Effects of the specific bradycardic agent zatebradine on hemodynamic variables and myocardial blood flow during the early postresuscitation phase in pigs

Resuscitation 42 (1999) 211 – 220 www.elsevier.com/locate/resuscitation

Effects of the specific bradycardic agent zatebradine on hemodynamic variables and myocardial blood flow during the early postresuscitation phase in pigs Hans-Ulrich Strohmenger a,*, Volker Wenzel a, Ralf Eberhard a, Brian D. Guth b, Keith G. Lurie c, Karl H. Lindner a a

Department of Anaesthesia and Intensi6e Care Medicine, Uni6ersity of Innsbruck, Anichstraße 35, A-6020 Innsbruck, Austria b Department of Pharmaceutical Research, Boehringer Ingelheim, Biberach, Germany c Department of Medicine, Cardiac Arrhythmia Center, Uni6ersity of Minnesota, Minneapolis, MN, USA Received 18 January 1999; received in revised form 23 March 1999; accepted 12 July 1999

Abstract Cardiopulmonary resuscitation (CPR) leads to an excessive stimulation of the sympathetic nervous system that may result in tachycardia and malignant arrhythmias in the postresuscitation phase. The attenuation of this reaction by a specific bradycardic agent has not been compared to b-blockade and placebo. After 4 min of ventricular fibrillation, and 3 min of CPR, 21 pigs were randomized to receive 45 mg/kg epinephrine in combination with either a specific bradycardic agent (0.5 mg/kg zatebradine; n=7), or a b-blocker (1 mg/kg esmolol; n=7), or placebo (normal saline; n =7). Two minutes after drug administration, defibrillation was performed to restore spontaneous circulation (ROSC). Hemodynamic variables, left ventricular contractility, right ventricular function, and myocardial blood flow were studied at prearrest, and for 3 h after ROSC. In comparison with esmolol and placebo, zatebradine resulted in a significant reduction in heart rate during the postresuscitation period, and reduced the number of premature ventricular contractions in the first 5 min after ROSC. This reduction in heart rate was associated with a significantly higher right ventricular ejection fraction, stroke volume, and endocardial/epicardial perfusion ratio at 5 min after ROSC. In comparison with placebo, esmolol administration decreased heart rate only moderately, but significantly reduced right ventricular stroke volume and cardiac output at 5 min after ROSC. Although only one dose and only one administration pattern of zatebradine has been investigated, we conclude that zatebradine administration during CPR effectively reduced heart rate without compromising myocardial contractility during the postresuscitation phase in pigs. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Antiarrhythmic drug therapy; Cardiopulmonary resuscitation (CPR); Epinephrine; Esmolol; Postresuscitation phase; Zatebradine

1. Introduction Cardiac arrest and cardiopulmonary resuscitation (CPR) are extreme forms of stress that lead to the highest catecholamine levels ever recorded in either humans or experimental animals [1–3]. Currently, epinephrine is the vasopressor of choice for  This study was supported, in part, by Boehringer Ingelheim, Biberach, Germany. * Corresponding author. Tel.: + 43-512-504-2400; fax: + 43-512504-2450.

the treatment of cardiac arrest [4,5], with its main beneficial effects being attributed to its peripheral a-adrenergic activation. However, extremely high plasma catecholamine levels are necessary in order to achieve adequate peripheral vasoconstriction during CPR [6]. In addition, the b-adrenergic action of epinephrine causes a mismatch in myocardial oxygen demand and supply, therefore aggravating the degree of myocardial ischemia, and increasing the probability of severe hypertension, tachycardia, and/or malignant arrhythmias in the postresuscitation phase [7,8].

0300-9572/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 0 - 9 5 7 2 ( 9 9 ) 0 0 0 9 3 - 3

