Resuscitation In Swine Research Articles

Multi-omics Study of Hypoxic-Ischemic Brain Injury After Cardiopulmonary Resuscitation in Swine

Multi-omics Study of Hypoxic-Ischemic Brain Injury After Cardiopulmonary Resuscitation in Swine

REMIMAZOLAM IMPROVES THE MARKERS OF POSTRESUSCITATION CEREBRAL INJURY IN A SWINE MODEL OF CARDIAC ARREST.

Introduction: Previous studies have manifested that those sedatives acting on γ-aminobutyric acid A (GABAa) receptor could produce effective brain protection against regional and global ischemic stimulation. The present study was designed to investigate the effect of a novel GABAa receptor agonist, remimazolam postconditioning (RP) on cerebral outcome after global ischemic stimulation induced by cardiac arrest and resuscitation in swine. Methods: A total of 24 swine were used in this study, in which the animals were randomly divided into the following three groups: sham group (n = 6), cardiopulmonary resuscitation (CPR) group (n = 9), and CPR + RP group (n = 9). The experimental model was established by the procedure of 10 min of cardiac arrest and 5 min of CPR. Those resuscitated swine in the CPR + RP group received an intravenous infusion of 2.5 mg/kg of remimazolam within 60 min. Postresuscitation cerebral injury biomarkers and neurological function were evaluated for a total of 24 h. At 24 h after resuscitation, brain cortex was harvested to evaluate the severity of pathologic damage, including tissue inflammation, oxidative stress, apoptosis, and necroptosis. Results: Baseline characteristics and CPR outcomes were not significantly different between the CPR and CPR + RP groups. After resuscitation, significantly greater cerebral injury and neurological dysfunction were observed in the CPR and CPR + RP groups than in the sham group. However, remimazolam postconditioning significantly alleviated cerebral injury and improved neurological dysfunction after resuscitation when compared with the CPR group. At 24 h after resuscitation, tissue inflammation, oxidative stress, and cell apoptosis and necroptosis were significantly increased in the CPR and CPR + RP groups when compared with the sham group. Nevertheless, the severity of pathologic damage mentioned previously were significantly milder in those swine treated with the remimazolam when compared with the CPR group. Conclusions: In a swine model of cardiac arrest and resuscitation, the remimazolam administered after resuscitation significantly improved the markers of postresuscitation cerebral injury and therefore protected the brain against global ischemic stimulation.

Protective role and mechanism of tubastatin A on renal and intestinal injuries after cardiopulmonary resuscitation in swine

To investigate the protective effect and potential mechanism of tubastatin A (TubA), a specific inhibitor of histone deacetylase 6 (HDAC6), on renal and intestinal injuries after cardiopulmonary resuscitation (CPR) in swine. Twenty-five healthy male white swine were divided into Sham group (n = 6), CPR model group (n = 10) and TubA intervention group (n = 9) using a random number table. The porcine model of CPR was reproduced by 9-minute cardiac arrest induced by electrical stimulation via right ventricle followed by 6-minute CPR. The animals in the Sham group only underwent the regular operation including endotracheal intubation, catheterization, and anesthetic monitoring. At 5 minutes after successful resuscitation, a dose of 4.5 mg/kg of TubA was infused via the femoral vein within 1 hour in the TubA intervention group. The same volume of normal saline was infused in the Sham and CPR model groups. Venous samples were collected before modeling and 1, 2, 4, 24 hours after resuscitation, and the levels of serum creatinine (SCr), blood urea nitrogen (BUN), intestinal fatty acid binding protein (I-FABP) and diamine oxidase (DAO) in serum were determined by enzyme-linked immunoadsordent assay (ELISA). At 24 hours after resuscitation, the upper pole of left kidney and terminal ileum were harvested to detect cell apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL), and the expression levels of receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL) were detected by Western blotting. After resuscitation, renal dysfunction and intestinal mucous injury were observed in the CPR model and TubA intervention groups when compared with the Sham group, which was indicated by significantly increased levels of SCr, BUN, I-FABP and DAO in serum. However, the serum levels of SCr and DAO starting 1 hour after resuscitation, the serum levels of BUN starting 2 hours after resuscitation, and the serum levels of I-FABP starting 4 hours after resuscitation were significantly decreased in the TubA intervention group when compared with the CPR model group [1-hour SCr (μmol/L): 87±6 vs. 122±7, 1-hour DAO (kU/L): 8.1±1.2 vs. 10.3±0.8, 2-hour BUN (mmol/L): 12.3±1.2 vs. 14.7±1.3, 4-hour I-FABP (ng/L): 661±39 vs. 751±38, all P < 0.05]. The detection of tissue samples indicated that cell apoptosis and necroptosis in the kidney and intestine at 24 hours after resuscitation were significantly greater in the CPR model and TubA intervention groups when compared with the Sham group, which were indicated by significantly increased apoptotic index and markedly elevated expression levels of RIP3 and MLKL. Nevertheless, compared with the CPR model group, renal and intestinal apoptotic indexes at 24 hours after resuscitation in the TubA intervention group were significantly decreased [renal apoptosis index: (21.4±4.6)% vs. (55.2±9.5)%, intestinal apoptosis index: (21.3±4.5)% vs. (50.9±7.0)%, both P < 0.05], and the expression levels of RIP3 and MLKL were significantly reduced [renal tissue: RIP3 protein (RIP3/GAPDH) was 1.11±0.07 vs. 1.39±0.17, MLKL protein (MLKL/GAPDH) was 1.20±0.14 vs. 1.51±0.26; intestinal tissue: RIP3 protein (RIP3/GAPDH) was 1.24±0.18 vs. 1.69±0.28, MLKL protein (MLKL/GAPDH) was 1.38±0.15 vs. 1.80±0.26, all P < 0.05]. TubA has the protective effect on alleviating post-resuscitation renal dysfunction and intestinal mucous injury, and its mechanism may be related to inhibition of cell apoptosis and necroptosis.

