Combination of cardiac pacing and epinephrine

does not always improve outcome of cardiopulmonary resuscitation^B

Meng-Hua Chen MD^a,*, Tang-Wei Liu MD^a, Zhi-Yu Zeng MD^a, Lu Xie DPharm^b,

Feng-Qing Song MD^a, Tao He MD^a, Shu-Rong Mo MD^b

^aInstitute of Cardiovascular Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China

^bDepartment of Physiology, School of Pre-Clinical Sciences, Guangxi Medical University, Nanning 530027, China

Received 13 November 2006; revised 27 January 2007; accepted 8 March 2007

Abstract We hypothesized that the combination of cardiac pacing and epinephrine would yield a better efficacy for cardiopulmonary resuscitation (CPR) and the combination of 2 therapies at different opportunity would achieve the same results of CPR.

Cardiac arrest was induced by clamping the tracheal tubes in 60 Sprague-Dawley rats. At 10 minutes of asphyxia, the animals were prospectively randomized into 5 groups (n = 12/group), and received saline (Sal-gro, 1 mL, intravenous [IV]), epinephrine (Epi-gro, 0.4 mg/kg, IV), pacing (Pac-gro, trans- esophageal cardiac pacing combined with saline 1 mL, IV), pacing + epinephrine group 1 (PE-gro1, transesophageal cardiac pacing combined with epinephrine 0.4 mg/kg, IV), or pacing + epinephrine group 2 (PE-gro2, transesophageal cardiac pacing combined with epinephrine 0.4 mg/kg, IV, 4 minutes after the transesophageal cardiac pacing initiating and failing to resuscitate the animals), followed by initiation of CPR.

restoration of spontaneous circulation in Sal-gro was lower than in Epi-gro, Pac-gro, PE-gro1, and PE- gro2 (16.67% vs 66.67%, 66.67%, 100%, and 100%; P b .05 or P b .001, respectively). The proportions of withdrawing ventilator and 2-hour survival proportions in Pac-gro and PE-gro2 were higher than in Epi-gro and PE-gro1 (8/8, 10/12 vs 1/8, 2/12, respectively, P b .01, and 7/8, 8/12 vs 1/8, 2/12, respectively, P b .05 or P b .01). Mean survival time in Pac-gro and PE-gro2 were longer than in Epi-gro and PE-gro1 ( P b .05 or P b .01).

Therefore, the combination of 2 therapies does not always improve outcome of CPR. It is obvious that the combination of transesophageal cardiac pacing with delayed administration of epinephrine yields a better outcome compared to the combination of 2 therapies at the same time during CPR in a rat asphyxia cardiac arrest model.

D 2007

^B This study received support from Guangxi Department of Education and Guangxi Natural Science Foundation of China (no. 0135038).

* Corresponding author. Tel.: +86 771 5356536; fax: +86 771 5350031.

E-mail address: [email protected] (M.-H. Chen).

0735-6757/$ - see front matter D 2007 doi:10.1016/j.ajem.2007.03.013

Introduction

Although epinephrine has been the preferred adrenergic amine for the treatment of human cardiac arrest for more than 40 years, its effectiveness is not optimized. The search for better therapies in CA and optimal cardiopulmo- nary resuscitation (CPR) strategies remains a big challenge. The use of external pacing as an alternative for CPR was first described by Zoll [1] in 1952. This technique increased the chances of reviving patients with acute and chronic complete heart block as well as some cases of bventricular standstill Q [2,3].

On one hand, transcutaneous cardiac pacing produces the same Hemodynamic effectiveness as conventional transvenous pacing [4], offers many advantages over temporary transvenous pacing, avoids some common complications of the invasive transvenous technique [5,6], and achieves many positive results during CPR [7-11]. On the other hand, transcutaneous cardiac pacing also shows several disadvantages: pain associated with stimulation of skin and skeletal muscle, electrically induced myocardial damage, and difficulty in recognition of Cardiac responses [12-14]. Furthermore, many nonef- fective results of cardiac pacing during CPR have been reported [15-18].

These conflicting reports provoked suspicions over the effect of cardiac pacing in CPR. The enthusiasm for the use of cardiac pacing in CPR has rapidly decreased and literature pertinent to the subject has nearly disappeared recently. An advantage of using animal models in CPR research is the ability to control differing variables that may be impossible to standardize in clinical trials. Trans- esophageal cardiac pacing is a form of noninvasive cardiac pacing [19] that has fewer side effects and higher pacing efficacy compared to transcutaneous cardiac pacing. We were prompted to investigate the effectiveness of the technique in an animal model of cardiac arrest. In our previous study, we found that transesophageal cardiac pacing could increase the rate of survival in asphyxia rat model compared to the control group [20]. We also observed that transesophageal cardiac pacing had better effectiveness than epinephrine during CPR under the same experimental condition [21]. However, whether the combi- nation of transesophageal cardiac pacing and epinephrine was further beneficial to the outcome of CPR and whether the different time points of the combination of 2 therapies previously described influences the outcome of CPR remained unclear. The purpose of this study, therefore, was to evaluate the efficacy of combination of trans- esophageal cardiac pacing and epinephrine, and determine the optimum timing of the combination of 2 therapies during CPR in a 10-minute asphyxia rat model. The hypothesis was that the combination of the 2 therapies would yield better efficacy for CPR and the different time points of combination of the both would not influence the outcome of CPR.

