Role of epinephrine and extracorporeal membrane oxygenation in the management of ischemic refractory ventricular fibrillation: a randomized trial in pigs.

xtracorporeal membrane oxygenation (ECMO) is used in cardiopulmonary resuscitation (CPR) of refractory cardiac arrest. We used a 2×2 study design to compare ECMO versus CPR and epinephrine versus placebo in a porcine model of ischemic refractory ventricular fibrillation (VF). Pigs underwent 5 minutes of untreated VF, 10 minutes of CPR, and were randomized to receive epinephrine versus placebo for another 35 minutes. Animals were further randomized to LAD reperfusion at minute 45 with ongoing CPR versus veno-arterial ECMO cannulation at minute 45 of CPR and subsequent LAD reperfusion. Four-hour survival was improved with ECMO while epinephrine showed no effect.

Early Effects of Prolonged Cardiac Arrest and Ischemic Postconditioning during Cardiopulmonary Resuscitation on Cardiac and Brain Mitochondrial Function in Pigs.

BACKGROUND: Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). METHODS: A total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. RESULTS: Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. CONCLUSIONS: Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.

Intracoronary Poloxamer 188 Prevents Reperfusion Injury in a Porcine Model of ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Poloxamer 188 (P188) is a nonionic triblock copolymer believed to prevent cellular injury after ischemia and reperfusion. OBJECTIVES: This study compared intracoronary infusion of P188 immediately after reperfusion with delayed infusion through a peripheral intravenous catheter in a porcine model of ST segment elevation myocardial infarction (STEMI). Cellular and mitochondrial injury were assessed. METHODS: STEMI was induced in 55 pigs using 45 minutes of endovascular coronary artery occlusion. Pigs were then randomized to four groups: control, immediate intracoronary (IC) P188, delayed peripheral P188, and polyethylene glycol (PEG) infusion. Heart tissue was collected after 4 hours of reperfusion. Assessment of mitochondrial function or infarct size was performed. RESULTS: Mitochondrial yield improved significantly with IC P188 treatment compared to control animals (0.25% vs. 0.13%) suggesting improved mitochondrial morphology and survival. Mitochondrial respiration and calcium retention were also significantly improved with immediate IC P188 compared to controls (complex I RCI: 7.4 vs. 3.7 and calcium retention (nmol): 1152 vs. 386). This benefit was only observed with activation of complex I of the mitochondrial respiratory chain suggesting a specific impact of ischemia and reperfusion on this complex. Infarct size and serum troponin I were significantly reduced by immediate IC P188 infusion (infarct size: 13.9% vs. 41.1% and troponin I (µg/L): 19.2 vs. 77.4 µg/L). Delayed P188 and PEG infusion did not provide a significant benefit. CONCLUSIONS: Intracoronary infusion of P188 immediately upon reperfusion significantly reduces cellular and mitochondrial injury after ischemia and reperfusion in this clinically relevant porcine model of STEMI. The timing and route of delivery were critical to achieve the benefit.

Reperfusion injury protection during Basic Life Support improves circulation and survival outcomes in a porcine model of prolonged cardiac arrest.

OBJECTIVE: Ischemic postconditioning (PC) using three intentional pauses at the start of cardiopulmonary resuscitation (CPR) improves outcomes after cardiac arrest in pigs when epinephrine (epi) is used before defibrillation. We hypothesized PC, performed during basic life support (BLS) in the absence of epinephrine, would reduce reperfusion injury and enhance 24h functional recovery. DESIGN: Prospective animal investigation. SETTING: Animal laboratory SUBJECTS: Female farm pigs (n=46, 39±1kg). INTERVENTIONS: Protocol A: After 12min of ventricular fibrillation (VF), 28 pigs were randomized to four groups: (A) Standard CPR (SCPR), (B) active compression-decompression CPR with an impedance threshold device (ACD-ITD), (C) SCPR+PC (SCPR+PC) and (D) ACD-ITD CPR+PC. Protocol B: After 15min of VF, 18 pigs were randomized to ACD-ITD CPR or ACD-ITD+PC. The BLS duration was 2.75min in Protocol A and 5min in Protocol B. Following BLS, up to three shocks were delivered. Without return of spontaneous circulation (ROSC), CPR was resumed and epi (0.5mg) and defibrillation delivered. The primary end point was survival without major adverse events. Hemodynamic parameters and left ventricular ejection fraction (LVEF) were also measured. Data are presented as mean±SEM. MEASUREMENTS AND MAIN RESULTS: Protocol A: ACD-ITD+PC (group D) improved coronary perfusion pressure after 3min of BLS versus the three other groups (28±6, 35±7, 23±5 and 47±7 for groups A, B, C, D respectively, p=0.05). There were no significant differences in 24h survival between groups. PROTOCOL B: LVEF 4h post ROSC was significantly higher with ACD-ITD+PC vs ACD-ITD alone (52.5±3% vs. 37.5±6.6%, p=0.045). Survival rates were significantly higher with ACD-ITD+PC vs. ACD-ITD alone (p=0.027). CONCLUSIONS: BLS using ACD-ITD+PC reduced post resuscitation cardiac dysfunction and improved functional recovery after prolonged untreated VF in pigs. PROTOCOL NUMBER: 12-11.

