Received 5 Feb 2013; first review completed 20 Feb 2013; accepted in final form 1 Apr 2013

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1 SHOCK, Vol. 39, No. 6, pp. 527Y532, 2013 QUALITY OF CARDIOPULMONARY RESUSCITATION AFFECTS CARDIOPROTECTION BY INDUCED HYPOTHERMIA AT 34-C AGAINST ISCHEMIA/REPERFUSION INJURY IN A RAT ISOLATED HEART MODEL Toshiaki Mochizuki,* Qiliang Jiang, Takasumi Katoh, Katsunori Aoki,* and Shigehito Sato Departments of *Emergency and Disaster Medicine and Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu City, Japan Received 5 Feb 2013; first review completed 20 Feb 2013; accepted in final form 1 Apr 2013 ABSTRACT In this study, we aimed to compare the effects of low- and high-quality cardiopulmonary resuscitation (CPR) on cardioprotection by induced hypothermia (IH) at 34-C and examine whether extracellular signalyregulated kinase or endothelial nitric oxide synthase mediates this cardioprotection. Left ventricle infarct sizes were evaluated in six groups of rat hearts (n = 6) following Langendorff perfusion and triphenyltetrazolium chloride staining. Controls underwent 30 min of global ischemia at 37-C, followed by 10 min of simulated low- or high-quality CPR reperfusion and 90 min of reperfusion at 75 mmhg. The IH groups underwent IH at 34-C during reperfusion. The U0126 group received U0126 (60 2M)Van extracellular signalyregulated kinase inhibitorvduring reperfusion at 34-C. The L-NIO (N 5 -(1-iminoethyl)-L-ornithine dihydrochloride) group received L-NIO (2 2M)Van endothelial nitric oxide synthase inhibitorv5 min before global ischemia at 37-C to the end of reperfusion at 34-C. Infarct size did not significantly differ between the control and IH groups receiving low-quality CPR. However, IH with high-quality CPR reduced the infarct size from 47.2% T 10.2% to 26.0% T 9.4% (P = 0.005). U0126 reversed the IH-induced cardioprotection (45.9% T 9.4%, P = 0.010), whereas L-NIO had no significant effect. Cardiopulmonary resuscitation quality affects IH-induced cardioprotection. Extracellular signalyregulated kinase may mediate IH-induced cardioprotection. KEYWORDS Langendorff isolated heart model, reactive oxygen species, left ventricular infarct size, coronary perfusion pressure, cardiopulmonary resuscitation INTRODUCTION Hypothermia is known to exert certain cardioprotective effects against ischemia/reperfusion (I/R) injuries (1Y7). Induced hypothermia (IH) has been shown to be the only treatment that improves survival in postycardiac arrest settings (8Y12). However, many patients who survive a sudden cardiac arrest (SCA) will experience an impaired functional level and quality of life because of cognitive or psychological problems and physical limitations, irrespective of whether they undergo IH (13). Although cardiac function is partly associated with these outcomes (14, 15), our previous study demonstrated that IH at 34-C produced a cardioprotective effect in a rat isolated heart model (2). Therefore, IH at 34-C in postycardiac arrest settings may potentially contribute to improved cardiac function and quality of life for patients following a SCA. The current international guidelines for cardiopulmonary resuscitation (CPR), including those from Europe and North America, recommend high-quality CPR to maintain cerebral and coronary perfusion pressure (CPP) in SCA patients (16, 17). Hypothermia exerts cardioprotective effects against I/R injuries in animal studies (1Y7). However, reports have failed to Address reprint requests to Toshiaki Mochizuki, MD, Department of Emergency and Disaster Medicine, Hamamatsu University School of Medicine, Handa-yama, Higashi-ward, Hamamatsu City, Shizuoka Prefecture, Japan. toshiaki@hama-med.ac.jp. Research support was received from a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (grant no ). The work was presented in part at the Resuscitation 2012 conference in Vienna, Austria. The authors have no conflicts of interest to declare. DOI: /SHK.0b013e318294e259 Copyright Ó 2013 by the Shock Society evaluate whether the differences in perfusion pressure during low CPP reperfusion periods affect the left ventricular (LV) infarct size. The CPR period, which was simulated by low CPP reperfusion, is invariably experienced after