Material and methods

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

Animal preparation

Sprague-Dawley rats of both sexes, weighing 180 to 220 g, were fasted overnight but were allowed free access to water. The animals were anesthetized via an intraperitoneal injection of 1 g/kg urethane and placed in a supine position on a surgical board, and then their 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. The cannula was advanced for a distance of 1 cm into the trachea and secured by ligature, which was also anchored to the skin.

Through the right external jugular vein, an 18-gauge polyethylene catheter (Intramedic PE 50; Becton Dickinson, Sparks, MD) 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 18-gauge polyethylene cathe- ter was advanced from the left carotid artery into the thoracic aorta for measurement of aortic pressure with the high sensitivity pressure transducer (YH-4, Chengdu Tech- nology & Market Co Ltd, Chengdu, China). The void space of the catheters was filled with a physiologic salt solution containing 5 IU/mL of bovine heparin. The core temperature was measured via a rectal temperature probe. Conventional lead II Electrocardiograms were recorded with subcutaneous needles.

The ECG (lead II), aortic, and right atrial pressures were continuously recorded on a desktop computer via 4-channel physiologic recorder (BL-420 E Bio-systems, Chengdu Technology & Market Co Ltd) for subsequent analyses. The coronary perfusion pressure was calculated as the difference between the diastolic aortic and right atrial pressures measured simultaneously [22].

Experimental protocol

After a 10- to 15-minute postsurgery equilibration period, 10 minutes of asphyxial CA was induced by clamping the tracheal tubes. Cardiac arrest was determined by loss of aortic pulsations and mean aortic pressure (MAP) of less than 10 mm Hg together with asystole or pulseless electrical activity [23]. Before CPR, 60 Sprague-Dawley rats of both sexes were randomized into 5 groups (n = 12/group): Sal-gro (saline group), treated with normal saline (1 mL, IV); Epi- gro (epinephrine group), treated with epinephrine (0.4 mg/ kg, IV); Pac-gro (pacing group), treated with transesopha- geal cardiac pacing combined with normal saline (1 mL, IV) at the same time; PE-gro1 (pacing + epinephrine group 1, drug was used at the same time), treated with trans-

esophageal cardiac pacing combined with administration of epinephrine (0.4 mg/kg, IV) at the same time; PE-gro2 (pacing + epinephrine group 2, drug was used and delayed 4 minutes if necessary) treated with transesophageal cardiac pacing combined with delayed administration of epinephrine (0.4 mg/kg, IV) 4 minutes after the transesophageal cardiac pacing was initiated and failed to restore spontaneous circulation (if the animal was successfully resuscitated within 4 minutes, epinephrine was not be administered).

After 10 minutes of asphyxia, CPR was applied. Each drug was administered and transesophageal cardiac pacing was initiated in Pac-gro, PE-gro1, and PE-gro2 at the same time. The drug was administered only once at this point in all groups, except for PE-gro2 (epinephrine was delayed or not administered in PE-gro2, depending on the resuscitation postresuscitation care“>of the animal). Ventilation was performed by a volume- controlled small animal ventilator (DH-150, the medical instrument of Zhejiang University, Hangzhou, China), with room air at 70 breaths per minute, and tidal volume was adjusted to 6 mL/kg. Ventilation was maintained until spontaneous breathing started, or until 1 hour after restoration of spontaneous circulation . This imitat- ed the scenario of no available oxygen in some circum- stances. Manual chest compression at a rate of 180 compressions per minute with equal compression-relaxation duration was always performed by the same investigator. This investigator was excluded from the hemodynamic monitor tracings and guided only by acoustical audio tones emitted from the cardiac electrophysiologic stimulus appa- ratus, which would ensure that the chest Compression quality was consistent for all animals. Compression depth was approximately 30% the anterioposterior chest diameter at maximal compression. Restoration of spontaneous circulation was defined as an unassisted pulse (ECG showed the return of supraventricular rhythm) with a mean arterial pressure of 20 mm Hg or higher for 5 min or more [23].

Failure to restore spontaneous circulation resulted in discontinuation of resuscitation efforts after 10 minutes.

