Eric S. Logue

Ventricular fibrillation scaling exponent can guide timing of defibrillation and other therapies.

Background—The scaling exponent (ScE) of the ventricular fibrillation (VF) waveform correlates with duration of VF and predicts defibrillation outcome. We compared 4 therapeutic approaches to the treatment of VF of various durations. Methods and Results—Seventy-two swine (19.5 to 25.7 kg) were randomly assigned to 1 of 9 groups (n=8 each). VF was induced and left untreated until the ScE reached 1.10, 1.20, 1.30, or 1.40. Animals were treated with either immediate countershock (IC); 3 minutes of CPR before the first countershock (CPR); CPR for 2 minutes, then drugs given with 3 more minutes of CPR before the first shock (CPR-D); or drugs given at the start of CPR with 3 minutes of CPR before the first shock (Drugs+CPR). Return of spontaneous circulation (ROSC) and 1-hour survival were analyzed with &khgr;2 and Kaplan-Meier survival curves. IC was effective when the ScE was low but had decreasing success as the ScE increased. No animals in the 1.30 or 1.40 groups had ROSC from IC (0 of 16). CPR did not improve first shock outcome in the 1.20 CPR group (3 of 8 ROSC). Kaplan-Meier survival analyses indicated that IC significantly delayed time to ROSC in both the 1.3 (P =0.0006) and the 1.4 (P =0.005) groups. Conclusions—VF of brief to moderate duration is effectively treated by IC. When VF is prolonged, as indicated by an ScE of 1.3 or greater, IC was not effective and delayed time to ROSC. The ScE can help in choosing the first intervention in the treatment of VF.

Lipid Emulsion Combined with Epinephrine and Vasopressin Does Not Improve Survival in a Swine Model of Bupivacaine-induced Cardiac Arrest

Background:This study sought to evaluate the efficacy of lipid emulsion in reversing bupivacaine-induced cardiovascular collapse when added to a resuscitation protocol that included the use of epinephrine and vasopressin. Methods:After induction of general anesthesia and instrumentation, 19 mixed-breed domestic swine had cardiovascular collapse induced by an intravenous bolus of 10 mg/kg bupivacaine. After 5 min of resuscitation including chest compressions, epinephrine (100 &mgr;g/kg) and vasopressin (1.5 U/kg), animals were randomized to receive either a bolus of 20% lipid emulsion (4 ml/kg) followed by a continuous infusion (0.5 ml · kg−1 · min−1) or an equal volume of saline. Investigators were blinded to the treatment assignment. The primary endpoint was return of spontaneous circulation (mean arterial pressure of at least 60 mmHg for at least 1 min). Results:Treatment groups were similar with respect to baseline measurements of weight, sex, and hemodynamic and metabolic variables. The rates of return of spontaneous circulation were similar between groups: (3 of 10) in the lipid group and 4 of 9 in the saline group (P = 0.65). Total serum bupivacaine concentrations were higher in the lipid group at the 10-min timepoint (mean ± SEM: 23.13 ± 5.37 ng/ml vs. 15.33 ± 4.04 ng/ml, P = 0.004). More norepinephrine was required in the lipid group compared to the saline group to maintain a mean arterial pressure above 60 mmHg during the 60-min survival period (mean ± SEM: 738.6 ± 94.4 vs.. 487.3 ± 171.0 &mgr;g). Conclusions:In this swine model, lipid emulsion did not improve rates of return of spontaneous circulation after bupivacaine-induced cardiovascular collapse.

Hypothermia after cardiac arrest does not alter serum inflammatory markers.