global ischemia periods in clinical SCA settings. Higher CPP during CPR may reduce the LV infarct size after the reperfusion period when IH at 34-C occurs. The extracellular signalyregulated kinase (ERK) and the phosphatidylinositol 3-OH kinase/akt endothelial nitric oxide synthaseynitric oxide (enos-no) cascades mediate the cardioprotective effect against an I/R injury (18). Furthermore, IH during an ischemic period preserves ERK activity (3). It remains unclear whether the quality of CPR affects IHassociated cardioprotection from I/R injury and whether ERK or enos mediates these cardioprotective effects during the reperfusion period. In out-of-hospital cardiac arrest patients, the minimum CPP required for return of spontaneous circulation (ROSC) is 15 mmhg, and 40 mmhg CPP is required to attain 100% ROSC (19). Therefore, the primary objectives of this study were to compare the effects of 15 mmhg as a Blow[-quality CPR, 40 mmhg as a Bhigh[-quality CPR, and IH during simulated CPR on the LV infarct size in a rat isolated heart model. We also examined whether ERK and enos mediate a decrease in the LV infarct size. MATERIALS AND METHODS This study was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The study protocol was approved by the Committee on the Ethics of Animal Experiments of Hamamatsu University School of Medicine (Hamamatsu City, Japan; permit no ). All surgeries were performed under diethyl ether anesthesia, with care taken to minimize discomfort. The isolated rat heart model was prepared, 527

2 528 SHOCK VOL. 39, NO. 6 and hemodynamic variables including an evaluation of the LV infarct size were measured after conclusion of the Langendorff perfusion, as previously described (2). Thirty-six male Sprague-Dawley rats with body weights of 396 to 438 g were anesthetized and then heparinized (300 IU/kg), before they were killed by excision of the heart. Diethyl ether was used as an inhalational anesthetic because it has a minimum effect on cardiac function when administered for a brief period of time. The hearts were first isolated and cannulated and then perfused at a constant pressure of 75 mmhg with a modified Krebs-Henseleit buffer (mkhb: NaCl, 118 mm; KCl, 4.7 mm; MgCl2, 1.24 mm; CaCl2, 1.24 mm; NaHCO3, 25 mm; KH2PO4, 1.24 mm; and glucose, 11 mm) saturated with 95% O2 + 5% CO2. The hearts were then divided into six groups of six hearts each: the low- and high-quality control groups, in which the hearts underwent 30 min of global ischemia by cessation of all perfusion, 10 min of reperfusion at 15 or 40 mmhg (i.e., simulated low- or high-quality CPR reperfusion, respectively) and reperfusion for 90 min with the circulatory temperature maintained at 37-C throughout the study; the low- and high-quality IH groups, in which the hearts underwent IH at 34-C from the time of simulated low- or high-quality CPR reperfusion to the end of the study, respectively; and the U0126 and the L-NIO (N5-(1-iminoethyl)-L-ornithine dihydrochloride) groups, in which the hearts underwent IH at 34-C from the time of simulated high-quality CPR reperfusion to the end of the study. The U0126 group was administered 60 2M of the ERK inhibitor U0126 (Promega KK, Tokyo, Japan) from the time of simulated high-quality CPR reperfusion to the end of the study, and the L-NIO group was administered 2.0 2M of the enos inhibitor L-NIO (Tocris Bioscience, Bristol, United Kingdom) starting 5 min before the 30 min of global ischemia to the end of the study (Fig. 1). U0126 was initially dissolved in dimethyl sulfoxide at 1 mg/ml before subsequent dilution to the final concentration in mkhb. Dimethyl sulfoxide had no effect on the isolated heart model in the study. We used L-NIO as the enos inhibitor because the half maximal (50%) inhibitory concentration dose for enos is 0.5 2M at 37-C, whereas the half maximal (50%) inhibitory concentration dose for inducible nitric oxide synthase is 2.2 2M at 37-C according to the manufacturer s data. Our isolated heart perfusion system has two separate perfusion channels. One channel was prepared to perfuse only mkhb, whereas the second consisted of mkhb with specific concentrations of U0126 or L-NIO. By switching the stopcock, the perfusate was changed accordingly. Each CPP was adjusted by