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In animal studies, blockade of the b-adrenergic effects of epinephrine improved both survival rates and myocardial function in the postresuscitation phase. Therefore, co-administration of a b-adrenergic blocking agent such as esmolol with epinephrine seems to be a logical recommendation [9,10]. However, with increasing duration of untreated cardiac arrest, myocardial function after successful resuscitation is substantially compromised [11]. As such, the significant negative inotropic action of b-blockers may be particularly deleterious in the postresuscitation phase, when myocardial function is severely impaired. Zatebradine, a blocker of the hyperpolarization activated mixed sodium/potassium pacemaker current If, inhibits sinus node function. This specific bradycardic effect [12,13] has been shown to reduce heart rate without a negative inotropic effect in the normal or failing heart [14–17] and without antagonizing the positive inotropic effects of badrenergic stimulation [15]. Although zatebradine is a structural analog of verapamil, this drug does not show calcium channel blocking activity [12]. In particular in intact animals, zatebradine reduced heart rate without or with no pronounced effect on other cardiovascular parameters, such as arterial blood pressure or systemic vascular resistance [18], ECG-parameters such as PQ-, QRS- or QTintervals [18], or action potential duration [13]. Therefore, the purpose of the present study was to assess how a combination of epinephrine and either zatebradine, esmolol, or placebo given during CPR affects hemodynamic variables, left ventricular contractility, right ventricular function, and myocardial perfusion during the postresuscitation phase in pigs.

2. Materials and methods

2.1. Surgical preparation and measurements This project was approved by the Animal Investigation Committee of our institution, and the animals were managed in accordance with guidelines of the National Institutes of Health. According to the Utstein-style guidelines for laboratory CPR [19], this study was performed on 21 healthy, 12–14-week-old male domestic pigs weighing 23– 30 kg. The animals were fasted overnight with free access to water. After premedication with azaper-

one (4 mg/kg IM) and atropine (0.1 mg/kg IM) 30 min before surgery, anesthesia was induced with pentobarbital (15 mg/kg IV). After intubation during spontaneous respiration, volume-controlled ventilation (Servo 900, Siemens, Erlangen, Germany) was performed with 65% N2O in O2 at 20 breaths/min with a tidal volume adjusted to maintain normocapnia. Anesthesia was maintained with a single dose of buprenorphine (0.015 mg/kg) and a continuous infusion of pentobarbital (0.4 mg/kg/min). Muscle paralysis was achieved with 10 mg alcuronium after intubation and subsequently with pancuronium as needed. During the entire experiment, 6 ml/kg/h of Ringer’s solution and 4 ml/kg/h of a 3% gelatine solution was given. Body temperature was maintained between 37.5 and 38.5°C using a heating blanket. A standard ECG signal was used to record heart rate and the number of premature ventricular contractions [wide, bizarre QRS complexes (QRS\0.12 s), a full compensatory pause, and absent P wave]. A 7F catheter was inserted into the descending aorta for monitoring blood pressure and withdrawal of arterial blood. A 5F catheter in the right atrium was used for drug administration and for monitoring right atrial pressure. A 7F pigtail catheter (Cordis, Haan, Germany) was advanced into the left ventricle in order to inject radiolabeled microspheres. A 7.5F pulmonary artery and right ventricular ejection fraction catheter (Edwards, Irvine, CA) was positioned into the pulmonary artery to measure cardiac output, right ventricular end-diastolic volume, stroke volume, and right ventricular ejection fraction using the thermodilution technique. In particular, 5 ml of iced saline were injected in triplicate into the right atrium at the end of an expiratory phase of a respiratory cycle prearrest and at 5, 15, 30, 60, and 180 min after ROSC. A micromanometer-tipped catheter (Millar, Houston, TX) was placed into the left ventricle for measurement of intraventricular pressure, left ventricular systolic and end-diastolic pressure, and the rate of positive and negative left ventricular pressure development (dP/dt; − dP/dt). The ratio of dP/dt to left ventricular systolic pressure has been shown to be independent of preload and afterload [20], and therefore, their values have also been calculated. Except for the micromanometer tipped catheter, all salinefilled catheters were flushed with normal saline containing 5 U/ml heparin at a rate of 3 ml/h.

