Cardiovascular response to epinephrine varies with increasing duration of cardiac arrest

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1 Resuscitation (2008) 77, available at journal homepage: EXPERIMENTAL PAPER Cardiovascular response to epinephrine varies with increasing duration of cardiac arrest Mark G. Angelos a,b,, Ryan L. Butke a, Ashish R. Panchal a, Carlos A.A. Torres a, Alan Blumberg a, Jim E. Schneider a, Sverre E. Aune a a Department of Emergency Medicine, The Ohio State University, Columbus, OH, United States b Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States Received 19 June 2007; received in revised form 23 October 2007; accepted 26 October 2007 KEYWORDS Cardiopulmonary resuscitation (CPR); Epinephrine; Adrenaline; Return of spontaneous circulation; Post-resuscitation period Summary Objective: Epinephrine (adrenaline) is widely used as a primary adjuvant for improving perfusion pressure and resuscitation rates during cardiopulmonary resuscitation (CPR). Epinephrine is also associated with significant myocardial dysfunction in the post-resuscitation period. We tested the hypothesis that the cardiac effects of epinephrine vary according to the duration of cardiac arrest. Methods and materials: Cardiac arrest (CA) was induced in Sprague Dawley rats with an IV bolus of KCl (40 g/g). Three series of experiments were performed with CPR begun after 2, 4, or 6 min of cardiac arrest. Epinephrine (0.01 mg/kg) IV or placebo was given immediately in the 2 and 4 min CA groups. In the 6 min group, CPR was started after 6 min CA and epinephrine was given at 15 min if no return of spontaneous circulation (ROSC) occurred. Time to ROSC was recorded in all groups. Cardiac function was determined with trans-thoracic echocardiography at baseline, 5, 30 and 60 min after ROSC. Results: After 2 min CA, 8/8 (100%) placebo animals and 8/8 (100%) epinephrine animals attained ROSC. Cardiac index was significantly increased during the first 60 min in the epinephrine group compared with the placebo group (p < 0.01). After 4 min of cardiac arrest, 14/29 (48%) placebo animals and 14/16 (88%) epinephrine animals attained ROSC (p < 0.01). Cardiac index after ROSC returned to baseline in both groups, although tended to be lower in the epinephrine group. After 6 min CA, 10/31 (32%) animals attained ROSC without epinephrine and 17/21 (81%) animals with A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi: /j.resuscitation Corresponding author at: Department of Emergency Medicine and Davis Heart and Lung Research Institute, The Ohio State University, 146 Means Hall, 1654 Upham Drive, Columbus, OH 43210, United States. Tel.: ; fax: address: angelos.1@osu.edu (M.G. Angelos) /$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved. doi: /j.resuscitation

2 102 M.G. Angelos et al. epinephrine (p < 0.01). Post-ROSC depression of cardiac index was greatest in the epinephrine group (p < 0.05). Conclusions: As the duration of cardiac arrest increases, a paradoxical myocardial epinephrine response develops, in which epinephrine becomes increasingly more important to attain ROSC, but is increasingly associated with post-rosc myocardial depression Elsevier Ireland Ltd. All rights reserved. Introduction After cardiac arrest with initial return of spontaneous circulation, significant depression of myocardial contractile function occurs frequently. 1 3 Post-resuscitation myocardial dysfunction has been studied primarily in animal models of ventricular fibrillation and asphyxial cardiac arrest, 2,4 supported by observations from clinical medicine. 5 This post-ischemic myocardial dysfunction is a primary contributor to the early post-resuscitation mortality in cardiac arrest patients. 6 It is speculated that preserving post-resuscitative cardiac function will improve long-term cardiac arrest survival. 7 Epinephrine (adrenaline) has long been considered the principal adrenergic agent to improve perfusion during cardiopulmonary resuscitation (CPR) as a result of its alpha adrenergic agonist properties. However, the role of the beta adrenergic effects of epinephrine is less well understood in the setting of cardiac arrest and may be detrimental in the post-resuscitative heart. 