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine.

The primary mission of cardiopulmonary resuscitation (CPR) is to provide adequate blood flow and oxygen delivery for restoring spontaneous circulation from cardiac arrest (CA) events. Previously, studies demonstrated that chest compression synchronized ventilation (CCSV) improved systemic oxygen supply during CPR, and aortic balloon occlusion (ABO) augments the efficacy of external CPR by increasing blood perfusion to vital organs. However, both them failed to make a significant improvement in return of spontaneous circulation (ROSC). In this study, we investigated the effects of combined CCSV and ABO on the outcomes of CPR in swine. Thirty-one male domestic swine were subjected to 8 min of electrically induced and untreated CA followed by 8 min of CPR. CPR was performed by continuous chest compressions and mechanical ventilation. At the beginning of CPR, the animals were randomized to receive intermittent positive pressure ventilation (IPPV, n = 10), CCSV (n = 7), IPPV + ABO (n = 7), or CCSV + ABO (n = 7). During CPR, gas exchange and systemic hemodynamics were measured, and ROSC was recorded. After resuscitation, the function and injury biomarkers of vital organs including heart, brain, kidney, and intestine were evaluated. During CPR, PaO2 was significantly higher accompanied by significantly greater regional cerebral oxygen saturation in the CCSV and CCSV + ABO groups than the IPPV group. Coronary perfusion pressure, end-tidal carbon dioxide, and carotid blood flow were significantly increased in the IPPV + ABO and CCSV + ABO groups compared with the IPPV group. ROSC was achieved in five of ten (IPPV), five of seven (CCSV), six of seven (IPPV + ABO), and seven of seven (CCSV + ABO) swine, with the rate of resuscitation success being significantly higher in the CCSV + ABO group than the IPPV group (P = 0.044). After resuscitation, significantly improved myocardial and neurological function, and markedly less cardiac, cerebral, renal, and intestinal injuries were observed in the CCSV + ABO group compared with the IPPV group. The combination of CCSV and ABO improved both ventilatory and hemodynamic efficacy during CPR, promoted ROSC, and alleviated post-resuscitation multiple organ injury in swine.

Enhanced Cerebral Blood Flow and Hemodynamic Status with an Alternative Left Ventricle Chest Compression Position during Cardiopulmonary Resuscitation in Swine

IntroductionThe standard chest compression (SCC) position for cardiopulmonary resuscitation (CPR) is the centre of the chest and typically central to the aortic root. An alternative left ventricle chest compression (LVCC) position may facilitate superior global blood flow. We tested the hypothesis that, consistent with improved ETCO2 (indicative of cardiac output) and blood pressure (BP), LVCC would promote greater cerebral blood flow (CBF) than SCC.MethodsFemale pigs (N=32; 35±2kg) were rotated systematically to receive either SCC (n=14) or LVCC (n=18). Transthoracic echocardiography was used to identify and externally mark: (1) the SCC position, the midline at the level of the aortic route, or (2) the LVCC position, the midpoint of the left ventricle. After 2 minutes of untreated asphyxiated cardiac arrest (CA), swine were treated with three 2‐minute cycles of mechanical chest compressions (LUCAS III). ETCO2 (in‐line sampling), BP (arterial catheter line), and CBF velocity (CBFv, transcranial Doppler, primary outcome) were measured during the pre‐CA, untreated‐CA, and CPR‐treated phases. Between‐group outcomes were compared using a mixed model ANOVA with significant differences considered at P&lt;0.05 and data are presented as mean±standard deviation.ResultsPre‐ and untreated‐CA ETCO2, BP and CBFv were similar between the SCC and LVCC groups (P&gt;0.100). During CPR, ETCO2 (36±6 mmHg versus 24±10 mmHg; P&lt;0.001), Mean Arterial Pressure (MAP; 49±9 mmHg versus 37±9 mmHg; P=0.002), and Mean CBFv (11±5 cm/s versus 5±2 cm/s; P&lt;0.001) were significantly higher in the LVCC, versus SCC, group.ConclusionIn comparison to SCC,LVCC resulted in higher ETCO2, MAP, and Mean CBFv values throughout CPR in a swine model of CA.New and NoteworthyWe provide novel evidence that compared with mechanical compressions performed over the centre of the chest, compressions performed over the left ventricle promote greater CBF during BLS CPR. Clinical validation of these results may improve survival rates and attenuate neurological deficits following CA.

