Min Of Untreated Cardiac Arrest Research Articles

The effects of methylene blue during and after cardiac arrest in a porcine model; a randomized, blinded, placebo-controlled study

PurposeTo evaluate the effect of methylene blue administered as a bolus on return of spontaneous circulation (ROSC), lactate levels, vasopressor requirements, and markers of neurological injury in a clinically relevant pig model of cardiac arrest. Materials and methods40 anesthetized pigs were subjected to acute myocardial infarction and 7 min of untreated cardiac arrest. Animals were randomized into three groups: one group received saline only (controls), one group received 2 mg/kg methylene blue and saline (MB + saline), and one group received two doses of 2 mg/kg methylene blue (MB + MB). The first intervention was given after the 3rd rhythm analysis, while the second dose was administered one hour after achieving ROSC. Animals underwent intensive care and observation for six hours, followed by cerebral magnetic resonance imaging (MRI). The primary outcome for this study was development in lactate levels after cardiac arrest. Categorical data were compared using Fisher's exact test and pointwise data were analyzed using one-way analysis of variance (ANOVA) or equivalent non-parametric test. Continuous data collected over time were analyzed using a linear mixed effects model. A value of p < .05 was considered statistically significant. ResultsLactate levels increased in all groups after cardiac arrest and resuscitation, however lactate levels in the MB + MB group decreased significantly faster compared with the control group (p = .007) and the MB + saline group (p = .02). The proportion of animals achieving initial ROSC was similar across groups: 11/13 (85%) in the control group, 10/13 (77%) in the MB + saline group, and 12/14 (86%) in the MB + MB group (p = .81). Time to ROSC did not differ between groups (p = .67). There was no significant difference in accumulated norepinephrine dose between groups (p = .15). Cerebral glycerol levels were significantly lower in the MB + MB group after resuscitation compared with control group (p = .03). However, MRI data revealed no difference in apparent diffusion coefficient, cerebral blood flow, or dynamic contrast enhanced MR perfusion between groups. ConclusionTreatment with a bolus of methylene blue during cardiac arrest and after resuscitation did not significantly improve hemodynamic function. A bolus of methylene blue did not yield the neuroprotective effects that have previously been described in animals receiving methylene blue as an infusion.

Feasibility of Magnetic Resonance-Based Conductivity Imaging as a Tool to Estimate the Severity of Hypoxic-Ischemic Brain Injury in the First Hours After Cardiac Arrest.

Early identification of the severity of hypoxic-ischemic brain injury (HIBI) after cardiac arrest can be used to help plan appropriate subsequent therapy. We evaluated whether conductivity of cerebral tissue measured using magnetic resonance-based conductivity imaging (MRCI), which provides contrast derived from the concentration and mobility of ions within the imaged tissue, can reflect the severity of HIBI in the early hours after cardiac arrest. Fourteen minipigs were resuscitated after 5min or 12min of untreated cardiac arrest. MRCI was performed at baseline and at 1h and 3.5h after return of spontaneous circulation (ROSC). In both groups, the conductivity of cerebral tissue significantly increased at 1h after ROSC compared with that at baseline (P = 0.031 and 0.016 in the 5-min and 12-min groups, respectively). The increase was greater in the 12-min group, resulting in significantly higher conductivity values in the 12-min group (P = 0.030). At 3.5h after ROSC, the conductivity of cerebral tissue in the 12-min group remained increased (P = 0.022), whereas that in the 5-min group returned to its baseline level. The conductivity of cerebral tissue was increased in the first hours after ROSC, and the increase was more prominent and lasted longer in the 12-min group than in the 5-min group. Our findings suggest the promising potential of MRCI as a tool to estimate the severity of HIBI in the early hours after cardiac arrest.

EFFECTS OF MESENCHYMAL STEM CELLS ON POSTRESUSCITATION RENAL AND INTESTINAL INJURIES IN A PORCINE CARDIAC ARREST MODEL.

