American Journal of Emergency Medicine 31 (2013) 1690–1696
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American Journal of Emergency Medicine
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Original Contribution
Differences of postresuscitation myocardial dysfunction in ventricular fibrillationversus asphyxiation☆,☆☆
Cai-Jun Wu, MD, Chun-Sheng Li, MD⁎, Yi Zhang, MD, Jun Yang, MM, Qin Yin, MD, Chen-Chen Hang, MMDepartment of Emergency, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
a b s t r a c ta r t i c l e i n f o
☆ Sources of funding: This study was supported boundation (No. 81372025).☆☆ Conflict of interest statement: The authors repor⁎ Corresponding author. Department of Emergenc
Received 28 June 2013Received in revised form 6 August 2013Accepted 9 August 2013
Purpose: This study aims to characterize postresuscitation myocardial dysfunction in 2 porcine models ofcardiac arrest (CA): ventricular fibrillation cardiac arrest (VFCA) and asphyxiation cardiac arrest (ACA).Methods: Thirty-two pigs were randomized into 2 groups. The VFCA group (n = 16) were subject toprogramed electrical stimulation, and the ACA group (n = 16) underwent endotracheal tube clamping toinduce CA. Once induced, CA remained untreated for 8 minutes. Two minutes after initiation of
cardiopulmonary resuscitation (CPR), defibrillation was attempted until return of spontaneous circulation(ROSC) was achieved or animals died.Results: Return of spontaneous circulation was 100% successful in VFCA and 50% successful in ACA.Cardiopulmonary resuscitation duration in VFCA was about half as short as in ACA. The survival time of VFCAwas significantly longer than that of ACA. Ventricularfibrillation cardiac arrest had bettermean arterial pressure,cardiac output, and left ventricular ± dp/dtmax after ROSC than ACA. Echocardiography revealed significantlylower left ventricular ejection fraction in ACA than in VFCA. Myocardial perfusion imaging using single-photonemission computed tomography demonstrated that myocardial injuries after ACA were more severe andwidespread than after VFCA. Under a transmission electronmicroscope, the overall heart morphologic structureand the mitochondrial crista structure were less severely injured in the VFCA group than in the ACA group.Moreover, the percentage of apoptotic cardiomyocytes was higher in ACA than in VFCA.Conclusions: Compared with VFCA, ACA causes more severe cardiac dysfunction associated with less successfulresuscitation and shorter survival time.
Cardiopulmonary resuscitation (CPR) yields a functional survivalrate of only 1.4% to 5% [1]. Profound postresuscitation myocardialdysfunction has been demonstrated in both laboratory and clinicalstudies [2-5]. Insights into the pathophysiological processes ofpostresuscitation myocardial dysfunction have, at least in part, beengained from animal studies. It is generally accepted that the closer theanimal models resemble human diseases, the more reliable is theextrapolation of results from animal studies.
The 2most prevalent causes of sudden cardiac death are ventricularfibrillation cardiac arrest (VFCA) and asphyxiation cardiac arrest (ACA)[6]. Correspondingly, VFCA and ACA are the 2 most frequently usedanimal models of CA in basic research that mirror more closely theclinical course of CA and CPR [7-9]. The development of ACA is gradualin contrast to the pulselessness and loss of consciousness after the
y the Beijing Natural Science
t no conflicts of interest.y, Beijing Chao-Yang Hospital,010 85231051.
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l rights reserved.
sudden onset of ventricular fibrillation (VF). It is well known thatpostresuscitation syndrome can be established and myocardialdysfunction is a critical issue contributing to low survival rates inthese 2 CA animal models. However, the strategies for resuscitation onunresponsive victims whose pathology cannot be immediately iden-tified by rescuers are identical. To date, there have been no consentguidelines or common criteria for selection of CA models forexperimental studies on CPR; thus, even under identical experimentalconditions, results from using ACA or VFCA have been largely variable[6,10-12]. We hypothesized that VFCA and ACA are 2 distinct models ofCA that can cause different secondary myocardial dysfunctions andderangements after return of spontaneous circulation (ROSC). Thepurpose of this study was to examine this hypothesis by carrying outcomprehensive comparative analyses on the characteristics of cardiacfunction and structure in pig models of VFCA and ACA.