Targeted high mean arterial pressure aggravates cerebral hemodynamics after extracorporeal resuscitation in swine

BackgroundExtracorporeal cardiopulmonary resuscitation (E-CPR) is used for the treatment of refractory cardiac arrest. However, the optimal target to reach for mean arterial pressure (MAP) remains to be determined. We hypothesized that MAP levels critically modify cerebral hemodynamics during E-CPR and tested two distinct targets (65–75 vs 80–90 mmHg) in a porcine model.MethodsPigs were submitted to 15 min of untreated ventricular fibrillation followed by 30 min of E-CPR. Defibrillations were then delivered until return of spontaneous circulation (ROSC). Extracorporeal circulation was initially set to an average flow of 40 ml/kg/min. The dose of epinephrine was set to reach a standard or a high MAP target level (65–75 vs 80–90 mmHg, respectively). Animals were followed during 120-min after ROSC.ResultsSix animals were included in both groups. During E-CPR, high MAP improved carotid blood flow as compared to standard MAP. After ROSC, this was conversely decreased in high versus standard MAP, while intra-cranial pressure was superior. The pressure reactivity index (PRx), which is the correlation coefficient between arterial blood pressure and intracranial pressure, also demonstrated inverted patterns of alteration according to MAP levels during E-CPR and after ROSC. In standard-MAP, PRx was transiently positive during E-CPR before returning to negative values after ROSC, demonstrating a reversible alteration of cerebral autoregulation during E-CPR. In high-MAP, PRx was negative during E-CPR but became sustainably positive after ROSC, demonstrating a prolonged alteration in cerebral autoregulation after ROSC. It was associated with a significant decrease in cerebral oxygen consumption in high- versus standard-MAP after ROSC.ConclusionsDuring early E-CPR, MAP target above 80 mmHg is associated with higher carotid blood flow and improved cerebral autoregulation. This pattern is inverted after ROSC with a better hemodynamic status with standard versus high-MAP.

The Effects of Dexmedetomidine Post-Conditioning on Cardiac and Neurological Outcomes After Cardiac Arrest and Resuscitation in Swine.

One of the main contents of post-resuscitation care is to alleviate cardiac and neurological damage in cardiac arrest (CA) victims. Recently, dexmedetomidine pre- and post-conditioning have been shown to both effectively protect the heart and brain against regional ischemia reperfusion injury. In this study, we investigated the effects of dexmedetomidine post-conditioning on cardiac and neurological outcomes after CA and resuscitation in swine. A total of 28 male domestic swine were randomized into four groups: sham, cardiopulmonary resuscitation (CPR), low-dose dexmedetomidine post-conditioning (LDP), and high-dose dexmedetomidine post-conditioning (HDP). Sham animals underwent the surgical preparation only. The animal model was established by 8 min of CA and then 5 min of CPR. After the animal was successfully resuscitated, a loading dose of 0.25 μg/kg of dexmedetomidine was intravenously injected followed by continuous infusion of 0.25 μg/kg/h for 6 h in the LDP group, and meanwhile a double dose of dexmedetomidine was similarly administered in the HDP group. The same amount of saline was given in the other two groups. All the resuscitated animals were monitored for 6 h and then returned to their cages for an additional 18 h of observation. After resuscitation, significantly greater cardiac, neurological dysfunction, and injuries were observed in all animals experiencing CA and resuscitation when compared with the sham group. However, the severity of cardiac and neurological damage was significantly milder in the two dexmedetomidine-treated groups than in the CPR group. Dexmedetomidine post-conditioning also significantly decreased post-resuscitation tissue inflammation, oxidative stress, and cell apoptosis and necroptosis in the heart and brain when compared with the CPR group. In addition, these protective effects produced by dexmedetomidine post-conditioning were significantly greater in the HDP group than in the LDP group. Dexmedetomidine post-conditioning dose-dependently improved post-resuscitation cardiac and neurological outcomes through the inhibition of tissue inflammation, oxidative stress, and cell apoptosis and necroptosis.

Recombinant Factor XIIIA and ACTH(1‐24) as Adjuncts During Prolonged Hypotensive Resuscitation in swine (Sus scrofa domesticus): Optimizing Outcomes for the Prolonged Field Care Environment