changing the height of the water level in the column of the Langendorff apparatus. We induced hypothermia by pouring iced water into the thermostat of the water-jacketed system (Fig. 2). In each experiment, a blind observer determined the cooling time, defined as the time from the initiation of cooling to the point at which the circulatory temperature first reached 34-C. In our preliminary study, we found that adding 20 2M or 40 2M of U0126 or 1.5 2M or 2.0 2M of L-NIO from the time of simulated high-quality CPR reperfusion to the end of the study did not reverse the LV infarct size (each n = 3, 23.2% T 10.3% [P vs. high-quality IH group], 37.1% T 3.1% [P vs. high-quality IH group], 34.6% T 8.4% [P vs. high-quality IH group], 30.4% T 4.5% [P vs. high-quality IH group], respectively). In this study, we therefore chose to administer 60 2M of U0126 and 2.0 2M of L-NIO 5 min before the 30-min global ischemia period. With the exception of the circulatory temperatures and CPPs, all data were analyzed by a two-way repeated-measures analysis of variance. When the repeated-measures analysis of variance was significant (P G 0.05), a post hoc FIG. 1. Study protocol. U0126 is an ERK inhibitor, whereas L-NIO is an enos inhibitor. MOCHIZUKI ET AL. FIG. 2. Langendorff apparatus. Iced water was poured into the thermostatically controlled water-jacketed system to induce hypothermia. The circulatory temperature was measured by a thermocouple placed at the distal end of the water-jacketed system. Coronary perfusion pressure was adjusted by changing the height of the water level in the column of the Langendorff apparatus. ECG indicates electrocardiogram; LV, left ventricle Tukey-Kramer test was applied by using the Aabel 3 software (Hulinks Inc, Tokyo, Japan). To determine the sample size, we estimated the upper one-sided limit of the 90% confidence interval of the SD of an 11.9% LV infarct size based on a preliminary study, which consisted of the following groups: low-quality control group, low-quality IH group, high-quality control group, and high-quality IH group (each n = 3). We subsequently determined that the minimal clinically important treatment difference between the control and IH groups was 20% of the LV infarct size. Based on these results, we estimated a required sample size of four animals with an! of 0.05 and a " of 0.1. In anticipation of potential dropouts or incomplete studies, we selected a sample size of six animals per group. Data are expressed as the means T SD. Statistical significance was considered for P G RESULTS Induced hypothermia at 34-C failed to significantly reduce the LV infarct size from 53.3% T 5.2% in the low-quality control group to 43.1% T 6.9% in the low-quality IH group (P = 0.413; Fig. 3). However, it significantly reduced the infarct size from 47.2% T 10.2% in the high-quality control group to 26.0% T 9.4% in the high-quality IH group (P = 0.005; Fig. 4). These findings indicated that IH at 34-C during simulated CPR reduced the LV infarct size when the CPP was maintained at 40 mmhg, but not when it was maintained at 15 mmhg. U0126 reversed the IH-associated reduction of the LV infarct size to 45.9% T 9.4% (P = 0.010, vs. the high-quality IH group). However, there were no significant differences in the LV infarct size (31.1% T 12.3%) when comparing the L-NIO group to the high-quality control group (P = 0.055) or to the high-quality IH group (P 9 0.5; Fig. 4). The cooling times were within 5 min in all groups subjected to IH at 34-C. Table 1 compares the hemodynamic variables among the four groups, whereas Table 2 compares the ratio of coronary flow to heart weight (HW), CPP, and circulatory temperatures. Although not statistically significant, coronary flow appeared to decrease when CPPs were reduced from 40 mmhg to 15 mmhg during the simulated reperfusion periods, from 1.64 T 0.42 ml/min per gram of HW (high-quality control group) to 0.05 T 0.01 ml/min per gram of HW (low-quality control group) and

