a fluid-filled (model 6523, USCI CR, Bart Inc, Papapostolou, Athens, Greece) arterial catheter was inserted into the aorta via the right Common carotid artery. Mean arterial pressure (MAP) was determined by the electronic integration of the aortic blood pressure waveform. The internal jugular vein was surgically prepared, and a Swan-Ganz catheter (Opticath 5.5F, 75 cm, Abbott, Ethicon Mersilk, Athens, Greece) was inserted into the right atrium for continuous measurement of right atrial pressure. Conventional external pressure transducers were used (Transpac IV, Abbott Critical Care Systems, Athens, Greece). Coronary perfusion pressure was electronically calculated as the difference between minimal aortic diastolic pressure and the simultaneously measured right atrial diastolic pressure. The second internal jugular vein was also surgically prepared and a 5F flow-directed pacing catheter (Pacel, 100 cm, St Jude Medical, Ladakis, Athens, Greece) was advanced into the apex of the right ventricle. Confirmation of correct placement was achieved by fluoroscopic imaging and by the ventricular ectopies recorded on the ECG tracing.

The animals were randomized into 2 groups with the use of a sealed envelope indicating the animal’s assignment to: group A, saline as placebo (20 mL dilution, bolus) + epinephrine (0.02 mg/kg); and group B, atenolol (0.05 mg/kg per 20 mL dilution, bolus) + epinephrine (0.02 mg/kg). The study was blinded as to the medication used, and only the principal investigator, who did not take part in any resusci- tation effort, knew the assignment of each animal. Further- more, the investigators involved in data recording, data entry, and data analysis were also blinded to the allocation.

Ventricular fibrillation was induced with a 9-V ordinary lithium battery. Arrhythmia was confirmed electrocardio- graphically and by a sudden drop in MAP. After induction of VF, mechanical ventilation was stopped. The animals were left untreated for 8 minutes. Resuscitation procedures started with inspired oxygen concentration of 100%, followed by the injection of the drugs to the marginal auricular vein according to the animal’s group; and precordial compression begun with a mechanical chest compressor (Thumper, Michigan Instruments) for 2 minutes. Compressions were maintained at a rate of 100/min with equal compression-

Fig. 1 Experimental protocol.

relaxation duration to maintain end-tidal PCO2 between 35 and 45 mm Hg. Compression depth was equivalent to 30% of the anteroposterior diameter of the chest. After 2 minutes of precordial compression, defibrillation was attempted with a 200-J monophasic waveform shock delivered between the right infraclavicular area and the cardiac apex (Porta Pak/90, Medical Research Laboratories Inc, Athens, Greece). While the defibrillator was being recharged, the ECG monitor was observed for any changes in the rhythm. In case of failure to convert to a cardiac rhythm compatible with pulse, precordial compression was resumed for 2 minutes before delivery of a second shock. The sequence of precordial compression followed by a single shock of 200 J was repeated for maximum of 3 times. Our experimental protocol is shown in Fig. 1. Successful resuscitation was defined as the return of spontaneous circulation (ROSC), with a MAP of at least 60 mm Hg, for a minimum of 5 minutes.

End points of the experiment were defined as either

asystole or ROSC or VF after 3 unsuccessful defibrillation attempts. The animals restoring spontaneous circulation were

monitored for 60 minutes while anesthesia was maintained. All animals were euthanized by intravenous overdose of thiopental (2 g). Necropsy was routinely performed after death. Thoracic and abdominal organs were examined for gross evidence of traumatic injuries due to surgical or resuscitation efforts and any underlying pathology.

Data are expressed as mean +- SD for continuous variables and as percentages for categorical data. The Kolmogorov- Smirnov test was used for normality analysis of the parameters. Comparisons of continuous variables were analyzed using Student t test and Mann-Whitney nonpara- metric test as appropriate. Comparisons of categorical variables were analyzed using Fisher exact test.