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Using radiolabeled microspheres, myocardial blood flow was measured as described by Heyman et al. [21] and as previously described in validation studies of the microsphere technique [22]. In brief, microspheres (New England Nuclear, Dreieich, Germany) (mean diameter of 159 1.5 mm) were labeled with 141cereum, 95niobium, 103ruthenium, 46 scandium and 85strontium. Each microsphere vial was placed into a water bath and subjected to ultrasonic vibration for 1 min before injection. Approximately 5× 105 microspheres diluted in 10 ml saline were then immediately injected into the left ventricle. Using an automatic withdrawal pump (Braun, Melsungen, Germany), blood was continuously withdrawn from the catheter lying in the descending aorta at a rate of 6 ml/min (= known ‘organ’ blood flow) for 2 min. At the end of the experiment, aliquots of left and right ventricular free wall, cortex, stomach, jejunum, colon, and kidney, were removed. The radioactivity of the blood collected (= counts of the reference ‘organ’ with known flow) was measured with a gamma scintillation spectrometer (LB 5300, Berthold, Wildbad, Germany) as was the radioactivity in the homogenized tissue samples (= counts of the organs with unknown flow). The flow of any organ (= unknown organ flow) could be calculated using the following relationship: Unknown organ flow= (known ‘organ’ blood flow/counts known ‘organ’ flow)*counts unknown organ flow. Organ blood flow measurements were performed prearrest and at 5, 15, 30, and 180 min after ROSC. Arterial blood gases were measured with a blood gas analyzer (Radiometer, ABL330, Copenhagen, Denmark) and corrected for temperature. After completion of surgery and before induction of cardiac arrest, 5000 U heparin were administered intravenously to prevent intracardiac clot formation.

2.2. Experimental protocol Fifteen minutes before cardiac arrest, the pentobarbital infusion was stopped, the FiO2 was increased to 1.0, and 0.3 mg buprenorphine was given intravenously. Before induction of ventricular fibrillation, prearrest variables were measured. Ventricular fibrillation was induced with a 50 Hz, 60 V alternating current administered via two subcutaneous needle electrodes; ventilation was

213

stopped at that point. After 4 min of untreated cardiac arrest, mechanical ventilation was resumed with 100% O2 using identical ventilation parameters as before cardiac arrest. Guided by audiotones, manual chest compression was resumed at a rate of 80/min and was always performed by the same investigator who was blinded to blood pressure and ETCO2 monitors. The compression force was applied to the animal’s midsternum while relaxation (decompression) was allowed to occur passively. After 3 min of CPR, animals were randomly assigned to receive a combination of 45 mg/kg epinephrine and either zatebradine (0.5 mg/kg; n=7), or esmolol (1 mg/kg; n=7), or placebo (normal saline; n=7). Each drug was given separately through the central venous catheter over a period of 5 s (investigators were blinded to the drugs). The zatebradine and esmolol dosages were chosen according to prior animal experiments [18,23], and according to recommendations for perioperative treatment in patients, respectively [24]. Two minutes after drug administration, up to three defibrillation attempts (Lifepak 6, Physio Control, Redmont, WA) with 3, 4, and 6 J/kg were performed, respectively. If two or three defibrillations were required, these defibrillation attempts were performed after each other without interposed phases of CPR. When ventricular fibrillation persisted, 45 mg/kg epinephrine was given, CPR was resumed for 90 s, and up to three defibrillation attempts were performed again with 6 J/kg. Return of spontaneous circulation (ROSC) was defined as coordinated electrical activity and a mean arterial pressure \50 mmHg for \5 min, and the first measurements were performed 5 min after the beginning of that 5 min phase with a mean arterial blood pressure \50 mmHg. Immediately after ROSC, anesthesia was resumed with pentobarbital (0.2 mg/kg/min) and buprenorphine (0.01 mg/kg). No further drugs were given during the postresuscitation period. At the end of the experiment, all animals were autopsied to check correct positioning of the catheters and to look for damage of the rib cage and internal organs.

2.3. Statistical analysis Values are expressed as mean9one standard deviation (S.D.). ANOVA and Newman–Keuls

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post-hoc test were used to determine differences between groups. Because the data did not satisfy the assumption of normal distribution, the Kruskal – Wallis ANOVA was used to determine differences in number of countershocks/animal until ROSC, and number of countershocks/animal

between groups. For investigation of correlation between endocardial blood flow/beat ratio and the number of premature ventricular contractions, the distribution-free rank correlation coefficient of Spearman (rs) was used. Statistical significance was considered at PB0.05.