Objectives: Systemic ischemia-reperfusion triggered by cardiac arrest (CA) and resuscitation often causes postresuscitation multiple organ injuries. Mesenchymal stem cells (MSCs) have been proven to be a promising treatment for regional renal and intestinal ischemia reperfusion injuries. This study aimed to investigate the effects of MSCs on renal and intestinal injuries after cardiopulmonary resuscitation (CPR) in a porcine CA model. Methods: Twenty-two male pigs were randomly assigned to the sham (n = 6), CA/CPR (n = 8), and CA/CPR + MSC (n = 8) groups. Mesenchymal stem cells were differentiated from human embryonic stem cells and then intravenously administered at a dose of 2.5 × 10 6 /kg at 1.5 and 3 d before the CA/CPR procedure. The experimental model was established by 8 min of untreated CA, followed by 8 min of CPR. Renal and intestinal injuries were evaluated based on the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase at 1, 2, 4, and 24 h after resuscitation. At the end of the experiment, pathological damage was determined by cell apoptosis and ferroptosis in the renal and intestinal tissues. Results: During CPR, five pigs in the CA/CPR group and seven pigs in the CA/CPR + MSC group were successfully resuscitated. After resuscitation, the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase were significantly increased in the CA/CPR and CA/CPR + MSC groups compared with those in the sham group. However, MSC administration significantly decreased the levels of renal and intestinal injury biomarkers compared with those in the CA/CPR group. Cell apoptosis and ferroptosis, which were indicated by the levels of apoptotic cells, iron deposition, lipid peroxidation, antioxidants, and ferroptosis-related proteins, were observed in renal and intestinal tissues after resuscitation in the CA/CPR and CA/CPR + MSC groups. Nevertheless, both were significantly milder in the CA/CPR + MSC group than in the CA/CPR group. Conclusions: MSC administration was effective in alleviating postresuscitation renal and intestinal injuries possibly through inhibition of cell apoptosis and ferroptosis in a porcine CA model.

Interaction between gender and post resuscitation interventions on neurological outcome in an asphyxial rat model of cardiac arrest

PurposePrevious clinical studies have suggested an effect of gender on outcome after out-of-hospital cardiac arrest, but the results are conflicting and there is no uniform agreement regarding gender differences in survival and prognosis. The present study was aimed to investigate the interaction between gender and post resuscitation interventions on neurological outcome in an asphyxial rat model of cardiac arrest.MethodsAsphyxia was induced by blocking the endotracheal tube in 120 adult Sprague–Dawley rats (60 males and 60 females) at the same age. Cardiopulmonary resuscitation (CPR) was started after 5 min of untreated cardiac arrest. Animals were randomized into one of the three post resuscitation care intervention groups (n = 40, 20 males) immediately after resuscitation: (1) normothermic control (NC): ventilated with 2% N2/98% O2 for 1 h under normothermia; (2) targeted temperature management (TTM): ventilated with 2% N2/98% O2 for 1 h under hypothermia; (3) hydrogen inhalation (HI): ventilated with 2% H2/98% O2 for 1 h under normothermia. Physiological variables were recorded during the 5 h post resuscitation monitoring period. Neurological deficit score (NDS) and accumulative survival were used to assess 96 h outcomes. Mutual independence analysis and Mantel–Haenszel stratified analysis were used to explore the associations among gender, intervention and survival.ResultsThe body weights of female rats were significantly lighter than males, but CPR characteristics did not differ between genders. Compared with male rats, females had significantly lower mean arterial pressure, longer onset time of the electroencephalogram (EEG) burst and time to normal EEG trace (TTNT) in the NC group; relatively longer TTNT in the TTM group; and substantially longer TTNT, lower NDSs, and higher survival in the HI group. Mutual independence analysis revealed that both gender and intervention were associated with neurological outcome. Mantel–Haenszel stratified analysis demonstrated that female rats had significantly higher survival rate than males when adjusted for the confounder intervention.ConclusionIn this rat model cardiac arrest and CPR, gender did not affect resuscitation but associated with neurological outcome. The superiority of female rats in neurological recovery was affected by post resuscitation interventions and female rats were more likely to benefit from hydrogen therapy.

