Electrical Induction Of Ventricular Fibrillation Research Articles

Splenic Modulation of Early Post-Resuscitation Inflammation in a Porcine Model of Sudden Cardiac Arrest

Objective: The spleen has been implicated as a potential therapeutic target for acute anti-inflammatory intervention via modulation of splenic nerve activity, but the translational viability of this approach is unclear due to limited mechanistic understanding of splenic leukocyte mobilization in clinically relevant models. In contrast to prior rodent studies, we recently demonstrated that the spleen is not required for leukocyte mobilization after focal myocardial ischemia/reperfusion in swine. However, the spleen's role in the early inflammatory response to whole-body ischemia/reperfusion following resuscitation from sudden cardiac arrest (SCA) remains unexplored. Therefore, we used a surgical approach to investigate the spleen's contribution to early post-resuscitation inflammation in a porcine model of SCA. Methods: Eighteen swine were randomized to splenectomy (SPLX; n=9) or sham surgery (SHAM; n=9), and subsequently underwent 8 minutes of electrically-induced ventricular fibrillation SCA one week later. Mechanical CPR with defibrillation and intravenous epinephrine (EPI; 0.015 mg/kg) was performed to achieve return of spontaneous circulation (ROSC; defined as sustained MAP>60mmHg). Hemodynamic parameters, cardiac function, circulating biomarkers of injury (cTnI) and inflammation (IL-6, TNF-⍺), and blood leukocyte levels were assessed for 4 hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis of leukocyte infiltration via flow cytometry. Results: SPLX and SHAM animals were resuscitated at a similar rate (SHAM vs SPLX: 56% vs. 44%) and required a similar number of defibrillation attempts (4.3±0.8 vs. 5.2±1.3), but SPLX required more EPI boluses during CPR (3.3±1.3 vs. 1.4±0.2; p<0.05) and took longer to achieve ROSC (779±196 vs. 455±37 sec; p<0.05). After ROSC, SPLX animals required more EPI (43±10 vs. 13±10 μg/kg; p<0.05) to maintain MAP >60mmHg and tended to have higher circulating cTnI levels compared to SHAM (19.5±4.4 vs. 5.8±4.4 ng/mL; p=0.07). A significant elevation in circulating leukocytes was observed from pre-SCA to 4-hours post-ROSC in both SPLX (19.5±1.3 to 32.0±2.6 103/μl; p<0.05) and SHAM (from 15.1±1.3 to 23.7±2.9 103/μl; p<0.05), along with an increase in circulating IL-6 and TNF-α vs. pre-SCA values that tended to be higher in SPLX. Flow cytometry revealed post-ROSC leukocyte infiltration that was particularly evident in the brain, with an increased number of inflammatory granulocytes (CD172+CD163-) and dendritic cells (CD172+CD16+) in multiple brain regions of SPLX and SHAM animals compared with healthy controls. Conclusion: These results demonstrate that, in swine, the spleen is not required for the robust early inflammatory response to resuscitation from SCA. This observation provides further evidence that, in contrast to rodents, the spleen is not a primary contributor to sterile inflammation following ischemia/reperfusion injury in large animals. This translational study suggests that neuromodulation of splenic leukocyte mobilization may not be a viable therapeutic strategy for mitigating acute inflammation in clinical post-cardiac arrest syndrome. Supported by funding from the NIH and US Department of Veteran's Affairs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Time-Dependent Association Between Agonal Respirations and Cardiopulmonary Resuscitation Hemodynamics in a Porcine Model of Cardiac Arrest