2. Methods
2.1. Preparation of animals
This prospective, randomized, animal study was conducted withthe approval of the Animal Care and Use Committee of ChaoyangHospital, affiliated with the Capital Medical University. The study was
Fig. 1. Survival function analysis of animals after ROSC in the VFCA group (n = 16) andACA group (n = 16).
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performed according to Utstein-style guidelines [13] on 32 healthyWu Zhishan inbred miniature pigs of both sexes aged 6 to 8 monthsand weighing 20 ± 2 kg. Before experimental procedures, animalswere randomized into 2 groups in a blinded manner: VFCA group(n= 16) and ACA group (n= 16). The number of animals used in thisstudy was determined on the basis of our pilot study and wasanticipated to ensure an adequate statistical power for ROSC analysis.
Initial sedation in each animal was achieved by intramuscularinjection of ketamine (10 mg/kg), followed by ear vein injection ofpropofol (1.0 mg/kg). The anesthetized animals were intubated with a6.5-mm cuffed endotracheal tube via direct laryngoscopy. Propofol (1.0mg/kg) and fentanyl (4 μg/kg) were then administered intravenouslyto reach the desired depth of anesthesia and analgesia, followed by 9mg kg−1 h−1 propofol and fentanyl 1 μg kg−1 h−1 (intravenously [IV])to maintain the anesthesia level. Additional doses of these drugs wereadministered when the heart rate exceeded 120 beats per minute and/or the systolic blood pressure exceeded 120 mm Hg. Animals weremechanically ventilated with a volume-controlled ventilator (Servo900c, Siemens, Berlin, Germany) using a tidal volume of 8 mL/kg and arespiratory frequency of 12/min with room air. End-tidal PCO2 wasmonitored with an inline infrared capnography system (CO2SMO Plusmonitor, Respironics Inc, Murrysville, Pennsylvania). The respiratoryfrequency was adjusted to maintain end-tidal PCO2 between 35 and 40mm Hg. Aortic pressure was measured with a fluid-filled catheteradvanced from the left femoral artery into the thoracic aorta. A Swan-Ganz catheter (7F; Edwards Life Sciences, Irvine, California) wasadvanced from the left femoral vein and flow-directed into thepulmonary artery to measure right atrial pressure and cardiac output(CO) and to collect the mixed venous blood. Cardiac output wasdetermined by the thermodilution technique. A 5F pacing catheter wasadvanced from the right internal jugular vein into the right ventricle toinduce VF. Left ventricular (LV) function was measured using a fluid-filled polyurethane catheter that was introduced from the right carotidartery to the LV to determine themaximum rate of LV pressure increase(+dp/dtmax) or decline (−dp/dtmax) (BL-420F Data Acquisition &Analysis System, China). All catheters were calibrated before use, andtheir tip positions were confirmed by the presence of characteristicpressure traces. An electrocardiographwas continuously recordedwitha multichannel physiological recorder (BL-420F Data Acquisition &Analysis System). All hemodynamic parameters were monitored by amultifunction monitor (M1165; Hewlett-Packard Co, Palo Alto,California). Total fluid management consisted of 250 to 500 mL ofnormal saline solution administered intravenously throughout the 2- to3-hour preparatory period.
2.2. Experimental protocols
After surgery, the animals were allowed to equilibrate for 60minutes to achieve a stable resting level, and then baseline data werecollected. In the VFCA group, VF was induced by programed electricalstimuli (GY-600A; KaiFeng Huanan Instrument Co, Kaifeng, Henan,China) and was verified by the presence of a characteristicelectrocardiographic waveform and an immediate drop in aorticblood pressure. In the ACA group, animals were paralyzed withcisatracurium (0.2 mg/kg) to avoid gasping, and then CA was inducedby clamping the endotracheal tube. The animals were asphyxiated
Table 1Characteristics of the baseline measurements (means ± SD)
until simulated pulselessness was observed, defined as an aorticsystolic pressure less than 30 mm Hg [7].
After CA had been successfully induced, mechanical ventilationand anesthetic/analgesic administration were ceased, and the endo-tracheal tube was opened in the ACA group. After 8 minutes ofuntreated CA (equivalent to the average time it takes for emergencymedical services to arrive [14]), mechanical ventilation was resumedwith 100% oxygen, and CPR was performed manually. Manual chestcompressions were conducted by a designated CPR technician whocompressed approximately one third of the anteroposterior diameterof the thorax at a rate of 100 compressions per minute with equalcompression-relaxation duration. The quality of chest compressionswas controlled by a HeartStart MRx Monitor/Defibrillator with Q-CPR(Philips Medical Systems, Best, Holland).