Paired-samples t test and Wilcoxon test were used for the comparison of different time measurement of parameters for each group. Comparison of percent change from baseline of parameters during the observation period between 2 groups was analyzed using the Mann-Whitney test.

Moreover, using the analysis of covariance model, we compared the difference between groups for all parameters at each time point, controlling for baseline difference using the value of parameter at each time point as dependent variable and the baseline measurements as covariates.

Differences were considered statistically significant if the null hypothesis could be rejected for P b .05. All analyses were conducted using the SPSS, version 13.00 (SPSS Inc, Chicago, Ill).

Results

Baseline hemodynamic measurements did not differ between the 2 groups as shown in Table 1. By the end of the 8th minute of VF, MAP decreased from 89.3 +- 7.5 to

22.5 +- 3.3 mm Hg in group A and from 91.2 +- 15.6 to

25.6 +- 3.1 mm Hg in group B (P = not significant). Coronary perfusion pressure declined rapidly and remained between 0 and 4 mm Hg during the 8th minute of untreated VF in both groups.

Just before the first defibrillation attempt, significant difference in various variables between the 2 groups was observed. More specifically, systolic and diastolic aortic pressures and CPP increased significantly in atenolol-treated

Table 1 Baseline variables in the 2 different groups
	HR	SAP	DAP	MAP	MRAP	SpO2
	(beats	(mm Hg)	(mm Hg)	(mm Hg)	(mm Hg)	(%)
	per minute)
Group A	108.3 +- 12.6	104.3 +- 7.9	77.6 +- 11.5	89.3 +- 7.5	11.1 +- 1.3	91.1 +- 3.8
Group B	108.2 +- 10.8	104.1 +- 11.3	79.5 +- 18.5	91.2 +- 15.6	11.2 +- 2.2	93.6 +- 3.1
P	NS	NS	NS	NS	NS	NS
HR indicates heart rate; SAP, systolic aortic pressure; DAP, diastolic aortic pressure; MRAP, mean right atrial pressure; SpO2, saturation of peripheral oxygenation; NS, not significant.

SAP (mm Hg)		DAP (mm Hg)	CPP (mm Hg)	RADP (mm Hg)
Group A	73.9 +- 11	32.9 +- 4.5	19.7 +- 7.0	14.7 +- 6.0
Group B	90.5 +- 11.3	49.1 +- 6.9	27.7 +- 5.3	17.2 +- 4.9
P	b.05	b.05	b.05	NS
95% CI ?	16.6 +- 10.5	16.2 +- 5.5	8 +- 5.8
RADP indicates right atrial diastolic pressure; CI, confidence interval. * For difference between means for statistical significant differences.

animals. Table 2 summarizes the values of the different parameters just before the first defibrillation attempt. Fig. 2 demonstrates how MAP fluctuated in both groups, whereas Fig. 3 demonstrates CPP’s fluctuation during resuscitation efforts.

Table 2 Different parameters in the 2 groups just before the first defibrillation attempt (8 minutes of untreated VF and 2 minutes of CPR)

Four animals restored spontaneous circulation in group A, whereas 9 animals restored spontaneous circulation in group B (P b .05). More specifically, 4 animals in group A were successfully resuscitated after the first defibrillation, and no animal restored spontaneous circulation in the following defibrillation attempts. In group B, 7 animals were success- fully resuscitated after the first defibrillation, whereas 2 more animals restored spontaneous circulation in the second defibrillation attempt. In the one animal that failed to restore spontaneous circulation in group B, necropsy revealed significant pulmonary fibrosis, whereas routine necropsy in the 6 animals that did not restore spontaneous circulation in

group A showed no evidence of pathology in the cardioPulmonary system.

The total amount of shocks in group A was 22, in contrast to group B where the total amount of shocks was

12. The energy mode (central tendency) for both groups was 200 J.

All animals that were successfully resuscitated were monitored for 1 hour. Postresuscitation heart rate in group A was significantly higher than that in group B during the first 10 minutes after ROSC. Blood pressures and right atrial pressure of both groups did not differ significantly during the whole postresuscitation phase. Table 3 summarizes the parameters measured during the 10th minute after ROSC and Fig. 4 demonstrates the fluctuation of mean heart rate during the postresuscitation period in both groups.