The Effect of Head Up Cardiopulmonary Resuscitation on Cerebral and Systemic Hemodynamics.

AIM: Chest compressions during cardiopulmonary resuscitation (CPR) increase arterial and venous pressures, delivering simultaneous bidirectional high-pressure compression waves to the brain. We hypothesized that this may be detrimental and could be partially overcome by elevation of the head during CPR. MEASUREMENTS: Female Yorkshire farm pigs (n=30) were sedated, intubated, anesthetized, and placed on a table able to elevate the head 30° (15cm) (HUP) and the heart 10° (4cm) or remain in the supine (SUP) flat position during CPR. After 8minutes of untreated ventricular fibrillation and 2minutes of SUP CPR, pigs were randomized to HUP or SUP CPR for 20 more minutes. In Group A, pigs were randomized after 2minutes of flat automated conventional (C) CPR to HUP (n=7) or SUP (n=7) C-CPR. In Group B, pigs were randomized after 2minutes of automated active compression decompression (ACD) CPR plus an impedance threshold device (ITD) SUP CPR to either HUP (n=8) or SUP (n=8). RESULTS: The primary outcome of the study was difference in CerPP (mmHg) between the HUP and SUP positions within groups. After 22minutes of CPR, CerPP was 6±3mmHg in the HUP versus -5±3 in the SUP (p=0.016) in Group A, and 51±8 versus 20±5 (p=0.006) in Group B. Coronary perfusion pressures after 22minutes were HUP 6±2 vs SUP 3±2 (p=0.283) in Group A and HUP 32±5 vs SUP 19±5, (p=0.074) in Group B. In Group B, 6/8 pigs were resuscitated in both positions. No pigs were resuscitated in Group A. CONCLUSIONS: The HUP position in both C-CPR and ACD+ITD CPR significantly improved CerPP. This simple maneuver has the potential to improve neurological outcomes after cardiac arrest.

Effect of regulating airway pressure on intrathoracic pressure and vital organ perfusion pressure during cardiopulmonary resuscitation: a non-randomized interventional cross-over study.

BACKGROUND: The objective of this investigation was to evaluate changes in intrathoracic pressure (Ppl), airway pressure (Paw) and vital organ perfusion pressures during standard and intrathoracic pressure regulation (IPR)-assisted cardiopulmonary resuscitation (CPR). METHODS: Multiple CPR interventions were assessed, including newer ones based upon IPR, a therapy that enhances negative intrathoracic pressure after each positive pressure breath. Eight anesthetized pigs underwent 4 min of untreated ventricular fibrillation followed by 2 min each of sequential interventions: (1) conventional standard CPR (STD), (2) automated active compression decompression (ACD) CPR, (3) ACD+ an impedance threshold device (ITD) CPR or (4) ACD+ an intrathoracic pressure regulator (ITPR) CPR, the latter two representing IPR-based CPR therapies. Intrapleural (Ppl), airway (Paw), right atrial, intracranial, and aortic pressures, along with carotid blood flow and end tidal CO2, were measured and compared during each CPR intervention. RESULTS: The lowest mean and decompression phase Ppl were observed with IPR-based therapies [Ppl mean (mean ± SE): STD (0.8 ± 1.1 mmHg); ACD (-1.6 ± 1.6); ACD-ITD (-3.7 ± 1.5, p < 0.05 vs. both STD and ACD); ACD-ITPR (-7.0 ± 1.9, p < 0.05 vs. both STD and ACD)] [Ppl decompression (mean ± SE): STD (-6.3 ± 2.2); ACD (-13.0 ± 3.8); ACD-ITD -16.9 ± 3.6, p < 0.05 vs. both STD and ACD); ACD-ITPR -18.7 ± 3.5, p < 0.05 vs. both STD and ACD)]. Interventions with the lower mean or decompression phase Ppl also demonstrated lower Paw and were associated with higher vital organ perfusion pressures. CONCLUSIONS: IPR-based CPR methods, specifically ACD-ITPR, yielded the most pronounced reduction in both Ppl and Paw and resulted in the most favorable augmentation of hemodynamics during CPR.