Table 1 Hemodynamic variables at prearrest and during the postresuscitation phasea Variable

Group

Prearrest

Postresuscitation phase (min) 5

HR (1/min)

CO (l/min)

RAP (mmHg)

LVEDP (mmHg)

dP/dt (mmHg/s)

−dP/dt (mmHg/s)

dP/dt/LVP (1/s)

RVSV (ml)

RVEDV (ml)

RVEF (%)

SVR (dynes s/cm5)

Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo

10698 1099 20 1089 10 4.1 9 0.9 3.9 90.8 3.890.8 4 91 5 91 591 592 492 491 2.1 90.3 2.09 0.3 2.290.4 2.990.3 2.690.5 2.69 0.7 1493 13 9 2 159 3 3899 359 8 3997 91 922 809 14 92916 42 9 4 44 96 4197 2260 9 467 22769357 21749456

15

30

60

180

144918+++ 1069 23++ 8098+++ 8099++ 839 13+++ 199 937** 1779 27** 138916*** 1389 22*** 118920** 223 9 20 161 939 134 928 139 926 111920 6.490.7 3.89 1.1 2.7 90.5 2.99 0.6 2.990.7 4.99 1.8* 4.19 0.7 3.79 0.7 4.490.7* 3.690.7 7.49 1.0 c c 3.99 1.6 3.691.4 3.691.2 3.690.9 491 4 91 591 491 491 7 91* 591 491 491 4 91 5 92 c 59 2 59 2 59 1 5 91 694 491 49 3 391 392 897 694 592 492 594 59 4 591 491 49 1 491 7.992.1+ 2.590.8 2.49 0.6 2.090.3 3.691.6 4.99 2.0* 2.3 9 0.9 2.0 9 0.4 2.29 0.5 2.0 90.4 10.691.8 c c c 2.49 1.4 2.09 0.8 2.290.7 2.090.4 4.390.7 2.490.5 2.29 0.6 2.590.6 2.9 90.4 2.9 91.4* 2.5 9 1.0 2.59 0.4 3.09 0.3 3.19 0.3 2.19 1.1 2.3 9 0.9 2.59 0.7 2.490.6 c 4.39 0.8 c 54911+ 33912+ 22 9 7 209 5 1692 36912** 20 9 3* 17 9 2 1693 1493 67 9 10 c c c 1795 1692 2499 18 96 3695++ 44 9 3++ 3694+++ 3295 3697 2598*** 2394*** 279 6 329 4 3197 269 4 c 33 9 5 c c 2395 26 96 3294 94922+ 93 919 91 9 16 94919 99922 879 19 769 10 7499 82920 85923 97916 c 1219 12 c 1039 25 c 100 9 21 110925 369 6+ 49 910+++ 3997+ 3998++ 38912 29 95*** 3199 37 99 3998 3799 2693 c c 31911 2995 2599 259 4 c 12999 168 1500 9 365 2446 9824 22699 409 24649578 15619493 1549 9 305 1857 9 229 18719 290 23359402 10719207 c 21609536 12659151 1726 9503 21389536

Data are given as mean 9S.D. HR, heart rate; CO, cardiac output; RAP, right atrial pressure; LVEDP, left ventricular end-diastolic pressure; dP/dt, maximal rate of left ventricular pressure development; −dP/dt, negative deflection of dP/dt; dP/dt/LVP, ratio of left ventricular pressure development to simultaneous left ventricular pressure; RVSV, right ventricular stroke volume; RVEDV, right ventricular end-diastolic volume; RVEF, right ventricular ejection fraction; SVR, systemic vascular resistance; *PB0.05 (esmolol vs. zatebradine); **PB0.01 (esmolol vs. zatebradine); ***PB0.001 (esmolol vs. zatebradine); + PB0.05 (zatebradine vs. placebo); ++PB0.01 (zatebradine vs. placebo); +++PB0.001 (zatebradine vs. placebo); c PB0.05 (placebo vs. esmolol); c c PB0.01 (placebo vs. esmolol); c c c PB0.001 (placebo vs. esmolol) at the same point of observation. a

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Table 2 Countershocks and premature ventricular contractions per animal in the early postresuscitation phasea Variable

Zatebradine

Esmolol

Placebo

P

Countershocks until ROSC (n) Total countershocks (n) Premature ventricular contractions until 5 min ROSC (n)

2.091.3 2.7 91.8 669 80

1.69 1.5 2.491.6 3099 215*

1.19 0.4 2.1 91.5 251 9 161*

NS NS B0.05

Data are given as mean 9S.D.; ROSC, return of spontaneous circulation; NS, non significant. * PB0.05 (vs. zatebradine).

a

3. Results

3.1. Prearrest and CPR Prearrest hemodynamic, myocardial blood flow, and arterial blood gas variables did not differ significantly among groups (Tables 1, 3 and 5). After drug administration during CPR, coronary perfusion pressure in the groups receiving epinephrine combined with either zatebradine, esmolol, or placebo, was 2994, 2692, and 2694 mmHg, respectively. All animals could be successfully defibrillated with a comparable amount of countershocks (Table 2). There were no significant differences in the duration of CPR and the administered doses (sum) of epinephrine between the groups nor were there any significant intergroup differences with regard to the incidence of ventricular fibrillation or ventricular tachycardia after ROSC.