The numbers of premature ventricular contractions in group A were significantly higher. This contrasted with

Fig. 2 Mean arterial pressure fluctuation in time in the 2 groups. The MAP after the 10th minute was calculated in animals that were not successfully resuscitated after the first defibrillation attempt. In the ROSC period, all animals successfully resuscitated were included. BL indicates baseline value; DF, defibrillation attempt.

Fig. 3 Mean coronary perfusion pressure fluctuation in time in both groups. The CPP after the 10th minute was calculated in animals that were not successfully resuscitated after the first defibrillation attempt. In the ROSC period, all animals successfully resuscitated were included.

group B after the ? effects of epinephrine were blocked, and ventricular ectopy was minimized. Table 4 elucidates ventricular dysrhythmias in both groups.

Discussion

In the setting of prolonged VF, the guidelines on resuscitation recommend the periodic use of epinephrine [13]. Epinephrine has remained the commonest used vasopressor agent for CPR, although a classic report more than 40 years ago has recommended more selective ?- adrenergic agonists [14]. Epinephrine is a mixed adrenergic agonist, acting on the ?- and ?-adrenergic receptors. The actions of epinephrine for ROSC are mostly mediated by its ?-adrenergic properties. Epinephrine increases CPP via systemic arteriolar vasoconstriction, which maintains per- ipheral vascular tone and prevents arteriolar collapse [15]. In contrast to the ?-adrenergic stimulation, ?-stimulation may have deleterious effects [16], by increasing the oxygen consumption of the fibrillating myocardium, augmenting the intrapulmonary shunting caused by hypoxic pulmonary vasoconstriction, and reducing subendocardial perfusion [17]. Furthermore, it is associated with poorer postresuscita- tion myocardial function [18]. During cardiac arrest, when there is cessation of Coronary blood flow, the severity of Ischemic injury is magnified because of the greatly increased myocardial oxygen demands that accompany VF [12].

The stress of cardiac arrest is a potent stimulus for the

release of endogenous catecholamines resulting in intense

sympathetic activation. During resuscitation efforts, very high levels of endogenous catecholamines have been reported [19,20]. These epinephrine plasma concentrations and further administration of exogenous epinephrine doses result in an excessive ?-stimulation. Furthermore, ?- adrenergic receptors are abundant in the myocardium [21]. For the aforementioned reason, it was logical to assume that ?-adrenergic blockade can reduce myocardial ischemic injury during cardiac arrest and could result in higher resuscitation success.

In earlier studies, ?-adrenergic blocking agents, when administered before inducing cardiac arrest, minimized myocardial injury and improved survival [22]. Huang et al

[23] reported that nonselective ?-blocking agent propranolol improved postresuscitation myocardial dysfunction in pre- treated rats, such that the beneficial effects were associated with better postresuscitation survival. Furthermore, pretreat- ment with ?-blocker, before VF induction, followed by the

Table 3 Postresuscitation variables in both groups (10th

minute postresuscitation)

HR (beats per minute)

Group A 199 +- 7.8

Group B 168 +- 24

P b.05 ?

SAP DAP RAMP

(mm Hg) (mm Hg) (mm Hg)

156 +- 28.6 117 +- 18.1 15.5 +- 3

150 +- 39 100 +- 27.7 17.2 +- 3.6

NS NS NS

RAMP indicates right atrial mean pressure.

* 95% CI for difference between means is 31 +- 16.8 mm Hg.

Fig. 4 Mean postresuscitation heart rate in both groups.

suggested epinephrine doses, leads to myocardial injury reduction, without compromising the possibility of success- ful defibrillation or left ventricular dysfunction in the postresuscitation period [22].

