Jennifer Rees

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.

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).

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.

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.

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.

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

ABSTRACT 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.

Improving microcirculation with therapeutic intrathoracic pressure regulation in a porcine model of hemorrhage

AIM OF STUDY Intrathoracic pressure regulation (IPR) has been used to treat hypotension and states of hypoperfusion by providing positive pressure ventilation during inspiration followed by augmentation of negative intrathoracic pressure during expiration. This therapy augments cardiac output and lowers intracranial pressure, thereby providing greater circulation to the heart and brain. The effects of IPR on microcirculation remain unknown. METHODS Using a hemorrhagic model, hemodynamics and sublingual microcirculation were evaluated after a 55% blood loss over a 30 min timeframe in 10 female farm pigs (30 kg) previously anesthetized with isoflurane. RESULTS After hemorrhage the mean arterial pressure was 27 ± 4 mm Hg. Blood cell velocity, the key indicator of microcirculation, was significantly reduced after the bleed from 1033 ± 175 μm/s pre-bleed to 147 ± 60 μm/s (p < 0.0001). Application of an IPR device reduced airway pressure during expiration to -9 mm Hg after each positive pressure breath (10 mL/kg, 10 breaths/min) and resulted in a rapid increase in systemic hemodynamics and microcirculation. During IPR treatment, average mean arterial pressure increased by 59% to 43 ± 6 mm Hg (p = 0.002) and blood cell velocity increased by 344% to 506 ± 99 μm/s (p = 0.001). CONCLUSION In this animal model, we observed that microcirculation and systemic blood pressures are correlated and may be significantly improved by using IPR therapy.

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.

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 &mgr;g/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.