BackgroundTraumatic injuries with hemorrhage are the leading cause of potentially survivable death in trauma. A permissive hypotension strategy (Goal resuscitation systolic blood pressure (SBP) of 80–90 mmHg) plus early blood product administration over a short transport interval has been linked to improved survival. If blood products are unavailable during this pre‐hospital time, crystalloids and colloids such as hydroxy ethyl starch (Hextend®) remain the standard fielded resuscitative fluid. However, studies have demonstrated the correlation of kidney injury and failure, increased risk of coagulopathy, and higher mortality risk with this treatment. To improve outcomes in this prolonged field care (PFC) setting, in the absence of blood products, we investigated the survival and therapeutic benefits of ACTH(1‐24) and rFXIIIA treatment as an adjunct to Hextend® in a permissively hypotensive PFC model of hemorrhagic shock in swine.MethodsAnesthetized male swine (n = 16) underwent pressure‐targeted, decompensated hemorrhagic shock (MAP = 30–35 mmHg) for 45 minutes followed by permissively hypotensive (SBP = 80–90) resuscitation with Hextend® for 8 hours (with or without adjuncts such as ACTH(1‐24)), simulating a PFC environment. At the end of PFC, animals were fully resuscitated (return of shed blood plus normal saline). Animals were then monitored for 24 hours and assessed for neurocognitive function via latency to food reward. Sham animals (n = 5) received only anesthesia for the same time period. Tissues and serum were isolated at euthanasia for histopathological and biomarker analysis. Results reported as mean ± SD, Statistics: two‐way ANOVA with P &lt; 0.05 significance.ResultsInitial results from this experiment indicate successful use of 500 mL (n = 5) versus 1L (n = 5) of Hextend® to model a survivable permissively hypotensive state (SBP 80–90) for up to 8 hours in swine. Hextend® treatment amount shows no significant deleterious cardiovascular (HR, BP; p &gt; 0.05) or metabolic effects (lactate, BD; p &gt; 0.05) following initial shock treatment. ROTEM analysis indicated ACTH treatment (n = 1) decreased the latency for clot formation time in the later stages of PFC compared to the Hextend® + vehicle control. Additionally, there were no significant neurological detriments induced by the prolonged permissive hypotensive state, which makes this model ideal for PFC studies of shock (p &gt; 0.05).ConclusionThis swine model of prolonged permissively hypotensive resuscitation was designed to align with pre‐hospital hemorrhage control. The use of ACTH as an adjunct to standard treatments may improve outcomes, specifically with regard to bleeding. These results extend beyond military application to the rural civilian environment, where extended pre‐hospital times are commonplace. Further investigation is underway to elucidate whether rFXIIIA + ACTH, as a combination treatment, could improve PFC outcomes.Support or Funding InformationThis work was supported by the Defense Medical Research and Development Program, Joint Program Committee 6/Combat Casualty Care Research Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 202: Fast Hypothermia Induced by Continuous Renal Replacement Therapy Alleviates Systemic Inflammation and Intestinal Injury After Cardiopulmonary Resuscitation in Swine

Introduction: Systemic inflammation and intestinal injury contribute to post-resuscitation multiple organ dysfunction and death in cardiac arrest victims, and they can be partly alleviated by therapeutic hypothermia. Recently, continuous renal replacement therapy (CRRT) was shown to be an effective cooling method to induce fast hypothermia. In this study, we investigated the effects of CRRT cooling (CRRT-C) on systemic inflammation and intestinal injury after cardiopulmonary resuscitation (CPR) in swine. Hypothesis: Fast hypothermia induced by CRRT-C would alleviate post-resuscitation systemic inflammation and intestinal injury better than surface cooling (SC). Methods: Twenty-seven male domestic swine weighing 36 ± 2 kg were utilized. Ventricular fibrillation was induced for 8 mins while defibrillation was attempted after 5 mins of CPR. At 5 mins after resuscitation, the animals were randomized to receive either CRRT-C, SC or normotherma (NT). In the two hypothermic groups, the animals were cooled by either the combination of 8-hr CRRT and 16-hr SC or the whole 24-hr SC. In animals treated with CRRT-C, a higher rate of 180 ml/min of blood flow was initially set with the infusion line submerged in 4 °C of ice water. The temperature was normally maintained in the NT group. Results: After resuscitation, the rate of temperature decrease was significantly faster in the CRRT-C group than in the SC group (9.8±1.6 vs. 1.5±0.4 °C/h, p &lt;0.01). The serum levels of tumor necrosis factor-α, interleukin-6, intestinal fatty acid binding protein and diamine oxidase after resuscitation were significantly lower in the two hypothermic groups compared with the NT group. However, post-resuscitation systemic inflammation and intestinal injury were further significantly alleviated in the CRRT-C group compared to the SC group (Table). Conclusion: Fast hypothermia induced by CRRT-C was superior to SC in alleviating post-resuscitation systemic inflammation and intestinal injury.

Effectiveness of Colonic Fluid Resuscitation in a Burn-Injured Swine.

To determine the effectiveness of colonic fluid absorption as a route for fluid resuscitation of a major burn. In order to assess the feasibility and performance of colonic resuscitation, the authors compared plasma volume expansion and hemodynamic parameters of animals submitted to colonic or intravenous fluid resuscitation. Twelve anesthetized swine were submitted to a 40% full thickness flame burn. Thirty minutes later fluid resuscitation was initiated with either intravenous or colonic infusion of crystalloid based on the Parkland formula. This treatment lasted 4.5 hours. The volume of fluid infused was 86 ± 18 ml/kg for the intravenous treatment and 89 ± 14 ml/kg for the colonic treatment. The percentage of fluid absorbed by the colon at the end of the protocol was 30 ± 13% of the infused fluid. Enteral resuscitation was equally effective in expanding plasma volume at the end of the protocol. Laboratorial and hemodynamic parameters were similar between the two resuscitation strategies throughout the study. Urine output was significantly higher in the intravenous group (7.9 ± 4.2 ml/kg/hr vs 0.9 ± 0.3 ml/kg/hr, P = .03). This study demonstrates that colonic infusion of normal saline in a severe burn injury model can restore hemodynamic stability and expand plasma volume to a degree that rivals the effect of direct intravenous infusion for early burn resuscitation in a swine model.

Real-Time Ventricular Fibrillation Amplitude-Spectral Area Analysis to Guide Timing of Shock Delivery Improves Defibrillation Efficacy During Cardiopulmonary Resuscitation in Swine.

