VASOPRESSORS are believed to improve the outcome

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1 Acta Anaesthesiol Scand 2006; 50: Printed in Singapore. All rights reserved # 2006 The Authors Journal compilation # 2006 Acta Anaesthesiol Scand ACTA ANAESTHESIOLOGICA SCANDINAVICA doi: /j x Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model M.-H. CHEN 1,L.XIE 2, T.-W. LIU 1, F.-Q. SONG 1 and T. HE 1 1 Institute of Cardiovascular Diseases, First Affiliated Hospital of Guangxi Medical University and 2 Department of Physiology, School of Pre-Clinical Sciences, Guangxi Medical University, Nanning, China Background: It is not known whether naloxone is as efficacious as epinephrine during cardiopulmonary resuscitation (CPR). The aim of the study was to compare the effects of naloxone and epinephrine on the outcomes of CPR following asphyxial cardiac arrest in rats. Methods: Cardiac arrest was induced with asphyxia by clamping the tracheal tubes. Twenty-four Sprague Dawley rats were randomized prospectively into a saline group (treated with normal saline, 1 ml intravenously, n ¼ 8), an epinephrine group (treated with epinephrine, 0.04 mg/kg intravenously, n ¼ 8) or a naloxone group (treated with naloxone, 1 mg/kg intravenously, n ¼ 8) in a blind fashion during resuscitation after asphyxial cardiac arrest. After 5 min of untreated cardiac arrest, conventional manual CPR was started and each drug was administered at the same time. Results: The rates of restoration of spontaneous circulation (ROSC) were one of eight (12.5%), seven of eight (87.5%) and seven of eight (87.5%) in the saline, epinephrine and naloxone groups, respectively. The rates of ROSC in the epinephrine and naloxone groups were equal and significantly greater than that in the saline group (P ¼ 0.01 and P ¼ 0.01, respectively). Conclusion: The administration of naloxone or epinephrine alone may increase the resuscitation rate, and both drugs are equally effective for CPR in a rat asphyxia model. However, the mechanism by which naloxone produces its efficacy during CPR remains unclear and further experimentation will be necessary. Accepted for publication 16 June 2006 Key words: animal; asphyxia; cardiac arrest; cardiopulmonary resuscitation; epinephrine; naloxone. # 2006 The Authors Journal compilation # 2006 Acta Anaesthesiol Scand VASOPRESSORS are believed to improve the outcome of patients with cardiac arrest by improving cardiac and brain blood flow during cardiopulmonary resuscitation (CPR). Although epinephrine has been used as a standard first-line drug in cardiac arrest for many years, the efficacy of the drug is still not completely satisfactory. CPR studies have shown that epinephrine may be associated with ventricular arrhythmias (1) and severe post-resuscitation myocardial dysfunction (2). Recently, it has been reported that vasopressin is more effective than epinephrine during CPR in a ventricular fibrillation model (3). However, asphyxial cardiac arrest is a very different insult from sudden cardiac arrest. In an unpublished experimental study, epinephrine yielded a much better outcome to CPR than vasopressin in asphyxial rabbit cardiac arrest. Sumann et al. (4) described the case of a 19- year-old female patient with prolonged, hypothermic, out-of-hospital cardiopulmonary arrest after near drowning, in whom cardiocirculatory arrest persisted despite 2 mg of intravenous epinephrine; however, immediate return of spontaneous circulation occurred after a single dose (40 IU) of intravenous vasopressin. Unfortunately, the patient died of multiorgan failure 15 h later. Schwarz et al. (5) also reported that, although vasopressin significantly increased coronary perfusion pressure and defibrillation success, the 60-min survival rate was not improved. These data suggest that the efficacy of vasopressin during CPR remains to be established, and that the search for a better resuscitation medication remains a challenge. Naloxone is used most often to reverse opioidinduced respiratory depression (6, 7). It has also been used in many varieties of shock (8 11). Except for death due to opioid overdose, little knowledge is available on the efficacy of naloxone during variants of cardiac arrest and CPR. In an earlier preliminary study, we attempted to identify whether naloxone 1125