3.2. Postresuscitation phase 3.2.1. Hemodynamic 6ariables Zatebradine caused a significant reduction in heart rate during the entire postresuscitation phase in comparison with esmolol and placebo (Table 1). During the first 5 min of ROSC, zatebradine resulted in significantly less premature ventricular contractions in comparison with esmolol and placebo (Table 2). At 5 min after ROSC, esmolol caused a significant reduction in cardiac output in comparison with zatebradine and placebo; and a significant increase in right atrial pressure in comparison with zatebradine, and the placebo group. At 5 min after ROSC, dP/dt and − dP/dt after zatebradine were significantly higher compared with esmolol, and dP/dt was significantly lower in comparison with placebo. At 5 min after ROSC, the ratio dP/dt to left ventricular systolic pressure after placebo was significantly higher in comparison with

zatebradine and esmolol; the ratio dP/dt to left ventricular systolic pressure after zatebradine was significantly higher compared with esmolol (Table 1). At 5, 15, and 60 min after ROSC, right ventricular stroke volume after zatebradine was significantly higher in comparison with placebo. At 5 and 15 min after ROSC, right ventricular stroke volume after zatebradine was significantly higher in comparison with esmolol. At 5, 15, and 30 min after ROSC, right ventricular end-diastolic volume after placebo was significantly higher in comparison with esmolol and at 5 min after ROSC, right ventricular end-diastolic volume after placebo was significantly higher in comparison with zatebradine. At 5 min after ROSC, right ventricular ejection fraction after zatebradine was significantly higher compared with esmolol and placebo; and at 15, 30 and 60 min after ROSC, right ventricular ejection fraction after zatebradine was significantly higher in comparison with placebo. At 30 and 60 min after ROSC, right ventricular ejection fraction after esmolol was significantly higher compared with placebo (Table 1). At 5 min after ROSC, systemic vascular resistance (SVR) in the esmolol group was significantly higher than in the placebo group.

3.2.2. Myocardial and organ blood flow 6ariables During the postresuscitation phase, there were no significant differences in left ventricular myocardial blood flow between zatebradine and placebo. In contrast, left ventricular myocardial blood flow after esmolol was significantly lower compared with placebo at 5 min after ROSC. At the same time, the endocardial/epicardial perfusion ratio of zatebradine was significantly higher in comparison with esmolol and placebo (Table 3). In addition, at 5 min after ROSC, the endocardial blood flow/ heart beat ratio after zatebradine and placebo were significantly higher than after esmolol. At 15 min after ROSC, the endocardial

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blood flow/heart beat ratio after zatebradine was significantly higher compared with esmolol and placebo. There was a negative correlation (r= − 0.54; n = 21; P B0.05) between endocardial blood flow/beat ratio at 5 min after ROSC and the number of premature ventricular contractions within 5 min after ROSC. At 5 min after ROSC in the esmolol group, regional organ blood flow of stomach, jejunum, colon was significantly lower (P B0.05) in comparison to the placebo group. There were no further significant intergroup differences in regional organ perfusion of cortex, stomach, kidney, jejunum, and colon prearrest and at 15, 30 and 180 min after ROSC (Table 4).

3.2.3. Arterial blood gas 6ariables At 5 min after ROSC, pCO2 in the placebo group was significantly higher than in the esmolol

group. At the same point of observation, pH in the esmolol group was significantly higher than in the placebo and zatebradine group. There were no further significant differences in arterial blood gas variables between the groups during the postresuscitation phase (Table 5). Necropsy confirmed appropriate catheter positions, and revealed no injuries to the rib cage or intrathoracic organs in all animals.