Objective: Agonal respirations (AR) are common in patients with cardiac arrest (CA) and are associated with a higher likelihood of successful return of spontaneous circulation (ROSC). Prior preclinical studies suggest that the favorable effects of AR may be mediated by improved coronary perfusion pressure (CPP) during subsequent cardiopulmonary resuscitation (CPR) efforts, but whether this relationship is influenced by the duration of CA has yet to be studied. Accordingly, we measured CPR hemodynamics in swine following 7 minutes or 10 minutes of untreated ventricular fibrillation (VF) to determine if the frequency of AR is associated with CPP after prolonged CA. Methods: Swine (n=71) were subjected to either 7 minutes (n=50) or 10 minutes (n=21) of electrically-induced VF CA, during which the frequency of AR was recorded before the initiation of CPR with chest compressions (100/minute) and mechanical ventilation (16-20 breaths/minute). CPP was assessed during CPR by calculating the difference between aortic pressure and right atrial pressure during decompression. Animals were retrospectively stratified into two groups (high and low frequency of AR) based on the median number of AR in each cohort (7-minute CA median = 6 AR; 10-minute CA median = 9 AR).>Results: In the 7-minute CA cohort, the high AR group (9.7±2.9 AR; n=28) had a significantly longer time from first to last AR (102±6 vs. 34±6 seconds; p<0.001), shorter time from final AR to CPR initiation (208±8 vs. 280±15 seconds; p<0.001), and higher CPP during CPR (14.4±1.0 vs. 9.3±0.6 mmHg; p<0.001) than the low AR group (2.9±0.4 AR; n=22). In contrast, following 10 minutes of CA, the high AR group (12.0±0.4 AR; n=11) did not have a significantly different CPP during CPR (8.7±1.8 vs. 10.4±1.5 mmHg; p=0.48) when compared to the low AR group (6.2±0.5 AR; n=10). A greater number of defibrillation attempts were required to terminate VF after 10 minutes of CA (3.0±0.6) vs. 7 minutes of CA (1.2±0.1; p<0.001), but this was not impacted by the frequency of AR in either cohort. Conclusion: Consistent with prior studies in swine subjected to 5 minutes of untreated CA, a high frequency of AR during a 7-minute episode of CA was associated with higher CPP upon initiation of CPR. However, the favorable effects of AR frequency on CPP during CPR were no longer apparent when the duration of untreated CA was extended to 10 minutes. These results demonstrate that the beneficial effects of AR on CPR hemodynamics are time-dependent and highlight the importance of early initiation of CPR following CA. Supported by funding from the NIH and US Department of Veteran's Affairs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 299: Effect of Start Position and Compression Depth on Mechanical CPR Hemodynamics in Swine

Introduction: Mechanical devices offer the ability to provide consistent fixed-depth chest compressions during CPR. Although compression depth is considered a primary determinant of CPR quality, the influence of other device settings has received less attention. Accordingly, we evaluated the combined effect of compression depth and device start position on CPR hemodynamics in a porcine model of cardiac arrest (CA). Methods: Swine (n=119) were subjected to 7-10 min of CA following electrical induction of ventricular fibrillation. CPR was subsequently performed manually (target peak aortic pressure: 100 mmHg; n=73) or with a mechanical compression system (LUCAS 3.1, Stryker; n=46). Within the mechanical CPR group, animals received 102 compressions/min using either factory default settings (“QuickFit” automated suction cup start position; compression depth: 2.1”; n=13) or custom settings (manual suction cup start position; compression depth: 1.8”; n=33). Aortic pressure (Ao), coronary perfusion pressure (CPP), and regional cerebral oxygen saturation (rSO 2 ; via near infrared spectroscopy) were compared between groups after 1 min of CPR. Results: Mechanical CPR with automated suction cup start position and compression depth of 2.1” resulted in significantly higher peak Ao and CPP than mechanical CPR with manual start position and compression depth of 1.8” ( Table ). Compared with manual CPR, only mechanical CPR with automated start position and compression depth of 2.1” led to a higher CPP. However, cerebral rSO 2 values fell from 61±1 % at baseline to 49±1 % during CA (p<0.01) and did not increase during CPR in any group. Conclusion: Compared with a manual start position and compression depth of 1.8”, use of the LUCAS “QuickFit” feature and compression depth of 2.1” led to a significantly higher CPP during mechanical CPR. Future studies are necessary to determine if differences persist during prolonged CPR with and without concomitant vasopressor administration.