2 M.-H. Chen et al. alone could increase the rate of restoration of spontaneous circulation (ROSC) during CPR. Different doses of naloxone (0.5 and 1.0 mg/kg body weight) were administered in an asphyxia rat model of cardiac arrest. It was found that high doses of naloxone alone could increase the resuscitation rate during CPR. The present study was performed to identify whether naloxone alone has the same efficacy as epinephrine during CPR. The hypothesis was that both drugs would exhibit the same efficacy for CPR. Materials and methods This study was approved by the Animal Investigation Committee at Guangxi Medical University, Nanning, China, and was conducted in accordance with National Institutes of Health guidelines for ethical animal research. Animal preparation Sprague-Dawley rats of both sexes, weighing g, were fasted overnight with the exception of free access to water. The animals were anesthetized by intraperitoneal injection of 1 g/kg urethane, placed in a supine position on a surgical board and the extremities were immobilized. The proximal trachea was surgically exposed in the animals and a 14-gauge cannula was inserted through a tracheostomy, 10 mm caudal to the larynx. Through the right external jugular vein, an 18- gauge polyethylene catheter was advanced through the superior vena cava into the right atrium. The right atrial pressure was measured with reference to the mid-chest with a high-sensitivity pressure transducer. Another 18-gauge polyethylene catheter was advanced from the left carotid artery into the thoracic aorta for the measurement of the aortic pressure. The void space of the catheters was filled with physiological salt solution containing 5 IU/ml of bovine heparin. The core temperature was measured through a rectal temperature probe. Conventional lead II electrocardiograms were recorded using subcutaneous needles. The electrocardiogram (lead II) and aortic and right atrial pressures were continuously recorded on a desktop computer via a four-channel physiological recorder (BL-420 E Bio-systems, Chengdu Technology & Market Co. Ltd., China) for subsequent analyses. The coronary perfusion pressure was calculated as the difference between the minimal diastolic aortic pressure and the simultaneously recorded right atrial pressure Experimental protocol After a min equilibration period following surgery, asphyxial cardiac arrest was induced by clamping of the endotracheal tube. Cardiac arrest was determined by the loss of aortic pulsations and a mean aortic pressure of less than 10 mmhg, together with asystole or pulseless electrical activity (12). The animals were randomized prospectively into a saline group (treated with normal saline, 1 ml intravenously, n ¼ 8), an epinephrine group (treated with epinephrine, 0.04 mg/kg intravenously, n ¼ 8) or a naloxone group (treated with naloxone, 1 mg/kg intravenously, n ¼ 8) in a blind fashion. After 5 min of untreated asphyxial cardiac arrest, CPR was initiated, and each drug was administered at the same time. Drug administration occurred only once at this point in all groups. Ventilation was performed by a volume-controlled small animal ventilator (DH- 150, Medical Instrument of Zhejiang University, Zhejiang, China) with room air at 70 breaths/min and a tidal volume adjusted to 6 ml/kg. This ventilation was consistently maintained in order to imitate the scenario of no oxygen available. Manual chest compression at a rate of 180 compressions/min, with equal compression relaxation duration, was performed by the same investigator, who was blind to the hemodynamic monitor tracings and guided by acoustic audio tones. The compression depth was about 30% of the anteroposterior chest diameter at maximal compression. ROSC was defined as the return of supraventricular rhythm with a mean aortic pressure of 20 mmhg or more for a minimum of 5 min. Failure to restore spontaneous circulation after 10 min resulted in the discontinuation of resuscitation efforts. Post-resuscitation care Hemodynamics and heart rate monitoring were continued for 1 h, and mechanical ventilation was continued for 1 h or less than 1 h after successful resuscitation depending on the condition of the animal s respiration. The appearance of spontaneous breathing was defined as the return of spontaneous breathing with more than 5 breaths/min under mechanical ventilation. If spontaneous breathing presented with 40 breaths/min or more for 5 min or more within 1 h after ROSC, and the blood pressure remained stable or gradually increased, mechanical ventilation was withdrawn. After 1 h of close observation, all catheters were removed with the tracheal tube left intact. The wound was then sutured. The animals were subsequently returned to their cages and allowed to recover spontaneously.

