High Serum Tumor Necrosis Factor Levels in the Early Post-Cardiac Arrest Period Are Associated with Poor Short-Term Survival in a Swine Model of Ventricular Fibrillation.

Most resuscitated victims of out-of-hospital cardiac arrest who survive to hospital expire due to the postresuscitation syndrome. This syndrome is characterized by a sepsis-like proinflammatory state. The objective of this investigation was to determine whether a relationship exists between the rise of tumor necrosis factor (TNF), a proinflammatory cytokine, following return of spontaneous circulation (ROSC), and early postarrest survival in a clinically relevant animal model of spontaneous ventricular fibrillation (VF). Mixed-breed Yorkshire swine (n = 20), weighing 39 ± 5 kg, were anesthetized and catheters placed in the right atrium and left ventricle/ascending aorta for continuous pressure monitoring. VF was induced by occluding the left anterior descending coronary artery with an angioplasty balloon. After 7 min of untreated VF, advanced life support resuscitation attempts were made for up to 20 min. Animals achieving ROSC were monitored for 3 h and fluid and pressor support was administered as needed. TNF levels were measured before VF and at 0, 15, and 30 min after ROSC using quantitative sandwich enzyme-linked immunosorbent assay. Twelve (60%) animals experienced early death, expiring during the 3 hour postarrest period (9 pulseless electrical activity, 2 VF, and 1 asystole). The TNF level at 15 min post-ROSC was significantly associated with death within the first 3 h post-ROSC with a univariate odds ratio of 1.4 [95% confidence interval (CI) 1.05-2.2, P = 0.01]. Using a cutoff TNF level of 525 pg/mL at 15 min post-ROSC had 100% negative predictive value (95% CI 0%-37%) and 67% positive predictive value (95% CI 35%-90%) for early death with a hazard ratio of 6.6 (95% CI 1.9-23.5). TNF increases shortly after ROSC and is predictive of early death. Early identification of resuscitated victims at greatest risk for hemodynamic collapse and recurrent arrest might facilitate the use of early hospital-based interventions to decrease the likelihood of a poor outcome.

Administration of amiodarone during resuscitation is associated with higher tumor necrosis factor-α levels in the early postarrest period in the swine model of ischemic ventricular fibrillation.

To compare the early postarrest inflammatory cytokine response between animals administered amiodarone (AMIO) and lidocaine (LIDO) intra-arrest during resuscitation from ventricular fibrillation (VF). Domestic swine (n=32) were placed under general anesthesia and instrumented before spontaneous VF was induced by balloon occlusion of the left anterior descending coronary artery. After 7 min of VF, standard ACLS resuscitation was performed and animals were randomized to either bolus AMIO (5 mg/kg, n=13) or LIDO (1 mg/kg, n=14) for recurrent or refractory VF. A non-antiarrhythmic (n=5) was also used for comparison. Following return of spontaneous circulation (ROSC), tumor necrosis factor (TNF)-α levels were drawn at 30 and 60 min. Groups were comparable with respect to prearrest hemodynamics and resuscitation variables. In the postarrest period, the LIDO and non-antiarrhythmic group demonstrated virtually identical TNF-α response trajectories. However, TNF-α levels were significantly higher in AMIO- than LIDO-treated animals at 30 min (geometric mean 539 versus 240 pg/mL, 2.2-fold higher, 95% confidence interval [CI] 1.3-3.8-fold higher, P=0.003) and at 60 min (geometric mean 570 versus 204 pg/mL, 2.8-fold higher, 95% CI 1.1-7.0-fold higher, P=0.03). Significant differences in the postarrest TNF-α levels were observed between animals treated with AMIO as compared to those treated with LIDO. Improved rates of ROSC seen with AMIO may come at the expense of a heightened proinflammatory state in the postcardiac arrest period.

A comparison of etanercept vs. infliximab for the treatment of post-arrest myocardial dysfunction in a swine model of ventricular fibrillation.