Transesophageal cardiac pacing protocol

A 5F pacing catheter with two 1-mm ring electrodes (interelectrode distance, 5 mm) was inserted orally into the esophagus of animals in 5 groups before CPR at a depth of about 7 cm. The pacing catheter was connected to a cardiac electrophysiologic stimulus apparatus (DF-5A, Suzhou DongFang Electric Apparatus Factory, Suzhou, China). In addition to transmitting electric stimuli, the stimulus apparatus can emit acoustical audio tones at a frequency of 180 per minute to guide the investigator in performing consistent chest compressions for the rats in all groups. Only animals in the pacing group, pacing + epinephrine group 1 and pacing + epinephrine group 2 received pacing stimuli (in other words, saline and epinephrine groups had only a sham catheter placed for pacing). Cardiac pacing was performed using 2 poles on the pacing catheter (stimulus duration width, 10 milliseconds and 25 V). Stimulation at a rate of 180 stimuli per minutes was performed continuously in early CPR. With the ROSC of the rats, the pacing frequency was altered to a rate of 20-30/min higher than the rate of intrinsic rhythm of the rats correspondingly and the left atrium was stimulated intermittently (20 seconds for stimulation and 10 seconds for pause alternately) for 30 minutes so as to quicken the heart rate (HR) and improve the cardiac output of the resuscitated animal.

Postresuscitation care

Hemodynamics and HR monitoring were continued for 1 hour. Mechanical ventilation was continued for 1 hour or less after a successful resuscitation depending on the condition of the animal’s respiration. The appearance of spontaneous breathing (AOSB)-defined as the return of spontaneous

Table 1 Variables at baseline
Item Statistic	Sal-gro (n = 12)	Epi-gro (n = 12)	Pac-gro (n = 12)	PE-gro1 (n = 12)	PE-gro1 (n = 12)
Weight (g) Mean (SD)	195.00 (12.43)	195.00 (9.05)	189.17 (12.4)	195.17 (12.37)	195.83 (12.4)
95% CI	187.96 to 202.04	189.89 to 200.12	182.15 to 196.19	188.17 to 202.17	188.81 to 202.85
HR (beats/min) Mean (SD)	412.67 (26.86)	417.67 (43.89)	386.08 (31.53)	387.25 (36.88)	394.42 (43.03)
95% CI	397.48 to 427.86	392.84 to 442.50	368.24 to 403.92	366.38 to 408.12	370.08 to 418.76
Systolic blood Mean (SD)	142.92 (8.31)	137.33 (13.01)	137.33 (13.61)	138.25 (15.07)	136.25 (13.15)
pressure 95% CI	138.22 to 147.62	129.96 to 144.70	129.62 to 145.03	129.72 to 146.78	128.80 to 143.70
(mm Hg)
Diastolic blood Mean (SD)	93.25 (11.95)	87.5 (8.85)	86.83 (16.21)	99.08 (17.48)	85.25 (11.73)
pressure 95% CI	86.49 to 100.01	82.50 to 92.50	77.66 to 96.00	89.18 to 108.98	78.61 to 91.89
(mm Hg)
MAP (mm Hg) Mean (SD)	114.83 (10.93)	108.25 (8.96)	108.58 (15.93)	117.67 (15.39)	104.67 (13.05)
95% CI	108.75 to 120.91	103.17 to 113.33	99.56 to 117.60	108.97 to 126.37	97.28 to 112.06
Center venous Mean (SD)	-3.24 (1.19)	-0.56 (1.08)	-0.56 (1.51)	-3.24 (1.19)	-3.52 (1.56)
pressure 95% CI	-3.91 to -2.56	-1.12 to 0.09	-1.42 to 0.29	-3.91 to -2.56	-4.40 to -2.63
(mm Hg) There were no differences in any variables at baseline between the groups.

Fig. 1 Changes in CPP during the earliest 10 minutes of resuscitation after 10 minutes of untreated asphyxia. Variables are presented as mean F SEM. Coronary perfusion pressure in PE- gro1, Pac-gro, PE-gro2, and Epi-gro was higher than that in Sal- gro ( P b .05 or P b .01, respectively). The lowest CPP in Sal-gro resulted in the lowest proportion of ROSC during the first 10 minutes of the resuscitation phase.

breathing with more than 5 breaths per minute under the circumstances of mechanical ventilation-in the animals was closely observed and immediately recorded. If spontaneous breathing presented with at least 40 breaths per minute for 5 minutes or more within 1 hour after ROSC, and blood pressure remained stable or increased gradually, mechanical ventilation could be withdrawn. After 1 hour of intensified observation, all catheters were removed with tracheal tube left in place. The wound was sutured. The animals were then returned to their cages and allowed to recover without further interventions. The investigators observed the animals until their spontaneous breathing stopped. The survival time was defined as the time from ROSC to the cessation of spontaneous breathing. (But under the circumstances of mechanical ventilation, survival time was defined as the time from ROSC to the time that MAP decreases to b20 mm Hg.) Necropsy was routinely performed after the death of animals, both resuscitated and unresuscitated ones. Thoracic and abdominal organs were examined for gross evidence of traumatic injures that associated with surgery and CPR

procedure. The position of catheters was documented.