First-time evaluation of ascending compared to rectangular transthoracic defibrillation waveforms in modelled out-of-hospital cardiac arrest

Aim of the studyPrognosis in out-of-hospital cardiac arrest (OHCA) depends on cardiopulmonary resuscitation (CPR) duration. Therefore, the optimal biphasic defibrillation waveform shows high conversion rates besides low energy. Matthew Fishler theoretically predicted it to be truncated ascending exponential. We realised a prototypic defibrillator and compared ascending with conventional rectangular waveforms in modelled OHCA and CPR. MethodsApproved by the authorities, 57 healthy swine (Landrace ​× ​Piétrain) were randomised to ASCDefib (n 26) or CONVDefib (n 26). Five swine served as sham control. We induced ventricular fibrillation (VF) electrically in anaesthetised swine randomised to ASCDefib or CONVDefib and discontinued mechanical ventilation. After 5 ​min of untreated cardiac arrest, we started CPR with mechanical chest compressions and ventilation. We performed transthoracic biphasic defibrillations after 2, 4, 6 and 8 ​min CPR targeting 4 ​J/kg in either group. Depending on the randomised group, the defibrillation protocol was either three ascending followed by one rectangular waveform (ASCDefib) or three rectangular followed by one ascending waveform (CONVDefib). ResultsUnder our model-specific conditions, VF was initially terminated by 13/80 ascending waveforms and 13/79 rectangular waveforms and persistent return of spontaneous circulation was achieved in 8/26 (ASCDefib) vs. 10/26 (CONVDefib) animals. Mean current rather than waveform design was predictive for defibrillation success in a generalised linear model. ConclusionContrary to theoretical assumptions, transthoracic biphasic defibrillation with ascending waveforms is not superior to rectangular waveforms in modelled OHCA. We advocate defibrillation dosage to be guided by current, that has proven its predictive value again. Institutional protocol number84–02.04.2017.A176.

Effects of the duration of postresuscitation hyperoxic ventilation on neurological outcome and survival in an asphyxial cardiac arrest rat model

Cardiac arrest leads to sudden cessation of oxygen supply and cerebral hypoxia occurs when there is not sufficient oxygen supplied to the brain. Current Guidelines for adult cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend the use of 100% oxygen during resuscitative efforts to maximize the probability of achieving the return of spontaneous circulation (ROSC). However, the optimal strategy for oxygen management after ROSC is still debatable. The aim of the present study was to evaluate the effects of the duration of post-resuscitation hyperoxic ventilation on neurological outcomes in asphyxial cardiac arrest rats treated with targeted temperature management (TTM). Asphyxia was induced by blocking the endotracheal tube in 80 adult male Sprague-Dawley rats. CPR begun after 7 min of untreated cardiac arrest. Animals were randomized to either the normoxic control under normothermia (NNC) group or to one of the 4 experimental groups (n = 16 each) immediately after ROSC: ventilated with 100% oxygen for 0 (O2_0h), 1 (O2_1h), 3 (O2_3h), or 5 (O2_5h) h and ventilated with room air thereafter under TTM. Physiological variables were recorded at baseline and during the 6 h postresuscitation monitoring period. Animals were closely observed for 96 h to assess neurologic recovery and survival. There were no significant differences in baseline measurements between groups, and all animals were successfully resuscitated. There were significant interactions between the duration of 100% oxygen administration and hemodynamics as well as, myocardial and cerebral injuries. Among all the durations of hyperoxic ventilation investigated, significantly lower neurological deficit scores and higher survival rates were observed in the O2_3h group than in the NNC group. In conclusion, postresuscitation hyperoxic ventilation leads to improved PaO2, PaCO2, hemodynamic, myocardial and cerebral recovery in asphyxial cardiac arrest rats treated with TTM. However, the beneficial effects of high concentration-oxygen are duration dependent and ventilation with 100% oxygen during induced hypothermia contributes to improved neurological recovery and survival after 96 h.

Inhaling Hydrogen Ameliorates Early Postresuscitation EEG Characteristics in an Asphyxial Cardiac Arrest Rat Model.

