Chest compressions do not disrupt the seal created by the laryngeal mask airway during positive pressure ventilation: a preliminary porcine study.

OBJECTIVE: Pulmonary aspiration of gastric contents occurs 20 to 30% of the time during cardiopulmonary resuscitation (CPR) of cardiac arrest due to loss of protective airway reflexes, pressure changes generated during CPR, and positive pressure ventilation (PPV). Although the American Heart Association has recommended the laryngeal mask airway (LMA) as an acceptable alternative airway for use by emergency medical service personnel, concerns over the capacity of the device to protect from pulmonary aspiration remain. We sought to determine the occurrence of aspiration after LMA placement, CPR, and PPV. METHODS: We inserted a size 4 LMA, modified so that a vacuum catheter could be advanced past the LMA diaphragm, into the hypopharynx of 16 consecutive postexperimental mixed-breed domestic swine. Fifteen millilitres of heparinized blood was instilled into the oropharynx. Chest compressions were performed for 60 seconds with asynchronous ventilation via a mechanical ventilator. We then suctioned through the LMA for 1 minute. The catheter was removed and inspected for signs of blood. The LMA cuff was deflated, removed, and inspected for signs of blood. RESULTS: None of 16 animals (95% CI 0-17%) had a positive test for the presence of blood in both the vacuum catheter and the intima of the LMA diaphragm. CONCLUSIONS: In this swine model of regurgitation after LMA placement, there were no cases with evidence of blood beyond the seal created by the LMA cuff. Future studies are needed to determine the frequency of pulmonary aspiration after LMA placement during CPR and PPV in the clinical setting.

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.

Feasibility of initiating extracorporeal life support during mechanical chest compression CPR: a porcine pilot study.

BACKGROUND: Recently, portable extracorporeal membrane oxygenation (ECMO) machines have become commercially available. This creates the potential to utilize extracorporeal life support (ECLS) for the treatment of sudden cardiac arrest in the emergency department, and potentially in the out-of-hospital setting. OBJECTIVE: We sought to determine the feasibility of installing the ECMO circuit during delivery of mechanical chest compression CPR. METHODS: We used 5 mixed-breed domestic swine with a mean mass of 26.0 kg. After induction of anesthesia, animals were instrumented with micromanometer-tipped transducers placed in the aorta and right atrium via the left femoral artery and vein. Ventricular fibrillation (VF) was induced electrically with a transthoracic shock and left untreated for 8 min. Then, mechanical chest compressions were begun (LUCAS, Jolife, Lund, Sweden) and manual ventilations were performed to maintain ETCO(2) between 35 and 45Torr. Compressions continued until ECMO flow was started. Ten minutes after induction of VF, drugs were given (epinephrine, vasopressin, and propranolol). ECMO installation was started via cutdown on the right external jugular vein and right femoral artery for placement of venous and arterial catheters while chest compressions continued. ECMO installation start time varied from 17 to 30 min after start of compressions and continued until ECG indicated a shockable rhythm. First rescue shocks were given at 22, 32, 35, 44, and 65 min. RESULTS: ECMO was successfully installed in all five animals without incident. It was necessary to briefly discontinue chest compressions during the most delicate part of inserting the catheters into the vessels. ECMO also allowed for very rapid cooling of the animals and facilitated post-resuscitation hemodynamic support. Only the 65-min animal did not attain return of spontaneous circulation (ROSC). CONCLUSION: Mechanical chest compression may be a suitable therapeutic bridge to the installation of ECMO and does not interfere with ECMO catheter placement.

Survival of verapamil-poisoned rats treated with triiodothyronine.