Enhanced perfusion during advanced life support improves survival with favorable neurologic function in a porcine model of refractory cardiac arrest.

OBJECTIVE: To improve the likelihood for survival with favorable neurologic function after cardiac arrest, we assessed a new advanced life support approach using active compression-decompression cardiopulmonary resuscitation plus an intrathoracic pressure regulator. DESIGN: Prospective animal investigation. SETTING: Animal laboratory. SUBJECTS: Female farm pigs (n = 25) (39 ± 3 kg). INTERVENTIONS: Protocol A: After 12 minutes of untreated ventricular fibrillation, 18 pigs were randomized to group A-3 minutes of basic life support with standard cardiopulmonary resuscitation, defibrillation, and if needed 2 minutes of advanced life support with standard cardiopulmonary resuscitation; group B-3 minutes of basic life support with standard cardiopulmonary resuscitation, defibrillation, and if needed 2 minutes of advanced life support with active compression-decompression plus intrathoracic pressure regulator; and group C-3 minutes of basic life support with active compression-decompression cardiopulmonary resuscitation plus an impedance threshold device, defibrillation, and if needed 2 minutes of advanced life support with active compression-decompression plus intrathoracic pressure regulator. Advanced life support always included IV epinephrine (0.05 µg/kg). The primary endpoint was the 24-hour Cerebral Performance Category score. Protocol B: Myocardial and cerebral blood flow were measured in seven pigs before ventricular fibrillation and then following 6 minutes of untreated ventricular fibrillation during sequential 5 minutes treatments with active compression-decompression plus impedance threshold device, active compression-decompression plus intrathoracic pressure regulator, and active compression-decompression plus intrathoracic pressure regulator plus epinephrine. MEASUREMENTS AND MAIN RESULTS: Protocol A: One of six pigs survived for 24 hours in group A versus six of six in groups B and C (p = 0.002) and Cerebral Performance Category scores were 4.7 ± 0.8, 1.7 ± 0.8, and 1.0 ± 0, respectively (p = 0.001). Protocol B: Brain blood flow was significantly higher with active compression-decompression plus intrathoracic pressure regulator compared with active compression-decompression plus impedance threshold device (0.39 ± 0.23 vs 0.27 ± 0.14 mL/min/g; p = 0.03), whereas differences in myocardial perfusion were not statistically significant (0.65 ± 0.81 vs 0.42 ± 0.36 mL/min/g; p = 0.23). Brain and myocardial blood flow with active compression-decompression plus intrathoracic pressure regulator plus epinephrine were significantly increased versus active compression-decompression plus impedance threshold device (0.40 ± 0.22 and 0.84 ± 0.60 mL/min/g; p = 0.02 for both). CONCLUSION: Advanced life support with active compression-decompression plus intrathoracic pressure regulator significantly improved cerebral perfusion and 24-hour survival with favorable neurologic function. These findings support further evaluation of this new advanced life support methodology in humans.

Intrathoracic Pressure Regulation Improves Cerebral Perfusion and Cerebral Blood Flow in a Porcine Model of Brain Injury.