Epinephrine Exacerbates Myocyte Injury in a Porcine Model of Cardiac Arrest

ObjectiveAlthough circulating cardiac troponin (cTn) concentrations are often elevated in patients following resuscitation from cardiac arrest (CA), this finding is commonly attributed to myocyte injury caused by ongoing myocardial infarction (MI) and/or defibrillation during resuscitation. To determine whether measurable cTn elevations occur independently of these factors, we employed serial sampling of systemic and coronary venous blood to quantify cTn release in a porcine model of CA devoid of ongoing MI or multiple defibrillation attempts. In light of recent concerns regarding potential detrimental effects of epinephrine (EPI) in CA, cTn levels were compared in animals that were resuscitated with vs. without exogenous EPI.MethodsSwine (n=41) were subjected to 7 min CA via electrical induction of ventricular fibrillation (VF) followed by cardiopulmonary resuscitation (CPR) with manual chest compressions and mechanical ventilation for up to 20 min. Biphasic defibrillation (200 J) was performed 1 min after the start of CPR and a subset of animals (n=10) received intravenous EPI (0.015 mg/kg) 1 min later. After return of spontaneous circulation (ROSC; defined as unassisted systolic blood pressure >80 mmHg for 1 min), animals were followed for up to 4 hours with serial blood sampling from the jugular vein and coronary sinus for assessment of cTnI via a porcine‐specific ELISA.ResultsAmong the entire cohort, 1.2±0.1 defibrillator shocks were required to terminate VF, ROSC was achieved 175±7 seconds after the initiation of CPR, and 15 animals (38%) survived for the entire 4‐hour recovery period (2/10 with EPI, 13/31 without EPI). Despite the absence of ongoing MI or prolonged resuscitation efforts, a significant 5‐fold rise in coronary sinus (from 106±17 to 526±74 ng/L, p<0.01) and systemic (from 67±14 to 350±54 ng/L, p<0.01) cTnI concentrations was observed 15 min post‐ROSC (trans‐coronary cTnI gradient from 39±7 to 176±29 ng/L, p<0.01). Widening of the trans‐coronary cTnI gradient continued throughout the recovery period, reaching 795±164 ng/L 4 hours post‐ROSC and leading to a 16‐fold increase in circulating cTnI concentrations at this timepoint (1087±208 ng/L, p<0.01 vs. baseline). Exogenous EPI exacerbated myocyte injury, as EPI‐treated animals exhibited a significantly higher trans‐coronary cTnI gradient 30 min post‐ROSC that persisted throughout the recovery period and led to significantly higher circulating cTnI concentrations vs. animals resuscitated without EPI at each timepoint (Figure ).ConclusionsThese results demonstrate that resuscitation from CA is associated with measurable elevations in cTnI as early as 15 min post‐ROSC, even in the absence of ongoing MI or prolonged CPR with multiple defibrillator shocks. Thus, assessment of circulating cTnI following resuscitation from CA is unlikely to accurately identify patients suffering from an acute coronary syndrome. Administration of exogenous EPI during resuscitation exacerbates the extent of myocyte injury, which may contribute to poor long‐term outcomes.Support or Funding InformationFunding SourcesNIH, AHA, ZOLL Foundation, Pro‐Al Medico Technologies, Inc., UB CAT, NCATS, and the Dept. of Veterans Affairs.Figure 1

Abstract 265: Deterioration of Hemodynamic Support During Prolonged Mechanical CPR in a Porcine Model of Cardiac Arrest

Introduction: Although mechanical CPR devices provide automated delivery of fixed depth chest compressions, the consistency of hemodynamic support during prolonged resuscitation efforts is unclear, particularly in the absence of concomitant vasopressor treatment. In light of recent concerns regarding potentially harmful effects of epinephrine, we evaluated the hemodynamic support generated by 20 min of mechanical CPR without concurrent vasopressor administration in a porcine model of cardiac arrest (CA). Methods: Swine (n=10) were subjected to 7-8 min of CA following electrical induction of ventricular fibrillation. CPR was subsequently performed for 20 min using a mechanical compression system (LUCAS 3.1, Stryker) programmed to administer 102 compressions/min at a fixed depth of 2.1 inches. Aortic pressure (Ao), coronary perfusion pressure (CPP), and cerebral oxygen saturation (rSO 2 ; near-infrared spectroscopy) were continuously recorded. Results were compared to a separate group of swine (n=11) that received manual CPR with a compression rate of 100/min and depth necessary to achieve peak Ao of 100 mmHg. Results: Initially, mechanical CPR generated significantly higher peak Ao and CPP vs. manual CPR ( Figure ). However, by 4 min CPR, peak Ao and CPP were no longer different between groups. Both parameters continued to decline in the mechanical CPR group but remained stable in animals receiving manual CPR. Cerebral rSO 2 values fell from 57±2 % at baseline to 42±4 % during CA (p<0.01) but were not significantly improved by mechanical or manual CPR. Conclusion: The superior hemodynamic support initially offered by mechanical CPR deteriorates during prolonged CPR when pharmacologic vasopressor support is absent. These results demonstrate that a fixed compression depth does not necessarily produce consistent hemodynamic support and suggest that concomitant vasopressor administration may be necessary to sustain Ao and CPP during prolonged mechanical CPR.

Cardioplegia defibrillation of circulatory and metabolic phase ventricular fibrillation in a swine model

IntroductionWe previously found potassium cardioplegia followed by rapid calcium reversal (Kplegia) can achieve defibrillation in a swine model of electrical phase of ventricular fibrillation (VF) comparable to standard care. HypothesisExploring 3 possible potassium dose and timing protocols, we hypothesize Kplegia may benefit resuscitation of longer duration untreated VF. MethodsThree separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6, 9, and 12min in a swine model. Experimental groups received infusion of 1 or 2 boluses of intravenous (IV) potassium followed by a single calcium reversal bolus. Potassium was replaced by saline in the control groups. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1h post ROSC. Binomial and interval data outcomes were compared with exact statistics. Serial interval data were assessed with mixed regression models. ResultsTwelve, 12, and 8 animals were included at 6, 9, and 12min VF durations for a total of 32. ROSC was achieved in: 4/6 Kplegia and 3/6 control animals in the 6min protocol, (p=1.00), 4/6 Kplegia and 2/6 control animals in the 9min protocol,(p=0.57), and 0/5 Kplegia and 1/3 control animals in the 12min protocol,(p=0.38). Two of 8 Kplegia animals achieved ROSC with chemical defibrillation alone. ConclusionsThe majority of animals achieved ROSC after up to 9min of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.Institutional Animal Care and Use Committee protocol #15127224.