4. Discussion During acute myocardial ischemia, decreasing heart rate has been shown to increase regional myocardial blood flow and contractile function [25]. Both b-blockers [26] and a specific bradycardic agent such as zatebradine [15], have been shown to be effective in this regard. Given the

Table 3 Myocardial blood flow at prearrest and during the postresuscitation phasea Variable

LVMBF (ml/g/min)

Epicardium (ml/g/min)

Mesocardium (ml/g/min)

Endocardium (ml/g/min)

Endo/Epi

Septum (ml/g/min)

RVMBF (ml/g/min)

Endo/HB (ml/100 g/min/beat)

Group

Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo

Prearrest

2.1 90.4 2.19 0.5 2.490.6 1.990.4 1.990.5 2.19 0.6 2.1 90.4 2.19 0.4 2.49 0.5 2.290.4 2.290.5 2.690.6 1.179 0.07 1.199 0.14 1.239 0.11 2.390.5 2.19 0.4 2.09 0.4 1.9 90.8 2.190.8 2.090.7 2.19 0.4 2.09 0.3 2.59 0.6

Postresuscitation phase (min) 5

15

30

180

7.8 93.3 5.6 9 1.9 11.19 4.8 c 8.1 93.5 6.491.7 12.595.1 c 7.7 9 4.0 5.5 9 2.1 11.0 95.1 c 7.892.6 4.99 2.0 9.9 94.3 c 1.0090.15+ 0.7490.14* 0.83 9 0.12 8.4 93.5 6.0 92.2 9.6 93.1 10.094.6 8.2 94.1 10.29 3.3 5.4 9 1.5 2.3 90.9** 4.3 91.4 c

2.691.1 2.59 0.8 2.99 1.5 2.7 91.5 2.59 0.7 3.091.7 2.591.2 2.49 0.8 2.891.3 2.790.9 2.591.0 2.991.5 1.1290.31 0.999 0.15 0.9790.17 2.6 9 1.1 2.29 0.4 2.39 1.1 2.99 1.5 2.69 0.4 2.59 1.3 2.69 0.5++ 1.490.4** 1.690.7

1.69 0.2 2.39 0.8 2.691.4 1.5 9 0.3 2.29 0.8 2.39 1.3 1.690.2 2.3 9 0.8 2.6 91.4 1.890.2 2.4 90.7 2.991.5 1.259 0.30 1.11 9 0.18 1.28 9 0.21 1.6 90.2 2.2 9 0.5 2.2 9 1.1 1.6 9 0.3 2.290.5 2.19 1.1 2.290.3 1.79 0.4 2.0 90.8

2.3 90.9 2.5 90.6 3.0 91.0 2.0 90.8 2.390.7 2.590.8 2.3 91.0 2.5 90.6 3.1 91.0 2.591.0 2.690.5 3.391.4 1.2690.08 1.16 90.18 1.30 90.16 2.3 90.8 2.5 90.5 2.6 90.9 1.7 90.6 2.191.0 1.790.8 3.1 91.1 2.390.3 2.8 90.8

Data are mean 9S.D. LVMBF, left ventricular myocardial blood flow; Endo/Epi, endocardial/epicardial blood flow ratio; RVMBF, right ventricular myocardial blood flow; Endo/HB, endocardial blood flow/heart beat ratio. *PB0.05 (esmolol vs. zatebradine); **PB0.01 (esmolol vs. zatebradine); ***PB0.001 (esmolol vs. zatebradine); +PB0.05 (zatebradine vs. placebo); ++ PB0.01 (zatebradine vs. placebo); +++PB0.001 (zatebradine vs. placebo); c PB0.05 (placebo vs. esmolol); c c PB0.01 (placebo vs. esmolol); c c c PB0.001 (placebo vs. esmolol) at the same point of observation. a

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Table 4 Regional organ blood flow at prearrest and during the postresuscitation phasea Parameter

Group

Cortex (ml/g/min)

Stomach (ml/g/min)

Kidney (ml/g/min)

Jejunum (ml/g/min)

Colon (ml/g/min)

a

Data are mean 9 S.D.

Prearrest

Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo c

0.44 9 0.10 0.409 0.06 0.399 0.10 0.36 90.04 0.309 0.13 0.3690.09 3.43 90.50 3.949 1.46 3.7390.60 0.28 90.08 0.2990.08 0.3590.09 0.43 90.13 0.529 0.32 0.6290.11

Postresuscitation phase (min) 5

15

30

180

2.159 0.61 1.869 0.50 1.779 1.1 0.399 0.09 0.279 0.10 0.549 0.23 c 3.759 0.81 3.179 1.80 4.129 0.60 0.459 0.19 0.469 0.12 0.789 0.32 c 0.469 0.12 0.519 0.34 0.859 0.24 c