3 SHOCK JUNE 2013 CPR AFFECTS CARDIOPROTECTION BY HYPOTHERMIA 529 FIG. 3. Changes in LV infarct sizes among the low-quality CPR reperfusion groups. Therewasnodifferenceinresultinginfarctsize between control and IH groups receiving low-quality CPR (P = 0.415) T 0.50 ml/min per gram of HW (high-quality IH group) to 0.05 T 0.01 ml/min per gram of HW (low-quality IH group), respectively. DISCUSSION Our study demonstrated that IH at 34-C during simulated CPR reduced the LV infarct size if the CPP was maintained at 40 mmhg but not at 15 mmhg. Thus, the quality of CPR affected the cardioprotective effect of IH against an I/R injury. Furthermore, the ERK inhibitor U0126 reversed the cardioprotective effect of IH at 34-C. In contrast, the enos inhibitor L-NIO did not have a statistically significant effect on the cardioprotection exerted by IH. It has previously been shown that, in 100 patients who experienced an out-of-hospital cardiac arrest, the minimum CPP required for ROSC was 15 mmhg, and a CPP of 40 mmhg resulted in 100% ROSC (19). In view of these results, we compared 15 mmhg as low-quality CPR to 40 mmhg as high-quality CPR. A cardiomyocyte model of I/R injury demonstrated that cardiomyocytes tolerated ischemia but sustained an accelerated injury associated with a burst of mitochondrial reactive oxygen species (ROS) within 5 min of reperfusion (5, 20). Furthermore, ischemia and reperfusion generate substances that are cytotoxic to the heart, including ROS (21, 22). We previously reported that IH at 34-C during the reperfusion period provided cardioprotection against I/R injury in the rat isolated heart model (2). Therefore, in this study, we hypothesized that a CPP of 40 mmhg rather than 15 mmhg was sufficient to remove the cytotoxic substances, including ROS, thus facilitating the cardioprotection conferred by IH at 34-C in isolated hearts for the first 10 min of reperfusion after global ischemia. Furthermore, it was reported that low-pressure reperfusion, which was similar to our high-quality groups, preserved adenosine triphosphate through myocardial acidosis during the reperfusion period (23). The myocardial acidosis caused by low-pressure reperfusion might have affected LV infarct sizes in this study. Hypothermia exerts cardioprotective effects against I/R injuries (1Y7). However, reports have failed to evaluate whether low CPP alters the cardioprotective effect of IH against I/R injury. This evaluation is clinically important as low CPP invariably occurs between periods of global ischemia and high CPP reperfusion, which originate from ROSC in CPR settings. In this study, during the low reperfusion period, the CPP of 40 mmhg, and not 15 mmhg, restored the cardioprotective effect of IH at 34-C against I/R injury. In clinical SCA settings, high-quality CPR, as often as possible, may maximize the cardioprotective effect of IH against I/R injuries. It was reported that, in patients with out-of-hospital cardiac arrest, emergency cardiopulmonary bypass (CPB) was useful for achieving early induction of hypothermia during cardiac arrest and improving neurological outcomes (11). The emergency CPB technique, including percutaneous cardiopulmonary support, may be effective for maintaining sufficient CPP and for inducing hypothermia as soon as possible. Therefore, we recommend the combination of emergency CPB and IH during CPR in patients with out-of-hospital cardiac arrest for optimal cardioprotection against I/R injury. The advantageous effects of a reduced perfusion rate and lower perfusion pressure from an I/R injury on cardiac function and high-energy phosphate compounds during the reperfusion period have been previously reported (24); furthermore, cardiac function and tissue cations (25), cardiac function and the bioenergetic recovery (26), infarct size, phosphatidylinositol 3-OH kinase, and mitochondrial permeability transition (27, 28) also show some benefit. However, no study has examined the use of a reduced perfusion rate and lower perfusion pressure as simulation tools to evaluate the effect of the quality of CPR. FIG. 4.Changes in LV infarct sizes among the high-quality CPR reperfusion groups. Compared with the control group, LV infarct size was reduced when IH at 34-C was initiated in simulated high-quality CPR (P = 0.005). Furthermore, U0126, an ERK inhibitor, reversed the reduction of LV infarct sizes by hypothermia (P =0.010).L-NIO had no statistically significant effect. *P G 0.05, vs. the high-quality control group. P G 0.05, vs. the high-quality IH group.