AIMS: To compare the effects of two TNF-α antagonists, etanercept and infliximab, on post-cardiac arrest hemodynamics and global left ventricular function (LV) in a swine model following ventricular fibrillation (VF). METHODS: Domestic swine (n=30) were placed under general anesthesia and instrumented before VF was induced electrically. After 7 min of VF, standard ACLS resuscitation was performed. Animals achieving return of spontaneous circulation (ROSC) were randomized to immediately receive infliximab (5 mg/kg, n=10) or etanercept (0.3 mg/kg [4 mg/m(2)], n=10) or vehicle (250 mL normal saline [NS], n=10) and LV function and hemodynamics were monitored for 3 h. RESULTS: Following ROSC, mean arterial pressure (MAP), stroke work (SW), and LV dP/dt fell from pre-arrest values in all groups. However, at the 30 min nadir, infliximab-treated animals had higher MAP than either the NS group (difference 14.4 mm Hg, 95% confidence interval [CI] 4.2-24.7) or the etanercept group (19.2 mm Hg, 95% CI 9.0-29.5), higher SW than the NS group (10.3 gm-m, 95% CI 5.1-15.5) or the etanercept group (8.9 gm-m, 95% CI 4.0-14.4) and greater LV dP/dt than the NS group (282.9 mm Hg/s, 95% CI 169.6-386.1 higher with infliximab) or the etanercep group (228.9 mm Hg/s, 95% CI 115.6-342.2 higher with infliximab). CONCLUSIONS: Only infliximab demonstrated a beneficial effect on post cardiac arrest hemodynamics and LV function in this swine model. Etanercept was no better in this regard than saline.

TNF-α blockade improves early post-resuscitation survival and hemodynamics in a swine model of ischemic ventricular fibrillation.

AIM OF THE STUDY: Inflammatory cytokines have been implicated in the pathophysiology of post cardiac arrest syndrome, including myocardial dysfunction and hypotension, often leading to multi-organ system dysfunction and death. We hypothesized that administration of infliximab after return of spontaneous circulation (ROSC) would ameliorate hypotension and myocardial dysfunction and prolong survival. METHODS: Domestic swine were anesthetized and instrumented. Balloon occlusion of the LAD coronary artery just distal to the first septal perforator was performed and VF followed spontaneously in all animals. After 7 min, chest compressions, defibrillation, and standard ACLS resuscitation was performed. Animals achieving ROSC (N=32) were randomized to receive infliximab (5 mg/kg, n=16) or vehicle (250 mL normal saline, n=16) immediately post-ROSC and survival and hemodynamics were monitored for 3 h. RESULTS: There were no differences in prearrest hemodynamic variables, TNF-α levels, or resuscitation variables between groups. Both groups demonstrated a time dependent decline in mean arterial pressure (MAP) and stroke work (SW) post-ROSC with a nadir at 1 h followed by recovery over hours 2 and 3. This decline was blunted in infliximab-treated swine (1-h between group difference in MAP 21 mm Hg, 95% CI 3-38 mm Hg and SW 6.7 gm-m, 95% CI 0.4-13 at 1 h). Left ventricular systolic dp/dt fell in the vehicle group (-437 mm Hg/s, 95% CI -183 to -690) but did not in the infliximab group. Tau rose only in the vehicle group (44 ms, 95% CI 1-87). Short-term survival was higher in the infliximab group (Kaplan-Meier p=0.022). CONCLUSIONS: Blockade of TNF-α in the immediate post-ROSC period improved survival and hemodynamic parameters in this swine model of ischemic VF.

Beta-blockade causes a reduction in the frequency spectrum of VF but improves resuscitation outcome: A potential limitation of quantitative waveform measures.