BackgroundThe ventricular fibrillation amplitude spectral area (AMSA) predicts whether an electrical shock could terminate ventricular fibrillation and prompt return of spontaneous circulation. We hypothesized that AMSA can guide more precise timing for effective shock delivery during cardiopulmonary resuscitation.Methods and ResultsThree shock delivery protocols were compared in 12 pigs each after electrically induced ventricular fibrillation, with the duration of untreated ventricular fibrillation evenly stratified into 6, 9, and 12 minutes: AMSA‐Driven (AD), guided by an AMSA algorithm; Guidelines‐Driven (GD), according to cardiopulmonary resuscitation guidelines; and Guidelines‐Driven/AMSA‐Enabled (GDAE), as per GD but allowing earlier shocks upon exceeding an AMSA threshold. Shocks delivered using the AD, GD, and GDAE protocols were 21, 40, and 62, with GDAE delivering only 2 AMSA‐enabled shocks. The corresponding 240‐minute survival was 8/12, 6/12, and 2/12 (log‐rank test, P=0.035) with AD exceeding GDAE (P=0.026). The time to first shock (seconds) was (median [Q1–Q3]) 272 (161–356), 124 (124–125), and 125 (124–125) (P<0.001) with AD exceeding GD and GDAE (P<0.05); the average coronary perfusion pressure before first shock (mm Hg) was 16 (9–30), 10 (6–12), and 3 (−1 to 9) (P=0.002) with AD exceeding GDAE (P<0.05); and AMSA preceding the first shock (mV·Hz, mean±SD) was 13.3±2.2, 9.0±1.6, and 8.6±2.0 (P<0.001) with AD exceeding GD and GDAE (P<0.001). The AD protocol delivered fewer unsuccessful shocks (ie, less shock burden) yielding less postresuscitation myocardial dysfunction and higher 240‐minute survival.ConclusionsThe AD protocol improved the time precision for shock delivery, resulting in less shock burden and less postresuscitation myocardial dysfunction, potentially improving survival compared with time‐fixed, guidelines‐driven, shock delivery protocols.

The effects of resolvin D1 on myocardial dysfunction after cardiopulmonary resuscitation in swine and its potential mechanisms

Objective To establish a porcine model of cardiopulmonary resuscitation to explore the effectiveness of resolvin D1 in improving post-resuscitation myocardial dysfunction and its potential mechanisms. Methods Twenty-eight male domestic pigs weighing 36±3 kg were utilized. The pig model was established by 8 mins of untreated ventricular fibrillation and then 5 mins of cardiopulmonary resuscitation. The animals were randomly divided into 4 groups (n=7 each): sham operation group (group S), cardiopulmonary resuscitation group (group CPR), low-dose resolvin D1 group (group LRD), and high-dose resolvin D1 group (group HRD). The animals in group S only got the general preparation without the procedure of cardiac arrest and resuscitation. At 5 min after resuscitation, the doses of resolvin D1 0.3 μg/kg and 0.6 μg/kg were respectively injected via the femoral vein of pigs in LRD and HRD groups, and meanwhile the equal volume of vehicle was given into the animals in the other two groups. At 3 h, 6 h and 24 h after resuscitation, the changes of stroke volume (SV) and global ejection fraction (GEF) were evaluated by a PiCCO monitor, and meanwhile the concentration of cardiac troponin I (cTNI) in serum was measured. At 24 h after resuscitation, the pigs were sacrificed, and myocardial tissue was obtained for the determination of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and superoxide dismutase (SOD) activity. Results Compared with group S, significantly decreased SV and GEF and markedly increased concentration of serum cTNI were observed in the other three groups with post-resuscitation myocardial dysfunction (all P<0.05). Compared with group CPR, the values of SV and GEF were significantly increased while the concentration of serum cTNI was significantly decreased in LRD and HRD groups[SV(ml): 28±5, 31±5 vs. 23±4 at 3 hrs, 32±3, 36±6 vs. 27±6 at 6 hrs, 35±5, 41±5 vs. 29±5 at 24 hrs; GEF(%): 17±2, 19±2 vs. 14±1 at 3 hrs, 20±2, 23±3 vs. 16±3 at 6 hrs, 23±2, 26±3 vs. 20±2 at 24 hrs; cTNI (pg/ml): 247±34, 230±26 vs. 324±56 at 3 hrs, 553±37, 501±34 vs. 611±44 at 6 hrs, 436±23, 371±29 vs. 553±47 at 24 hrs, all P<0.05]. Compared with group LRD, myocardial function and serum markers were further significantly improved in group HRD (all P<0.05). The inflammation and oxidative stress in myocardial tissue were observed in all the animals experiencing cardiac arrest and resuscitation, which were indicated by increased levels of TNF-α, IL-6 and MDA and decreased SOD activity. Compared with group CPR, the levels of TNF-α, IL-6 and MDA were significantly decreased while SOD activity was significantly increased in LRD and HRD groups[TNF-α(pg/ml): 442±87, 218±55 vs. 653±112; IL-6(pg/ml): 563±68, 403±61 vs. 824±117; MDA(nmol/mg): 3.95±0.96, 2.54±1.21 vs. 6.37±1.26; SOD(U/mg): 2.27±0.93, 3.36±0.74 vs. 0.89±0.31, all P<0.05]. The morbidity of myocardial inflammation and oxidative stress were further significantly ameliorated in group HRD evidenced by the figure of biomarkers compared with group LRD (all P<0.05). Conclusions Resolvin D1 can improve post-resuscitation myocardial dysfunction in a dose-dependent manner in swine, and the mechanism is related to the inhibition of inflammation and oxidative stress. Key words: Cardiac arrest; Cardiopulmonary resuscitation; Myocardial dysfunction; Cardiac injury; Resolvin D1; Inflammation; Oxidative stress; Swine