Brain injury is a leading cause of death and disability in children and adults in their most productive years. Use of intrathoracic pressure regulation (IPR) to generate negative intrathoracic pressure during the expiratory phase of positive pressure ventilation improves mean arterial pressure and 24-h survival in porcine models of hemorrhagic shock and cardiac arrest and has been demonstrated to decrease intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these models. Application of IPR for 240 min in a porcine model of intracranial hypertension (ICH) will increase CPP when compared with controls. Twenty-three female pigs were subjected to focal brain injury by insertion of an epidural Foley catheter inflated with 3 mL of saline. Animals were randomized to treatment for 240 min with IPR set to a negative expiratory phase pressure of -12 cmH2O or no IPR therapy. Intracranial pressure, mean arterial pressure, CPP, and cerebral blood flow (CBF) were evaluated. Intrathoracic pressure regulation significantly improved mean CPP and CBF. Specifically, mean CPP after 90, 120, 180, and 240 min of IPR use was 43.7 ± 2.8 mmHg, 44.0 ± 2.7 mmHg, 44.5 ± 2.8 mmHg, and 43.1 ± 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 ± 1.7 mmHg) compared with control animals in which mean CPP was 36.7 ± 1.4 mmHg (ICH study baseline) and then 35.9 ± 2.1 mmHg, 33.7 ± 2.8 mmHg, 33.9 ± 3.0 mmHg, and 36.0 ± 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P < 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 ± 4 mL/100 g-min to 49 ± 7 mL/100 g-min at 90 min) but not in controls (27 ± 1 mL/100 g-min to 25 ± 5 mL/100 g-min at 90 min) (P = 0.01). Arterial pH remained unchanged during the entire period of IPR compared with baseline values and control values. In this anesthetized pig model of ICH, treatment with IPR significantly improved CPP and CBF. This therapy may be of clinical value by noninvasively improving cerebral perfusion in states of compromised cerebral perfusion.

Tilting for perfusion: head-up position during cardiopulmonary resuscitation improves brain flow in a porcine model of cardiac arrest.

INTRODUCTION: Cerebral perfusion is compromised during cardiopulmonary resuscitation (CPR). We hypothesized that beneficial effects of gravity on the venous circulation during CPR performed in the head-up tilt (HUT) position would improve cerebral perfusion compared with supine or head-down tilt (HDT). METHODS: Twenty-two pigs were sedated, intubated, anesthetized, paralyzed and placed on a tilt table. After 6min of untreated ventricular fibrillation (VF) CPR was performed on 14 pigs for 3min with an automated CPR device called LUCAS (L) plus an impedance threshold device (ITD), followed by 5min of L-CPR+ITD at 0° supine, 5min at 30° HUT, and then 5min at 30° HDT. Microspheres were used to measure organ blood flow in 8 pigs. L-CPR+ITD was performed on 8 additional pigs at 0°, 20°, 30°, 40°, and 50° HUT. RESULTS: Coronary perfusion pressure was 19±2mmHg at 0° vs. 30±3 at 30° HUT (p<0.001) and 10±3 at 30° HDT (p<0.001). Cerebral perfusion pressure was 19±3 at 0° vs. 35±3 at 30° HUT (p<0.001) and 4±4 at 30° HDT (p<0.001). Brain-blood flow was 0.19±0.04mlmin(-1)g(-1) at 0° vs. 0.27±0.04 at 30° HUT (p=0.01) and 0.14±0.06 at 30° HDT (p=0.16). Heart blood flow was not significantly different between interventions. With 0, 10, 20, 30, 40 and 50° HUT, ICP values were 21±2, 16±2, 10±2, 5±2, 0±2, -5±2 respectively, (p<0.001), CerPP increased linearly (p=0.001), and CPP remained constant. CONCLUSION: During CPR, HDT decreased brain flow whereas HUT significantly lowered ICP and improved cerebral perfusion. Further studies are warranted to explore this new resuscitation concept.

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

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

Sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-arrest therapeutic hypothermia in a porcine model of prolonged ventricular fibrillation.