Background Electroencephalography (EEG) is commonly used to assess the neurological prognosis of comatose patients after cardiac arrest (CA). However, the early prognostic accuracy of EEG may be affected by postresuscitation interventions. Recent animal studies found that hydrogen inhalation after CA greatly improved neurological outcomes by selectively neutralizing highly reactive oxidants, but the effect of hydrogen inhalation on EEG recovery and its prognostication value are still unclear. The present study investigated the effects of hydrogen inhalation on early postresuscitation EEG characteristics in an asphyxial CA rat model. MethodsCardiopulmonary resuscitation was initiated after 5 min of untreated CA in 40 adult female Sprague-Dawley rats. Animals were randomized for ventilation with 98% oxygen plus 2% hydrogen (H2) or 98% oxygen plus 2% nitrogen (Ctrl) under normothermia for 1 h. EEG characteristics were continuously recorded for 4 h, and the relationships between quantitative EEG characteristics and 96 h neurological outcomes were investigated. ResultsNo differences in baseline and resuscitation data were observed between groups, but the survival rate was significantly higher in the H2 group than in the Ctrl group (90% vs. 40%, P < 0.01). Compared to the Ctrl group, the H2 group showed a shorter burst onset time (21.85 [20.00–23.38] vs. 25.70 [22.48–30.05], P < 0.01) and time to normal trace (169.83 [161.63–208.55] vs. 208.39 [186.29–248.80], P < 0.01). Additionally, the burst suppression ratio (0.66 ± 0.09 vs. 0.52 ± 0.17, P < 0.01) and weighted‐permutation entropy (0.47 ± 0.16 vs. 0.34 ± 0.13, P < 0.01) were markedly higher in the H2 group. The areas under the receiver operating characteristic curves for the 4 EEG characteristics in predicting survival were 0.82, 0.84, 0.88, and 0.83, respectively. ConclusionsIn this asphyxial CA rat model, the improved postresuscitation EEG characteristics for animals treated with hydrogen are correlated with the better 96 h neurological outcome and predicted survival.

Variations of Postresuscitation Lung Function after Thrombolysis Therapy in a Cardiac Arrest Porcine Model Caused by Pulmonary Thromboembolism.

Background:Study of lung function in survivor from cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) was rare. The aim of this study was to investigate the variations of postresuscitation lung function after thrombolysis treatment in a CA porcine model caused by PTE.Methods:After 2 min of untreated CA, pigs of 10–12 weeks with a weight of 30 ± 2 kg (n = 24) were treated with recombinant human tissue plasminogen activator (50 mg). Cardiopulmonary resuscitation (CPR) and ventilation were initiated after drug administration. Pulmonary function and arterial blood gas parameters were measured at baseline, return of spontaneous circulation (ROSC) immediately, and 1 h, 2 h, 4 h, and 6 h after ROSC.Results:The dynamic lung compliance decreased significantly at ROSC immediately and 1 h after ROSC compared to baseline (21.86 ± 2.00 vs. 26.72 ± 2.20 ml/mmHg and 20.38 ± 1.31 vs. 26.72 ± 2.20 ml/mmHg, respectively; P < 0.05; 1 mmHg = 0.133 kPa). Compared with baseline, airway resistance increased significantly at ROSC immediately and 1 h after ROSC (P < 0.05). Respiratory index also increased after ROSC and showed significant differences among baseline, ROSC immediately, and 2 h after ROSC (P < 0.05). Oxygen delivery decreased at ROSC immediately compared to baseline (P < 0.05). The oxygenation index decreased significantly at any time after ROSC compared to baseline (P < 0.05). Extravascular lung water index and pulmonary vascular permeability index (PVPI) showed significant differences at ROSC immediately compared to baseline and 1 h after ROSC (P < 0.05); PVPI at ROSC immediately was also different from 6 h after ROSC (P < 0.05). Ventilation/perfusion ratios increased after ROSC (P < 0.05). Histopathology showed fibrin effusion, bleeding in alveoli, and hemagglutination in pulmonary artery.Conclusions:Lung function remains abnormal even after CPR with thrombolysis therapy; it is essential to continue anticoagulation and symptomatic treatment after ROSC.

Correlation of Impedance Threshold Device use during cardiopulmonary resuscitation with post-cardiac arrest Acute Kidney Injury