Electrically-Induced Ventricular Fibrillation Alters Cardiovascular Function and Expression of Apoptotic and Autophagic Proteins in Rat Hearts.

Background: The pathological heart contractions, called arrhythmias, especially ventricular fibrillation (VF), are a prominent feature of many cardiovascular diseases leading to sudden cardiac death. The present investigation evaluates the effect of electrically stimulated VF on cardiac functions related to autophagy and apoptotic mechanisms in isolated working rat hearts. Methods: Each group of hearts was subjected to 0 (Control), 1, 3, or 10 min of spacing-induced VF, followed by 120 min of recovery period and evaluated for cardiac functions, including aortic flow (AF), coronary flow (CF), cardiac output (CO), stroke volume (SV), and heart rate (HR). Hearts were also evaluated for VF effects on infarcted zone magnitude and Western blot analysis was conducted on heart tissue for expression of the apoptotic biomarker cleaved-caspase-3 and the autophagy proteins: p62, P-mTOR/mTOR, LC3BII/LC3BI ratio, and Atg5-12 complexes. Results: Data revealed that VF induced degradation in AF, CF, CO, and SV, which prominently included-variable post-VF capacity for recovery of normal heart rhythm; increased extent of infarcted heart tissue; altered expression of cleaved-caspase-3 suggesting potential for VF-mediated amplification of apoptosis. VF influence on expression of p62, LC3BII/LC3BI, and Atg5-12 proteins was complex, possibly due to differential effects of VF-induced expression on proteins comprising the autophagic program. Conclusions: VF was observed to cause time-dependent changes in autophagy processes, which with additional analysis under ongoing investigations, likely to yield novel therapeutic targets for the prevention of VF and sudden cardiac death.

Abstract 149: Role of Pre and Intra-Arrest Hemodynamics in Evolution of the Ventricular Fibrillation Electrocardiogram Waveform

Purpose: Quantitative waveform measures (QWM) of the ventricular fibrillation (VF) waveform have been shown in laboratory and clinical studies to be predictive of return of spontaneous circulation (ROSC) and survival to hospital discharge. During resuscitation, QWM are responsive to hemodynamic changes resulting from CPR. It is not known whether the trajectory of QWM are affected by pre-arrest hemodynamics or intra-arrest arterio-venous pressure equilibration. We sought to investigate the role of hemodynamics on the evolution of VF before and during prolonged VF. Methods: We pooled data from six previous porcine experiments. Each modeled prolonged VF and included electrical induction of VF which was left untreated for up to 10 minutes, followed by attempted resuscitation. All animals were instrumented with pressure transducers (Millar, MikroTip) placed via femoral cutdown in the aorta and right atrium, as well as Lead II surface ECG. Signals were recorded continuously at 1000Hz with a data acquisition unit (PowerLab, ADInstruments). Mean baseline central arterial (CAP) and central venous pressure (CVP) were calculated from 1- minute of immediate pre-VF pressure traces. Coronary perfusion pressure (CPP) during untreated VF was calculated as the continuous difference between the CAP and CVP channels. Median slope (MS), a QWM, was calculated in 1-second windows and interpolated to the full length of the intra-arrest ECG. For trajectory analysis, CPP and MS traces were normalized on a 0-1 scale and grouped by morphological similarity. Pearson’s Correlation coefficient was calculated between corresponding CPP and MS traces. Results: A total of 141 experiments were included in the analysis. Overall mean (SD) correlation between CPP and MS was 0.56 (0.29). CPP-MS correlation strength did not correlate with baseline pressures. However, trajectory analysis revealed multiple patterns of hemodynamic and QWM evolution through untreated VF, with the most well-defined (mean coeff. = 0.58) indicating a shared bimodality temporally offset between CPP and MS. Conclusions: Hemodynamics during untreated VF show some correlation with the trajectory of QWM of the VF signal. More work is needed to understand the mechanism of this relationship.

Abstract 334: Cardioplegia Defibrillation of Circulatory Phase Ventricular Fibrillation in a Swine Model: Three Randomized Controlled Trials

Introduction: We previously found potassium cardioplegia followed by rapid calcium reversal (K plegia) can achieve defibrillation in a swine model of electrical phase ventricular fibrillation (VF) comparable to standard care. Hypothesis: Exploring 3 possible potassium (K) dose and timing protocols, we hypothesize K plegia may benefit resuscitation of circulatory phase VF. Methods: Three separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6,9, and 12 minutes in a swine model. All experimental groups received infusion of 1 or 2 boluses of intravenous (IV) K followed by a single calcium reversal bolus. Only K was replaced by saline in the control groups. All other treatments were the same. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1 hour post ROSC. Single nominal and interval outcomes were compared with Fisher’s Exact test and Mann-Whitney U, respectively. Results: Twelve, 12, and 8 animals were included at 6, 9 , and 12 minute VF durations for a total of 32. ROSC, average number of shocks, and post-ROSC norepinephrine requirement are listed below. 4/6 K plegia and 2/6 control animals achieved ROSC in the 9 minute protocol, (p=0.24). Two of 8 animals that achieved ROSC with K plegia did so without electrical defibrillation. Conclusions: The majority of animals achieved ROSC after up to 9 minutes of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.