Life-threatening toxicity due to calcium channel blocker ingestion is commonly encountered by emergency medicine physicians and toxicologists. Despite a vast array of research on its treatment, results have proven inconsistent. The goal of this study is to evaluate potential vasopressor effects of triiodothyronine (T3) in rats poisoned with verapamil. Following anesthesia and intubation, ten Sprague-Dawley rats were given intravenous verapamil infusion of 10 mg/kg/h. This dose was titrated until a mean arterial pressure (MAP) of 50-55 mmHg was achieved and maintained for a period of at least 5 min. The verapamil infusion was then maintained at that rate. Five rats were randomized to receive a T3 bolus of 0.4 mcg/kg preceding an infusion of 1.5 mcg/kg/day which was doubled every 2 min until any of the following endpoints: systolic blood pressure of 100 mmHg, an elapsed time of 60 min, or death. The other five received an equal volume of normal saline solution. The primary outcome measure was survival with secondary outcomes of MAP and heart rate. The T3 group did have a slightly longer, yet not statistically significant, average time to cessation of electrical activity-30.0 +/- 14.4 min versus 23.8 +/- 9.5 min in the placebo group. Average MAP decreased nearly identically in the two groups. Heart rates were not reliable indicators of toxicity in this rat model as there was little decrease until immediately prior to death in most animals. Despite significant variability in toxicity among individual animals, no statistically significant difference in survival time, heart rate, or MAP was found between groups treated with T3 and those receiving saline.

Ethyl pyruvate enhances intra-resuscitation hemodynamics in prolonged ventricular fibrillation arrest.

AIMS: As the duration of untreated cardiac arrest increases, the effectiveness of standard therapies declines, and may be more harmful than helpful. We investigated the hemodynamic, metabolic and anti-inflammatory effects of Ringer's ethyl pyruvate solution (REPS) versus Ringer's solution (RS) in the acute model of prolonged porcine arrest. METHODS: Seventeen mixed-breed swine were induced into ventricular fibrillation (VF) and left untreated for 8min. CPR was begun using a mechanical chest compression device at a rate of 100 per minute. At the onset of CPR, animals were randomly assigned to treatment with either 25mL/kg of RS or 25mL/kg of REPS containing 40mg/kg of ethyl pyruvate, infused over 5min in blinded fashion. CPR continued with administration of a drug cocktail at 2min and the first rescue shock was delivered at minute 13 of VF. Animals having ROSC were supported with standardized care for 2h. RESULTS: Both groups had 100% ROSC and 100% 2-h survival. The REPS group exhibited higher median CPP (27.3mmHg) than the control group (16.5mmHg) by 3min of CPR, which continued throughout the duration of CPR (p=0.02). The median time to hypotension following ROSC was 9.64min in the REPS group and 7.25min in controls (p=0.04) and there was a non-significant trend of decreased use of vasopressors for the duration of resuscitation. There was no difference in systemic or cerebral metabolism between groups. There were non-significant trends of decreased IL-6, increased Il-10 and decreased mesenteric bacterial colony growth in those treated with REPS when compared to RS. CONCLUSIONS: The administration of REPS with CPR significantly improved intra- and post-resuscitation hemodynamics in this swine model of prolonged cardiac arrest, but did not definitely change the metabolic or inflammatory profile during the acute resuscitation period.

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 microg/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 x kg(-1) x 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 microg). CONCLUSIONS: In this swine model, lipid emulsion did not improve rates of return of spontaneous circulation after bupivacaine-induced cardiovascular collapse.

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 Fisher's 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.

Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats.

Increased brain-derived neurotrophic factor (BDNF) levels and extracellular-signal regulated kinase (ERK) signaling are associated with reduced brain injury after cerebral ischemia. In particular, mild hypothermia after cardiac arrest increases BDNF and ERK signaling. This study tested whether intracerebroventricular infusions (0.025 microg/h x 3 days) of BDNF also improved recovery of rats resuscitated from cardiac arrest and maintained at 37 degrees C. BDNF infusions initiated at the time of cardiac arrest did not alter survival, neurological recovery, or histological injury. Separate experiments confirmed that BDNF infusions increased tissue levels of BDNF. However, these infusions did not increase ERK activation in hippocampus. These data suggest that increased BDNF levels are not sufficient to explain the beneficial effects of mild hypothermia after cardiac arrest, and that exogenous BDNF administration does not increase extracellular ERK signaling.

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 degrees C throughout the experiment (normothermia) or reduced to 33 degrees 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-alpha; macrophage inflammatory protein-1alpha; 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.

The effect of adenosine A1 receptor antagonism on return of spontaneous circulation and short-term survival in prolonged ventricular fibrillation.