4 530 SHOCK VOL. 39, NO. 6 MOCHIZUKI ET AL. TABLE 1. Comparison of hemodynamic variables Baseline End of simulated CPR reperfusion 30 min After reperfusion 90 min After reperfusion LVDP, mmhg Low-quality control 73 T T T T 26 Low-quality IH 84 T 12 4 T 9 21 T T 10 High-quality control 69 T T T T 15 High-quality IH 75 T T T T 25 U T T T T 11 L-NIO 79 T T T T 20 LVSP, mmhg Low-quality control 80 T T T T 11 Low-quality IH 91 T T T T 6 High-quality control 75 T9 76 T T T 12 High-quality IH 82 T T T T 9 U T T T T 6 L-NIO 85 T T T 7 97 T 28 LVEDP, mmhg Low-quality control 7 T 1 23 T 9 60 T T 24 Low-quality IH 7 T 1 26 T 7 70 T T 13 High-quality control 6 T 2 27 T 9 35 T T 17 High-quality IH 6 T 1 31 T T T 23 U T 0 32 T 6 55 T T 10 L-NIO 6 T 2 35 T 7 53 T T 16 dp/dt max, mmhg/s Low-quality control 2,257 T T T 563 1,397 T 791 Low-quality IH 2,550 T T T 269 1,200 T 288 High-quality control 2,268 T 303 1,221 T 572 1,878 T 794 2,046 T 407 High-quality IH 2,170 T 165 1,274 T 272 1,422 T 809 1,662 T 719 U0126 2,367 T 288 1,073 T 513 1,110 T 261 1,530 T 218 L-NIO 2,151 T T 523 1,128 T 439 1,447 T 368 dp/dt min, mmhg/s Low-quality control j1,635 T 227 j223 T 94 j562 T 363 j1,006 T 600 Low-quality IH j1,913 T 261 j177 T 53 j458 T 251 j909 T 217 High-quality control j1,529 T 255 j937 T 476 j1,469 T 593 j1,469 T 322 High-quality IH j1,691 T 170 j739 T 332 j1,030 T 561 j1,154 T 384 U0126 j1,773 T 213 j741 T 312 j914 T 224 j1,152 T 158 L-NIO j1,872 T 208 j744 T 378 j936 T 484 j1,114 T 269 HR, beats/min Low-quality control 289 T 31 5 T T T 43 Low-quality IH 262 T 36 4 T T T 31 High-quality control 270 T T T T 43 High-quality IH 248 T T T T 42 U T T T T 27 L-NIO 274 T T T T 17 The data are presented as the means T SD. The LVDP, LVSP, LVEDP, HR, dp/dt max, and dp/dt min remained constant throughout the study. LVDP indicates LV developed pressure; LVSP, LV systolic pressure; LVEDP, LV end-diastolic pressure; HR, heart rate; dp/dt max, maximum rate of rise of LV pressure; dp/dt min, minimal rate of rise of LV pressure. In particular, no previous studies have evaluated low perfusion pressure in a manner relevant to CPR. To our knowledge, this is the first study that clarifies that the quality of CPR affects the cardioprotective effect of IH against I/R injury. We regarded the high-quality CPR groups of this study as the sole I/R model because the LV infarct size was similar to our previous study, which used the same model (2). Although we examined only one ERK inhibitor and did not investigate ERK knockdown animals in this study, we were able to demonstrate that ERK might mediate the cardioprotective effect of IH against an I/R injury during the reperfusion period. A previous study demonstrated that U0126 (1 2M) reduced the expression of phospho-erk 1/2 in the intact LV of the rat isolated heart model (29). U0126 administered during the reperfusion period might reduce the expression of phospho-erk and thus remove the cardioprotective effect of IH against I/R injury during the reperfusion period in this study. Furthermore, it has been reported that, in a rabbit isolated heart model, IH during

5 SHOCK JUNE 2013 CPR AFFECTS CARDIOPROTECTION BY HYPOTHERMIA 531 TABLE 2. Comparison of coronary flow to HW, CPP, and circulatory temperature Baseline End of simulated CPR reperfusion 30 min After reperfusion 90 min After reperfusion CF/HW, ml/min per gram of HW Low-quality control 8.45 T 1.62* 0.05 T T 1.11* 5.20 T 1.00* Low-quality IH 8.57 T 1.74* 0.05 T T 1.72* 5.27 T 1.55* High-quality control 7.94 T 1.53* 1.64 T T 1.53* 5.18 T 1.32* High-quality IH 8.47 T 1.74* 1.76 T T 2.49* 5.90 T 3.18* U T 0.92* 1.58 T T 0.92* 4.71 T 1.71* L-NIO 7.82 T 1.70* 1.75 T T 1.70* 6.01 T 3.34* CPP, mmhg Low-quality control 77 T 2 15 T T 2 79 T 2 Low-quality IH 76 T 2 15 T T 2 79 T 2 High-quality control 79 T 1 39 T 2 80 T 1 81 T 2 High-quality IH 77 T 3 40 T 1 79 T 1 79 T 1 U T 2 40 T 1 77 T 1 78 T 1 L-NIO 78 T 2 40 T 0 79 