Predictors of amplitude-spectral area (AMSA) during CPR in a swine model of electrically-induced ventricular fibrillation

Predictors of amplitude-spectral area (AMSA) during CPR in a swine model of electrically-induced ventricular fibrillation

A Rat Model of Ventricular Fibrillation and Resuscitation by Conventional Closed-chest Technique.

A rat model of electrically-induced ventricular fibrillation followed by cardiac resuscitation using a closed chest technique that incorporates the basic components of cardiopulmonary resuscitation in humans is herein described. The model was developed in 1988 and has been used in approximately 70 peer-reviewed publications examining a myriad of resuscitation aspects including its physiology and pathophysiology, determinants of resuscitability, pharmacologic interventions, and even the effects of cell therapies. The model featured in this presentation includes: (1) vascular catheterization to measure aortic and right atrial pressures, to measure cardiac output by thermodilution, and to electrically induce ventricular fibrillation; and (2) tracheal intubation for positive pressure ventilation with oxygen enriched gas and assessment of the end-tidal CO2. A typical sequence of intervention entails: (1) electrical induction of ventricular fibrillation, (2) chest compression using a mechanical piston device concomitantly with positive pressure ventilation delivering oxygen-enriched gas, (3) electrical shocks to terminate ventricular fibrillation and reestablish cardiac activity, (4) assessment of post-resuscitation hemodynamic and metabolic function, and (5) assessment of survival and recovery of organ function. A robust inventory of measurements is available that includes - but is not limited to - hemodynamic, metabolic, and tissue measurements. The model has been highly effective in developing new resuscitation concepts and examining novel therapeutic interventions before their testing in larger and translationally more relevant animal models of cardiac arrest and resuscitation.

A 10 min “no-touch” time - is it enough in DCD? A DCD Animal Study

Donation after cardiac death (DCD) is under investigation because of the lack of human donor organs. Required times of cardiac arrest vary between 75s and 27min until the declaration of the patients' death worldwide. The aim of this study was to investigate brain death in pigs after different times of cardiac arrest with subsequent cardiopulmonary resuscitation (CPR) as a DCD paradigm. DCD was simulated in 20 pigs after direct electrical induction of ventricular fibrillation. The "no-touch" time varied from 2min up to 10min; then 30min of CPR were performed. Brain death was determined by established clinical and electrophysiological criteria. In all animals with cardiac arrest of at least 6min, a persistent loss of brainstem reflexes and no reappearance of bioelectric brain activity occurred. Reappearance of EEG activity was found until 4.5min of cardiac arrest and subsequent CPR. Brainstem reflexes were detectable until 5min of cardiac arrest and subsequent CPR. According to our experiments, the suggestion of 10min of cardiac arrest being equivalent to brain death exceeds the minimum time after which clinical and electrophysiological criteria of brain death are fulfilled. Therefore shorter "no-touch" times might be ethically acceptable to reduce warm ischemia time.

Further observations on the experimental antidysrhythmic activity of indoramin hydrochloride.

Abstract Indoramin showed potent activity in reversing severe myocardial conduction disorders and ventricular fibrillation induced by hypothermia, and protected against the precipitation of electrically-induced ventricular fibrillation at low doses in pentobarbitone-anaesthetized cats. It would appear that the α-adrenoceptor blocking and local anaesthetic membrane stabilizing properties of indoramin are responsible for the mechanisms by which these dysrhythmias are reversed as they are with those induced by ouabain and adrenaline, previously described.