BACKGROUND: Endogenous adenosine (ADO) is cardioprotective during ischemia and its myocardial concentration increases during untreated ventricular fibrillation (VF). We have previously shown that ADO A1 receptor (ADOA1R) antagonism hastens the time-dependent decay in VF waveform morphology during the circulatory phase of cardiac arrest. OBJECTIVE: To determine the effect of ADOA1R antagonism on ROSC and short-term survival in prolonged VF. METHODS: Thirty-six swine were assigned by block randomization to one of three groups: a group that received only vehicle (CONTROL), an ADOA1R antagonist pretreatment group (PRE), and a group that was given ADOA1R antagonist during resuscitation (DURING). The animals were instrumented under anesthesia, and ADOA1R antagonist or vehicle, per group assignment, was infused 5 minutes prior to VF induction. At minute 8 of untreated VF, chest compression with ventilation was initiated and a standard drug cocktail, with ADOA1R antagonist or vehicle, was given. The first rescue shock (150 J biphasic) was delivered after 11 minutes of VF. Proportions with 95% confidence intervals (CIs) were calculated for the two outcome measures. RESULTS: The baseline characteristics and chemistry values for the three groups were mathematically the same. The DURING group had a greater proportion of female animals (seven of 12) in comparison with the CONTROL group (two of 12) (p=0.03). ADOA1R antagonism hastened the decay of VF as previously demonstrated, but the rate of ROSC was the same for all groups: CONTROL=seven of 12, PRE=six of 12, and DURING=seven of 12. There were also no differences in short-term survival: CONTROL=four of 12, PRE=five of 12, and DURING=seven of 12. CONCLUSIONS: In this study, ADOA1R antagonism had no effect on outcome whether given before induction of VF or upon resuscitation after 8 minutes of untreated VF. The role of endogenous ADO in prolonged VF remains unclear.

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), and short-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 and ventilation began, and drugs (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), and survival. Data were analyzed with Fisher's exact test and generalized 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, and 14/18 (78%) in the S-CPR group (p = 0.02). Survival occurred in 3/18 (17%) ITD-CPR and 13/18 (72%) S-CPR group (p = 0.003). CONCLUSIONS: ITD-CPR did not improve CPP compared to S-CPR. ROSC and survival were significantly lower with ITD-CPR.

Comparison of the effects of hypothermia at 33 degrees C or 35 degrees C after cardiac arrest in rats.

OBJECTIVES: Hypothermia of 32 degrees C-34 degrees C induced after resuscitation from cardiac arrest improves neurologic recovery, but the optimal depth of cooling is unknown. Using a rat model, the authors tested the hypothesis that cooling to 35 degrees C between hours 1 and 24 after resuscitation would improve neurologic outcome as much as cooling to 33 degrees C. METHODS: Halothane-anesthetized rats (n = 38) underwent 8 minutes of asphyxial cardiac arrest and resuscitation. Cranial temperature was maintained at 37 degrees C before, during, and after arrest. Between one and 24 hours after resuscitation, cranial temperature was maintained at 33 degrees C, 35 degrees C, or 37 degrees C using computer-controlled cooling fans and heating lamps. Neurologic scores were measured daily, and rats were killed at 14 days for histologic analysis. Neurons per high-powered field were counted in the CA1 region of the anterior hippocampus using neuronal nuclear antigen staining. RESULTS: After 14 days, 12 of 12 rats (100%) cooled to 33 degrees C, 11 of 12 rats (92%) cooled to 35 degrees C, and ten of 14 rats (71%) cooled to 37 degrees C survived, with hazard of death greater in the rats cooled to 37 degrees C than in the combined hypothermia groups. Neurologic scores were worse in the rats cooled to 37 degrees C than in the hypothermia groups on days 1, 2, and 3. Numbers of surviving neurons were similar between the groups cooled to 33 degrees C and 35 degrees C and were higher than in the group cooled to 37 degrees C. CONCLUSIONS: These data illustrate that hypothermia of 35 degrees C or 33 degrees C over the first day of recovery improves neurologic scores and neuronal survival after cardiac arrest in rats. The benefit of induced hypothermia of 35 degrees C appears to be similar to the benefit of 33 degrees C.

Adenosine A1 receptor antagonism hastens the decay in ventricular fibrillation waveform morphology during porcine cardiac arrest.