INTRODUCTION: Methods to identify appropriate treatments for the various stages of ventricular fibrillation (VF) involve differentiating groups of subjects who will respond to defibrillation with return of spontaneous circulation (ROSC) and those who require other therapies (e.g., CPR, drugs) prior to defibrillation. The use of quantitative waveform measures (QWM) which measure the frequency and fractal dimension of the VF electrocardiogram have shown success in predicting response to defibrillatory shock in animal models. Patients in cardiac arrest are often taking medications affecting adrenergic activity such as the beta blocker metoprolol and the combined alpha and beta blocker, labetalol. How this exposure might alter the QWM and ROSC rates is not known. HYOTHESIS: We sought to determine how pretreatment with adrenergic agents alters two QWM measures, the amplitude spectrum area (AMSA) and the detrended fluctuation analysis (DFA). We also examined how these medications alter the probability of ROSC after shock. METHODS: A swine model of ischemically induced VF cardiac arrest was used in which metoprolol and labetalol were administered prior to VF onset. 30 swine were randomly assigned to three groups of 10; control, metoprolol and labetalol. They were anesthetized, intubated and given the appropriate study drug. A balloon catheter was placed in the LAD coronary artery and inflated until VF occurred. ECG was recorded at 1000Hz for 7min of untreated VF. Closed chest compressions were then begun and after 1min a 200J shock was delivered. Resuscitation was continued with repeat defibrillation shocks as indicated for 15min or until ROSC was achieved (defined: systolic BP>60 for 10min). The Fourier frequency spectra, AMSA and DFA measures from VF onset to 7min were calculated using custom MATLAB routines. The QWM were compared over the electrical and circulatory phases of VF using generalized estimating equations. The rates of ROSC in the three groups were compared using relative risk measures. RESULTS: All 10 control animals fibrillated after coronary occlusion, 8 metoprolol and 7 labetalol animals fibrillated. The frequency spectrum in metoprolol treated animals demonstrated a reduction in mean frequencies from 1 to 3min (electrical phase) and from 3 to 7min (circulatory phase). Labetalol produced an even greater reduction in frequencies in these intervals. The decline in AMSA was similar in all three groups over the first 3min. From 3 to 7min the metoprolol group was significantly lower than the control group (p<0.001) and the labetalol group was lower still (p<0.001). The DFA demonstrated little difference between the control and metoprolol groups, but showed a linear increase over 7min in the labetalol group (p<0.001 vs compared to control and metoprolol groups). ROSC was noted in 2/10 in the control group, 7/8 in metoprolol group and 2/7 in the labetalol group. The frequentist analysis of ROSC showed a relative risk (RR) of ROSC of 4.4 when comparing control to metoprolol animals and 1.4 comparing control to labetalol animals. DISCUSSION: Metoprolol results in a reduction in frequencies in the Fourier spectrum of VF as compared with controls. There is a further decrease in frequencies with labetalol. The AMSA reflects this reduction in frequencies with lower AMSA values from 3 to 7min of VF. The DFA demonstrates consistent changes with labetalol treated animals over the 7min, but the metoprolol treated animals do not differ from the controls. The marked improvement in ROSC seen with metoprolol (RR 4.4) is unexpected and is not seen in labetalol treated animals. Adrenergic blockade prior to VF induction affects quantitative measures of the VF waveform and may limit the ability of such measures to predict downtime or defibrillation outcome.

Endothelin-1 attenuates the hemodynamic response to exogenous epinephrine in a porcine ischemic ventricular fibrillation cardiac arrest model.

Endothelin-1 (ET-1) increases in the ischemically induced ventricular fibrillation (VF) swine model of cardiac arrest and affects outcome by potentially attenuating the hemodynamic response to epinephrine. Fifty-one swine underwent percutaneous left anterior descending occlusion. Seven minutes postonset of ischemic VF, cardiopulmonary resuscitation (CPR) was initiated. If VF persisted after 3 shocks, 1 mg of epinephrine was given. ET-1 (collected at baseline and every 5 min until VF onset) was assayed with ELISA. Bayesian multivariate logistic regression analysis compared peak ET-1 levels with the binary outcome of a positive coronary perfusion pressure response of >20 mmHg following epinephrine. Sixteen animals (31%) failed to achieve a positive response. Restoration of spontaneous circulation (ROSC) was observed in 1/16 (6.3%) of epinephrine nonresponders and 20/35 (57.1%) of epinephrine responders (P = 0.0006). The median peak ET-1 level was 2.71 pg/mL [interquartile range (IQR) 1.06-4.40] in nonresponders and 1.69 pg/mL (IQR 0.99-2.35) in responders. ET-1 levels were inversely associated with epinephrine response with a median posterior odds ratio (OR) of a coronary perfusion pressure response of 0.72 (95% confidence interval [CI] 0.48-1.06) for each one-unit increase in ET-1 and a probability that the associated OR is <1 of 0.95. Peak ET-1 levels predict a lack of a hemodynamic response to epinephrine during treatment of cardiac arrest during ischemic VF.

Does early postresuscitation stress hyperglycemia affect 72-hour neurologic outcome? Preliminary observations in the Swine model.