Objective:Hypothermia improves survival and neurologic recovery after cardiac arrest. Cardiac arrest also triggers release of cytokines and inflammatory molecules, and it is unknown whether therapeutic hypothermia alters this inflammatory response. This study tested whether therapeutic hypothermia altered levels of inflammatory markers in serum. Design:Prospective, randomized study. Setting:University research laboratory. Subjects:Adult, male, Sprague-Dawley rats. Interventions:Halothane-anesthetized rats were subjected to 8 mins of asphyxial cardiac arrest and resuscitation. Rat temperature was controlled at 37°C throughout the experiment (normothermia) or reduced to 33°C between 1 and 24 hrs after cardiac arrest (hypothermia). Serum cytokines were measured at baseline, 0.5, 1, 3, 6, 12, and 24 hrs after resuscitation using multiplex analyzer or enzyme-linked immunosorbent assay. Measurements and Main Results:Hypothermic rats showed improved neurologic recovery at 12 and 24 hrs. Serum levels of tumor necrosis factor-α; macrophage inflammatory protein-1α; growth-related oncogene/keratinocyte chemokine; interleukin-2, -9, and -10; monocyte chemotactic protein-1; leptin; and intracellular adhesion molecule-1 increased over time, and the levels of interleukin-18 declined over time. No temporal trends in other molecules were detected. Levels of these molecules did not differ between temperature groups during the hypothermia phase (1–24 hrs). Conclusions:These data suggest that altering the inflammatory response after cardiac arrest is not necessary for the beneficial effects of hypothermia. These data do not support a specific role of circulating cytokines in the neurologic injury after cardiac arrest.

Association of intramyocardial high energy phosphate concentrations with quantitative measures of the ventricular fibrillation electrocardiogram waveform

BACKGROUND Quantitative measures of the ventricular fibrillation (VF) electrocardiogram (ECG) have been correlated with the success of rescue shocks, making them ideal measures for guiding resuscitative interventions. Correlation of intramyocardial energy stores with the change in quantitative VF ECG measures would provide mechanistic insight into their utility. We sought to investigate the relationship between intramyocardial energy stores and four quantitative ECG measures. METHODS Eighteen mixed-breed, domestic swine were sedated, anaesthetized and paralyzed. Swine were block randomized into three groups receiving 5, 10, or 15 min of untreated VF. Thoracotomy was performed and the heart was delivered. VF was induced by a 100 mA transthoracic shock while ECG was recorded. Biopsies of myocardial tissue were taken from the left and right ventricles after the prescribed duration of VF. Adenosine triphosphate (ATP) and adenosine diphosphate (ADP) concentrations in the tissue samples were measured. ECG data immediately prior to each biopsy were analyzed by each of four quantitative ECG methods: Scaling Exponent (ScE), Median Slope (MS), Amplitude Spectrum Area (AMSA), and logarithm of the Absolute Correlation (LAC). ATP and ADP concentrations of VF duration groups were compared. ATP and ADP concentrations were regressed against each quantitative ECG measure. RESULTS ATP concentrations differed between VF duration groups, but ADP concentrations differed only between 5 and 10 min groups. A significant association existed between ATP and three quantitative measures--ScE, MS, and AMSA--but no significant relationship was found for ADP. CONCLUSION Intramyocardial ATP levels correlate with quantitative measures of the ECG during ventricular fibrillation.

Effects of pre-arrest and intra-arrest hypothermia on ventricular fibrillation and resuscitation

BACKGROUND Hypothermia has been shown to improve survival and neurological outcomes for ventricular fibrillation (VF) cardiac arrest. The electrophysiological mechanisms of hypothermia are not well-understood, nor are the effects of beginning cooling during the resuscitation. METHODS AND RESULTS We hypothesized that inducing hypothermia prior to the onset of VF would slow the deleterious changes seen in the ECG during VF and that inducing hypothermia at the start of resuscitation would increase the rates of ROSC and short-term survival in a porcine model of prolonged VF. We randomly assigned 42 domestic swine (27.2+/-2.3 kg) to either pretreatment with hypothermia before induction of VF (PRE), normothermic resuscitation (NORM) or intra-resuscitation hypothermia (IRH). During anesthesia, animals were instrumented via femoral cutdown. Lead II ECG was recorded continuously. PRE animals were cooled before the induction of VF, with a rapid infusion of 4 degrees normal saline (30mL/kg). VF was induced electrically, left untreated for 8min, then mechanical CPR began. During CPR the NORM animals got 30mL/kg body-temperature saline and the IRH animals got 30mL/kg 4 degrees saline. In all groups first rescue shocks were delivered after 13min of VF. We calculated the VF scaling exponent (ScE) for the entire 8min period (compared using GEE). ROSC and survival were compared with Fishers exact test. Mean temperature in degrees C at the onset of VF was PRE=34.7 degrees (+/-0.8), NORM=37.8 (+/-0.9), and IRH=37.9 (+/-0.9). The ScE values over time were significantly lower after 8min in the PRE group (p=0.02). ROSC: PRE=10/14 (71%), NORM=6/14 (43%) and IRH=12/14 (86%); p for IRH vs. NORM=0.02. Survival: PRE=9/14 (64%), NORM=5/14 (36%), IRH 8/14 (57%). CONCLUSION Hypothermia slowed the decay of the ECG waveform during prolonged VF. IRH improved ROSC but not short-term survival compared to NORM. It is possible to rapidly induce mild hypothermia during CPR using an IV infusion of ice-cold saline.

Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion

Oxidative stress after cerebral ischemia and reperfusion activates extracellular signal-regulated kinases (ERK) in brain. However, the mechanism of this activation has not been elucidated. We have previously reported that in an in vitro model of oxidative stress in immature cortical neuronal cultures, the inhibition of ERK phosphatase activity contributes to ERK1/2 activation and subsequent neuronal toxicity. This study examined whether ERK activation was associated with altered activity of ERK phosphatases in a rat cardiac arrest model. Rats in experimental groups were subjected to asphyxial cardiac arrest for 8 min and then resuscitated for 30 min. Significant ERK activation was detected in both cortex and hippocampus following ischemia/reperfusion by immunoblotting. ERK phosphatase activity was reversibly inhibited in cerebral cortex but not affected in hippocampus following ischemia/reperfusion. MEK1/2 was activated in both cerebral cortex and hippocampus following ischemia/reperfusion. Using a specific inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), we have identified PP2A to be the major ERK phosphatase that is responsible for regulating ERK activation in ischemic brain tissues. Orthovanadate inhibited ERK phosphatase activity in brain tissues, suggesting that tyrosine phosphatases and dual specificity phosphatases may also contribute to the ERK phosphatase activity in brain tissues. Together, these data implicate ERK phosphatase in the regulation of ERK activation in distinct brain regions following global ischemia.

Hypothermia and ERK activation after cardiac arrest.

Mild hypothermia improves survival and neurological outcome after cardiac arrest, as well as increasing activation of the extracellular-signal-regulated kinase (ERK) in hippocampus. ERK signaling is involved in neuronal growth and survival. We tested the hypothesis that the beneficial effects of hypothermia required ERK activation. ERK activation was measured by immunoblotting with phosphorylation-specific antibodies. Rats (n = 8 per group) underwent 8 min of asphyxial cardiac arrest and were resuscitated with chest compressions, ventilation, epinephrine and bicarbonate. At 30 min after resuscitation, vehicle (50% saline:50% DMSO) or the ERK kinase inhibitor U0126 (100 microg) was infused into the lateral ventricle. Cranial temperature was kept at either 33 degrees C (hypothermia) or 37 degrees C (normothermia) between 1 and 24 h. Neurological function was assessed daily for 14 days. Surviving neurons were counted in the hippocampus. A dose of 100 mug U0126 inhibited ERK bilaterally for 12 to 24 h and decreased phosphorylation of the ERK substrates ATF-2 and CREB. As in previous studies, hypothermia improved survival, neurological and histological outcome after cardiac arrest. However, survival, neurological score and histology did not differ between U0126 and vehicle-treated rats after cardiac arrest. Therefore, a dose of U0126 sufficient to inhibit biochemical markers of ERK signaling in hippocampus does not alter the beneficial effects of hypothermia induced after resuscitation in rats and did not affect recovery of normothermia-treated rats. These results suggest that hypothermia-induced improvement in outcomes does not require ERK activation.

Effects of an impedance threshold device on hemodynamics and restoration of spontaneous circulation in prolonged porcine ventricular fibrillation.