8 In earlier work, epinephrine given during CPR, was found to increase myocardial oxygen consumption and worsen the already tenuous ratio of oxygen delivery to oxygen consumption during ventricular fibrillation (VF). 9,10 However, under the high flow reperfusion conditions of cardiopulmonary bypass during VF, we have shown that epinephrine significantly reduces time to restoration of spontaneous circulation (ROSC) and improves functional cardiac recovery when high flow alone fails to restore cardiac function. 11 These studies suggest some variability in the cardiovascular response to epinephrine in accordance with the level of circulation generated during cardiac arrest. The effects of epinephrine are not limited to the CPR period of cardiac arrest, but also have significant effects on myocardial function immediately following ROSC. Past studies with high dose epinephrine have noted severe adrenergic side effects in the post-cardiac arrest heart attributed to epinephrine. 8,12 Although, not well understood, the effect of epinephrine on the post-arrest heart is likely to vary depending on the severity of the preceding ischemic injury. Indeed, in an asphyxial rat cardiac arrest model, shorting the duration of asphyxia results in improved recovery of contractile function and acidosis following initial resuscitation. 4 Certainly, the duration of cardiac arrest is a principal determinant in obtaining ROSC, even when key outcome measures of perfusion such as coronary perfusion pressure and end tidal CO 2 do not differ. 13 In this study we tested the hypothesis that epinephrine s effects on ROSC success and post-rosc myocardial function vary with the duration of cardiac arrest preceding its administration. Materials and methods Model Sprague Dawley rats weighing approximately g (Harlan, Indianapolis, IN) were used in accordance with the guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No , revised 1996) and the approval of the University Laboratory Animal Resources Committee. Animals were fasted overnight and anesthetized with intraperitoneal pentobarbital (50 mg/kg) and intubated with a 16-gauge catheter (angiocath) via a tracheotomy. Animals were ventilated at 75 breaths/min using a rodent ventilator (Harvard Model 683, South Natick, MA) with a FiO 2 of 0.21 and a tidal volume of 0.65 ml/100 mg body weight to maintain arterial blood gases in the normal range (po 2 >80mmHg, pco mm Hg, and ph ). The jugular vein and femoral artery were cannulated with a 24-gauge catheter (angiocath) and sutured in place. Continuous arterial pressure was measured in the femoral artery. Animals were heparinized (1000 U kg 1 bolus). Arterial pressure and heart rate were recorded continuously using an on-line data acquisition system (Digi-Med Heart Performance Analyzer). Rectal temperature was maintained between 36.5 and 37.5 C throughout the duration of the experiment with a heating lamp. Using a standardized cardiac arrest model, 14 adapted to the rat, cardiac arrest was induced by infusing a bolus of potassium chloride (40 g/g KCl) into the jugular vein followed by a 0.2 ml bolus of saline to ensure that the full KCl dose was delivered to the heart. Ventilation was discontinued simultaneously. Cardiac arrest was confirmed by the loss of the arterial trace with a MAP of <20 mm Hg. Manual chest compressions were started after the pre-determined cardiac arrest duration at a rate of /min with ventilation at 25 breaths/min. Rate and force of compression were maintained by continuous observation of the arterial wave form generated during the CPR period. Epinephrine, based on current recommended weight-based dose (0.01 mg/kg), 15 was given via the jugular vein at the pre-determined time during CPR. CPR was continued until the ROSC, defined as the time of return of a spontaneous arterial blood pressure tracing with a MAP of >60 mm Hg without chest compressions. Following ROSC, all animals received identical care consisting of mechanical ventilation with 100% O 2 at prearrest values and continuous arterial blood pressure, heart rate and temperature monitoring for 60 min. Animals were given a further dose of pentobarbital if there were any signs of awakening. Fluid administration consisted of intermittent 1 ml boluses of normal saline if the animal developed hypotension (MAP < 60 mm Hg). At the conclusion of the