Table 2 Comparison of ROSC and time from CPR to ROSC among 5 groups

Time from CPR to ROSC was presented as median (25th, 75th percentiles).

* P b .05 vs Sal-gro.

** P b .001 vs Sal-gro.

^y P b .05 vs, PE-gro2.

Statistical analysis

Data were presented as mean F SD (95% confidence interval [CI]) for approximately normally distributed vari- ables and otherwise as median (25th, 75th percentiles). One- way analysis of variance was used to determine the statistical significance among the 5 groups. Mann-Whitney U test was used to determine differences for variables that were not normally distributed between groups. Using Fisher exact test, discrete variables such as ROSC, survival proportion, and proportions of ventilator withdrawal were tested. A 2-tailed value of P b .05 was considered statistically significant.

Results

Before asphyxia, no significant differences were ob- served among the 5 groups in regard to body weight, HR, systolic blood pressure, diastolic blood pressure, MAP, center venous pressure, and body temperature ( P = NS between groups, Table 1). There was no significant difference in the time from initiation of asphyxia to CA among the 5 groups (ranging between 4 and 5 minutes in all groups; P = NS between groups). Time from initiation of asphyxia to termination of spontaneous breathing was also not significantly different among the 5 groups (ranging between 0.8 and 1.1 minutes in all groups; P = NS between groups). Pulseless electrical activity occurred in all animals during the subsequent 5 to 6 minutes of nonintervention CA interval. No ventricular fibrillation was observed until CPR was started. Cardiac rhythms in 52 of 60 animals subsequently resulted in asystole, whereas 8 of 60 animals remained in pulseless electrical activity until initiation of CPR ( P = NS between groups).

During CPR, ventricular tachycardia and ventricular fibrillation repeatedly occurred only in 4 animals of PE- gro1 and terminated spontaneously without Electric shock. Coronary perfusion pressure in Epi-gro, Pac-gro, PE-gro1, and PE-gro2 were significantly higher than in Sal-gro ( P b

.05 or P b .01, respectively) during the first 10 minutes of the resuscitated phase (Fig. 1).

The proportion of ROSC in Sal-gro was significantly lower than those in Epi-gro, Pac-gro, PE-gro1, and PE-gro2

Groups	Rats	Rats (%) of ROSC	Time from CPR to ROSC (s)
Sal-gro	12	2 (16.67)	142 (60, 153)
Epi-gro	12	8 (66.67)*	47 (33, 119)y
Pac-gro	12	8 (66.67)*	105 (60, 201)
PE-gro1	12	12 (100)**	50 (44, 165)y
PE-gro2	12	12 (100)**	160 (63, 381)

Groups	ROSC (n)	Rats (%) of AOSB	Rats (%) of ventilator withdrawal	Time from CPR to AOSB (min)	Time of ventilator withdrawal (min)
Epi-gro	8	5 (62.5)	1 (12.5)	14 (5) (10.64, 18.36)	50
Pac-gro	8	8 (100)*	8 (100)**	14 (6) (10.00, 18.50)	33 (12) (24.65, 41.10)
PE-gro1	12	6 (50.0)	2 (16.67)	21 (7) (15.53, 26.47)	50 (7) (52.94, 61.34)
PE-gro2	12	10 (83.3)	10 (83.3)**	20 (12) (12.57, 26.83)	41 (11) (35.96, 52.22)

( P = .036, P = .036, P = .000, and P = .000, respectively), but no differences were noted among Epi-gro, Pac-gro, PE- gro1, and PE-gro2. Time from CPR to ROSC in PE-gro2 was longer than those in Epi-gro ( P = .02) and in PE-gro1 ( P = .014), but no differences were noted among Sal-gro, Epi-gro, Pac-gro, and Pac-gro1 (Table 2).

Table 3 Comparison of changes in respiration within 60 minutes after ROSC among 4 groups

Data are presented as mean F SD (95% CI) in time from CPR to AOSB and time of ventilator withdrawal. Time from CPR to AOSB was not different among the 4 groups. Time of ventilator withdrawal was not different among Pac-gro, PE-gro1, and PE-gro2. Sal-gro data were excluded because of the low survival proportion.

* P b .05 vs PE-gro1.