3 Naloxone and epinephrine during CPR The investigators observed the animals until spontaneous breathing stopped. The survival time was defined as the time from ROSC to the cessation of spontaneous breathing. Necropsy was routinely performed after death, including resuscitated and non-resuscitated animals. The thoracic and abdominal organs were examined for gross evidence of traumatic injuries that followed the intraperitoneal injection of anesthesia, airway management, vascular cannulation or precordial compression, and the position of the catheters was documented. Statistical analysis Data were presented as the mean standard deviation for approximately normally distributed variables and, otherwise, as the median (25th and 75th percentiles). One-way analysis of variance (ANOVA) was used to determine the statistical significance between the three groups. For the data after ROSC, Student s t-test was applied to examine the difference between the epinephrine and naloxone groups with regard to blood pressure and heart rate. The Mann Whitney U-test was used to determine the differences in variables not normally distributed between the groups. Fisher s exact test was used for discrete variables, such as ROSC. A two-tailed value of P < 0.05 was considered to be statistically significant. Results Before asphyxia, no significant differences were observed between the three groups with regard to body weight, heart rate, systolic blood pressure, diastolic blood pressure, mean aortic pressure, central venous pressure and body temperature. The time from the initiation of asphyxia to cardiac arrest was min in the saline group, min in the epinephrine group and min in the naloxone group (P ¼ NS between the groups). The time from the initiation of asphyxia to the termination of spontaneous breathing was s in the saline group, 56 8 s in the epinephrine group and 44 4 s in the naloxone group (P ¼ NS between the groups). During the consecutive 5 min of untreated cardiac arrest, all animals presented with pulseless electrical activity and no spontaneous ventricular fibrillation occurred. Cardiac rhythms subsequently resulted in asystole in 18 of the 24 animals before CPR (P ¼ NS between the groups). The rates of ROSC in the epinephrine and naloxone groups were equal and significantly higher than that in the saline group (P ¼ 0.01 and P ¼ 0.01, respectively). The time of ROSC in the epinephrine group was shorter than that in the naloxone group (P ¼ 0.002), as was the survival time in the epinephrine group, but no statistically significant difference was observed (Table 1). There was no significant difference between the epinephrine and naloxone groups with regard to the rate of appearance of spontaneous breathing. The time of appearance of spontaneous breathing and the time of ventilation withdrawal in the epinephrine group were longer than those in the naloxone group, but did not reach statistical significance (Table 2). The saline group data were not compared with those of the other groups because of the low survival rate. The coronary perfusion pressure in the epinephrine group was much higher than that in the saline and naloxone groups. The coronary perfusion pressure in the naloxone group was higher than that in the saline group, but did not reach statistical significance, except at 10 min (Fig. 1). There were no statistically significant differences between the epinephrine and naloxone groups with regard to the mean aortic pressure during 60 min of monitoring after ROSC, except at 5 min (P ¼ 0.001; Fig. 2). The changes in heart rate in both the epinephrine and naloxone groups were similar during 60 min of monitoring after ROSC (Fig. 3). The saline group was excluded because of the low survival rate and, consequently, was not compared with the other groups. Discussion In this study, although the coronary perfusion pressure in the epinephrine group was much higher than that in the naloxone and saline groups, the rates of Table 1 Comparison of restoration of spontaneous circulation (ROSC), time of cardiopulmonary resuscitation (CPR) and survival time between the three groups. Group Rats (n) ROSC, n (%) Time of ROSC (s) Survival time (h) Saline 8 1 (12.5) Epinephrine 8 7 (87.5)* 40 (32, 51) 2 (1, 6) Naloxone 8 7 (87.5)* 58 (55, 65) 4 (1, 26) Time is presented as median (25th, 75th percentiles). Time of ROSC represents the time from CPR to ROSC; survival time represents the time from ROSC to the termination of spontaneous breathing. *P < 0.05 vs. saline group. P < 0.01 vs. naloxone group. 1127

4 M.-H. Chen et al. Table Comparison of the changes in respiration within 60 min after restoration of spontaneous circulation (ROSC) between the three groups (mean SD) Group ROSC (n) Rate of appearance of spontaneous breathing (n) Time of appearance of spontaneous breathing (min) Time of ventilation withdrawal (min) Saline Epinephrine Naloxone MAP (mmhg) Nal gro Epi gro Time of appearance of spontaneous breathing represents the time from ROSC to the appearance of spontaneous breathing Time (min) ROSC in the epinephrine and naloxone groups were equal, and both groups showed significantly higher coronary perfusion pressure than that in the saline group. Therefore, the data suggest that naloxone and epinephrine are equally effective for CPR in a rat asphyxia model. The satisfactory resuscitation results demonstrated after the administration of naloxone in cardiorespiratory arrest (13) have stimulated further investigation into the efficacy of naloxone in CPR. In this study, the mechanism by which naloxone was as effective as epinephrine during CPR after asphyxial arrest remains unclear. Many reports have indicated that hypoxia may cause cerebrospinal fluid or plasma Coronary perfusion pressure (mmhg) Epi gro Nal gro Sal gro Time (min) Fig. 1. Changes in coronary perfusion pressure