3 Cardiovascular response to epinephrine min-monitoring period, animals were sacrificed painlessly with pentobarbital. Study protocols Three cardiac arrest series were performed (Figure 1) to determine the effects of epinephrine on recovery of myocardial function following ROSC after different durations of cardiac arrest. In each series of experiments, the same KCl rat cardiac arrest model, anesthetic, single dose of epinephrine, CPR methods and post-resuscitation support were used. Series were done sequentially. In series 1, epinephrine (0.01 mg/kg) or placebo (normal saline) was given in a blinded fashion after 2 min of untreated cardiac arrest and CPR was provided until ROSC or the duration of cardiac arrest exceeded 15 min. In series 2, epinephrine (0.01 mg/kg) or placebo (normal saline) was given in a blinded fashion after 4 min of untreated cardiac arrest and CPR was provided until ROSC or the duration of cardiac arrest exceeded 15 min. In series 3, CPR was started after 6 min of untreated cardiac arrest and continued until ROSC or 15 min of cardiac arrest. If no ROSC was attained at 15 min, then epinephrine (0.01 mg/kg), was given and CPR was continued until ROSC or until the duration of cardiac arrest exceeded 20 min. In this series, epinephrine was given as a rescue therapy after a longer cardiac arrest duration and outcome compared to the shorter non-epinephrine group. Echocardiography Trans-thoracic echocardiographic examination of myocardial function was completed pre- and post-cardiac arrest using standard echocardiographic methods. 16 Animals were examined in the supine position after the chest was shaved and a layer of acoustic gel was applied. 2D and M-mode measurements were made with a Vivid 7 Ultrasound machine (GE Medical Systems, Horten, Norway) using an 11 MHz probe. Views were taken after optimization of gain, angulation, and rotation. M-mode measurements were made at or just below the level of the papillary muscles. Ultrasound measurements obtained included, LV posterior wall and chamber diameter during systole (LVIDs) and diastole (LVIDd) and heart rate. Calculations of cardiac output were made by machine software utilizing the formula below described previously by Teichholz et al. 17 cardiac output = (diastolic volume systolic volume) heart rate 1000 diastolic volume = systolic volume = (1) LVIDd (LVIDd)3 (2) LVIDs (LVIDs)3 (3) Figure 1 Experimental protocols. Three series of experiments were performed. In series 1, following a 2 min KCl-induced cardiac arrest, CPR was started and epinephrine (0.01 mg/kg) or placebo was given. In series 2, animals underwent a 4 min KCl-induced cardiac arrest at which time CPR was started and epinephrine (0.01 mg/kg) or placebo was given. In series 3, animals underwent a 6 min KCl-induced cardiac arrest, with CPR until ROSC or 15 min at which time epinephrine (0.01 mg/kg) was given. CA = cardiac arrest, EPI = epinephrine, PL = placebo, ROSC = restoration of spontaneous circulation.

4 104 M.G. Angelos et al. Outcome measures Table 1 Baseline group comparisons of CA survivors Ultrasound measurements were determined at baseline, 5, 30 and 60 min following ROSC. Arterial pressure, heart rate and temperature were measured continuously throughout the study. Arterial blood gases, drawn at baseline, following ROSC and at 60 min post-rosc, were measured on a blood gas analyzer (Critical Care Laboratory Synthesis 45, IL). ROSC rates and time to ROSC were determined in each group. Data analysis Data are presented as mean ± SEM. ROSC rates were determined and compared within series using Mann Whitney U-test. Parametric data were analyzed within series using a one-way analysis of variance followed by a Tukey post hoc test with p < 0.05 set as significant. Results There were no baseline group differences within each series in weight, pentobarbital dose or fluid requirements (Table 1). Echocardiographic evaluation of left ventricular function was performed in all animals. Representative echocardiographic images pre-arrest and 5 min post-rosc illustrate the early change in LV function following resuscitation from cardiac arrest in an animal receiving epinephrine in the 4 min series (Figure 2). After a short cardiac arrest duration of 2 min before starting CPR, ROSC with 60 min survival was 100% in both epinephrine (8/8) and non-epinephrine (8/8) groups (Figure 3a). However, with increasing cardiac arrest dura- Series 1: (2 min CA) No EPI (n = 8) EPI (n =8) Weight (g) ± ± 9.9 Pentobarbital (ml) 0.60 ± ± 0.0 Fluids-pre-arrest (ml) 2.20 ± ± 0.31 Frequency of ROSC 8/8 8/8 ROSC time (min) 2:40 ± 0:11 2:23 ± 0:06 Fluids-post-arrest (ml) 2.30 ± ± 0.81 Series 2: (4 min CA) No EPI (n = 14) EPI (n = 14) Weight (g) ± ± 7.4 Pentobarbital (ml) 0.57 ± ± 0.02 Fluids-pre-arrest (ml) 1.4 ± ± 0.16 Frequency of ROSC 14/29 14/16* ROSC time (min) 5:16 ± 0:18 5:17 ± 0:14 Fluids-post-arrest (ml) 2.2 ± ± 0.2 Series 3: (6 min CA) No EPI (n = 10) EPI (n = 17) Weight (g) ± ± 7.4 Pentobarbital (ml) 0.53 ± ± 0.03 Fluids-pre-arrest (ml) 2.84 ± ± 0.29 Frequency of ROSC 10/31 17/21* ROSC time (min) 11:50 ± 1:28 16:54 ± 0:08 Fluids-post-arrest (ml) 7.5 ± ± 1.3* All animals completed the 60 min post-resuscitation protocol. ROSC rates were significantly higher in the EPI groups after both 4 and 6 min CA. ROSC times were similar within series except for the 6 min CA series, in which the EPI group was longer by design. CA = cardiac arrest, EPI = epinephrine, ROSC = restoration of spontaneous circulation (*p < 0.05 between EPI and no EPI groups). Table 2a 60 min survivor outcome after 2 min cardiac arrest (series 1) Group Baseline ROSC 5 min ROSC 30 min ROSC 60 min Heart rate Placebo 390 ± ± ± ± 29 Epi 378 ± ± ± ± 14 SV (ml) Placebo 0.28 ± ± ± ± 0.04 Epi 0.25 ± ± ± ± 0.04* EF (%) Placebo 83.6 ± ± ± ± 5.0 Epi 88.1 ± ± ± 3.8* 53.0 ± 5.8* CI (L/(min kg)) Placebo ± ± ± ± Epi ± ± ± 0.034* ± 0.032* FS (%) Placebo 48.3 ± ± ± ± 7.2 Epi 53.6 ± ± ± 2.7* 23.5 ± 4.6* ph Placebo 7.49 ± ± ± 0.05 Epi 7.49 ± ± ± 0.05 P a CO 2 Placebo 32 ± 2 50 ± 6 37 ± 6 Epi 29 ± 2 32 ± 6 39 ± 2 P a O 2 (FiO 2 ) Placebo 82 ± 7 (0.21) 245 ± 79 (1.0) 402 ± 52 (1.0) Epi 91 ± 4 (0.21) 227 ± 51 (1.0) 335 ± 69 (1.0) Hct Placebo 41 ± 2 42 ± 1 37 ± 6 Epi 41 ± 2 43 ± 3 39 ± 2 Syst art press Placebo 162 ± ± ± ± 8 Epi 159 ± ± ± ± 7 *p < 0.05 compared with placebo group (placebo group n = 8, epinephrine group n = 8). SV = stroke volume, CI = cardiac index, EF = ejection fraction, FS = fractional shortening, Hct = hematocrit.

5 Cardiovascular response to epinephrine 105 Figure 2 Representative echocardiography at baseline and 60 min following ROSC in a short cardiac arrest (a) with ROSC time of 2:20 and a longer cardiac arrest (b) with a ROSC time of 5:17. Cardiac output following a short cardiac arrest with epinephrine was increased above baseline at 60 min following ROSC (a) in contrast to a lower than baseline cardiac output after a longer cardiac arrest with epinephrine (b). Trans-thoracic 2D and M-mode short axis views of the left ventricle were obtained at the level of the papillary muscles. tion before CPR (4 min), ROSC rates were significantly higher with epinephrine compared to non-epinephrine groups (Figure 3a). With still longer durations of cardiac arrest before beginning CPR (6 min), ROSC was successful only 32% of the time without epinephrine, but 81% successful with epinephrine in this same group initially refractory to ROSC with CPR only (Figure 3a). In all three series, animals attaining ROSC survived to 60 min. ROSC times were similar between epinephrine and non-epinephrine groups after 2 and 4 min CA, but were significantly longer in the epinephrine group after 6 min of cardiac arrest by design (see Table 1). Relative to baseline, cardiac index at 60 min post-rosc was increased in the epinephrine group in the 2 min series, unchanged in the 4 min series and significantly depressed in the 6 min series (Figure 3b). Following resuscitation from cardiac arrest in the 2 min series, cardiac index was significantly increased in the epinephrine group relative to the non-epinephrine group (Table 2a). This increase in cardiac index was primarily due to an increase in stroke volume (both systolic and diastolic LV volume), but was also accompanied by a reduction in ejection fraction and fractional shortening compared with the non-epinephrine group (Table 2a). Thus, although overall CI was increased, ventricular efficiency (ejection fraction) was decreased, indicating some degree of myocardial dysfunction. In the 4 min series, the cardiac index increased transiently in both groups but returned to baseline cardiac index by 60 min (Table 2b). In this series, stroke volume was largely unchanged in both groups (Table 2b). In the 6 min series, the cardiac index was significantly decreased in the non-epinephrine and epinephrine group compared with baseline; however the