After 2minutes of CPR, epinephrine (0.02mg/kg) was injected intothe right atrium, and then CPR was performed manually for another 2minutes. After 4 minutes of CPR, defibrillation (SMART Biphasic) wasattempted using 4 J/kg for the first attempt. Cardiopulmonaryresuscitation was resumed for another 2 minutes after the attempteddefibrillation. The sequence continued until ROSC or for 30 minutes ifROSC was not achieved. Return of spontaneous circulation wasdefined as the maintenance of a systolic blood pressure 50 mm Hgor greater for 10 min or more.
The animals, in which spontaneous circulation was restored,received intensive care for 6 hours, and mechanical ventilation wasresumed with the same settings as before CA. In 6 hours after ROSC,dopaminewas injected tomaintain the systolic blood pressure 50mmHg or greater if the systolic blood pressure less than 50mmHg and theinitial dosage of dopamine was 2 μg kg−1 min−1. After 6 hours ofpostresuscitation monitoring, all catheters were removed by surgicalprocedure [15]. Six hours after ROSC, the animals were killed with abolus of propofol 60 mg (IV) and then 20 mL of 10 mol/L potassiumchloride (IV).
2.3. Echocardiography
Echocardiography was conducted by an observer blinded to theexperiment, andmeasurementswere taken before CA and at 3.5 hoursafter ROSC. A 2- or 4-chamber long-axis view was obtained using theHewlett-Packard Sonos 2500 echocardiographic system (Hewlett-Packard, Andover, Massachusetts) with a 5.5/7.5-Hz biplane Dopplertransesophageal echocardiographic transducer and a four-way
Fig. 2. Comparison of cardiac function and hemodynamic parameters between VFCA and ACA groups. The measurements were made at baseline and varying time points up to 6hours after ROSC. Heart rate (A); MAP (B); CO (C); LV+dp/dtmax (D); LV−dp/dtmax (E). The values are presented asmean± SD. *P b .05 and **P b .01 vs baseline (one-way repeated-measures analysis of variance); #P b .05 and ##P b .01 vs ACA group (Student t test).
Table 2Echocardiographic measurements at baseline and 3.5 hours after successfulresuscitation
Abbreviations: LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricularend-systolic diameter; EF, ejection fraction. Values are presented as mean ± SD.*P b .05 vs baseline (paired t test).#P b .05 vs VFCA (Student t test).⁎⁎ P b .01 vs baseline (paired t test).## P b .01 vs VFCA (Student t test).
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flexure. Left ventricular end-systolic (LVESV) and end-diastolicvolumes (LVEDV) were calculated by the disk method (AcousticQuantification Technology, Hewlett-Packard). These parameters wereused to determine LV ejection fraction (LVEF).
2.4. Myocardial perfusion imaging
To assess myocardial perfusion, we performed technetium Tc 99mhexakis-2- methoxyisobutylisonitrile (Tc-99m-MIBI) single-photonemission computed tomography (SPECT) at baseline and 4 hours afterROSC. The SPECT image of the LVwas divided into 17 semiquantifiablesegments for assessment of the regional defect score. Severity ofperfusion deficit for each segment was visually graded by assigningscores between 0 and 4 (0, normal tracer uptake; 1, mildly reducedtracer uptake; 2, moderately reduced tracer uptake; 3, obviouslyreduced tracer uptake; and 4, absent tracer uptake) [4]. A score 1 orhigher indicated a significant perfusion deficit. Scores for all 17segments were added to create a summed score of perfusion (SSP)and were calculated by 2 experienced cardiologists who wereunaware of any clinical data for this study.
2.5. Pathologic examination and TUNEL assay
After the animals were killed at 6 hours after ROSC, the heart wasexcised and the right ventricle and both atria were removed. Leftventricular tissue samples were quickly dissected and preserved in10% formaldehyde and 4% paraformaldehyde for pathologic exami-nations of tissue ultramicrostructure under a transmission electronmicroscope (TEM) by one experienced pathologists whowas unawareof any clinical data for this study. Terminal deoxynucleotidyltransferase mediated 2-deoxyuridine 5-triphosphate nick end label-
ing (TUNEL) assay was used to label cells that suffered severe DNAdamage/fragmentation induced by apoptotic signaling cascades. TheTUNEL-positive cells were counted by 2 experienced pathologists whowere unaware of any clinical data for this study to determine theapoptotic index (AI). AI = (apoptotic cells stained brown)/(totalTUNEL-positive cells).