BACKGROUND: Hyperglycemia is common in the early period following resuscitation from cardiac arrest and has been shown to be a predictor of neurologic outcome in retrospective studies. OBJECTIVE: To evaluate neurologic outcome and early postarrest hyperglycemia in a swine cardiac arrest model. METHODS: Electrically induced ventricular fibrillation cardiac arrest was induced in 22 anesthetized and instrumented swine. After 7 minutes, cardiopulmonary resuscitation (CPR) and Advanced Cardiac Life Support were initiated. Twenty-one animals were resuscitated and plasma glucose concentration was measured at intervals for 60 minutes after resuscitation. The animals were observed for 72 hours and the neurologic score was determined at 24-hour intervals. RESULTS: Ten animals had a peak plasma glucose value ≥ 226 mg/dL during the initial 60 minutes after resuscitation. The neurologic scores at 72 hours in these animals (mean score = 0, mean overall cerebral performance category = 1) were the same as those in the animals with a peak plasma glucose value <226 mg/dL. The end-tidal carbon dioxide (CO(2)) values measured during CPR, times to restoration of spontaneous circulation, and epinephrine doses were not significantly different between the animals with a peak glucose concentration ≥ 226 mg/dL and those with lower values. The sample size afforded a power of 95% to detect a 50-point difference from the lowest score (0 points) of the porcine neurologic outcome scale. CONCLUSION: In this standard porcine model of witnessed out-of-hospital cardiac arrest, early postresuscitation stress hyperglycemia did not appear to affect neurologic outcome. During the prehospital phase of treatment and transport, treatment of hyperglycemia by emergency medical services providers may not be warranted.

Markers of progenitor cell recruitment and differentiation rise early during ischemia and continue during resuscitation in a porcine acute ischemia model.

Clinical administration of bone marrow-derived stem cells in the setting of acute myocardial infarction (AMI) leads to improved left ventricular ejection fraction. Thymosin beta-4 (TB4) and vascular endothelial growth factor (VEGF) are linked to adult epicardial progenitor cell mobilization and neovascularization and is cardioprotective after myocardial ischemia. This study investigated the time course of TB4 and VEGF during AMI, cardiac arrest, and resuscitation. Fifteen anesthetized and instrumented domestic swine underwent balloon occlusion of the proximal left anterior descending coronary artery. During occlusion, venous blood samples were collected from the right atrium at 5-min intervals until 15 min after the onset of cardiopulmonary resuscitation (CPR). Plasma levels of TB4, VEGF, and matrix metalloproteinase-9 (MMP-9, selected as a marker for remodeling and repair) were measured by ELISA. Generalized linear mixed models were employed to model the time-dependent change in plasma concentration. All variables were natural log transformed, except TB4 values, to normalize distributions. Fifteen animals successfully underwent balloon occlusion of the left anterior descending coronary artery and samples were collected from these subjects. The average onset of spontaneous ventricular fibrillation was 28 min. TB4, VEGF, and MMP-9 demonstrated a statistically significant, time-dependent increase in concentration during ischemia. Following arrest and throughout the first 15 min of resuscitation, MMP-9 had an unchanged rate of rise when compared with the prearrest, ischemic period, with VEGF showing a deceleration in its time-dependent concentration trajectory and TB4 demonstrating an acceleration. Endogenous TB4 and VEGF increase shortly after the onset of AMI and increase through cardiac arrest and resuscitation in parallel to remodeling proteases. These markers continue to rise during successful resuscitation and may represent an endogenous mechanism to recruit undifferentiated stem cells to areas of myocardial injury.

Does prearrest adrenergic integrity affect pressor response? A comparison of epinephrine and vasopressin in a spontaneous ventricular fibrillation swine model.

OBJECTIVES: Coronary perfusion pressure (CPP) during resuscitation from cardiac arrest has been shown to correlate with return of spontaneous circulation. Adrenergic blockade of beta-1 and alpha-1 receptors is common in the long-term management of ischemic heart disease and congestive heart failure. We sought to compare the CPP response to vasopressin vs. epinephrine in a swine model of cardiac arrest following pre-arrest adrenergic blockade. METHODS: Eight anesthetized and instrumented swine were administered 0.1mg epinephrine and arterial pressure and heart rate response were measured. An infusion of labetalol was then initiated and animals periodically challenged with epinephrine until adrenergic blockade was confirmed. The left anterior descending coronary artery was occluded to produce ventricular fibrillation (VF). After 7min of untreated VF, mechanical chest compressions were initiated. After 1min of compressions, 1mg epinephrine was given while CPP was recorded. When CPP values had returned to pre-epinephrine levels, 40U of bolus vasopressin was given. Differences in CPP (post-vasopressor-pre-vasopressor) were compared within animals for the epinephrine and vasopressin response and with eight, non-adrenergically blocked, historical controls using Bayesian statistics with a non-informative prior. RESULTS: The CPP response following epinephrine was 15.1mmHg lower in adrenergically blocked animals compared to non-adrenergically blocked animals (95% Highest Posterior Density [HPD] 2.9-27.2mmHg lower). CPP went up 18.4mmHg more following vasopressin when compared to epinephrine (95% HPD 8.2-29.1mmHg). The posterior probability of a higher CPP response from vasopressin (vs. epinephrine) in these animals was 0.999. CONCLUSIONS: Pre-arrest adrenergic blockade blunts the CPP response to epinephrine. Superior augmentation of CPP is attained with vasopressin under these conditions.