6 106 M.G. Angelos et al. Figure 2 (Continued ). depression in the epinephrine group was greater relative to the non-epinephrine group (Table 2c). Within the 6 min epinephrine group, a significant reduction in heart rate and a greater metabolic acidosis was present compared with the non-epinephrine group. Discussion The present study demonstrates the variable and discordant effects of epinephrine on initial resuscitation rates and myocardial dysfunction after varying durations of cardiac arrest. Utilizing a standardized cardiac arrest model and current 2005 American Heart Association recommended weight-based epinephrine dose, 15 we noted equal resuscitation rates with or without epinephrine after very short durations of cardiac arrest, but significant improvement in initial resuscitation rates with epinephrine, as the duration of cardiac arrest increased. Concurrently, we noted increased myocardial depression in the post-resuscitation period with epinephrine as the duration of cardiac arrest increased. In clinical cardiac arrest, the greatest percentage of resuscitation failures consists of the inability to restart the heart, i.e. to obtain ROSC. Data from the National Registry of Cardiopulmonary Resuscitation show that of 14,720 in-hospital cardiac arrests, only 44% had restoration of spontaneous circulation and 17% survived to hospital discharge. 18 Similarly, in out-of-hospital cardiac arrest victims, an initial return of spontaneous circulation occurs in only about 30%. 19 Consequently, approximately 70% of cardiac arrest victims never recover any functional contractile heart activity despite CPR and other interventions. Epinephrine or the non-adrenergic agent, vasopressin, are currently the recommended agents to improve initial resuscitation rates in all cardiac arrest rhythms, including electrically susceptible rhythms if initial defibrillation fails. 15 However, epinephrine has been associated with increased myocardial depression in the early post-resuscitation period, particularly with in high doses. 8,12

7 Cardiovascular response to epinephrine 107 Table 2b 60 min survivor outcome after 4 min cardiac arrest (series 2) Group Baseline ROSC 5 min ROSC 30 min ROSC 60 min Heart rate Placebo 358 ± ± ± ± 16 Epi 368 ± ± ± ± 16 SV (ml) Placebo 0.32 ± ± ± ± 0.04 Epi 0.30 ± ± ± ± 0.04 EF (%) Placebo 83.5 ± ± ± ± 4.8 Epi 79.2 ± ± ± ± 4.8 CI (L/(min kg)) Placebo ± ± ± ± Epi ± ± ± ± FS (%) Placebo 47.5 ± ± ± ± 4.2 Epi 42.7 ± ± ± ± 2.5 ph Placebo 7.45 ± ± ± 0.02 Epi 7.50 ± ± ± 0.05 P a CO 2 Placebo 35 ± 3 59 ± 5 40 ± 2 Epi 30 ± 1 57 ± 4 32 ± 3 P a O 2 (FiO 2 ) Placebo 148 ± 60 (0.21) 88 ± 22 (1.0) 202 ± 48(1.0) Epi 101 ± 6 (0.21) 117 ± 20 (1.0) 282 ± 33(1.0) Hct Placebo 44 ± 2 41 ± 2 44 ± 2 Epi 45 ± 1 45 ± 1 45 ± 1 Syst art press Placebo 146 ± ± ± ± 30 Epi 171 ± ± ± ± 8 There were no significant differences between groups (placebo group n = 12, epinephrine group n = 14). SV = stroke volume, CI = cardiac index, EF = ejection fraction, FS = fractional shortening, Hct = hematocrit. Using non-invasive echocardiographic measures of LV function, the present study demonstrates that significant myocardial depression occurs in the early post-cardiac arrest period after relatively short durations of cardiac arrest with and without the use of epinephrine. In previous studies, myocardial dysfunction following resuscitation from cardiac arrest has been characterized by decreased LV ejection fraction, fractional shortening, dp/dt 40 and increased tau (isovolumetric relaxation time). 5,20 In this study, epinephrine was associated with an increased cardiac output state after a very short cardiac arrest, mild reversible myocardial depression after a slightly longer cardiac arrest Table 2c 60 min survivor outcome after 6 min cardiac arrest (series 3) Group Baseline ROSC 5 min ROSC 30 min ROSC 60 min Heart rate Placebo 353 ± ± ± ± 29 Epi 358 ± ± 23* 272 ± 18* 267 ± 17* SV (ml) Placebo 0.26 ± ± ± ± 0.04 Epi 0.29 ± ± ± ± 0.03 EF (%) Placebo 85 ± 3 94 ± 5 88 ± 3 89 ± 4 Epi 83 ± 2 72 ± ± 5 76 ± 9 CI (L/(min kg)) Placebo ± ± ± ± Epi ± ± 0.025* ± ± FS (%) Placebo 50 ± 5 77 ± ± 5 59 ± 6 Epi 47 ± 2 48 ± 5 46 ± 5 52 ± 8 ph Placebo 7.46 ± ± ± 0.06 Epi 7.39 ± ± ± 0.02* P a CO 2 Placebo 33 ± 3 51 ± 6 40 ± 6 Epi 37 ± 2 55 ± 7 32 ± 4 P a O 2 (FiO 2 ) Placebo 120 ± ± 56 (1.0) 393 ± 52 (1.0) Epi 87 ± 5 (0.21) 76 ± 20 (1.0) 317 ± 36 (1.0) Hct Placebo 44 ± 2 39 ± 2 33 ± 4 Epi 44 ± 1 39 ± 2 39 ± 3 Syst art press Placebo 147 ± ± ± 8 91 ± 8 Epi 137 ± ± 16* 135 ± 10* 120 ± 8* *p < 0.05 compared with placebo group (placebo group n = 10, epinephrine group n = 17). SV = stroke volume, CI = cardiac index, EF = ejection fraction, FS = fractional shortening, Hct = hematocrit.