T 1 80 T 2 Circulatory temperature, -C Low-quality control 37.1 T T T T 0.4 Low-quality IH 37.0 T T T T 0.2 High-quality control 37.0 T T T T 0.2 High-quality IH 37.0 T T T T 0.2 U T T T T 0.1 L-NIO 37.1 T T T T 0.3 The data are presented as the means T SD. *P G 0.05 vs. the end of simulated CPR value within the group. P G 0.05 vs. the baseline value within the group. CF indicates coronary flow. ischemia facilitates the preservation of ERK activity (3). Hence, IH preserves ERK during global ischemia and may thus be cardioprotective during the reperfusion period. The expression of phospho-erk 1/2 was preserved after the reperfusion period and when hypothermia was induced during the ischemia period in the rabbit isolated heart model (3). Although Akt is an important survival kinase that results in increased I/R tolerance when it is overexpressed in cardiomyocytes, it is also a key regulator of NO through the activation of enos, which is downstream of Akt in the survival pathway. One report showed that IH is associated with increased NO generation in a simulated I/R model of chick cardiomyocytes (7). Furthermore, IH increased Akt phosphorylation by the end of ischemia at the Thr308 and Ser473 sites in a simulated I/R model of rat cardiomyocytes (5). Therefore, there was no direct evidence that enos was expressed by IH against I/R injury; we believed that both ERK and enos play key roles in the cardioprotection conferred by IH against I/R injury. However, L-NIO did not have a significant effect on the cardioprotection by IH at 34-C against I/R injury. We withhold the conclusion whether enos mediates the cardioprotective effect of IH at 34-C against I/R injury in this study. The assessment of recovery from an I/R injury using the Langendorff-isolated perfused heart preparation is limited by the denervation of hearts during the isolation process. In this model, spontaneous HR and coronary flow differ from the in vivo situation. Moreover, the effects of the inflammatory response mediated by white blood cells carried through the returning blood flow were not considered. Nevertheless, the isolated heart model has important advantages in evaluating the effects of altered systemic hemodynamics, such as preload and afterload, and appraising changes in the humoral and autonomic nervous systems. The ph, electrolyte, glucose, and perfusate gas concentrations can also be maintained at constant levels, and continuous administration of anesthetics is unnecessary. The target circulatory temperatures and CPPs can also be easily changed or maintained constant. Finally, global ischemia produced in this model simulated clinical SCA. Our study found that IH at 34-C during reperfusion reduced the LV infarct size if the CPP was maintained at 40 mmhg, and not at 15 mmhg, during the first 10 min of reperfusion. In clinical SCA settings, high-quality CPR, as often as possible, may therefore maximize the cardioprotective effect of IH against I/R injuries. Furthermore, ERK mediated the cardioprotective effect of IH at 34-C during reperfusion. REFERENCES 1. Tissier R, Ghaleh B, Cohen MV, Downey JM, Berdeaux A: Myocardial protection with mild hypothermia. Cardiovasc Res 94:217Y225, Mochizuki T, Yu S, Katoh T, Aoki K, Sato S: Cardioprotective effect of therapeutic hypothermia at 34-C against ischaemia/reperfusion injury mediated by PI3K and nitric oxide in a rat isolated heart model. Resuscitation 83:238Y242, Yang X, Liu Y, Yang X-M, Hu F, Cui L, Swingle MR, Honkanen RE, Soltani P, Tissier R, Cohen MV, et al.: Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity. Basic Res Cardiol 106: 421Y430, Chenoune M, Lidouren F, Ghaleh B, Couvreur N, Dubois-Rande J-L, Berdeaux A, Tissier R: Rapid cooling of the heart with total liquid ventilation prevents transmural myocardial infarction following prolonged ischemia in rabbits. Resuscitation 81:359Y362, 2010.

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