BACKGROUND: Endogenous adenosine (ADO) is known to be cardioprotective during acute myocardial ischemia. Coronary sinus ADO concentration has recently been shown to increase nearly 13-fold over baseline levels after 5 min of untreated ventricular fibrillation (VF). The role of ADO in VF has never been previously examined. The objective of this study was to determine the effect of ADO receptor antagonism, as measured by the scaling exponent (ScE), on the degeneration of VF over time during the circulatory phase of cardiac arrest. METHODS AND RESULTS: A well-established swine model of prolonged VF arrest was used for this experiment. Eighteen domestic mixed-breed swine were assigned by block randomization to receive either DTI-0017 (5mg/kg), a potent ADO A(1) receptor antagonist or placebo in a double-blind fashion. The animals were instrumented under general anesthesia and acclimatized. The assigned solution was infused over 5 min. One minute after the infusion was completed, VF was induced with a 3s, 60 Hz, 100 mA transthoracic shock and left untreated. Lead II ECG was monitored continuously and recorded at 1000 samples/s. It was determined a priori that evaluation of the plots would be limited to a previously observed plateau phase historically occurring between 5 and 8 min corresponding to the circulatory phase of cardiac arrest. The scaling exponent values over this period were calculated for each of the 18 recordings using custom MATLAB routines. Using the Wald statistic to produce the Chi square distributions the null hypothesis, that there was no difference between the two groups, was tested. The Wald statistic calculation based on eight epochs from 300 to 475 s in placebo and DTI groups was significant to reject the null hypothesis of no difference in the groupxtime interaction at the 0.015 level (Chi square distribution for Wald=17.49, d.f.=7). CONCLUSIONS: In this swine model, adenosine A(1) receptor antagonism accelerated the natural decay in the ECG VF waveform during the circulatory phase of cardiac arrest. Our findings would suggest that endogenous adenosine has cardioprotective effects during sudden cardiac arrest by slowing the time-dependent degeneration of VF.

A randomized comparison of manual, mechanical and high-impulse chest compression in a porcine model of prolonged ventricular fibrillation.

BACKGROUND: Elevated coronary perfusion pressure (CPP) during CPR is associated with return of spontaneous circulation (ROSC). We compared CPP achieved with three methods of chest compression: manual (MAN), mechanical (MECH) and high-impulse mechanical (HI) in a porcine model of prolonged ventricular fibrillation (VF). We hypothesized that HI (very rapid acceleration of the down-stroke) would produce greater CPPs than MAN or MECH, and that HI would also produce a higher rate of ROSC. METHODS: Twenty-eight domestic swine (mean 27.8 kg) were randomly assigned to three methods of chest compression. Animals were instrumented under anesthesia, and VF was induced and untreated for 8 min. After 2 min of CPR, epinephrine (adrenaline) (0. 1 mg/kg), vasopressin (40 U) and propranolol (1.0 mg) were administered. CPR continued for three more minutes, after which up to three rescue shocks were delivered. CPP was determined in an automated fashion by measuring the difference between aortic and right atrial pressures 0.1s prior to the down-stroke of each compression (i.e. end-relaxation). ROSC was defined as a systolic pressure greater than 80 mmHg sustained for at least 1 min. We analyzed CPP and ROSC using repeated measures ANOVA and Fisher's exact test. RESULTS: Over the 5 min of CPR, CPP increased more with HI compression than with MAN compression (p=0.017). ROSC was attained in 4/9 MAN, 6/9 MECH and 10/10 HI (HI versus MAN p=0.01). CONCLUSIONS: Over the course of CPR, HI compression increased CPP more than MAN compression. HI compression produced a significantly higher rate of ROSC than MAN, but not MECH compression.

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.

Delayed hypothermia preferentially increases expression of brain-derived neurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest.

Brain-derived neurotrophic factor (BDNF) protein levels increase in rats treated with a regimen of delayed, mild hypothermia that improve neurological recovery after asphyxial cardiac arrest. BDNF transcription in rat brain involves at least five different BDNF exons (exons I-V) that produce four different varieties of mRNA, each containing exon V paired with one of exons I-IV. This study examined whether these different BDNF transcripts are differentially affected by cardiac arrest and by therapeutic hypothermia in rat hippocampus using a reverse transcription and PCR-based method. At 24 h after asphyxial cardiac arrest, transcripts containing exons I and III increased. In rats treated with hypothermia after cardiac arrest, transcripts containing exon III were further increased. No significant alterations in transcripts from exons II or IV were observed, though there was a trend for hypothermia to decrease message from these exons. These data suggest that hypothermia after cardiac arrest produces exon-specific changes in BDNF transcription.

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 chi2 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.