2.6. Statistical analysis
Statistical analysis was performed using SPSS 17.0 software (SPSSInc, Chicago). Data are shown as mean ± SD. Continuous variableswere compared between groups using the Student t test. One-wayrepeated-measures analysis of variance or paired t test was used todetermine differences over time within groups, as appropriate, andthe Bonferroni t test for multiple comparisons. A log-rank test was
Fig. 3. Examples of porcine cardiac perfusion at rest by Tc-99m-MIBI SPECT obtained at baseline and 4 hours after ROSC. A, Myocardial perfusion imaging before cardiac arrest; B,myocardial perfusion imaging of the VFCA group 4 hours after successful resuscitation; C, myocardial perfusion imaging of the ACA group 4 hours after successful resuscitation. Thebright areas indicate blood flow. In (C), the axial direction was different from (A) and (B).
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Fig. 4. The SSP of myocardial perfusion imaging of the VFCA group (n = 14) and theACA group (n = 7) at baseline and 4 hours after successful resuscitation. The SPECTimage of the left ventricle was divided into 17 semiquantifiable segments forassessment of the regional defect score. Severity of perfusion deficit for each segmentwas visually graded by assigning scores between 0 and 4 (0, normal tracer uptake; 1,mildly reduced tracer uptake; 2, moderately reduced tracer uptake; 3, obviouslyreduced tracer uptake; and 4, absent tracer uptake). Scores for all 17 segments wereadded to create an SSP. We found that the SSP was significantly increased in bothgroups at 4 hours after successful resuscitation when compared with baseline. Inaddition, this increase was more in the ACA group when compared with the VFCAgroup. Deep black represents the VFCA group, and light gray represents the ACA group.**P b .01 vs baseline (paired t test); ##P b .01 vs VFCA group (Student t test).
Fig. 5. Images showing the ultrastructural changes of the myocardial ultramicrostructure 6Ventricular fibrillation cardiac arrest animals (A and C) demonstrated less degrees of ultrfibrillation cardiac arrest hearts showed no obviously broken myofilaments. Most of the mitbroken with vague mitochondrial cristae. By comparison, in ACA hearts, myocardial fiber, mMost of the mitochondria were severely broken with vacuolar degeneration and deranged
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used for survival analysis. Fisher exact test was used for ROSC analysis.A two-sided P b .05 was considered statistically significant.
3. Results
3.1. Characteristics of animals and dosages of vasopressors
The extra doses of propofol and fentanyl administered during thepreparatory phase did not differ significantly between the groups(propofol: 121± 11 vs 123± 9mg and fentanyl: 73± 9 vs 71± 10 μgin the VFCA and ACA group, respectively). The characteristics andbaselinemeasurements were not significantly different between the 2groups of animals (Table 1).
The average dosages of vasopressors used in resuscitated animalsin the VFCA group were lower than those in the ACA group(epinephrine: 0.03 ± 0.01 vs 0.07 ± 0.02 mg/kg and dopamine:1.97 ± 1.30 vs 7.57 ± 1.76 μg kg−1 min−1).
3.2. Comparison of survival function and arrhythmias
CAwas induced in all animals in both study groups. The duration ofasphyxia between clamping of the tube and CA ranged between 13and 18 minutes (15.4 ± 1.3 min). Return of spontaneous circulationwas achieved in 16 (100%) of 16 of the VFCA animals and in only8 (50%) of 16 of the ACA animals (P b .01). At the observation endpoint of 6 hours after ROSC, 14 animals survived in VFCA group and 6animals in ACA group. Six-hour survival function analysis (6 hours
hours after successful resuscitation (magnification: A and B, ×4000; C and D, ×10000).astructural deterioration in cardiomyocytes than ACA animals (B and D). Ventricularochondria and myocardial fiber were normal, and only a small proportion was partiallyyocomma, and cross striation were obviously disordered, broken, and even dissolved.or disrupted cristae.