Neurologically intact survival in a porcine model of cardiac arrest: manual cardiopulmonary resuscitation vs. LifeBelt cardiopulmonary resuscitation.

OBJECTIVE: To compare the LifeBelt (Deca-Medica, Inc., Columbus, OH), a novel cardiopulmonary resuscitation (CPR) device, with manual CPR on the outcome of neurologically intact survival in a porcine model of cardiac arrest. METHODS: Twenty-two adolescent swine were randomized by permuted block design to resuscitation using LifeBelt (n = 12) or manual CPR (n = 10). The animals were instrumented with right atrial and aortic pressure catheters while they were under general anesthesia with isoflurane and nitrous oxide. Ventricular fibrillation (VF) was induced with a bipolar pacing catheter placed in the right ventricle. After 7 minutes of untreated VF, chest compressions with either LifeBelt or manual CPR were initiated along with standard Advanced Cardiac Life Support. Survivors were assigned a neurologic score using the neurologic deficit score and the cerebral performance category (CPC) score at 24, 48, and 72 hours following resuscitation by a veterinarian blinded to treatment allocation. RESULTS: There were no significant differences in prearrest hemodynamic parameters or in important resuscitation variables between the groups. One of 12 of the LifeBelt animals failed to achieve return of spontaneous circulation (0.08, 95% confidence interval [CI] 0.002-0.38). The remaining 11 had a neurologic deficit score of 0 and a CPC score of 1, indicating normal neurologic function. All of the manual CPR animals survived. One of 10 manual CPR survivors (0.10, 95% CI 0.003-0.45) had a neurologic deficit score of 260 and a CPC score of 3, indicating moderate disability, while the remaining animals had a neurologic deficit score of 0 and a CPC score of 1. CONCLUSIONS: In this porcine model of cardiac arrest, we did not detect significant differences in neurologically intact survival between LifeBelt CPR and manual CPR.

Transthoracic defibrillation potential gradients in a closed chest porcine model of prolonged spontaneous and electrically induced ventricular fibrillation.

OBJECTIVE: The purpose of this study was to measure the local electrical field or potential gradient, measured with a catheter-based system, required to terminate long duration electrically or ischaemically induced ventricular fibrillation (VF). We hypothesized that prolonged ischaemic VF would be more difficult to terminate when compared to electrically induced VF of similar duration. METHODS: Thirty anesthetized and instrumented swine were randomized to electrically induced VF or spontaneous, ischaemically induced VF, produced by balloon occlusion of the left anterior descending coronary artery. After 7 min of VF, chest compressions were initiated and rescue shocks were attempted 1 min later. The potential gradient for each shock was measured and the mean values required for defibrillation compared for the VF groups. RESULTS: The number of shocks and the shock strength required for termination of VF were not significantly different for the groups. The potential gradient of the first successful defibrillating shock was significantly greater in the spontaneous, occlusion-induced VF group (12.80+/-2.82 V/cm vs 9.60+/-2.48 V/cm, p=0.002). The number of refibrillations was greater in the ischaemic group than in the non-ischaemic electrical group (6+/-4 vs 1+/-1, p<0.001). The number of animals requiring a shock at 360J was 2.5 times greater for the ischaemic group. CONCLUSIONS: Defibrillation of prolonged VF produced by acute myocardial ischaemia requires a significantly greater potential gradient to terminate than prolonged VF induced by electrical stimulation of the right ventricular endocardium. The VF duration used in this study approximates that occurring in victims of out-of-hospital cardiac arrest. Our findings may be of clinical importance in the management of such patients.

Infliximab attenuates early myocardial dysfunction after resuscitation in a swine cardiac arrest model.