PurposeTo assess whether use of Impedance Threshold Device (ITD) during cardiopulmonary resuscitation (CPR) reduces the degree of post-cardiac arrest Acute Kidney Injury (AKI), as a result of improved hemodynamics, in a porcine model of ventricular fibrillation (VF) cardiac arrest. MethodsAfter 8 min of untreated cardiac arrest, the animals were resuscitated either with active compression-decompression (ACD) CPR plus a sham ITD (control group, n=8) or with ACD-CPR plus an active ITD (ITD group, n=8). Adrenaline was administered every 4 min and electrical defibrillation was attempted every 2 min until return of spontaneous circulation (ROSC) or asystole. After ROSC the animals were monitored for 6 h under general anesthesia and then returned to their cages for a 48 h observation, before euthanasia. Two novel biomarkers, Neutrophil Gelatinase-Associated Lipocalin (NGAL) in plasma and Interleukin-18 (IL-18) in urine, were measured at 2 h, 4 h, 6 h, 24 h and 48 h post-ROSC, in order to assess the degree of AKI. ResultsROSC was observed in 7 (87.5%) animals treated with the sham valve and 8 (100%) animals treated with the active valve (P=NS). However, more than twice as many animals survived at 48 h in the ITD group (n=8, 100%) compared to the control group (n=3, 37.5%). Urine IL-18 and plasma NGAL levels were augmented post-ROSC in both groups, but they were significantly higher in the control group compared with the ITD group, at all measured time points. ConclusionUse of ITD during ACD-CPR improved hemodynamic parameters, increased 48 h survival and decreased the degree of post-cardiac arrest AKI in the resuscitated animals.

Abstract 12447: Early Coronary Reperfusion Improves Cerebral and Systemic Hemodynamics After Ischemic Refractory Cardiac Arrest and Extracorporeal Resuscitation in Pigs

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is widely proposed for the treatment of refractory cardiac arrest. It should be associated to etiologic determination, especially if acute coronary artery occlusion is suspected. However, prioritization of care remains unclear in this situation. Hypothesis: Our goal was to determine whether reperfusion should be instituted as soon as possible during ischemic refractory cardiac arrest treated by extracorporeal cardiopulmonary resuscitation (ECPR) in pigs. Methods: Pigs were instrumented and submitted to coronary artery occlusion prior to ventricular fibrillation. After 5 min of untreated cardiac arrest, life support was started using external chest compression (ECC) during 15 min followed by ECPR during 240 min, respectively. Animals randomly underwent either early or late coronary reperfusion after 20 or 120 min of ECPR, respectively. Return of spontaneous circulation (ROSC) was determined as organized ECG rhythm with systolic blood pressure above 80 mmHg. Results: Hemodynamic parameters were not different between groups at baseline or during ECC. Since the onset of ECPR, carotid blood flow was improved by ≈70% vs ECC in both groups. No animal (0/7) elicited ROSC after late reperfusion vs 4/7 after early reperfusion (p&lt;0.05). Hemodynamic parameters, such as mean arterial pressure and carotid blood flow, were improved in early vs late reperfusion groups (Figure), along with infarct size decrease (71±4 vs 84±2 % of the risk zone, respectively; p&lt;0.05). Conclusions: Early reperfusion improved hemodynamic status and increased ROSC chances after ischemic refractory cardiac arrest treated by ECPR. This supports the need of rapid reperfusion in this situation. Figure: Carotid blood flow after extracorporeal cardiopulmonary resuscitation (ECPR) and successful defibrillation (*, p&lt;0.05 between groups; comparisons were only made at the end of the follow-up).

Monitoring of brain oxygenation during hypothermic CPR – A prospective porcine study

Background and aimLimited data are available concerning the impact of CPR interventions on cerebral oxygenation during hypothermic cardiac arrest. We therefore studied cerebral perfusion pressure (CPP), brain tissue oxygen tension (PbtO2), cerebral venous oxygen saturation (ScvO2) and regional cerebral oxygen saturation (rSO2) in an animal model of hypothermic CPR. We also assessed the correlation between rSO2 and CPP, PbtO2 and ScvO2 to clarify whether near-infrared spectroscopy (NIRS) may be used to non-invasively monitor changes in cerebral oxygenation during hypothermic CPR. MethodsNine pigs were surface-cooled to a core temperature of 28°C and underwent a period of asphyxia before cardiac arrest was induced. After 2min of untreated cardiac arrest they were resuscitated for 45min. CPP, PbtO2, ScvO2 and rSO2 were monitored after periods of stable external chest compression, a short interruption of CPR and after epinephrine administration. ResultsDuring external chest-compressions before adrenalin administration CPP, PbtO2, ScvO2 and rSO2 increased in parallel and changes in rSO2 closely correlated with changes in CPP (r=.844; p<.001) and ScvO2 (r=.868; p<.001). After adrenaline administration CPP and PbtO2 increased, ScvO2 decreased and rSO2 values did not change and there was no significant correlation between rSO2 and CPP, PbtO2, or ScvO2. ConclusionIn this animal model of hypothermic cardiac arrest adrenaline was associated with an increase in global cerebral oxygen extraction despite an increase in CPP. Discrepancies in the time course of PbtO2 and ScvO2 suggest differences in regional oxygen metabolism after adrenalin. rSO2 values correlated closely with CPP and ScvO2 only during periods of external chest compression without adrenaline administration.