The effects of resolvin D1 on brain injury after cardiopulmonary resuscitation in swine and its potential mechanisms

Objective To explore the role of resolvin D1 in reducing brain injury after porcine cardiopulmonary resuscitation and its potential mechanisms. Methods Twenty-eight male domestic pigs weighing (36±3)kg were utilized. The animals were randomly divided into 4 groups (n=7 each): sham operation group (group S), cardiopulmonary resuscitation group (group CPR), low-dose resolvin D1 group (group LRD), and high-dose resolvin D1 group (group HRD). The animals in group S only got the general preparation without the procedure of cardiac arrest and resuscitation. The pig model was established by 8 mins of untreated ventricular fibrillation and then 5 mins of cardiopulmonary resuscitation. At 5 min post-resuscitation, the doses of resolvin D1 0.3 μg/kg, and 0.6 μg/kg were correspondingly injected via the femoral vein in LRD and HRD groups, and meanwhile the same amount of vehicle was given into the animals in the other two groups. At 3 h, 6 h and 24 h post-resuscitation, the concentrations of neuron specific enolase (NSE) and S100B protein (S100B) in serum was measured. At 24 h post-resuscitation, neurological deficit score (NDS) was evaluated; thereafter the pigs were sacrificed, and cerebral cortex was obtained for the determination of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA) contents, and superoxide dismutase (SOD) activity. Results Compared to group S, post-resusci-tation brain injury was observed in the other three groups, which was indicated by significantly increased NDS score, and markedly elevated concentrations of serum NSE and S100B. Compared to group CPR, the NDS was significantly decreased at 24 h post-resuscitation, and the concentrations of serum NSE and S100B were significantly reduced at 6 h and 24 h post-resuscitation in LRD and HRD groups. Compared to group LRD, the NDS score and its serum markers were further significantly decreased in group HRD. The inflammatory response and oxidative stress in brain tissue were observed in all the animals experiencing cardiac arrest and resuscitation, which were indicated by increased contents of TNF-α, IL-6 and MDA and decreased SOD activity. Compared to group CPR, the contents of TNF-α, IL-6 and MDA were significantly decreased while SOD activity was significantly increased in LRD and HRD groups. The indicators of inflammatory response and oxidative stress in brain tissue were further significantly improved in group HRD when compared to group LRD. Conclusions Resolvin D1 can reduce post-resuscitation brain injury in a dose-dependent manner in swine, and the mechanism is related to the inhibition of inflammatory response and oxidative stress. Key words: Fatty acids, unsaturated; Cardiopulmonary resuscitation/AE; Brain injuries/ET; Swine

Effect of limb ischemic post-conditioning in combination with hypothermia on brain injury after cardiopulmonary resuscitation in swine

Objective To evaluate the effect of limb ischemic post-conditioning (LIPC) in combination with hypothermia on brain injury after cardiopulmonary resuscitation (CPR) in swine. Methods Eighteen adult male white swine, weighing 35-40 kg, were used.The swine model of brain injury was established by inducing ventricular fibrillation for 10 min followed by 5 min of CPR.The animals were randomly divided into 3 groups (n=6 each) using a random number table: cardiac arrest-CPR group (group CA-CPR), group LIPC, and LIPC combined with hypothermia group (group LIPC+ H). In LIPC and LIPC+ H groups, LIPC was performed at the onset of CPR.In addition, the body temperature was cooled down to 32-34 ℃ by using a cooling blanket after successful resuscitation, and then maintained at this level until 4 h after resuscitation, followed by 4 h of re-warming at a rate of 1 ℃/h in group LIPC+ H.At 24, 48 and 72 h after resuscitation (T1-3), neurologic deficit score (NDS) and neurologic alertness score (NAS) were evaluated.Blood samples were collected from the auricular vein for determination of the concentrations of neuron-specific enolase (NSE) and S100B protein in serum by enzyme-linked immunosorbent assay. Results Compared with group CA-CPR, the NDS was significantly decreased, and the NAS was increased at T1-3, and the concentrations of NSE and S100B protein in serum were decreased at T2, 3 in LIPC and LIPC+ H groups (P<0.05). Compared with group LIPC, the NDS was significantly decreased, and the NAS was increased at T1-3, and the concentrations of NSE and S100B protein in serum were decreased at T3 in group LIPC+ H (P<0.05). Conclusion The combination of LIPC and hypothermia provides better efficacy than either alone in reducing brain injury after CPR in swine. Key words: Hypothermia, induced; Ischemic postconditioning; Extremities; Heart arrest; Cardiopulmonary resuscitation; Reperfusion injury; Brain