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after ROSC was observation end point in this study and then theanimals were killed to obtain their heart tissues) indicated that theaverage survival time in VFCA (n = 16) was longer than in the ACAgroup (n = 16) (5.7 ± 0.2 vs 2.4 ± 0.9 hours, P b .01; Fig. 1).
At 8 minutes after untreated CA, all animals in the VFCA groupdeveloped persistent VF, whereas in the ACA group, VF occurred in 5,pulseless electrical activity occurred in 1, and asystole occurred in 10animals. Asystole and pulseless electrical activity did not deterioratein VF in ACA group.
3.3. Comparisons of hemodynamic parameters
Heart rate, mean arterial pressure (MAP), CO, +dp/dtmax, and−dp/dtmax at baseline did not differ significantly between the VFCAand ACA groups (P N 0.05; Fig. 2). The values of CO, +dp/dtmax,and −dp/dtmax were significantly decreased after ROSC relative tothe baseline values in both groups (P b .05; Fig. 2). The values ofthese parameters were significantly greater in the VFCA group thanof those in the ACA group 1 to 6 hours after ROSC (P b .05; Fig. 2),indicating less severe impairment of LV function in VFCA animals.
3.4. Left ventricular function as reported by echocardiography
The baseline values of LV end-diastolic diameter, LV end-systolicdiameter, LVEDV, LVESV, and LVEF were in the same range for theVFCA and ACA animals. However, 3.5 hours after ROSC, LVEF declinedsignificantly from the baseline value in both groups (P b .05), but theextent of reduction was greater in the ACA animals than in the VFCAanimals, resulting in a significantly higher LVEF in the VFCA groupthan in the ACA (0.45 ± 0.04 vs 0.31 ± 0.06, P b .01; Table 2).
Fig. 6. Representative images of TUNEL staining of myocardial apoptosis 6 hours aftersuccessful resuscitation (original magnification, ×400). There were significantly highernumbers of apoptotic cells in the ACA group (B) than in the VFCA group (A). Brownnucleolus indicated apoptotic cardiomyocytes.
3.5. Left ventricular function as reported by myocardialperfusion imaging
Severe radioactive sparse defects in the inferior, posterior, andanterior wall of the left ventricle in both VFCA and ACA animals wereobserved with myocardial perfusion imaging. However, the radioac-tive sparse defects were less severe in the VFCA group than in the ACAgroup (Fig. 3). When compared with the baseline the SSP values at 4hours after ROSC, both groups were significantly increased: 0.4 ± 0.6vs 9.4 ± 3.1 (P b .05) in the VFCA group (n= 14) and 0.4 ± 0.5 vs 21.9± 3.4 (P b .05) in the ACA group (n= 7). In addition, this increase wasmore in the ACA group when compared with the VFCA group (21.9 ±3.4 vs 9.4 ± 3.1, P b .05; Fig. 4).
3.6. Myocardial histology and apoptosis
Several derangements in the myocardium were identified under aTEM. The intercalated disks were disorganized, fragmented, and evendissolved. Some of the mitochondria were severely damaged,exhibiting vacuolar degeneration, and the cristae were vague,irregularly arranged, or disrupted. By comparison, the overall heartmorphologic structure and the mitochondrial crista structure wereless severely injured in the VFCA group than that in the ACA group(Fig. 5). TUNEL assay revealed that there were greater numbers ofapoptotic cardiomyocytes in the ACA group than in the VFCA group;thus, the AI was significantly higher in the ACA than that in the VFCA(78.91 ± 11.21% vs 49.63 ± 9.23%, P b .01; Fig. 6).
4. Discussion
Here, we presented a comprehensive study comparing the basiccharacteristics of ACA and VFCA and a wide spectrum of parametersrelevant to cardiac dysfunction, myocardial injuries, and morpholog-ical/structural derangements in both models. The major finding in thepresent study was that although significant myocardial dysfunctionand derangements occur in both VFCA and ACAmodels, comparedwithVFCA, ACA caused more severe cardiac dysfunction, myocardiuminjury, and energy metabolism hindrance associated with lesssuccessful resuscitation and shorter survival time. These results implythat ACA and VFCA should be treated as different pathological entities.