Improved Survival and Neurological Outcomes after Cardiopulmonary Resuscitation in Toll-like Receptor 4-mutant Mice

Background:Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system and noninfectious immune responses. It has been reported that TLR4 participates in the pathological course of ischemia/reperfusion (I/R) injury. However, the role of TLR4 in the process of I/R injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is still unknown. In this study, we investigated the effects of TLR4 mutation on survival and neurological outcome in a mouse model of CA/CPR.Methods:A model of potassium-induced CA was performed on TLR4-mutant mice (C3H/HeJ) and wild-type mice (C3H/HeN). After 3 min of untreated CA, resuscitation was attempted with chest compression, ventilation, and intravenous epinephrine. Behavioral tests were performed on mice on day 3 after CPR. The morphological changes in hippocampal neurons were assessed by light and electron microscopy. Expressions of TLR4 and intercellular adhesion molecule-1 (ICAM-1) were detected by Western blot. Levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) were measured with enzyme-linked immunosorbent assay (ELISA).Results:On day 3 after resuscitation the overall mortality was 33.33% in C3H/HeJ group compared with 53.33% in C3H/HeN group (P < 0.05). And there was much higher central tendency in C3H/HeJ group than C3H/HeN group during open field test (P < 0.05). Meanwhile, the percentage of nonviable neurons was 21.16% in C3H/HeJ group compared with 53.11% in C3H/HeN group (P < 0.05). And there were significantly lower levels of hippocampal TNF-α and MPO in C3H/HeJ mice (TNF-α: 6.85±1.19 ng/mL, MPO: 0.33±0.11 U/g) than C3H/HeN mice (TNF-α: 11.36±2.12 ng/mL, MPO: 0.54±0.17 U/g) (all P < 0.01). CPR also significantly increased the expressions of TLR4 and ICAM-1 in C3H/HeN group. However, the expression of ICAM-1 was much lower in C3H/HeJ group than in C3H/HeN group after CPR (P < 0.01).Conclusion:TLR4 signaling is involved in brain damage and in inflammation triggered by CA/CPR.

Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest

ObjectiveIschemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15min of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. MethodsFollowing 17min of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR+ITD+sevoflurane+P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. ResultsBundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48h), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48h). ConclusionsBundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17min of untreated cardiac arrest in pigs.All studies were performed with approval from the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation (protocol #12-11).

Postresuscitation Treatment With Argon Improves Early Neurological Recovery in a Porcine Model of Cardiac Arrest

Effects of postresuscitation treatment with argon on neurologic recovery were investigated in a porcine model of cardiac arrest (CA) with an underlying acute myocardial infarction. The left anterior descending coronary artery was occluded in 12 pigs, and CA was induced. After 8 min of untreated CA, cardiopulmonary resuscitation was performed for 5 min before defibrillation. Following resuscitation, animals were subjected to 4-h ventilation with 70% argon/30% oxygen or 70% nitrogen/30% oxygen. Myocardial function was echocardiographically assessed, and serum neuron-specific enolase was measured. Animals were observed up to 72 h for assessment of survival and neurologic recovery. All the animals were resuscitated and survived for 72 h, except for a control pig. Ventilation with argon did not have any detrimental effects on hemodynamics and respiratory gas exchange. All the six argon-treated animals had a fast and complete 72-h neurologic recovery, in contrast to only two of the six controls (P < 0.05). Seventy-two-hour neurologic alertness score and neurologic deficit score were, respectively, 100 and 0 in the argon group and 79 and 29 in the control one (P < 0.01 and P < 0.05). Significantly lower increases in serum neuron-specific enolase (12% vs. 234%) and minimal histological brain injury (neuronal degeneration: 0 vs. 1) were also observed in argon-treated animals, in comparison to controls. In this model, postresuscitation treatment with argon allowed for a faster and complete neurologic recovery, without detrimental effects on hemodynamics and respiratory gas exchanges.

Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest

Induced mild hypothermia and administration of methylene blue (MB) have proved to have neuroprotective effects in cardiopulmonary resuscitation (CPR); however, induction of hypothermia takes time. We set out to determine if MB administered during CPR could add to the histologic neuroprotective effect of hypothermia. A piglet model of extended cardiac arrest (12 min of untreated cardiac arrest and 8 min of CPR) was used to assess possible additional neuroprotective effects of MB when administered during CPR before mild therapeutic hypothermia induced 30 min after restoration of spontaneous circulation (ROSC). Three groups were compared: C group (n = 8) received standard CPR; PH group (n = 8) received standard CPR but 30 min after ROSC these piglets were cooled to 34°C; the PH+MB group (n = 8) received an MB infusion 1 min after commencement of CPR and the same cooling protocol as the PH group. Three hours later, the animals were killed. Immediately after death, the brains were harvested pending histological and immunohistological analysis. Circulatory variables were similar in the groups except that cardiac output was greater in the PH+MB group 2-3 h after ROSC. Cerebral cortical neuronal injury and blood-brain barrier disruption was greatest in the C group and least in the MB group. The neuroprotective effect of MB and hypothermia was significantly greater than that of delayed hypothermia alone. Administration of MB during CPR added to the short term neuroprotective effects of induced mild hypothermia induced 30 min after ROSC.

Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation

Aim of the studyWe investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival. MethodsProspective randomized animal study. Following 15min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34±2kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0–4 scale with (0=no injury to 4 ≥50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48h survival was reported. ResultsPost-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59%±9%, 52%±14%, 52%±14% vs. 35%±11%, respectively, p<0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8±2.6, 2.8±1.8 vs. 10±2.1, respectively, p<0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p<0.01). ConclusionsIPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15min of untreated cardiac arrest in pigs.

Effects of exogenous hydrogen sulfide on brain metabolism and early neurological function in rabbits after cardiac arrest

Some of the neuroprotective effects of hydrogen sulfide (H(2)S) have been attributed to systemic hypometabolism and hypothermia. However, systemic metabolism may vary more dramatically than brain metabolism after cardiac arrest (CA). The authors investigated the effects of inhaled exogenous hydrogen sulfide on brain metabolism and neurological function in rabbits after CA and resuscitation. Anesthetized rabbits were randomized into a sham group, a sham/H(2)S group, a CA group, and a CA/H(2)S group. Exogenous 80 ppm H(2)S was administered to the sham/H(2)S group and the CA/H(2)S group which suffered 3 min of untreated CA by asphyxia and resuscitation. Effects on brain metabolism (cerebral extraction of oxygen (CEO(2)), arterio-jugular venous difference of glucose [AJVD(glu)] and lactate clearance), S100B, viable neuron counts, neurological dysfunction score, and survival rate were evaluated. CEO(2), AJVD(glu), and lactate increased significantly after CA. Inhalation of 80 ppm H(2)S significantly increased CEO(2) (25.04 ± 7.11 vs. 16.72 ± 6.12 %) and decreased AJVD(glu) (0.77 ± 0.29 vs. 1.18 ± 0.38 mmol/L) and lactate (5.11 ± 0.43 vs. 6.01 ± 0.64 mmol/L) at 30 min after resuscitation when compared with the CA group (all P < 0.05). In addition, neurologic deficit scores, viable neuron counts, and survival rate were significantly better whereas S100B was decreased after H(2)S inhalation. The present study reveals that inhalation of 80 ppm H(2)S reduced neurohistopathological damage and improves early neurological function after CA and resuscitation in rabbits. The increased CEO(2) and decreased AJVD(glu) and enhanced lactate clearance may be involved in the protective effects.

Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation

ObjectivesIschemic postconditioning (PC) with “stuttering” reintroduction of blood flow after prolonged ischemia has been shown to offer protection from ischemia reperfusion injury to the myocardium and brain. We hypothesized that four 20-s pauses during the first 3min of standard CPR would improve post resuscitation cardiac and neurological function, in a porcine model of prolonged untreated cardiac arrest. Methods18 female farm pigs, intubated and isoflurane anesthetized had 15min of untreated ventricular fibrillation followed by standard CPR (SCPR). Nine animals were randomized to receive PC with four, controlled, 20-s pauses, during the first 3min of CPR (SCPR+PC). Resuscitated animals had echocardiographic evaluation of their ejection fraction after 1 and 4h and a blinded neurological assessment with a cerebral performance category (CPC) score assigned at 24 and 48h. All animals received 12h of post resuscitation mild therapeutic hypothermia. ResultsSCPR+PC animals had significant improvement in left ventricular ejection fraction at 1 and 4h compared to SCPR (59±11% vs 35±7% and 55±8% vs 31±13% respectively, p<0.01). Neurological function at 24h significantly improved with SCPR+PC compared to SCPR alone (CPC: 2.7±0.4 vs 3.8±0.4 respectively, p=0.003). Neurological function significantly improved in the SCPR+PC group at 48h and the mean CPC score of that group decreased from 2.7±0.4 to 1.7±0.4 (p<0.00001). ConclusionsIschemic postconditioning with four 20-s pauses during the first 3min of SCPR improved post resuscitation cardiac function and facilitated neurological recovery after 15min of untreated cardiac arrest in pigs.

Quantitative waveform measures of the electrocardiogram as continuous physiologic feedback during resuscitation with cardiopulmonary bypass

BackgroundThere are few if any real-time physiologic measures that currently provide feedback during resuscitation from cardiac arrest. Such measures could be used to guide therapy not simply based on process guidelines but on the physiologic response of the patient from moment to moment. To this end, we applied an existing technology – quantitative waveform measures (QWMs) of the ventricular fibrillation (VF) electrocardiogram (ECG) – as a continuous measure of myocardial response to reperfusion with cardiopulmonary bypass (CPB) after prolonged cardiac arrest. MethodsSixteen domestic, mixed-breed swine were sedated, anesthetized and paralyzed. Mechanical ventilation with room air was provided. Large diameter bypass catheters were placed in the right external jugular vein and right femoral artery for cardiopulmonary bypass (CPB). VF was induced with a 3-s 100mA transthoracic shock and left untreated for 15, 20, 25, or 30min, followed by 10min of centrifugal pump CPB (Bard CPS). Continuous Lead II ECG was recorded with an electronic data acquisition system (Power Lab, ADInstruments). Four QWMs representing 4 signal characteristics of the VF ECG were calculated in 5-s windows throughout the course of untreated VF and resuscitation with CPB. ResultsFour animals were assigned to each VF duration group. QWM recovery was inversely correlated with untreated VF duration, and was drastically reduced above 20min of untreated VF. Return of spontaneous circulation (ROSC) was highly unlikely after 20min of untreated VF. ConclusionQWMs of the VF ECG provided a real-time metric of myocardial electrophysiologic response to reperfusion with CPB. Resuscitation from greater than 20min of untreated cardiac arrest was unlikely. QWMs may be useful for titrating CPB duration before defibrillation and assessing CPR quality independently of process guidelines.

Combination pharmacotherapy improves neurological outcome after asphyxial cardiac arrest

AimTo study the effects of the combination of adrenaline (epinephrine) and vasopressin compared to adrenaline alone on initial resuscitation success, 24h survival, and neurological outcome in a swine model of asphyxial cardiac arrest (CA). MethodsThis prospective randomized experimental study was conducted at a laboratory research department. Twenty female Landrace/Large-White pigs, 12–15weeks of age, were investigated. Asphyxial CA was induced by clamping of the endotracheal tube. After 4min of untreated CA, resuscitation was initiated by unclamping the endotracheal tube, mechanical ventilation, chest compressions and adrenaline (Group A) or a combination of adrenaline with vasopressin (Group A+V) administered intravenously. In case of restoration of spontaneous circulation (ROSC), the animals were monitored for 30min and then observed for 24h. ResultsHemodynamic variables were measured at baseline during CPR and in the post-resuscitation period. Statistically significant difference was observed in groups A and A+V regarding coronary perfusion pressure (CPP) during the first minute of CPR. In both groups, ROSC and survival rates were comparable (p=NS). Neurological deficit score (NDS) was significantly higher in the combination group 24h following CA (p<0.001). Brain histological damage score (HDS) was also better in the combination group (p<0.001). Total HDS and NDS showed a statistical significant correlation (p<0.001). ConclusionsIn this porcine model of asphyxial CA, adrenaline alone as well as the combined administration of adrenaline and vasopressin resulted in similar ROSC and survival rates, but the combination of adrenaline and vasopressin resulted in improved neurological and cerebral histopathological outcomes.