In Vivo Effects of Platelet Apheresis on Oxygen Metabolism in Pigs

IntroductionPlatelet apheresis is a routine clinical practice. Although the efficacy of collected platelets has been studied, the impact of apheresis on the physiology of the donor is less clear. This study investigated oxygen metabolism in pigs during a 4 hour platelet apheresis as a prelude to initiating studies of hemorrhage and resuscitation in swine with reduced platelets.MethodsForty pigs (39.8±0.6 kg) were catheterized with a femoral vein catheter for platelet apheresis, using a Haemonetics MCS9000. Hemodynamics was recorded during the apheresis process. Arterial and venous samples were collected before and after apheresis for blood gases and CBC.ResultsDuring apheresis, blood‐withdrawing decreased MAP from 74&lt;a name=”OLE_LINK2”&gt;&lt;/a&gt;&lt;a name=”OLE_LINK1”&gt;±&lt;/a&gt;2 to 45±1 mmHg and increased heart rate from 104±3 to 129±4 bpm (both p&lt;0.05); blood‐returning recovered MAP and HR to baseline values, with no changes observed in cardiac output. Platelet counts in pigs decreased to 40±3% of baseline values after 4 hours of apheresis (p&lt;0.05). Pig blood glucose was increased by apheresis from 4.1±0.3mM to 5.2±0.2mM, Ca++ decreased from 1.34±0.01mM to 1.13±0.02mM, and lactate decreased from 2.2±0.1mM to 1.3±0.1mM (all p&lt;0.05), with no changes in Hct, Hgb and RBCs. Oxygen delivery was not affected by apheresis, but oxygen extraction was decreased from 27±2% to 20±1%, and oxygen consumption was decreased from 4.0±0.2 O2/dL blood to 3.1±0.2 ml O2/dL blood (both p&lt;0.05).ConclusionIn addition to reducing platelet counts, platelet apheresis caused large fluctuations in MAP and compromised oxygen metabolism, which can impact the physiologic response to hemorrhage in these animals.

Investigation of Noninvasive Muscle pH and Oxygen Saturation During Uncontrolled Hemorrhage and Resuscitation in Swine

This study evaluated noninvasively determined muscle pH (pHm) and muscle oxygen saturation (SmO2) in a swine shock model that used uncontrolled hemorrhage and restricted volume resuscitation. Anesthetized 40-kg female swine underwent hemorrhage until 24 mL/kg of blood was removed (n = 26), followed by transection of the spleen, causing uncontrolled hemorrhage throughout the remainder of the protocol. After 15 min, 15 mL/kg of resuscitation fluid (Hextend, fresh-frozen plasma or platelets) was given for 30 min. Arterial and venous blood gases were measured at baseline, shock, end of resuscitation, and end of the study (death or 5 h), along with lactate and base excess. In addition, seven animals underwent a sham procedure. Spectra were collected continuously from the posterior thigh using a prototype CareGuide 1100 Oximeter, and pHm and SmO2 were calculated from the spectra. A two-factor analysis of variance with repeated measures followed by Tukey post hoc comparisons was used to compare experimental factors. It was shown that, for both pH and SO2, venous and muscle values were similar to each other at the end of the resuscitation period and at the end of the study for both surviving and nonsurviving animals. pH and SO2, venous and muscle, significantly declined as a result of bleeding, but lactate and base excess did not show significant changes during this period. Noninvasive pHm and SmO2 tracked the adequacy of resuscitation in real time, indicating at the time all of the fluid was delivered, which animals would live and which would die. The results of this swine study indicate that further evaluation on trauma patients is warranted.

Correlation Between Capnography and Arterial Carbon Dioxide Before, During, and After Severe Chest Injury in Swine

The relationship between end-tidal carbon dioxide (EtCO(2)) and arterial carbon dioxide (PaCO(2))-if better defined-could facilitate the difficult task of ventilation in prehospital trauma patients. We aimed to study the PaCO(2)-EtCO(2) relationship before, during, and after chest trauma, hemorrhage, and resuscitation in swine. Twenty-four swine were intubated, anesthetized, and monitored in an animal intensive care unit during three phases: phase 1 (day 1, healthy animals); phase 2 (day 2, injury), which consisted of blunt chest trauma, hemorrhage, and resuscitation; and phase 3 (day 2, after injury). "Respiratory maneuvers" (changes in respiratory rate and tidal volume [TV], intended to vary the PaCO(2) over a range of 25 to 85 mmHg, were performed during phases 1 and 3. End-tidal CO(2) and PaCO(2) were recorded after each respiratory maneuver and analyzed using linear regression. During phase 1, PaCO(2) and EtCO(2) were strongly correlated (r(2) = 0.97, P < 0.01). During phase 2, animals developed decreased oxygenation (PaO(2):FiO(2) [fraction of inspired oxygen] ratio <200) and hypotension (mean arterial pressure, 20-50 mmHg); the PaCO(2)-EtCO(2) relationship deteriorated (r(2) = 0.25, P < 0.0001). During phase 3, oxygenation, hemodynamics, and the PaCO(2)-EtCO(2) relationship recovered (r(2) = 0.92, P < 0.01). End-tidal CO(2) closely correlates to PaCO(2) in healthy animals and after injury/resuscitation across a wide range of respiratory rates and tidal volumes. Once oxygenation and hemodynamics are restored, EtCO(2) can be used to predict PaCO(2) following chest trauma/hemorrhage and should be considered for patient monitoring. This work demonstrated that EtCO(2) alone can reliably be used to estimate PaCO(2) in uninjured subjects and in those subjects who have been resuscitated from severe injury. Immediately after blunt chest injury, the correlation between EtCO(2) and PaCO(2) is temporarily unstable. Under these circumstances (with abnormal oxygenation and/or hemodynamics), greater caution and other monitoring tools may be required.