** P b .01 vs Epi-gro and vs PE-gro1.

Only 4 of 12 animals in PE-gro2 needed administration of epinephrine in addition to transesophageal cardiac pacing to restore spontaneous circulation. Appearance of sponta- neous breathing was observed in Epi-gro, Pac-gro, PE-gro1, and PE-gro2, but the proportions of ventilator withdrawal within 60 minutes after resuscitation in Pac-gro and PE-gro2 were much higher than those in Epi-gro and PE-gro1 ( P =

.001 and P = .005, respectively) (Table 3).

The 1-hour survival proportion in PE-gro1 was signifi- cantly lower than in Epi-gro, Pac-gro, and PE-gro2 ( P b .05 or P b .01, respectively). The 2-hour survival proportions in Pac-gro and PE-gro2 were significantly higher than in Epi- gro and PE-gro1 ( P b .05 or P b .01, respectively). Mean survival time was longer in Pac-gro and PE-gro2 than in Epi-gro and PE-gro1 after resuscitation ( P b .05 or P b .01, respectively) (Table 4).

Mean aortic pressure in Pac-gro remained stable, in contrast to Epi-gro and PE-gro1, which indicated a falling tendency during the 60-minute monitoring phase after CPR. Changes in MAP in PE-gro2 shared the similarity between Epi-gro and Pac-gro (Fig. 2).

Among 4 groups, HR in PE-gro1 was highest at 5 and 10 minutes during the 60-minute monitoring phase after CPR. Heart rate in Pac-gro was higher than in Epi-gro and remained stable; alternately, HR in the Epi-gro and PE-gro1

Table 4 Comparison of survival time after resuscitation among the 4 groups

Mean survival time was presented as median (25th, 75th percentiles).

* P b .05 vs PE-gro1.

** P b .01 vs PE-gro1.

^y P b .05 vs Epi-gro.

showed a decreasing tendency 15 minutes later. Changes in HR in PE-gro2 shared the similarity between Epi-gro and Pac-gro (Fig. 3).

Necropsy results confirmed the correct placement of catheters in all animals. No adverse side effects of invasive procedures or other traumatic injures were documented.

Discussion

In the present study, transesophageal cardiac pacing combined with delayed administration of epinephrine (if necessary) could improve the outcome of CPR in the rat asphyxia model. Although transesophageal cardiac pacing combined with administration of epinephrine at the same time during CPR could increase the proportion of ROSC, it also resulted in a shorter survival time. These data show that the combination of transesophageal cardiac pacing and epinephrine does not always produce beneficial effects, and different opportunities of combining 2 therapies may yield different outcomes of CPR.

Because high doses of epinephrine enhanced myocardial perfusion pressure and Myocardial blood flow, leading to improved proportions of ROSC [24,25] without increased direct complications in the CA population, compared to standard dose epinephrine [26], we chose a relatively high dose of epinephrine in the present study. Although no difference was noted in the proportion of ROSC between Epi-gro and Pac-gro, shorter survival time and worse respiration situation after ROSC was observed in the Epi- gro than in the Pac-gro. It was suggested that transesophageal

Groups	ROSC (n)	1 h survival, n (%)	2 h survival, n (%)	Longest survival time (h)	Median survival time (h)
Epi-gro	8	8 (100)*	1 (12.5)	9	1 (1, 1)
Pac-gro	8	8 (100)*	7 (87.5)**,y	24	3.5 (2, 18.3)**,y
PE-gro1	12	5 (41.7)	2 (16.7)	2	1 (0.8, 1)
PE-gro2	12	12 (100)**	8 (66.7)*,y	22	3 (1, 5)**

Fig. 2 Changes in MAP during the 60-minute monitoring phase after CPR (mean F SEM). *PE-gro1: n = 12 (before 35 minutes), n = 11 (35-45 minutes), n = 9 (50 minutes), n = 8 (55 minutes), n = 7 (60 minutes). Mean aortic pressure in Epi-gro and PE-gro1 was significantly higher than in Pac-gro and PE-gro2 at 5 and

10 minutes during the 60-minute monitoring phase after CPR ( P b .05 or b .01, respectively). Thirty-five minutes later, MAP in PE-gro1 was significantly lower than in Epi-gro, PE-gro2, and Pac- gro ( P b .05 or P b .01, respectively). In Pac-gro, MAP remained stable 15 minutes later. In PE-gro1 and Epi-gro, in contrast, MAP showed a rapidly falling tendency and had much lower value from 25 and 35 minutes, respectively, to 60 minutes, compared with that at 15 minutes ( P b .05 or P b .01, respectively). Changes in MAP in PE-gro2 shared the similarity between Epi-gro and Pac-gro. Sal- gro data were excluded because of the low survival proportion.

cardiac pacing alone offers a better outcome of CPR than epinephrine alone in the rat asphyxia model. The reason for this phenomenon may be related to the beneficial effect of transesophageal cardiac pacing [20,21] and the adverse side effect of epinephrine [27-29] during and after CPR.