8 108 M.G. Angelos et al. Figure 3 (a) The rate of restoration of spontaneous circulation (ROSC) is shown as both a fraction and percentage in each of the three series with and without epinephrine. There was no difference in ROSC rates when epinephrine was given after 2 min of cardiac arrest. However, with lengthening cardiac arrest times, ROSC rates were significantly higher in animals receiving epinephrine after 4 min (*p < 0.05) and 6 min ( p < 0.01) of cardiac arrest. (b) Cardiac index at 60 min post-resuscitation period with and without epinephrine in survivors following cardiac arrest times of 2, 4 and 6 min before starting CPR. The cardiac index increased significantly in the epinephrine group compared with the non-epinephrine group following ROSC in the 2 min series (*p < 0.05), and then decreased relative to the non-epinephrine group in the 4 min series (p = 0.06). In the 6 min series, the cardiac index was depressed in both epinephrine and non-epinephrine groups, but was more severe in the epinephrine group ( p < 0.05). The cardiac index at 60 min is expressed as botha%ofbaseline in each group and in L/(kg min). and more severe myocardial depression noted after a more prolonged cardiac arrest. As the epinephrine dose and CPR were similar in all groups, the differences in post-arrest LV function were primarily a function of the duration of cardiac arrest. The duration of cardiac arrest is then a key determinant of the cardiovascular response of epinephrine in cardiac arrest. As, epinephrine has both important preand post-rosc effects on the myocardium in the setting of cardiac arrest, any depression in post-myocardial function induced by epinephrine must be balanced against any improvement in ROSC rates associated with epinephrine. Indeed it is the pre-rosc effect, for which epinephrine is indicated, although the effects of epinephrine given during cardiac arrest may persist after ROSC. Recent studies have again highlighted the potential adverse effects of epinephrine during cardiac arrest. In the pediatric cardiac arrest population, epinephrine doses of >15 g/kg were associated with an increased incidence of secondary VF, with worse outcome than primary VF. 21 In an adult out-of-hospital cardiac arrest population resuscitated successfully with early myocardial dysfunction, epinephrine was noted to be an independent factor for low ejection fraction. 22 The effect of epinephrine on the microcirculation may be an important factor in the early post-resuscitation period. Utilizing direct visualization of the sublingual capillary bed in a swine cardiac arrest model, a significant decrease in microcirculatory blood flow was noted in animals receiving epinephrine (25 g/kg). 23 This decrease was most pronounced in the first minutes following ROSC. If a similar response is found to occur in the microcirculatory flow of the myocardium after epinephrine, this could contribute to the decreased myocardial function observed. As expected with a short arrest time, there was no advantage with epinephrine during cardiac arrest. Of note, however, is the absence of cardio-depressant effects with epinephrine in the short arrest period as has been reported after longer cardiac arrests and higher doses of epinephrine. This increase in cardiac output and absence of early mortality is in contrast to a recent report of increased mortality and myocardial depression after a 1 min asphyxial rat cardiac arrest with 10 or 30 g/kg epinephrine. 