Two published studies have generated experimental evidencesuggesting that ACA resulted in significantly lesser impairment ofpostresuscitation myocardial function than VFCA [6,16], which is incontrast to our results presented in this study. Several possibleexplanations may account for this disparity. The first possibility is thedifferent animal species used for investigation. Swine, whose heartsize, structure, and functional properties more closely resemble thoseof the human heart, were used in the present study, whereas rodents,whose hearts have certain important differences from the humanheart in many aspects including automated defibrillation, were usedin the previous studies [17-19]. The second explanation is that thedurations of CA before CPR were different: CA was left untreated for8 minutes in our study, while 4- and 7-minute lags for CPR wereallowed in the studies reported by the other 2 laboratories [6,16].Finally, we used a longer duration (13-16 minutes) of asphyxia beforeCA for our ACA model, whereas a much shorter pre-CA asphyxiaduration (only 3-8 minutes) was used in the other studies. We used avalidated model of asphyxiation by clamping the endotracheal tube inthe presence of room air ventilation with full muscle paralysis, whichreliably prevented any forms of gasping that would be a severeconfounding variable in an asphyxiamodel. Some studies showed thatafter ACA, a period of 8 minutes without intervention is absolutelynecessary to avoid successful resuscitation with ventilation and chestcompressions alone [7,20]. Except for the longer lag time between thecommencement of asphyxia and of CA, other conditions wereessentially the same as in previously published studies.
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Our results clearly showed that ejection fractionof LVweremarkedlyimpaired after successful resuscitation in both CA models. The ACAmodelhad significantly greater decreases inMAPandCOcomparedwiththe VFCAmodel. These results strongly indicate that cardiac dysfunctionand myocardial damage are more severe in the ACA model than in theVFCA model in otherwise identical experimental conditions.
The etiology of postresuscitation myocardial injuries is as yetunclear but is thought to mimic ischemia/reperfusion injuries:ischemia during CA and CPR efforts, and reperfusion after resuscita-tion or restoration of circulation. To get some mechanistic insight intowhat makes the 2 models have such distinct cardiac outcomes, weused SPECT to comparemyocardial perfusion. Our results showed thatmyocardial radioactive sparse defects were significantly increased inthe ACA group when compared with the VFCA group, whichdemonstrated that myocardial perfusion and microcirculation distur-bance after ACA were much more severity. The SPECT myocardialperfusion defects are characterized by their extent, severity, andlocation. American College of Cardiology/American Heart Association/American Society for Nuclear Cardiology guidelines recommend asemiquantitative analysis on a validated segmental scoring system[21]. A 17-segment model analysis is proposed using a 5-point scalesystem in direct proportion to the observed count density of thesegment. Calculations of the summed scores can also be performedincorporating the total extent and severity of a perfusion abnormality.In this study, the average SSP at 4 hours after ROSC suggested thatmyocardial perfusion reduce more heavily in ACA group.
To further investigate thedifferences ofmyocardialdysfunctionafterCAbetween the 2 groups,weperformedhistological examination undera TEM, which revealed significant derangements of myocardium andorganelles such as mitochondria within the cells. Compared with VFCA,ACA caused more diffuse myocardial injuries and mitochondrialdamage and, thus, less successful resuscitation [22]. This notion wasalso supported by the data showing more apoptotic cells in the ACAgroup than in the VFCA group and was consistent with the fact thatVFCA animals were more susceptible to resuscitation than the ACAanimals. It also may be an explanation why the average dosages ofvasopressors used in resuscitated animals in theVFCAgroupwere lowerthan in the ACA group including both stages of CPR and after ROSC.
4.1. Limitations
Some limitations of this study should be noted, including usage ofpotent anesthetics, epinephrine, and dopamine used after ROSC,which may have impaired cardiovascular function and autonomiccontrol [23].We used young, healthy pigs, whereas in clinical practice,most individuals with CA have underlying pathologic alterations.Thus, precaution must be exercised when extrapolating our resultsinto clinical practice.
5. Conclusions
In summary, our findings suggest that in the 2 most frequentlyused animal models of CA in basic research, the myocardial injurycaused by ACA and subsequent resuscitation appears to be moresevere and more widespread than by VFCA under otherwise identicalconditions. Therefore, researchers should choose the most appropri-ate CA models based on their study design.
Acknowledgments
The authors thank Zhi-Jun Guo, Shuo Wang, Xin-Hua He, and WeiJiang for excellent technical assistance.
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