However, studies of ?-blockade administration during CPR are limited. The ?-antagonist esmolol administered immediately after defibrillation, but before CPR, improved ROSC and added 4-hour survival after prolonged VF in pigs [24]. Also, Cammarata et al [25] administered esmolol in a rat model during CPR and concluded that initial Cardiac resuscitation was improved, postresuscitation myocardial dysfunction was minimized, and duration of postresuscita- tion survival was increased. Those results are in accordance with our findings, where initial resuscitation success was statistically significant in the atenolol group.

In previous studies, CPP has been found to be the key determinant for successful defibrillation in humans [10] and various animal models [26].

In our study, CPP in the ?-blockade group increased during cardiopulmonary resuscitation. This finding is in accordance with the findings of Ditchey et al [22] who has also demonstrated that phenylephrine combined with a ?- blocking agent increased CPP, suggesting that the ?- adrenergic blockade can enhance vasoconstriction by allow- ing unopposed ?-adrenergic stimulation of resistant vessels. The results therefore affirm our hypothesis. ?-Adrenergic blockade increased CPP that predicted and accomplished successful resuscitation.

Elizur et al [27] demonstrated that the tracheal adminis- tration of epinephrine after pretreatment with the nonselec- tive ?-blocker propranolol is associated with a greater increase in diastolic blood pressure than the tracheally administered epinephrine alone. Moreover, the endotracheal

administration of epinephrine in a dog model produced an early significant decrease in systolic and diastolic pressures, and MAP. These effects were abolished when the dogs were pretreated with the nonselective ?-blocker propranolol [28]. Although these effects have yet to be confirmed in the Intravenous use of epinephrine, our results regarding systolic and diastolic blood pressures point to the unopposed ?- adrenergic stimulation of epinephrine on resistant vessels in cardiac arrest.

By blocking the positive chronotropic and inotropic effects of catecholamines, atenolol is also considered to reduce the oxygen requirements of the heart. Furthermore, atenolol is considered to be a relative cardioselective blocking agent [29]. After intravenous administration, atenolol exerts its effects rapidly and peak plasma levels are reached within 5 minutes. It was therefore logical to assume that a 2-minute period of CPR before defibrillation would suffice to ensure ?-adrenergic blockade.

Postresuscitation effects of ?-blockers are proven to be useful in experimental studies [22,23,25]. ?-Blockers are known to protect the ischemic heart against fatal dysrhyth-

Table 4 Postresuscitation dysrhythmias

PVC			Salvos	Episodes of VF
Group A	85 +-	30	14 +- 3	18 +- 6
Group B	40 +-	27	4 +- 3	2 +- 1
P	b.05		b.05	b.05
95% CI ?	45 +-	26.8	10 +- 2.8	16 +- 4
PVC indicates premature ventricular contractions; VT, ventricular tachycardia. * 95% CI for difference between means for statistical significant differences.

mic events [30]. Furthermore, it has been shown that propranolol pretreatment in a rat model was associated with significantly greater cardiac output [23]. In addition, the incidence of ventricular arrhythmia in our study was significantly higher in the epinephrine group.

This experimental procedure demonstrates that the combined administration of atenolol with epinephrine during CPR improves success of initial resuscitation and increases diastolic pressure during precordial compression as well as coronary perfusion pressure. Atenolol, as a ?-blocking adrenergic agent, could have an important place in cardiopulmonary resuscitation. This study adds some evidence to the existing literature of ?-adrenergic blockade benefits, and further evaluation of these results should be held in the future.

The authors recognize several limitations in the interpretation of the present findings. The study was conducted on apparently healthy pigs and its direct application to human victims of cardiac arrest has yet to be addressed. Furthermore, species differences in the effects of atenolol have not been evaluated in the present study. In addition, the experimental animals were anesthe- tized and the potential interactions of the different agents were not assessed.

Acknowledgment

The statistical evaluation of the present data was done by Mr Sotirios Bassiakos.

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