An Observational Study to Assess Changes in Arterial Blood Gas Values During Untreated Porcine Ventricular Fibrillation

Background. Cardiocerebral resuscitation (CCR) is reportedly superior to cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) even though active ventilation is not initially provided. Understandably, concerns have been raised regarding the withholding of positive pressure ventilation (PPV) during CCR because of the longstanding belief that respiratory gas exchange is a critical action during resuscitation. Objective. In this observational study, we sought to quantify the effect of prolonged untreated ventricular fibrillation (VF) on arterial pH, partial pressure of carbon dioxide (pCO2), and partial pressure of oxygen (pO2) values in a swine model of witnessed cardiac arrest to begin exploring the validity of these concerns. Methods. Both included studies were approved by the institutional animal care and use committee (IACUC). Eighty-three animals (25–35 kg) were instrumented under general anesthesia. Baseline characteristics were recorded. An arterial blood gas (ABG) sample was drawn from each animal via femoral catheter just prior to electrical induction of VF. After 8 minutes of untreated VF in one study (study 1 [n = 30]) and 10 minutes of untreated VF in the other study (study 2 [n = 53]), a second ABG sample was drawn. All samples were processed immediately using an i-STAT portable whole blood analyzer. Baseline characteristics of animals in the two studies were assessed using descriptive statistics. For the second ABG sample in each study, the mean pH, pCO2, and pO2 values, with 95% confidence intervals (95% CIs), were determined. The paired ABG results for each animal were then compared and the average pH, pCO2, and pO2 proportions, with 95% CIs, for each study were calculated. Results. The baseline characteristics of the animals in the two studies were similar. After 8 and 10 minutes of untreated VF cardiac arrest, the pH values were 7.35 (95% CI = 7.32, 7.37) and 7.37 (95% CI = 7.36, 7.38), the pCO2 increased to 44.1 mmHg (95% CI = 41.1, 47.1) and 52.7 mmHg (95% CI = 51.0, 54.4), and the pO2 decreased to 44.8 mmHg (95% CI = 42.2, 47.4) and 45.5 mmHg (95% CI = 43.3, 47.6), respectively. Conclusions. Using our swine model of witnessed cardiac arrest with prolonged untreated VF, the arterial pH remained essentially unchanged and the pCO2 increased to 1.42 times baseline after 10 minutes, while almost half of the initial O2 concentration in the blood at the beginning of resuscitation remained.

UP-REGULATION OF MYOCARDIAL CONNEXIN-43 AND PKCE IS MOST LIKELY INVOLVED IN CARDIOPROTECTIVE-ANTIARRHYTHMIC EFFECTS OF OMEGA-3 FATTY ACIDS IN OLD HYPERTENSIVE RATS: PP.29.162

Background: Hypertension-induced myocardial remodelling contributes to both heart failure and occurrence of life-threatening arrhythmias. Clinical studies showed that omega-3 polyunsaturated fatty acids (omega-3) reduce the incidence of cardiovascular diseases and sudden cardiac death. However, mechanisms are not fully elucidated. Myocardial connexin (Cx) channels at the gap junctions ensure electrical coupling and cardiac synchronisation. The aim of this study was to investigate whether omega-3 affect distribution, expression and/or phosphorylation of Cx-43 in aged spontaneously hypertensive rats (SHR). Myocardial ultrastructure and susceptibility of the heart to ventricular fibrillation (VF) were examined as well. Design and Methods: Male, 14-months-old SHR and non-hypertensive Lewis rats (NLR) were fed with omega-3 (Vesteralens, Norway, 40 mg/day/2mth) and compared with untreated. Blood pressure was registered and left ventricular tissues were processed for ‘in situ’ immunodetection of Cx43 and electron microscopy. Western blotting was used to assess total Cx43 expression, its phosphorylation status and expression of protein kinases C (which phopshorylate Cx43). Susceptibility to electrically-induced VF was tested using Langendorff isolated heart model. Results showed that omega-3 supplementation led to a significant decline of blood pressure in SHR and reduced incidence of VF despite myocardial fibrosis, hypertrophy and abnormal Cx43 distribution (remodelling) were not eliminated but integrity of the cardiomyocytes and their junctions were improved. Total myocardial Cx43 expression and its phosphorylated forms were markedly decreased in SHR, while significantly increased due to omega-3. It was accompanied by enhanced PKCe expression different to its suppression in untreated SHR. Conclusions: Findings indicate that up-regulation of myocardial connexin-43 and PKC-e is most likely involved in the mechanisms of antiarrhytmic effects of omega-3 fatty acids in old hypertensive rats. Results challenge to know a possible beneficial effects of omega-3 fatty acids supplementation in patients suffering from hypertension.

Non-selective cyclooxygenase inhibition before periodic acceleration (pGz) cardiopulmonary resuscitation (CPR) in a porcine model of ventricular fibrillation