24 Compared to this study we used the lower epinephrine dose, 10 g/kg and a non-asphyxial model of cardiac arrest. However, despite the increased cardiac output state noted in the 2 min epinephrine group, a significant increase in ventricular volume and a decrease in ejection fraction were noted simultaneously. These findings suggest some degree of myocardial dysfunction, albeit compensated, was present following epinephrine. An important limitation of this study is the relatively short study time frame following ROSC, which does not allow for assessment of the duration and full extent of myocardial dysfunction over time. Instead the focus of this study was on the early post-rosc myocardial depression which occurs during the very vulnerable time when a significant portion of cardiac arrest patients initially achieve ROSC, but then re-arrest and die prior to hospital admission. In a recent study only 47% of out-of-hospital cardiac arrest patients in whom ROSC was obtained survived to hospital admission. 25 This study reaffirms the importance of early epinephrine to facilitate ROSC and highlights the epinephrine dichotomy in cardiac arrest. This dichotomous epinephrine response is based on the observations that the longer the duration of cardiac arrest, the more difficult to achieve ROSC and thus the greater need for epinephrine. However, as the duration of cardiac arrest increases, the benefit of epinephrine to attain ROSC is offset by increased epinephrine mediated post-arrest myocardial dysfunction. Achieving ROSC is the first priority in cardiac arrest and only then can the secondary problem of post-arrest myocardial dysfunction be addressed. Not surprising both issues are largely dependent on the duration of cardiac arrest. Currently

9 Cardiovascular response to epinephrine 109 the recommended guidelines for epinephrine use during cardiac arrest call for the same epinephrine dose for all cardiac arrest conditions. As noted in this study, the effect of this same dose concentration is likely to vary depending on a number of factors including duration of cardiac arrest, but also likely vary according to various factors which affect the level of CPR generated blood flow. Support for this premise is found in a recent study in a swine cardiac arrest model in which epinephrine (0.02 mg/kg) was given during different chest compression protocols and significant differences in epinephrine plasma concentrations, coronary perfusion pressure, cerebral and femoral blood flow were noted during CPR. 26 Ultimately, optimization of epinephrine (or other adrenergic agents) doses during cardiac arrest must vary in accordance with specific cardiac arrest factors, such as length of arrest. Recent studies have focused on use of selective alpha-2 adrenergic agents to promote ROSC in cardiac arrest but minimize effects on postarrest myocardial function. 27,28 These agents may yet be an alternative to epinephrine use in cardiac arrest. However, more work is needed to understand the effects of these agents in the post-arrest setting, before they can be recommended. Conclusions As the duration of cardiac arrest increases, a paradoxical myocardial epinephrine response develops, in which epinephrine becomes increasingly more important for ROSC, but is increasingly associated with post-rosc myocardial depression. This study demonstrates both the benefit and detriment of epinephrine in cardiac arrest over time and re-emphasizes the need for short acting agents designed to improve ROSC without depressing post-myocardial function. Conflict of interest None. Acknowledgements This research was supported by the Roessler Scholarship Fund, Ohio State University (RL Butke), SAEM Institutional Research Training Award (CA Torres) and Ohio State Strategic Initiatives Grant and the American Heart Association Ohio Affiliate (MG Angelos). References 1. Kern KB, Hilwig RW, Berg RA, et al. Postresuscitation left ventricular systolic and diastolic dysfunction. Treatment with dobutamine. Circulation 1997;95: Tang W, Weil MH, Sun S, Gazmuri RJ, Bisera J. Progressive myocardial dysfunction after cardiac resuscitation. Crit Care Med 1993;21: Klouche K, Weil MH, Sun S, Tang W, Zhao DH. A comparison of alpha-methylnorepinephrine, vasopressin and epinephrine for cardiac resuscitation. Resuscitation 2003;57: McCaul CL, McNamara P, Engelberts D, Slorach C, Hornberger LK, Kavanagh BP. The effect of global hypoxia on myocardial function after successful cardiopulmonary resuscitation in a laboratory model. 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