Considering that transesophageal cardiac pacing may possibly influence the neurohumoral regulation of the animal and cause endogenic vasoconstrictive substances to be released, which may result in contractive reaction of systemic vessel, increase in CPP, and improvement in resuscitation [21], it is very likely that the combination of transesophageal cardiac pacing with epinephrine enhanced CPP during CPR and improved the proportion of ROSC. This assumption was validated in the present study. The proportion of ROSC in PE-gro1 and PE-gro2 was 100%.

Ventricular fibrillation occurred only in animals of PE- gro1 during CPR in the present study. The proportion of AOSB and the proportion of ventilator withdrawal after ROSC were also lower in PE-gro1. Furthermore, survival time was shortest in PE-gro1 among groups. These data indicated that the combination of 2 therapies at the same time during CPR did not yield a better outcome in rat asphyxia model. The familiar side effects of epinephrine include increasing myocardial oxygen consumption during ventricular fibrillation [27], inducing ventricular arrhyth-

mias [28], and causing myocardial dysfunction in the postresuscitation phase [29], probably due to its b-receptor agonistic effect. Although the combination of the 2 therapies at the same time enhances the efficacy of increasing CPP and proportion of ROSC, the adverse effect of epinephrine was strengthened synchronously as well. Consequently, the situation of postresuscitation in the animals of PE-gro1 was significantly worsened in compar- ison to that in Epi-gro and Pac-gro.

By contrast, transesophageal cardiac pacing combined with delayed administration of epinephrine could yield a better outcome of CPR. The decision to apply a delayed administration of epinephrine was based on the following: according to our preliminary study, nearly all animals treated with cardiac pacing alone returned to spontaneous circulation within 4 minutes after CPR, and no animal was resuscitated beyond 4 minutes by transesophageal cardiac pacing alone. We hypothesized that a delayed administration of epinephrine might increase the possibility of ROSC and reduce the adverse effects of epinephrine. That assumption was validated by the present study as well. The resuscitation proportion in PE-gro2 increased to 100% from 66.67% owing to administration of epinephrine 4 minutes after transesophageal cardiac pacing was initiated and there was a failure to resuscitate the animal. In PE-gro2, only 8 of 12 animals were successfully resuscitated by transesophageal cardiac pacing alone, whereas 4 of 12 animals needed

Fig. 3 Changes in HR during the 60-minute monitoring phase after CPR (mean F SEM). *PE-gro1: n = 12 (before 35 minutes), n = 11 (35-45 minutes), n = 9 (50 minutes), n = 8 (55 minutes), n = 7 (60 minutes). Heart rate in PE-gro1 was significantly higher than in Epi-gro, Pac-gro, and PE-gro at 5 and 10 minutes during the 60- minute monitoring phase after CPR ( P b .05 or P b .01, respectively). However, at 15 minutes and beyond, HR in Pac- gro was higher than in Epi-gro ( P b .05) and remained stable. In contrast, HR in Epi-gro and PE-gro1 showed a falling tendency, and a lower HR was noted from 30 to 60 minutes compared with that at 15 minutes ( P b .05 or P b .01, respectively). Changes in HR in PE-gro2 shared the similarity between Epi-gro and Pac-gro. Sal-gro data were excluded because of the low survival proportion.

administration of epinephrine in addition to cardiac pacing to return spontaneous circulation. That is why the time from CPR to ROSC in PE-gro2 was longer than that in Epi-gro, and why the Resuscitated animals in the PE-gro2 shared similar characteristics between Epi-gro and Pac-gro in regard to changes in respiratory efficiency, survival time, MAP, and HR after ROSC.

There have been considerable professional debate on the effect of cardiac pacing during CPR, and many clinical investigations have differed in their conclusion in this regard [7-11,15-18]. Unfortunately, little attention has been paid to the optimum timing of cardiac pacing combined with epinephrine during CPR in the clinical settings. This may be 1 of the reasons why there are so many discrepancies about the effect of cardiac pacing on the outcome of CPR in clinical investigations. Consequently, our findings may provide some implications for the improvement of applica- tion of cardiac pacing and epinephrine during CPR in the clinical setting. There is no doubt that choosing a well-timed occasion for a combination of cardiac pacing with epineph- rine is essential to increase the efficacy of cardiac pacing and avoid the disadvantages of 2 therapies during CPR.