during the first 10 min of resuscitation after 5 min of untreated cardiac arrest. Variables are expressed as the mean SEM. The coronary perfusion pressure in the epinephrine group (Epi-gro) was much higher than that in the saline group (Sal-gro) from 0.5 to 10 min (P ¼ ). The coronary perfusion pressure in the epinephrine group was much higher than that in the naloxone group (Nal-gro) from 0.5 to 5 min (P ¼ ), but there was no significant difference between the two groups at 10 min (P ¼ 0.413). In addition, there was no significant difference in the coronary perfusion pressure between the naloxone and saline groups, except at 10 min (P ¼ 0.004) Fig. 2. Changes in mean aortic pressure (MAP) during 60 min of monitoring after restoration of spontaneous circulation (ROSC). There were no significant differences between the epinephrine (Epi-gro) and naloxone (Nal-gro) groups with regard to MAP during 60 min of monitoring after ROSC, except at 5 min (P ¼ 0.001). levels of b-endorphin-like immunoreactivity to increase. This is associated with respiratory difficulties, inhibits vasoconstriction and plays a role in the pathophysiology of prolonged infant apnea (14 17). It has been postulated that asphyxial cardiac arrest may cause a similar reaction in the body, and lead to the release of endogenous opiates that are partially responsible for respiratory, cardiac and peripheral vascular depression. In addition, the response to epinephrine may be attenuated by these substances, but this effect can be reversed by naloxone. An alternative hypothesis is the involvement of catecholamines and the autonomic nervous system. Naloxone can quickly stimulate catecholamine release (18 20), increase sympathetic nerve activity (21) and significantly elevate heart rate and blood HR (beats/min) Time (min) Nal gro Epi gro Fig. 3. Changes in heart rate (HR) during 60 min of monitoring after restoration of spontaneous circulation. Epi-gro, epinephrine group; Nal-gro, naloxone group.

5 Naloxone and epinephrine during CPR pressure (22, 23). This could potentially improve the survival rate in the asphyxial rat model compared with the control group. Naloxone may induce hypertension, pulmonary edema, atrial and ventricular arrhythmias, or cardiac arrest in certain patients. These adverse effects may be a result of extreme sympathetic nervous system activity (24) and an unexpected catecholamine surge. The administration of too much naloxone, or administering it too quickly, can easily precipitate these adverse effects. However, in the case of cardiac arrest and CPR, it is hypothesized that these adverse effects may be beneficial. Asphyxial cardiac arrest can be viewed simply as the ultimate respiratory and cardiovascular suppression state. The higher sympathetic nervous system activity and the higher concentration of plasma catecholamines may help to return spontaneous circulation. The administration of a large bolus of naloxone may result in a reaction consistent with the administration of epinephrine, which may be a possible explanation of why naloxone alone increased the resuscitation rate in the asphyxial rat model. The most serious side-effect of epinephrine is to increase myocardial oxygen consumption during ventricular fibrillation. It may also cause myocardial dysfunction in the post-resuscitation phase, probably as a result of its b-agonistic effect. Two different types of myocardial dysfunction have been identified. Mechanical dysfunction is characterized by decreased systolic and diastolic function. Electrical dysfunction is characterized by potentially fatal ectopic ventricular rhythms (25). The severity of both mechanical and electrical dysfunction increase with prolonged duration of cardiac arrest, increased power of electrical defibrillation shock and the administration of [b]-adrenergic agonists (especially epinephrine) (26). As naloxone produces the effect of anti-arrhythmia (27, 28) and ameliorates cardiac function (29, 30), it may be a beneficial adjunct to improve post-resuscitation myocardial dysfunction. In this study, however, because no adverse effects of epinephrine were observed, the theoretically beneficial effects of naloxone during CPR were not documented. There was no significant difference between the epinephrine and naloxone groups with regard to the rate of appearance of spontaneous breathing, the time of appearance of spontaneous breathing and the time of ventilation withdrawal. Therefore, the changes in respiration after ROSC in both groups were not significantly different in this study. Some conflicting reports on the action of naloxone should be noted. For example, naloxone has been reported not to affect the hemodynamics after ROSC (31), not to influence catecholamine levels (32) and to have no effect on survival in opiate overdose patients in cardiopulmonary arrest (33). The reason for this may be species differences or different animal models. In an asphyxial cardiac arrest rat model, numerous resuscitation-related variables appeared to be different between Sprague-Dawley rats and Wistar rats (12). Therefore, the results of animal experiments cannot be directly extrapolated immediately to clinical settings. In conclusion, the administration of naloxone or epinephrine alone may increase the resuscitation rate, and both drugs are equally effective and better than placebo for CPR in a rat asphyxia model. The mechanism by which naloxone produces its efficacy in this situation remains unclear, and further experimentation will be required. Acknowledgements This study was supported by the Guangxi Natural Science Foundation of China (No ). The authors express their gratitude to the staff of the Department of Physiology for excellent technical help, professional input and advice. References 1. 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