Whole body periodic acceleration (pGz) along the spinal axis is a novel method of cardiopulmonary resuscitation (CPR). Oscillatory motion of the supine body in a horizontal fashion provides ventilation and blood flow to vital organs during cardiac arrest and pulsatile shear stress to the vascular endothelium. We previously showed in pigs that pGz-CPR affords better overall survival, post resuscitation myocardial function, and neurological outcomes compared to conventional chest compression CPR. pGz through pulsatile shear stress on the vascular endothelium elicits acute production of prostaglandins and endothelial-derived nitric oxide (eNO) in whole animal models and in vitro preparations. The salutary effects associated with pGz-CPR compared to chest compression CPR are in part related to endothelial-derived nitric oxide. Both eNO and prostaglandins are cardioprotective in ischemia reperfusion models. To differentiate between the roles of these mediators, indomethacin a non-selective cyclooxygenase inhibitor (COX) was used as a tool to investigate prostaglandin effects during pGz-CPR by acute outcomes of survival, cardioprotection and regional blood flows (RBF). Two groups of anesthetized, intubated pigs weighing 25-36kg were studied. Prior to electrical induction of ventricular fibrillation (VF) animals received equal volumes of either saline placebo Control (CONT) (n=9) or indomethacin (INDO), (n=8), (2mg/kg). After 3min of unsupported VF, both groups received 15min of pGz-CPR followed by pharmacologic and electrical attempts for resuscitation. Return of circulation (ROSC) to 3h occurred in (78%) in CONT and (63%) in INDO pretreated animals. There was no statistically significant difference in hemodynamics between groups at baseline or during the protocol. At baseline, INDO caused a decrease in brain RBF. Two hours after ROSC, INDO blunted the hyperemia response to brain and heart. Echocardiographic evidence of myocardial dysfunction was most notable for the INDO group in the wall motion score index (WMSI). After 3h of ROSC there was a 4-fold difference in both creatine phosphokinase (CPK) and Troponin I concentration between INDO and CONT. Therefore, non-specific acute inhibition of COX in part blunts the salutary effects of pGz-CPR. These data suggest that prostaglandins in part are involved in the cardio protection induced by pGz during CPR.

Is all ventricular fibrillation the same? A comparison of ischemically induced with electrically induced ventricular fibrillation in a porcine cardiac arrest and resuscitation model*

The standard porcine cardiac arrest model uses electrical induction of ventricular fibrillation. Reported restoration of spontaneous circulation and survival rates in this model are as high as 90% for ventricular fibrillation durations of 7-10 mins, values substantially greater than rates in the clinical population (i.e., 20% to 30%). A high first shock success rate, infrequent refibrillation, and short times for restoration of spontaneous circulation are typical of the model. The purpose of this study was to determine whether ischemic induction of ventricular fibrillation in swine followed by standard advanced cardiac life support would result in short-term outcomes approximating those observed in human victims of out-of-hospital ventricular fibrillation. Randomized comparative trial. Translational research laboratory. Domestic swine (n = 40, mean weight 40 +/- 4 kg, range 34-47 kg) of both genders. Swine were instrumented and randomized to either electrical ventricular fibrillation induction or ischemic ventricular fibrillation, produced by balloon occlusion of the mid-left anterior descending coronary artery (n = 20 per group). Transthoracic impedance was measured and 30 Omega added in series for all animals. The balloon remained inflated during resuscitation efforts in ischemic ventricular fibrillation animals. After 7 mins of ventricular fibrillation, cardiopulmonary resuscitation was initiated and defibrillation was attempted 1 min later. Epinephrine and antiarrhythmics were administered as per guidelines. Resuscitation was terminated if restoration of spontaneous circulation had not occurred after 15 mins of advanced cardiac life support. Although the number of countershocks required to initially terminate ventricular fibrillation was not different (electrical ventricular fibrillation 1.9 +/- 1.6, ischemic ventricular fibrillation 2.4 +/- 2.0), the refibrillation rate was higher in the ischemic ventricular fibrillation group (4.9 +/- 4 vs. 0.8 +/- 1 episodes/animal, p < .001), resulting in a greater number of shocks before restoration of spontaneous circulation (total shocks for ischemic ventricular fibrillation 9.4 +/- 5.6 vs. electrical ventricular fibrillation 2.7 +/- 2.2, p < .001). Time to restoration of spontaneous circulation was longer in the ischemic ventricular fibrillation group (430 +/- 234 secs vs. 149 +/- 120 secs, p < .001). Restoration of spontaneous circulation rates were not different (electrical ventricular fibrillation 90% vs. ischemic ventricular fibrillation 65%). However, survival to 6 hrs was greater in the electrical ventricular fibrillation group (18 of 20, 90%) than in the ischemic ventricular fibrillation group (8 of 20, 40%, p = .002). Resuscitation from ischemic ventricular fibrillation is more difficult than electrical ventricular fibrillation and is characterized by greater time to restoration of spontaneous circulation, frequent refibrillation, greater number of countershocks, higher epinephrine dose during resuscitation efforts, profound cardiac dysfunction, and a short-term survival rate approaching clinical experience. Ischemically induced ventricular fibrillation is a more clinically relevant model for the evaluation of resuscitation interventions.