We did not stop the pacing when ROSC was attained, because we thought that continuing transesophageal cardiac pacing for 20 to 30 minutes after ROSC might help to quicken HR or induce increase in HR in the resuscitated animals. White et al [30] reported that the use of external pacing increased the proportion of pulseless idioventricular rhythm and profound bradycardias even without evidence of electrical capture. The rate gradually slowed again after discontinuation of pacing, and increased with reinstitution of pacing. This always occurred in the absence of any sign of electrical capture and was not temporally related to the administration of medications or to the changes in CPR. It is possible that external electrical stimulation of the heart, even in the absence of electrical capture, can induce myocardium to become more responsive to exogenous catecholamines. These authors believed that the application of rhythmic electrical stimulation in the area of the thoracic ganglia could produce sympathetic stimulation of the cardiac plexus. In the present study, cardiac output was not measured because of the difficulty in the procedure of advancing the catheter to the left ventricular cavity without damnification of the heart during CPR. Theoretically speaking, a slightly faster HR could enhance the cardiac output, improve perfusion pressure of vital organs, and rectify metabolic turbulence of the animals. Some limitations should be noted in the present study.

First, the Asphyxial cardiac arrest rat model is an unusual model. Only a few of incidences of cardiac arrest are caused by asphyxia. Therefore, our results would not apply to most cardiac arrest victims.

Second, administration of high dose of epinephrine in this study was contradictive with some of the recent findings that high-dose epinephrine resulted in higher mortality immediately after resuscitation and did not improve survival time. It is possible that lung oxygen transfer was reduced as

a consequence of shunt caused by high-dose epinephrine

[29] in this experiment, and this would influence survival and weaning time in the Epi-gro and PE-gro1. Perhaps these are also the reasons why Epi-gro and PE-grop1 were associated with worse outcome when compared to Pac-gro and PE-gro2. However, the optimum dose of epinephrine during CPR in rat asphyxia model remains to be established. Third, there were no parameters to evaluate postre- suscitation myocardial function. There were no blood gas results, and not even end tidal carbon dioxide (ETCO₂) monitoring to support the benefits of transesophageal cardiac pacing on respiration. Lack of presentation of key data might

result in less objective conclusions.

Finally, most animals in PE-gro2 were treated only by cardiac pacing without administration of epinephrine. Therefore, PE-gro2 actually included some cardiac pacing alone data, which make the data a little confusing. However, this type of grouping was designed to clarify whether delayed administration of epinephrine could increase survival proportion when transesophageal cardiac pacing alone failed to restore spontaneous circulation, and deter- mine the optimum timing of the combination of trans- esophageal cardiac pacing with epinephrine during CPR. Furthermore, no better grouping was considered eligible for this research design. Consequently, notwithstanding its limitation, this study does suggest that different opportuni- ties of combination of cardiac pacing with epinephrine may influence the outcome of CPR.

Conclusion

Although the different opportunities of combination of transesophageal cardiac pacing with epinephrine make no difference in regard to the increase in the proportion of ROSC, changes in respiration, MAP, HR, and survival time after ROSC vary significantly between groups. Therefore, we conclude that combination of cardiac pacing and epinephrine does not always improve outcome of CPR. It is obvious that the combination of transesophageal cardiac pacing with delayed administration of epinephrine yields a better outcome when compared with the combination of 2 therapies at the same time during CPR in a rat asphyxia CA model.

Acknowledgments

The authors express their gratitude to the staff of the department of physiology for excellent technical help and constructive criticism.