OBJECTIVES: The aim of this study was to assess the effect of sodium nitroprusside-enhanced cardiopulmonary resuscitation on heat exchange during surface cooling. We hypothesized that sodium nitroprusside-enhanced cardiopulmonary resuscitation would decrease the time required to reach brain temperature less than 35°C compared to active compression-decompression plus impedance threshold device cardiopulmonary resuscitation alone, in the setting of intra-cardiopulmonary resuscitation cooling. We further hypothesized that the addition of epinephrine during sodium nitroprusside-enhanced cardiopulmonary resuscitation would mitigate heat exchange. DESIGN: Prospective randomized animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Female farm pigs (n=28). INTERVENTIONS: After 10 minutes of untreated ventricular fibrillation, animals were randomized to three different protocols: sodium nitroprusside-enhanced cardiopulmonary resuscitation (n=8), sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (n=10), and active compression-decompression plus impedance threshold device alone (control, n=10). All animals received surface cooling at the initiation of cardiopulmonary resuscitation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation included active compression-decompression plus impedance threshold device plus abdominal binding and 2 mg of sodium nitroprusside at 1, 4, and 8 minutes of cardiopulmonary resuscitation. No epinephrine was used during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group. Control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups received 0.5 mg of epinephrine at 4.5 and 9 minutes of cardiopulmonary resuscitation. Defibrillation occurred after 10 minutes of cardiopulmonary resuscitation. After return of spontaneous circulation, an Arctic Sun (Medivance, Louiseville, CO) was applied at maximum cooling on all animals. The primary endpoint was the time required to reach brain temperature less than 35°C beginning from the time of cardiopulmonary resuscitation initiation. Data are presented as mean±SEM. MEASUREMENTS AND MAIN RESULTS: The time required to reach a brain temperature of 35°C was decreased with sodium nitroprusside-enhanced cardiopulmonary resuscitation versus control or sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (24±6 min, 63±8 min, and 50±9 min, respectively; p=0.005). Carotid blood flow was higher during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group (83±15 mL/min vs 26±7 mL/min and 35±5 mL/min in the control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups, respectively; p=0.001). CONCLUSIONS: This study demonstrates that sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-cardiopulmonary resuscitation hypothermia. The addition of epinephrine to sodium nitroprusside-enhanced cardiopulmonary resuscitation during cardiopulmonary resuscitation reduced its improvement in heat exchange.

Anaesthetic Postconditioning at the Initiation of CPR Improves Myocardial and Mitochondrial Function in a Pig Model of Prolonged Untreated Ventricular Fibrillation.

BACKGROUND: Anaesthetic postconditioning (APoC) attenuates myocardial injury following coronary ischaemia/reperfusion. We hypothesised that APoC at the initiation of cardiopulmonary resuscitation (CPR) will improve post resuscitation myocardial function along with improved mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. METHODS: In 32 pigs isoflurane anaesthesia was discontinued prior to induction of ventricular fibrillation that was left untreated for 15 min. At the initiation of CPR, 15 animals were randomised to controls (CON), and 17 to APoC with 2 vol% sevoflurane during the first 3 min CPR. Pigs were defibrillated after 4 min of CPR. After return of spontaneous circulation (ROSC), isoflurane was restarted at 0.8-1.5 vol% in both groups. Systolic and diastolic blood pressures were measured continuously. Of the animals that achieved ROSC, eight CON and eight APoC animals were randomised to have their left ventricular ejection fraction (LVEF%) assessed by echocardiography at 4h. Seven CON and nine APoC were randomised to euthanasia 15 min after ROSC to isolate mitochondria from the left ventricle for bioenergetic studies. RESULTS: ROSC was achieved in 10/15 CON and 15/17 APoC animals. APoC improved haemodynamics during CPR and post-CPR LVEF%. Mitochondrial ATP synthesis, coupling of oxidative phosphorylation and calcium retention capacity were improved in cardiac mitochondria isolated after APoC. CONCLUSIONS: In a porcine model of prolonged untreated cardiac arrest, APoC with inhaled sevoflurane at the initiation of CPR, is associated with preserved mitochondrial function and improved post resuscitation myocardial dysfunction. Approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation of Hennepin County Medical Center (protocol number 11-05).

Early coronary revascularization improves 24h survival and neurological function after ischemic cardiac arrest. A randomized animal study.

BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) remains poor. Acute coronary obstruction is a major cause of OHCA. We hypothesize that early coronary reperfusion will improve 24h-survival and neurological outcomes. METHODS: Total occlusion of the mid LAD was induced by balloon inflation in 27 pigs. After 5min, VF was induced and left untreated for 8min. If return of spontaneous circulation (ROSC) was achieved within 15min (21/27 animals) of cardiopulmonary resuscitation (CPR), animals were randomized to a total of either 45min (group A) or 4h (group B) of LAD occlusion. Animals without ROSC after 15min of CPR were classified as refractory VF (group C). In those pigs, CPR was continued up to 45min of total LAD occlusion at which point reperfusion was achieved. CPR was continued until ROSC or another 10min of CPR had been performed. Primary endpoints for groups A and B were 24-h survival and cerebral performance category (CPC). Primary endpoint for group C was ROSC before or after reperfusion. RESULTS: Early compared to late reperfusion improved survival (10/11 versus 4/10, p=0.02), mean CPC (1.4±0.7 versus 2.5±0.6, p=0.017), LVEF (43±13 versus 32±9%, p=0.01), troponin I (37±28 versus 99±12, p=0.005) and CK-MB (11±4 versus 20.1±5, p=0.031) at 24-h after ROSC. ROSC was achieved in 4/6 animals only after reperfusion in group C. CONCLUSIONS: Early reperfusion after ischemic cardiac arrest improved 24h survival rate and neurological function. In animals with refractory VF, reperfusion was necessary to achieve ROSC.