Hypetriglycerolemia affects myocardial connexin-43 remodelling and increased incidence of lethal arrhythmias

Aim of this work was to examine whether hypetriglycerolemia (hHTG) affects distribution and/or expression of major cell-to-cell gap junction protein, connexin-43 (Cx43), since Cx43 remodelling is known to facilitate occurrence of malignant arrhythmias. Ventricular tissues taken from the heart of 4 month-old male hHTG and age-matched Wistar rats were processed for in situ coronary and capillary enzyme histochemistry, immunolabelling of Cx43 and for electron microscopy examination. Isolated perfused heart model was used to test vulnerability of the heart to electrically-induced ventricular fibrillation (VF). Results showed that hHTG rat hearts exhibited decreased coronary artery-related ATPase and capillary-related alkaline phosphatase activities as well as subcellular alterations suggesting endothelial impairment. Moreover, myocardial fibres disarrays and interstitial fibrosis indicated ventricular structural remodelling. Notably, an immunolabelling of Cx43 revealed pronounced changes in distribution of gap junctions, i.e. increased number of Cx43-positive gap junctions on lateral surfaces of the cardiomyocytes, cytoplasmic annular profiles of the gap junctions in the vicinity of intercalated discs were observed. These changes, i.e. “lateralisation” and “internalisation” of Cx43 containing gap junctions were linked with significantly higher incidence of VF in hHTG rat hearts (7 of 8) when compared to Wistar controls (2 of 8).

Efficacy of lower-energy biphasic shocks for transthoracic defibrillation:: A follow-up clinical study

ObjectiveThis clinical study prospectively evaluated the first-shock defibrillation efficacy of 150-joule impedance-compensated, 200-μF biphasic truncated exponential (BTE) shocks in patients with electrically-induced ventricular fibrillation (VF), and compared it with a historical control group treated with 200-J monophasic damped sine (MDS) shocks. MethodsVentricular tachyarrhythmias were induced in patients undergoing electrophysiologic (EP) testing for ventricular arrhythmias or testing of an implantable cardioverter-defibrillator (ICD). A 150-J shock was delivered as the primary therapy to terminate induced arrhythmias in the EP group, and as a “rescue” shock when a single ICD shock failed to terminate the arrhythmias in the ICD group. ResultsNinety-six patients received study shocks. The preshock rhythm was classified as VF in 77 patients and as ventricular tachycardia (VT) in 19 patients. First-shock success rates for VF and VT were 75 out of 77 (97.4%) and 19 out of 19 (100%) for the 150-J BTE compared with the historical control rates of 61 out of 68 (89.7%) and 29 out of 31 (94%) for 200-J MDS. The first-shock success rate for VF treated with 150-J BTE was technically equivalent to that of 200-J MDS (p=0.001). The transthoracic impedance did not vary between groups, yet the peak current delivered by the 150-J BTE shock was about 50% lower. ConclusionsThis study demonstrated that 150-J shocks of this impedance-compensated, 200-μF BTE waveform provided very high efficacy for defibrillation of short duration, electrically-induced VF. These lower-energy biphasic shocks had a success rate equivalent to that of 200-J MDS shocks, and they provided this efficacy while exposing patients to much less current than the monophasic shocks.

EFFICACY OF LOWER-ENERGY BIPHASIC SHOCKS FOR TRANSTHORACIC DEFIBRILLATION: A FOLLOW-UP CLINICAL STUDY

Objective. This clinical study prospectively evaluated the first-shock defibrillation efficacy of 150-joule impedance-compensated, 200-µF biphasic truncated exponential (BTE) shocks in patients with electrically-induced ventricular fibrillation (VF), and compared it with a historical control group treated with 200-J monophasic damped sine (MDS) shocks. Methods. Ventricular tachyarrhythmias were induced in patients undergoing electrophysiologic (EP) testing for ventricular arrhythmias or testing of an implantable cardioverter-defibrillator (ICD). A 150-J shock was delivered as the primary therapy to terminate induced arrhythmias in the EP group, and as a “rescue” shock when a single ICD shock failed to terminate the arrhythmias in the ICD group. Results. Ninety-six patients received study shocks. The preshock rhythm was classified as VF in 77 patients and as ventricular tachycardia (VT) in 19 patients. First-shock success rates for VF and VT were 75 out of 77 (97.4%) and 19 out of 19 (100%) for the 150-J BTE compared with the historical control rates of 61 out of 68 (89.7%) and 29 out of 31 (94%) for 200-J MDS. The first-shock success rate for VF treated with 150-J BTE was technically equivalent to that of 200-J MDS (p = 0.001). The transthoracic impedance did not vary between groups, yet the peak current delivered by the 150-J BTE shock was about 50% lower. Conclusions. This study demonstrated that 150-J shocks of this impedance-compensated, 200-µF BTE waveform provided very high efficacy for defibrillation of short duration, electrically-induced VF. These lower-energy biphasic shocks had a success rate equivalent to that of 200-J MDS shocks, and they provided this efficacy while exposing patients to much less current than the monophasic shocks.