OBJECTIVE: Left ventricular dysfunction after successful cardiopulmonary resuscitation contributes to early death after resuscitation. Proinflammatory cytokines are known to decrease myocardial function, and tumor necrosis factor-alpha has been shown to increase after successful resuscitation. We hypothesized that blocking the effects of tumor necrosis factor-alpha with infliximab would prevent or minimize postresuscitation cardiac dysfunction. DESIGN: Randomized, placebo-controlled comparative study. SETTING: Large animal research laboratory. SUBJECTS: Twenty-eight anesthetized and instrumented domestic male swine (Yorkshire and Yorkshire/Hampshire mix; weight, 35-45 kg). INTERVENTIONS: Infusion of infliximab (5 mg/kg) or normal saline after resuscitation from ventricular fibrillation cardiac arrest. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables, indices of left ventricular function, and tumor necrosis factor-alpha were measured before and after 8 mins of cardiac arrest during the early postresuscitation period (3 hrs). Within 5 mins of restoration of spontaneous circulation, 14 animals received infliximab, 5 mg/kg, infused over 30 mins. Fourteen animals received an infusion of normal saline. Inotropes and vasopressors were not administered to either group after resuscitation. Tumor necrosis factor-alpha increased after restoration of circulation and remained elevated throughout the observation period. Differences between groups were not significant. Interleukin-1beta concentration did not change significantly during the observation period in either study group. Mean arterial pressure and stroke work were significantly greater in the infliximab group within 30 mins of resuscitation, and these differences were sustained throughout the 3-hr postresuscitation period. The effect of tumor necrosis factor-alpha blockade was evident only in animals with a significant increase (doubling) in plasma tumor necrosis factor-alpha at 30 mins after arrest. CONCLUSION: Tumor necrosis factor-alpha plays a role in cardiac dysfunction after arrest and infliximab may attenuate or prevent postresuscitation myocardial dysfunction when administered immediately after resuscitation.

Hypocalcemia following resuscitation from cardiac arrest revisited.

OBJECTIVE: Hypocalcemia associated with cardiac arrest has been reported. However, mechanistic hypotheses for the decrease in ionized calcium (iCa) vary and its importance unknown. The objective of this study was to assess the relationships of iCa, pH, base excess (BE), and lactate in two porcine cardiac arrest models, and to determine the effect of exogenous calcium administration on post-resuscitation hemodynamics. METHODS: Swine were instrumented and VF was induced either electrically (EVF, n=65) or spontaneously, ischemically induced (IVF) with balloon occlusion of the LAD (n=37). Animals were resuscitated after 7 min of VF. BE, iCa, and pH, were determined prearrest and at 15, 30, 60, 90, 120 min after ROSC. Lactate was also measured in 26 animals in the EVF group. Twelve EVF animals were randomized to receive 1g of CaCl(2) infused over 20 min after ROSC or normal saline. RESULTS: iCa, BE, and pH declined significantly over the 60 min following ROSC, regardless of VF type, with the lowest levels observed at the nadir of left ventricular stroke work post-resuscitation. Lactate was strongly correlated with BE (r=-0.89, p<0.0001) and iCa (r=-0.40, p<0.0001). In a multivariate generalized linear mixed model, iCa was 0.005 mg/dL higher for every one unit increase in BE (95% CI 0.003-0.007, p<0.0001), while controlling for type of induced VF. While there was a univariate correlation between iCa and BE, when BE was included in the regression analysis with lactate, only lactate showed a statistically significant relationship with iCa (p=0.02). Post-resuscitation CaCl(2) infusion improved post-ROSC hemodynamics when compared to saline infusion (LV stroke work control 8+/-5 gm vs 23+/-4, p=0.014, at 30 min) with no significant difference in tau between groups. CONCLUSIONS: Ionized hypocalcemia occurs following ROSC. CaCl(2) improves post-ROSC hemodynamics suggesting that hypocalcemia may play a role in early post-resuscitation myocardial dysfunction.

Cardiac function and the proinflammatory cytokine response after recovery from cardiac arrest in swine.

Increased levels of cytokines have been reported after resuscitation from cardiac arrest. We hypothesized that proinflammatory cytokines, released in response to ischemia/reperfusion, increase following resuscitation and play a role in post-cardiac arrest myocardial dysfunction. Ventricular fibrillation (VF) was induced by coronary occlusion in 20 swine. After 7 min of VF, resuscitation was performed as per guidelines. Plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were measured 15 min after the start of resuscitation in all animals and at intervals of 6 h in resuscitated animals. Intravascular pressures and cardiac output (CO) were also recorded. TNF-alpha abruptly increased after resuscitation, peaking at 15 min following return of spontaneous circulation, and declined to baseline levels after 3 h. IL-1beta increased more slowly, reaching a maximum 2 h after reperfusion. IL-6 concentrations were not significantly different from control values at any time point. Males demonstrated greater elevations of TNF-alpha and IL-1beta than females. Stroke work was significantly depressed at all time points with a nadir at 15-30 min after reperfusion, corresponding to the peak TNF-alpha values. The anti-TNF-alpha antibody infliximab attenuated the decrease in myocardial function observed 30 min after reperfusion. TNF-alpha increases during recovery from cardiac arrest are associated with depression of left ventricle (LV) function. The effect of TNF-alpha can be attenuated by anti-TNF-alpha antibodies.