Induction, maintenance, and reversal of therapeutic hypothermia with an esophageal heat transfer device.

AIM OF THE STUDY: To evaluate a novel esophageal heat transfer device for use in inducing, maintaining, and reversing hypothermia. We hypothesized that this device could successfully induce, maintain (within a 1 °C range of goal temperature), and reverse, mild therapeutic hypothermia in a large animal model over a 30-h treatment protocol. METHODS: Five female Yorkshire swine, weighing a mean of 65 kg (range 61-70) kg each, were anesthetized with inhalational isoflurane via endotracheal intubation and instrumented. The esophageal device was connected to an external chiller and then placed into the esophagus and connected to wall suction. Reduction to goal temperature was achieved by setting the chiller to cooling mode, and a 24h cooling protocol was completed before rewarming and recovering the animals. Histopathologic analysis was scheduled for 3-14 days after protocol completion. RESULTS: Average baseline temperature for the 5 animals was 38.6 °C (range 38.1-39.2 °C). All swine were cooled successfully, with average rate of temperature decrease of 1.3 °C/h (range 1.1-1.9) °C/h. Standard deviation from goal temperature averaged 0.2 °C throughout the steady-state maintenance phase, and no treatment for shivering was necessary during the protocol. Histopathology of esophageal tissue showed no adverse effects from the device. CONCLUSION: A new esophageal heat transfer device successfully and safely induced, maintained, and reversed therapeutic hypothermia in large swine. Goal temperature was maintained within a narrow range, and thermogenic shivering did not occur. These findings suggest a useful new modality to induce therapeutic hypothermia.

"Fluidless" resuscitation with permissive hypotension via impedance threshold device therapy compared with normal saline resuscitation in a porcine model of severe hemorrhage.

BACKGROUND: One approach to improve outcomes after trauma and hemorrhage is to follow the principles of permissive hypotension by avoiding intravascular overpressure and thereby preventing dislodgement of platelet plugs early in the clotting process. We hypothesized that augmentation of negative intrathoracic pressure (nITP) by treatment with an impedance threshold device would improve hemodynamics without compromising permissive hypotension or causing hemodilution, whereas aggressive fluid resuscitation with normal saline (NS) would result in hemodilution and SBPs that are too high for permissive hypotension and capable of clot dislodgement. METHODS: Thirty-four spontaneously breathing anesthetized female pigs (30.6 ± 0.5 kg) were subjected to a fixed 55% hemorrhage over 30 minutes; block randomized to nITP, no treatment, or intravenous bolus of 1-L NS; and evaluated over 30 minutes. Results are reported as mean ± SEM. RESULTS: Average systolic blood pressures (SBPs) (mm Hg) 30 minutes after the study interventions were as follows: nITP, 82.1 ± 2.9; no treatment, 69.4 ± 4.0; NS 89.3 ± 5.2. Maximum SBPs during the initial 15 minutes of treatment were as follows: nITP, 88.0 ± 4.3; no treatment, 70.8 ± 4.3; and NS, 131 ± 7.6. After 30 minutes, mean pulse pressure (mm Hg) was significantly higher in the nITP group (nITP, 32.3 ± 2.2) versus the no-treatment group (21.5 ± 1.5 controls) (p < 0.05), and the mean hematocrit was 25.2 ± 0.8 in the nITP group versus 19 ± 0.6 in the NS group (p < 0.001). CONCLUSION: In this porcine model of hemorrhagic shock, nITP therapy significantly improved SBP and pulse pressure for 30 minutes without overcompensation compared with controls with no treatment. By contrast, aggressive fluid resuscitation with NS but not nITP resulted in a significant rise in SBP to more than 100 mm Hg within minutes of initiating therapy that could cause a further reduction in hematocrit and clot dislodgment.