0.849 0.36 0.579 0.14 0.539 0.23 0.319 0.10 0.279 0.07 0.379 0.16 3.199 0.71 3.30 90.99 3.639 0.87 0.419 0.31 0.3490.12 0.419 0.25 0.529 0.14 0.55 90.25 0.709 0.07

0.339 0.08 0.329 0.04 0.32 9 0.10 0.249 0.05 0.269 0.06 0.35 90.16 2.6290.42 3.289 0.99 3.62 91.06 0.319 0.18 0.3090.06 0.40 90.19 0.4990.11 0.609 0.26 0.76 90.16

0.4490.08 0.4290.07 0.4290.12 0.4090.11 0.4390.10 0.6990.43 3.8390.51 4.4991.14 4.3990.76 0.4090.12 0.5190.07 0.5390.13 0.6790.12 0.8690.44 0.9490.28

PB0.05 (placebo vs. esmolol).

extraordinary concentrations of circulating catecholamines during cardiac arrest [3], we hypothesized that both a bradycardic agent and b-blockade may be beneficial in the immediate postresuscitation phase. Accordingly, zatebradine resulted in a significant reduction in both heart rate and the number of premature ventricular contractions without compromising myocardial contractility. Esmolol had a significant negative inotropic effect, even at a dose that only resulted into a moderate heart rate reduction.

Administration of zatebradine resulted in a significantly reduced heart rate without altering global myocardial and endocardial perfusion. In agreement with other studies, the bradycardic effects of zatebradine during the postresuscitation phase included improvement in ventricular contractility and relaxation [27,28]. What are the possible causes of improved stroke volume resulting from zatebradine administration? First, at 5 and 15 min after ROSC, the endocardial/epicardial perfusion ratio after zatebradine was higher in

Table 5 Arterial blood gases at prearrest and during the postresuscitation phasea Variable

pH

pO2 (mmHg)

pCO2 (mmHg)

BE (mmol/l)

a

Group

Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo Zatebradine Esmolol Placebo

Prearrest

7.4890.01 7.499 0.01 7.48 9 0.01 4199 13 434 910 4239 13 399 1 399 1 4091 5.890.5 5.79 0.8 5.390.7

Postresuscitation phase (min) 5

15

30

60

180

7.3190.02 7.409 0.01* 7.319 0.02 c 3769 20 3959 34 3159 26 489 2 439 1 5192 c 0.29 0.8 1.3 9 0.7 −0.69 0.6

7.389 0.02 7.4090.02 7.379 0.02 413920 426 9 32 3459 23 399 4 429 1 4492 0.3 90.8 1.19 0.8 −0.390.5

7.4090.01 7.419 0.03 7.3990.02 4479 14 4619 19 4139 17 419 1 439 1 429 2 0.59 0.7 1.79 0.9 0.29 0.5

7.479 0.01 7.489 0.02 7.4690.01 4229 14 4429 19 3949 21 409 1 399 1 409 1 4.89 0.8 5.09 0.7 4.79 0.6

7.4990.01 7.5090.01 7.4990.01 435923 457921 391927 4091 39 91 4191 6.590.9 6.5 90.5 6.890.4

Data are given as mean 9 S.D. *PB0.05 (esmolol vs. zatebradine);

c

PB0.05 (placebo vs. esmolol).

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comparison with both esmolol group and placebo. The decreased number of contractions, and the relative increase in subendocardial blood flow reduces oxygen consumption and improves myocardial oxygen supply. The highest values of the quotient subendocardial blood flow/heart beat, a parameter which has been previously reported to predict myocardial wall function independently of heart rate [29], were found after zatebradine administration at 5 and 15 min after ROSC. Second, right ventricular end-diastolic volume after zatebradine was significantly lower, reflecting decreased ventricular size, wall stress, and hence potentially lower oxygen demand in comparison with placebo. The significantly greater right ventricular stroke volume and ejection fraction after zatebradine, compared with placebo, may be due to this possible mechanism. The concomitant decrease of dP/dt in the zatebradine group can be attributed to the force–frequency relation with slowing heart rate [30]. After 5 min of ROSC, the consistently lower cardiac output in the zatebradine group compared with the esmolol or placebo groups may suggest an unfavorable effect of zatebradine. However, this lower cardiac output must be attributed to the reduced heart rate (due to the long half-life of zatebradine), an effect that can be easily reversed by b-adrenoreceptor-activation [31]. At 15, 30 and 180 min after ROSC, no significant differences in arterial blood gases or in regional organ perfusion of cortex, stomach, kidney, jejunum, colon between the three groups were found (microsphere technique). In contrast in the zatebradine group, the increase in endocardial blood flow/heart beat ratio persisted beyond the change in endocardial/ epicardial blood flow ratio, which would suggest a favorable effect of zatebradine on myocardial function. Although esmolol resulted only in a moderate heart rate reduction compared with placebo, this was associated with a significant decrease in global myocardial and endocardial blood flow, particularly 5 min after ROSC. The negative inotropism due to b-blockade, as reflected by the changes in right ventricular ejection fraction and right ventricular stroke volume, may be responsible for an impaired myocardial perfusion. In addition, we speculate that b-blockade in the presence of a profound sympathetic stimulation may result in an a-adrenoreceptor mediated vasoconstriction, and