Effects of sustained abdominal aorta compression on coronary perfusion pressures and restoration of spontaneous circulation during cardiopulmonary resuscitation in swine

Objectives The present study was undertaken to explore whether sustained abdominal aorta compression-cardiopulmonary resuscitation (SAAC-CPR), as a means, can raise coronary perfusion pressure (CPP) as well as restoration of spontaneous circulation (ROSC) during CPR. In the present study, we hypothesised that SAAC-CPR elevates CPP during CPR and improves ROSC, without causing liver laceration. Methods Animals were randomised into one of two groups (Standard CPR and SAAC-CPR). Ten domestic swine (22–25 kg) were anaesthetised, intubated and mechanically ventilated. Ventricular fibrillation was induced, and after 3 min of untreated ventricular fibrillation, the animals were treated with standard CPR (with simplex chest compression (SCC) and epinephrine) or SAAC-CPR (SCC with sustained abdominal aorta compression, without epinephrine). CPP and ROSC were compared. Results SCC with sustained abdominal aorta compression (SCC + SAAC) significantly increased CPP in comparison with SCC during CPR ( p < 0.05). The increase in CPP with SCC + SAAC is equivalent to that achieved with epinephrine ( p > 0.05). All animals in the standard CPR and SAAC-CPR groups restored spontaneous circulation. No liver damage was found in post-mortem examinations of the swine subjects. Conclusions During CPR, non-invasive SAAC can rapidly and reversibly raise the CPP as much as can epinephrine and is especially suitable for out-of-hospital CPR.

Predictors of resuscitation in a swine model of ischemic and nonischemic ventricular fibrillation cardiac arrest: Superiority of amplitude spectral area and slope to predict a return of spontaneous circulation when resuscitation efforts are prolonged*

We have demonstrated that a return of spontaneous circulation in the first 3 mins of resuscitation in swine is predicted by ventricular fibrillation waveform (amplitude spectral area or slope) when untreated ventricular fibrillation duration or presence of acute myocardial infarction is unknown. We hypothesized that in prolonged resuscitation efforts that return of spontaneous circulation immediately after a second or later shock with postshock chest compression is independently predicted by end-tidal CO2, coronary perfusion pressure, and ventricular fibrillation waveform measured before that shock in a swine model of ischemic and nonischemic ventricular fibrillation arrest. Animal intervention study with comparison to a control group. University animal laboratory. Twenty swine. Myocardial infarction was induced by steel plug occlusion of the left anterior descending coronary artery. Ventricular fibrillation was untreated for 8 mins in normal swine (n=10) and acute myocardial infarction swine (n=10). End-tidal CO2, coronary perfusion pressure, and ventricular fibrillation waveform characteristics of amplitude spectral area and slope were analyzed before second or later shocks. For an amplitude spectral area>35 mV-Hz, the odds ratio for achieving return of spontaneous circulation after that shock was 72 (95% confidence interval, 3.8-1300; p=.004) compared with an amplitude spectral area<28 mV-Hz and with an area under the receiver operator characteristic curve of 0.86. For slope>3.6 mV/s, the odds ratio for achieving return of spontaneous circulation was 36 (95% confidence interval, 2.7-480; p=.007) compared with slope<2.72 mV/s with an area under the curve of 0.86. End-tidal CO2 and coronary perfusion pressure were not predictive of return of spontaneous circulation after a shock, although coronary perfusion pressure was significantly related to both amplitude spectral area (p<.001) and slope (p<.001). : In prolonged untreated ventricular fibrillation arrest, the waveform characteristics of amplitude spectral area and slope predict the attainment of return of spontaneous circulation with a second or later shock. This has implications for the ideal means to customize the timing of shocks and chest compressions when return of spontaneous circulation is not promptly obtained.

Influence of asymptomatic pneumonia on the response to hemorrhage and resuscitation in swine

INTRODUCTION:Investigation of resuscitation fluids in our swine hemorrhage model revealed moderate to severe chronic pneumonia in five swine at necropsy. Our veterinary staff suggested that we perform a retrospective analysis of prospectively collected data from these animals. We compared the data to that of ten healthy swine to determine the physiologic consequences of the added stress on our hemorrhage/resuscitation model.METHODS:Anesthetized, immature female swine (40 ± 5 kg) were instrumented for determining arterial and venous pressures, cardiac output and urine production. A controlled hemorrhage of 20 ml/kg over 4 min 40 sec was followed at 30 min by a second hemorrhage of 8 ml/kg and resuscitation with 1.5 ml/kg/min of LR solutions to achieve and maintain systolic blood pressure at 80 ± 5 mmHg for 3.5 hrs. Chemistries and arterial and venous blood gasses were determined from periodic blood samples along with hemodynamic variables.RESULTS:There were significant decreases in survival, urine output, cardiac output and oxygen delivery at 60 min and O2 consumption at 120 min in the pneumonia group compared to the non‐pneumonia group. There were no differences in other metabolic or hemodynamic data between the groups.CONCLUSION:Although pneumonia had little influence on pulmonary gas exchange, it influenced cardiac output, urine output and survival compared to healthy swine, suggesting a decrease in the physiologic reserve. These data may be relevant to patients with subclinical infection who are stressed by hemorrhage and may explain in part why some similarly injured patients require more resuscitation efforts than others.