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

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

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

OBJECTIVES: Ischemic postconditioning (PC) with "stuttering" reintroduction of blood flow after prolonged ischemia has been shown to offer protection from ischemia reperfusion injury to the myocardium and brain. We hypothesized that four 20-s pauses during the first 3 min of standard CPR would improve post resuscitation cardiac and neurological function, in a porcine model of prolonged untreated cardiac arrest. METHODS: 18 female farm pigs, intubated and isoflurane anesthetized had 15 min of untreated ventricular fibrillation followed by standard CPR (SCPR). Nine animals were randomized to receive PC with four, controlled, 20-s pauses, during the first 3 min of CPR (SCPR+PC). Resuscitated animals had echocardiographic evaluation of their ejection fraction after 1 and 4 h and a blinded neurological assessment with a cerebral performance category (CPC) score assigned at 24 and 48 h. All animals received 12 h of post resuscitation mild therapeutic hypothermia. RESULTS: SCPR+PC animals had significant improvement in left ventricular ejection fraction at 1 and 4 h compared to SCPR (59±11% vs. 35±7% and 55±8% vs. 31±13% respectively, p<0.01). Neurological function at 24h significantly improved with SCPR+PC compared to SCPR alone (CPC: 2.7±0.4 vs. 3.8±0.4 respectively, p=0.003). Neurological function significantly improved in the SCPR+PC group at 48 h and the mean CPC score of that group decreased from 2.7±0.4 to 1.7±0.4 (p<0.00001). CONCLUSIONS: Ischemic postconditioning with four 20-s pauses during the first 3 min of SCPR improved post resuscitation cardiac function and facilitated neurological recovery after 15 min of untreated cardiac arrest in pigs.

Improved cerebral perfusion pressures and 24-hr neurological survival in a porcine model of cardiac arrest with active compression-decompression cardiopulmonary resuscitation and augmentation of negative intrathoracic pressure.

OBJECTIVE: Generation of negative intrathoracic pressure during the decompression phase of cardiopulmonary resuscitation enhances the refilling of the heart. We tested the hypothesis that when compared with closed-chest manual compressions at 80 chest compressions per min, treatment with active compression-decompression cardiopulmonary resuscitation at 80 chest compressions/min combined with augmentation of negative intrathoracic pressure would lower intracranial pressure and increase cerebral perfusion, thereby improving neurologically intact survival rates following prolonged untreated cardiac arrest. DESIGN: Prospective, randomized animal study. SETTING: Animal laboratory facilities. SUBJECTS: A total of 26 female farm pigs in two different protocols (n = 17 and n = 9). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Seventeen pigs were subjected to 8.5 mins of untreated ventricular fibrillation and prospectively randomized to cardiopulmonary resuscitation at 80 chest compressions/min or active compression-decompression cardiopulmonary resuscitation at 80 chest compressions/min plus an impedance threshold device. Coronary perfusion pressures (29.5 ± 2.7 mm Hg vs. 22.4 ± 1.6 mm Hg, p = .03), carotid blood flow (44.0 ± 12.2 vs. 30.9 ± 10.4, p = .03), and 24-hr neurological survival (88% vs. 22%, p = .015) were higher with active compression-decompression cardiopulmonary resuscitation + an impedance threshold device. Cerebral perfusion pressures, measured in nine additional pigs, were improved with active compression-decompression cardiopulmonary resuscitation + an impedance threshold device (21.9 ± 1.2 mm Hg vs. 8.9 ± 0.8 mm Hg, p < .0001). With active compression-decompression cardiopulmonary resuscitation + impedance threshold device, mean diastolic intracranial pressure during decompression was lower (12.2 ± 0.2 mm Hg vs. 16.6 ± 1.2 mm Hg, p = .02) and the downward slope of the decompression phase intracranial pressure curve was steeper (-60.3 ± 12.9 mm Hg vs. -46.7 ± 11.1 mm Hg/sec, p < .001). CONCLUSIONS: Active compression-decompression cardiopulmonary resuscitation + an impedance threshold device increased cerebral perfusion pressures and lowered diastolic intracranial pressure and intracranial pressure rate during the decompression phase. These mechanisms may underlie the observed increase in cerebral perfusion pressure, carotid blood flow, and survival rates with favorable neurologic outcomes in this pig model of cardiac arrest.

Impairment of carotid artery blood flow by supraglottic airway use in a swine model of cardiac arrest.