References

1. Zoll PM. Resuscitation of the heart in ventricular standstill by external electric stimulation. N Eng J Med 1952;247(20):768 - 71.
2. Zoll PM, Linenthal AJ, Norman LR. Treatment of Stokes-Adams disease by external electric stimulation of the heart. Circulation 1954;9(4):482 - 93.
3. Zoll PM, Linenthal AJ, Norman LR, Paul MH, Gibson W. Treatment of the unexpected cardiac arrest by external electric stimulation of the heart. N Eng J Med 1956;254(12):541 - 6.
4. Syverud SA, Hedges JR, Dalsey WC, Gabel M, Thomson DP, Engel PJ. Hemodynamics of transcutaneous cardiac pacing. Am J Emerg Med 1986;4(1):17 - 20.
5. Austin JL, Preis LK, Crampton RS, Beller GA, Martin RP. Analysis of pacemaker malfunction and complications of temporary pacing in the coronary care unit. Am J Cardiol 1982;49(2):301 - 6.
6. Hynes JK, Holmes Jr DR, Harrison CE. Five-year experience with Temporary pacemaker therapy in the coronary care unit. Mayo Clin Proc 1983;58(2):122 - 6.
7. White JD, Brown CG. Immediate transthoracic pacing for cardiac asystole in an emergency department setting. Am J Emerg Med 1985; 3(2):125 - 8.
8. Olson CM, Jastremski MS, Smith RW, Tyndall GJ, Montgomery GF, Daye MC. External cardiac pacing for out-of-hospital bradyasystolic arrest. Am J Emerg Med 1985;3(2):129 - 31.
9. Zoll PM, Zoll RH, Falk RH, Clinton JE, Eitel DR, Antman EM. External noninvasive temporary cardiac pacing: clinical trials. Circulation 1985;71(5):937 - 44.
10. O’Toole KS, Paris PM, Heller MB, Stewart RD. Emergency transcutaneous pacing in the management of patients with bradya- systolic rhythms. J Emerg Med 1987;5(4):267 - 73.
11. Tachakra SS, Jepson E, Beckett MW, Barrie R. Successful transcu- taneous external pacing for asystole following cardiac arrest. Arch Emerg Med 1988;5(3):184 - 5.
12. Falk RH, Zoll PM, Zoll RH. Safety and efficacy of noninvasive cardiac pacing. A preliminary report. N Engl J Med 1983;309(19):1166 - 8.
13. Kicklighter EJ, Syverud SA, Dalsey WC, Hedges JR, Van der el-Kahn JM. Pathological aspects of transcutaneous cardiac pacing. Am J Emerg Med 1985;3(2):108 - 13.
14. Holger JS, Minnigan HJ, Lamon RP, Gornick CC. The utility of ultrasound to determine ventricular capture in external cardiac pacing. Am J Emerg Med 2001;9(2):134 - 6.
15. Dalsey WC, Syverud SA, Hedges JR. Emergency department use of transcutaneous pacing for cardiac arrests. Crit Care Med 1985; 13(5):399 - 401.
16. Knowlton AA, Falk RH. External cardiac pacing during in-hospital cardiac arrest. Am J Cardiol 1986;57(15):1295 - 8.
17. Quan L, Graves JR, Kinder DR, Horan S, Cummins RO. Transcu- taneous cardiac pacing in the treatment of out-of-hospital Pediatric cardiac arrests. Ann Emerg Med 1992;21(8):905 - 9.
18. Cummins RO, Graves JR, Larsen MP, Hallstrom AP, Hearne TR, Ciliberti J, et al. Out-of-hospital transcutaneous pacing by emergency medical technicians in patients with asystolic cardiac arrest. N Engl J Med 1993;328(19):1377 - 82.
19. Hartley JM. transoesophageal cardiac pacing. Anaesthesia 1982;37(2):192 - 4.
20. Song FQ, Xie L, Chen MH. Transoesophageal cardiac pacing is effective for cardiopulmonary resuscitation in a rat of asphyxial model. Resuscitation 2006;69(2):263 - 8.
21. Chen MH, Liu TW, Xie L, Song FQ, He T. A comparison of transoesophageal cardiac pacing and epinephrine for cardiopulmonary resuscitation. Am J Emerg Med 2006;24(5):545 - 52.
22. Chen MH, Xie L, Liu TW, Song FQ, He T. Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model. Acta Anaesthesiol Scand 2006;50(9):1125 - 30.
23. Chen MH, Liu TW, Xie L, Song FQ, He T. Does naloxone alone increase resuscitation proportion during cardiopulmonary resuscitation in a rat asphyxia model? Am J Emerg Med 2006; 24(5):567 - 72.
24. Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton TJ, et al. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA 1991;265(9):1139 - 44.
25. Chase PB, Kern KB, Sanders AB, Otto CW, Ewy GA. Effects of graded doses of epinephrine on both noninvasive and in- vasive measures of myocardial perfusion and blood flow during cardiopulmonary resuscitation. Crit Care Med 1993;21(3): 413 - 9.
26. Callaham M, Barton CW, Kayser S. potential complications of high- dose epinephrine therapy in patients resuscitated from cardiac arrest. JAMA 1991;265(9):1117 - 22.
27. Klouche K, Weil MH, Tang W, Povoas H, Kamohara T, Bisera J. A selective alpha(2)-adrenergic agonist for Cardiac resuscitation. J Lab Clin Med 2002;140(1):27 - 34.
28. Niemann JT, Haynes KS, Garner D, Rennie III CJ, Jagels G, Stormo

O. Postcountershock pulseless rhythms: response to CPR, artificial cardiac pacing, and adrenergic agonists. Ann Emerg Med 1986;15(2):112 - 20.

1. Tang W, Weil MH, Gazmuri RJ, Sun S, Duggal C, Bisera J. pulmonary ventilation/Perfusion defects induced by epinephrine during cardiopulmonary resuscitation. Circulation 1991;84(5): 2101 - 7.
2. White JM, Nowak RM, Martin GB, Best R, Carden DL, Tomlano- vich MC. Immediate emergency department external cardiac pacing for prehospital bradyasystolic arrest. Ann Emerg Med 1985;14(4): 298 - 302.