Plasma endothelin-1 level at the onset of ischemic ventricular fibrillation predicts resuscitation outcome.

BACKGROUND: Endogenous vasopressors, including endothelin-1 (ET-1), have been shown to be elevated in patients following resuscitation from out-of-hospital cardiac arrest and are likely a physiologic response to global ischaemia. The importance of ET-1 in the setting of arrest and resuscitation has not been established. Prior work has demonstrated that ET-1 increases significantly after coronary occlusion. The purpose of this study was to assess changes in ET-1 following induction of ischaemia and VF. METHODS: VF was induced in 30 anesthetized and instrumented swine by balloon occlusion of the LAD. Blood was collected from the right atrium at baseline and at 5 min intervals following LAD occlusion until VF occurred. After 7 min of VF, resuscitation was attempted in accordance with guidelines. ET-1 and matrix metalloproteinase-9 (MMP-9), a measure of infarct size, were measured using ELISA. RESULTS: ET-1 and MMP-9 levels increased significantly from baseline within 20 min of occlusion of the LAD. Animals that could not be resuscitated had a higher ET-1 (p=0.031) at VF onset but similar ischaemia time (time to VF) and MMP-9, reflecting infarct size. An ET-1 level >4 pg/ml had a likelihood ratio of 4 for predicting resuscitation failure. CONCLUSIONS: Elevated levels of ET-1 during acute ischaemia predict resuscitation failure independent of the time to VF. This finding may be due to the known effect of ET-1 on coronary vascular resistance or ventricular compliance, resulting in early ischemic contracture.

The central nervous system cytokine response to global ischemia following resuscitation from ventricular fibrillation in a porcine model.

AIM OF THE STUDY: Pro-inflammatory cytokines have been implicated as culprits in neurotoxicity following ischemia in small animal models of stroke. The aim of this study was to measure the central nervous system (CNS) cytokine response following resuscitation from ventricular fibrillation (VF) in a porcine model of cardiac arrest and global hypoxic ischemia. METHODS: VF was induced electrically in 11 anesthetized swine. Following 7 min of untreated VF, animals were resuscitated. Cerebrospinal fluid (CSF) and serum was sampled prior to VF and at 60, 120, and 180 min post-resuscitation from which levels of TNF-alpha, IL-1 beta, and IL-6 were measured. Levels were also drawn in three sham pigs, instrumented but not fibrillated. RESULTS: CSF levels of TNF-alpha rose following resuscitation and were associated with CSF levels of IL-1 beta (p=0.0002). CSF levels of all cytokines except TNF-alpha were associated with their serum counterparts. CONCLUSIONS: Measurable increases in pro-inflammatory cytokines in the CSF follow resuscitation from cardiac arrest in this porcine model. The CNS response TNF-alpha and IL-1 beta are associated. However, serum levels of TNF-alpha did not seem to predict CSF levels in this study, consistent with the concept of immune privilege of the CNS.

Endothelin-1 is not predictive of ventricular ectopy or ventricular fibrillation during acute myocardial ischemia.

Endothelin(ET)-1 (ET-1) increases after myocardial infarction and may have effects on myocardial function. ET-1 has also been shown to affect the action potential (AP) which may be arrhythmogenic and predispose to ventricular fibrillation (VF). The effects of ET-2 and ET-3 are uncertain. We hypothesized that the ETs increase during acute ischemia and that plasma levels are predictive of ischemically induced VF. Thirty-four domestic swine underwent balloon occlusion of the proximal LAD coronary artery. Occlusion was confirmed angiographically. Venous samples were collected from the right atrium at baseline and at 5 min intervals for 30 min or until VF induction. ET-1, ET-2, and ET-3 were measured using ELISA. Changes in plasma concentrations were assessed using repeated measures ANOVA with Dunnett's. A p < 0.05 was considered statistically significant. All animals had angiographic evidence of successful proximal LAD occlusion. ET-1 levels were significantly increased from a baseline at 20 min and remained elevated during 30 min of occlusion. ET-2 and ET-3 levels did not change from baseline values (figure, mean +/- SE). VF occurred in 60% of animals. Peak ET-1 values were not significantly different between VF and non-VF animals (6.2 +/- 2.2 vs. 4.8 +/- 2.3 pg/mL). No single ET-1 value had a VF predictive value >50%. There is a significant increase in ET-1 level within 20 min of acute myocardial ischemia. Despite known effects of ET-1 on the AP, this increase did not correlate with the occurrence of VF.