OBJECTIVE: Supraglottic airway devices (SGDs) are often used as an alternative to endotracheal tube (ETT) during cardiopulmonary resuscitation (CPR). SGDs can be inserted 'blindly' and rapidly, without stopping compressions. These devices utilize pressurized balloons to direct air to the trachea and prevent esophagus insufflation. We hypothesize that the use of a SGD will compress the carotid artery and decrease carotid blood flow (CBF) during CPR in pigs. METHODS: Ventricular fibrillation (VF) was induced in 9 female pigs (32 ± 1 kg) followed by 4 min without compressions. CPR was then performed continuously for 3-6-min intervals. During each interval, an ETT was used for the first 3 min, followed by 3 min of each SGD (King LTS-D™, LMA Flexible™, Combitube™) in a random order. The primary endpoint was mean CBF (ml/min). Statistical comparisons among the 4 airway devices were performed by Wilcoxon Rank test. Post mortem carotid arteriographies were performed with SGDs in place. RESULTS: CBF (median ml/min; 25/75 percentile) was significantly lower with each SGD [King (10; 6/41), LMA (10; 4/39), and Combitube (5; -0.4/15)] versus ETT (21; 14/46) (p<0.05 for each SGD compared with ETT). Arteriograms showed that with each SGD there was compression of the internal and external carotid vessels. CONCLUSION: The use of 3 different SGDs during CPR significantly decreased CBF in a porcine model of cardiac arrest. While the current study is limited to pigs, the findings suggest that further research on the effects of SGD use in humans and the effects on carotid artery blood flow is warranted.

Controlled pauses at the initiation of sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitate neurological and cardiac recovery after 15 mins of untreated ventricular fibrillation.

OBJECTIVE: A multipronged approach to improve vital organ perfusion during cardiopulmonary resuscitation that includes sodium nitroprusside, active compression-decompression cardiopulmonary resuscitation, an impedance threshold device, and abdominal pressure (sodium nitroprusside-enhanced cardiopulmonary resuscitation) has been recently shown to increase coronary and cerebral perfusion pressures and higher rates of return of spontaneous circulation vs. standard cardiopulmonary resuscitation. To further reduce reperfusion injury during sodium nitroprusside-enhanced cardiopulmonary resuscitation, we investigated the addition of adenosine and four 20-sec controlled pauses spread throughout the first 3 mins of sodium nitroprusside-enhanced cardiopulmonary resuscitation. The primary study end point was 24-hr survival with favorable neurologic function after 15 mins of untreated ventricular fibrillation. DESIGN: Randomized, prospective, blinded animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Thirty-two female pigs (four groups of eight) 32±2 kg. INTERVENTIONS: After 15 mins of untreated ventricular fibrillation, isoflurane-anesthetized pigs received 5 mins of either standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine. After 4 mins of cardiopulmonary resuscitation, all animals received epinephrine (0.5 mg) and a defibrillation shock 1 min later. Sodium nitroprusside-enhanced cardiopulmonary resuscitation-treated animals received sodium nitroprusside (2 mg) after 1 min of cardiopulmonary resuscitation and 1 mg after 3 mins of cardiopulmonary resuscitation. After 1 min of sodium nitroprusside-enhanced cardiopulmonary resuscitation, adenosine (24 mg) was administered in two groups. MEASUREMENTS AND MAIN RESULTS: A veterinarian blinded to the treatment assigned a cerebral performance category score of 1-5 (normal, slightly disabled, severely disabled but conscious, vegetative state, or dead, respectively) 24 hrs after return of spontaneous circulation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, and controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine resulted in a significantly higher 24-hr survival rate compared to standard cardiopulmonary resuscitation (7 of 8, 8 of 8, and 8 of 8 vs. 2 of 8, respectively p<.05). The mean cerebral performance category scores for standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine were 4.6±0.7, 3±1.3, 2.5±0.9, and 1.5±0.9, respectively (p<.01 for controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine compared to all other groups). CONCLUSIONS: Reducing reperfusion injury and maximizing circulation during cardiopulmonary resuscitation significantly improved functional neurologic recovery after 15 mins of untreated ventricular fibrillation. These results suggest that brain resuscitation after prolonged cardiac arrest is possible with novel, noninvasive approaches focused on reversing the mechanisms of tissue injury.