thereby decrease myocardial perfusion [32]. Due to the short half-life of esmolol, the negative side-effects of b-adrenergic blockade on right ventricular stroke volume and cardiac output were particularly pronounced during the immediate postresuscitation phase. Ventricular relaxation may also be compromised by b-adrenergic blockade since both −dP/dt and right ventricular end-diastolic volume were significantly lower after esmolol compared with both placebo and zatebradine 5 min after ROSC. Epinephrine has been shown to be associated with a high incidence of malignant ventricular dysrhythmias in pigs [8]. In another CPR investigation, epinephrine in combination with esmolol reduced the total energy required for successful resuscitation [10]. In our experiment, the incidence of premature ventricular contractions after placebo and esmolol were similar; but we observed significantly less ventricular ectopy in the zatebradine group. A negative correlation (r= −0.54; n=21; PB0.05) was observed between endocardial blood flow/beat ratio at 5 min after ROSC and the number of premature ventricular contractions within 5 min after ROSC. This may suggest that the relation of subendocardial oxygen supply/ demand, i.e. the degree of endocardial ischemia, rather than b-adrenergic stimulation per se, is responsible for ectopic ventricular arrhythmia. On the other hand, the interaction of zatebradine with sodium/potassium channels may not only result in a specific bradycardic effect. The interaction with these channels may also result in a membrane-stabilization effect and, thus, may lead to a specific reduction in premature ventricular contractions via anti-arrythmic properties [33,34]. This study is limited in several ways. First, this investigation included only healthy animals with a short cardiac arrest duration, and did not address severe myocardial dysfunction due to prolonged cardiac arrest and/or preexisting cardiac disease. Second, we only assessed the short-term effects, but we did not investigate the effects on long-term survival or neurologic outcome. Third, this study lacks dose–response data, and a different treatment regime with repetitive drug administration remains to be elucidated. In addition, the dosages of zatebradine and esmolol were not equipotent with respect to heart rate reduction. Fourth, we used 45 mg/kg epinephrine [22], which may be more efficient in pigs when compared with 15

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mg/kg epinephrine that is currently used and recommended for patients [4,5]. The higher efficacy of the epinephrine dose chosen in this porcine model may be due to the barbiturate infusion used for anesthetic purposes [35]. In addition, there is some evidence that myocardial stress produced by epinephrine may be age-dependent [36]. Fifth, although propranolol is likely to represent the ‘goldstandard’ of a b-blocker, esmolol is the best b-blocker for intravenous emergency management because of its extremely short half-life [24]. Lastly, asystole or pulseless electrical activity have been shown to be relatively common after countershock of prolonged ventricular fibrillation [37]. Therefore, the important aspect remains to be evaluated whether administration of zatebradine or esmolol during periods of prolonged ventricular fibrillation would affect postcountershock rhythm and outcome. In summary, at the doses administered in this study, our results demonstrate a greater efficiency of zatebradine than esmolol in reducing heart rate. Although only one dose and only one administration pattern of zatebradine has been investigated, we conclude that during the early postresuscitation phase in pigs, the bradycardic agent zatebradine effectively reduced heart rate without having a direct depressant action on the myocardium. In contrast, the b-blocker esmolol had significant negative inotropic actions even at a dose that led only to a moderate reduction in heart rate. Based upon this study, additional investigations seem warranted to assess the potential clinical efficacy of zatebradine during CPR and the postresuscitation phase.

Acknowledgements The authors would like to thank Thomas Dietze for performing microsphere blood flow measurements. We are further indebted to Wolfgang Siegler for his expertise in animal surgery and instrumentation.

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