Is the tumour necrosis factor-alpha response following resuscitation gender dependent in the swine model?

INTRODUCTION: Reperfusion results in a proinflammatory cytokine response, as has been observed following resuscitation from cardiac arrest. Variations in the inflammatory response have been shown to be gender dependent and mediated by steroid hormones. The purpose of this study was to determine whether the tumour necrosis factor-alpha response following resuscitation was gender dependent. METHODS: Anaesthetized swine (15 males and 15 females, weighs 32-47 kg) underwent 7 min of electrically induced cardiac arrest, followed by conventional resuscitation and then measurement of tumour necrosis factor-alpha by enzyme-linked immunosorbent assay at intervals for up to 3h. Testosterone and 17-estradiol were measured in 8 males and 8 females. RESULTS: In all animals 17-estradiol was undetectable. Testosterone exceeded the lower limit of detection in 3 females and 1 male. Levels of tumour necrosis factor-alpha were higher in males than females, from 30 min after resuscitation to 3h. In females, tumour necrosis factor-alpha levels were significantly higher than control values only at 15 min following restoration of circulation; the levels in males demonstrated marked inter-animal variation. CONCLUSIONS: In this swine model, males demonstrated an augmented post-resuscitation tumour necrosis factor-alpha response when compared with females. This difference was not related to steroid hormone levels.

The effect of ischemia on ventricular fibrillation as measured by fractal dimension and frequency measures.

INTRODUCTION: Most animal studies of ventricular fibrillation (VF) waveform characteristics involve healthy animals with VF initiated by electric shock. However, clinical VF is usually the result of ischemia. The waveform characteristics in these two types of VF may differ. The angular velocity (AV), frequency ratio (FR) and median frequency (MF) are three frequency-based measures of VF. The scaling exponent (ScE), the logarithm of the absolute correlations (LAC) and the Hurst exponent (HE) are three measures of the fractal dimension of VF. HYPOTHESIS: We hypothesized that these quantitative measures would differ between ischemic and electrically initiated VF. METHODS: VF was induced in 14 swine by electric shock and in 12 swine by ischemia. For ischemia induced VF animals, an angioplasty catheter was positioned in the mid-LAD and the balloon inflated. A mean of 891+/-608 (S.D.)s later, VF occurred. For electrically induced animals, an AC current was passed through a catheter in the RV. Following initiation by either method, VF was recorded for 7min. Sequential 5s epochs were analyzed for AV, FR, MF and fractal dimension measures. RESULTS: Ischemic VF demonstrated a significantly higher fractal dimension as estimated by the ScE for the first 0-90s (p=0.021) and for 90-180s (p=0.016). The Hurst exponent was significantly higher for ischemic VF for both 0-90s (p<0.0001) and 90-180s (p<0.0001). The fractal dimension as estimated by the LAC method was not significantly different for 0-90s (p=0.056) but was highly significant for 90-180s (p=0.001). During the initial 90s the groups did differ in all measures of frequency as follows: AV (p<0.001), FR (p<0.001), MF (p<0.001). These differences did not persist beyond 90s except for a mild elevation of the FR after 270s (p<0.02). CONCLUSION: Fractal based measures indicate an increase in the fractal dimension of ischemia induced VF for the first 180s when compared to electrically induced VF. Frequency-based measures uniformly demonstrate a pattern of higher frequencies for electrically induced VF for the first 90s. The increased fractal dimension and decreased frequencies associated with ischemia induced VF may reflect changes in the underlying myocardial physiology that can be used to guide therapies.

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

OBJECTIVES: 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. DESIGN: Randomized comparative trial. SETTING: Translational research laboratory. SUBJECTS: Domestic swine (n = 40, mean weight 40 +/- 4 kg, range 34-47 kg) of both genders. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.