Background. An impedance threshold device (ITD) has been designed to enhance circulation during CPR by creating a negative intrathoracic pressure during the relaxation phase of chest compression. Hypothesis. We sought to determine the effects of the ITD on coronary perfusion pressure (CPP), return of spontaneous circulation (ROSC), andshort-term survival (20 minutes after ROSC). We hypothesized that the ITD would improve all 3 variables when compared to standard CPR. Methods. Using a case-control design nested within a randomized primary study, we compared CPR with the ITD (ITD-CPR) to standard CPR without the device (S-CPR). We systematically assigned 36 domestic swine, weighing 23–29 kg, (18 per group) to resuscitation with either ITD-CPR or S-CPR after 8 minutes of untreated ventricular fibrillation (VF). At minute 8, mechanical chest compression andventilation began, anddrugs (0.1 mg/kg epinephrine, 40U vasopressin, 1.0 mg propranolol, 1 mEq/kg sodium bicarbonate) were given. The first rescue shock (150J biphasic) was delivered at minute 11 of VF. We recorded CPP, ROSC (systolic pressure > 80 mmHg sustained for 60 s continuously), andsurvival. Data were analyzed with Fishers exact test andgeneralized estimating equations (GEE), with alpha = 0.05. Results. We analyzed 3,150 compressions. CPP for the ITD-CPR group (28.1 mmHg [95% CI 27–29.3 mmHg]), did not differ from the S-CPR group (32.3 mmHg [95% CI 31.2–33.4 mmHg]). ROSC occurred in 6/18 (33%) animals in the ITD-CPR, and14/18 (78%) in the S-CPR group (p = 0.02). Survival occurred in 3/18 (17%) ITD-CPR and13/18 (72%) S-CPR group (p = 0.003). Conclusions. ITD-CPR did not improve CPP compared to S-CPR. ROSC andsurvival were significantly lower with ITD-CPR.

Quantitative Waveform Measures of the Electrocardiogram as Continuous Physiologic Feedback During Resuscitation with Cardiopulmonary Bypass

BACKGROUND There 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. METHODS Sixteen 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. RESULTS Four 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. CONCLUSION QWMs 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.

Increasing CPR duration prior to first defibrillation does not improve return of spontaneous circulation or survival in a swine model of prolonged ventricular fibrillation

INTRODUCTION The optimum duration of cardiopulmonary resuscitation (CPR) prior to first rescue shock is unknown. Clinical trials have used 90 and 180 s. Neither of these durations may be optimal. We sought to determine the optimum duration of CPR prior to first defibrillation attempt and whether this varied depending on the duration of ventricular fibrillation (VF). In this porcine model of basic life support, our outcomes were rates of return of spontaneous circulation (ROSC), survival, and coronary perfusion pressure (CPP). METHODS We anesthetized and instrumented 45 swine and then induced VF. After 5 or 8 min of untreated VF, we randomized the swine to mechanical CPR for 90, 180, or 300 s. A single rescue shock (150 J biphasic) was then administered. If this shock failed, 2 min of mechanical CPR were completed prior to the next rescue shock. CPP was calculated for each 30s epoch. ROSC was defined as a blood pressure >80 mmHg sustained for 60s. Survival was defined as sustained ROSC for 20 min. Data were analyzed with descriptive statistics, Fishers exact test, and ANOVA. RESULTS In the 5 min VF cohort, the rate of ROSC did not differ between the three groups (90 s: 25%; 180 s: 38%; 300 s: 38%, p>.05). Survival rates did not differ (90 s: 25%; 180 s: 25%; 300 s: 25%, p>0.05). In the 8 min VF cohort, no animals experienced ROSC or survival. CPP were calculated by 30s epoch and did not differ between the three groups (p>0.05). CPPs decline after 180 s of CPR. CONCLUSIONS ROSC and survival were equivalent regardless of VF duration and CPR duration. When CPR begins late, CPPs are low, stressing the importance of early CPR. We do not recommend 300 s of CPR unless a defibrillator is unavailable.