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.

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.

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.

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.

Sodium nitroprusside-enhanced cardiopulmonary resuscitation improves resuscitation rates after prolonged untreated cardiac arrest in two porcine models.

OBJECTIVE: Sodium nitroprusside-enhanced cardiopulmonary resuscitation consists of active compression-decompression, an impedance threshold device, abdominal binding, and large intravenous doses of sodium nitroprusside. We hypothesize that sodium nitroprusside-enhanced cardiopulmonary resuscitation will significantly increase carotid blood flow and return of spontaneous circulation compared to standard cardiopulmonary resuscitation after prolonged ventricular fibrillation and pulseless electrical activity cardiac arrest. DESIGN: Prospective randomized animal study. SETTING: Hennepin County Medical Center Animal Laboratory. SUBJECTS: Forty Yorkshire female farm-bred pigs weighing 32 ± 2 kg. INTERVENTIONS: In protocol A, 24 isoflurane-anesthetized pigs underwent 15 mins of untreated ventricular fibrillation and were subsequently randomized to receive standard cardiopulmonary resuscitation (n = 6), active compression-decompression cardiopulmonary resuscitation + impedance threshold device (n = 6), or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 12) for up to 15 mins. First defibrillation was attempted at minute 6 of cardiopulmonary resuscitation. In protocol B, a separate group of 16 pigs underwent 10 mins of untreated ventricular fibrillation followed by 3 mins of chest compression only cardiopulmonary resuscitation followed by countershock-induced pulseless electrical activity, after which animals were randomized to standard cardiopulmonary resuscitation (n = 8) or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 8). MEASUREMENTS AND MAIN RESULTS: The primary end point was carotid blood flow during cardiopulmonary resuscitation and return of spontaneous circulation. Secondary end points included end-tidal CO2 as well as coronary and cerebral perfusion pressure. After prolonged untreated ventricular fibrillation, sodium nitroprusside-enhanced cardiopulmonary resuscitation demonstrated superior rates of return of spontaneous circulation when compared to standard cardiopulmonary resuscitation and active compression-decompression cardiopulmonary resuscitation + impedance threshold device (12 of 12, 0 of 6, and 0 of 6 respectively, p < .01). In animals with pulseless electrical activity, sodium nitroprusside-enhanced cardiopulmonary resuscitation increased return of spontaneous circulation rates when compared to standard cardiopulmonary resuscitation. In both groups, carotid blood flow, coronary perfusion pressure, cerebral perfusion pressure, and end-tidal CO2 were increased with sodium nitroprusside-enhanced cardiopulmonary resuscitation. CONCLUSIONS: In pigs, sodium nitroprusside-enhanced cardiopulmonary resuscitation significantly increased return of spontaneous circulation rates, as well as carotid blood flow and end-tidal CO2, when compared to standard cardiopulmonary resuscitation or active compression-decompression cardiopulmonary resuscitation + impedance threshold device.

Intrathoracic pressure regulation improves 24-hour survival in a pediatric porcine model of hemorrhagic shock.

Hemorrhagic shock is a common cause of mortality and morbidity in the pediatric population. Intrathoracic pressure regulation (IPR) lowers intrathoracic pressure, thereby decreasing intracranial pressure and increasing venous return, cardiac output, and cerebral perfusion without the need for immediate fluid resuscitation. We hypothesized that IPR would improve hemodynamics and 24-h survival in a pediatric porcine model of hemorrhagic shock. Twenty piglets were subjected to a 50% total blood volume hemorrhage over 15 min and then randomized to treatment with either IPR or no treatment. After 60 min, survivors were autotransfused, weaned from the ventilator, and assessed and autopsied at 24 h. Mean arterial pressures (MAPs), cardiac index (CI), and arterial blood gases were recorded. MAP (mm Hg) was significantly higher in the IPR group (60.8 ± 3.7) versus controls (41.2 ± 4.6, p < 0.01). Mean CI (L/min/m²) was significantly higher with IPR (3.9 ± 0.24) versus controls (2.5 ± 0.39, p < 0.01). IPR survival rates were significantly improved with IPR [9/9 (IPR) versus 5/11 (controls); p < 0.02]. In this piglet model of hemorrhagic shock, IPR treatment safely and significantly improved MAP, CI, and 24-h survival rates.

No assisted ventilation cardiopulmonary resuscitation and 24-hour neurological outcomes in a porcine model of cardiac arrest.

OBJECTIVES: To evaluate the effect of no assisted ventilation cardiopulmonary resuscitation on neurologically intact survival compared with ten positive pressure ventilations/minute cardiopulmonary resuscitation in a pig model of cardiac arrest. DESIGN: Prospective randomized animal study. SETTING: Animal laboratory. SUBJECTS: Sixteen female intubated pigs (25.2 +/- 2.1 kg) anesthetized with propofol. INTERVENTIONS: : fter 8 mins of untreated ventricular fibrillation, the intubated animals were randomized to 8 mins of continuous chest compressions (100/min) and either no assisted ventilation (n = 9) or 10 positive pressure ventilations/min (Smart Resuscitator Bag with 100% O2 flow at 10 L/min) (n = 7). The primary end point, neurologically intact 24-hr survival, was evaluated using a pig cerebral performance category score by a veterinarian blinded to the cardiopulmonary resuscitation method. MEASUREMENTS, AND MAIN RESULTS: During cardiopulmonary resuscitation, aortic and coronary perfusion pressure were similar between groups but cerebral perfusion pressure was significantly higher in the positive pressure ventilation group (33 +/- 15 vs. 14 +/- 14, p = .04). After 7.5 mins of cardiopulmonary resuscitation, arterial pO2 (mm Hg) and mixed venous O2 saturation (%) were significantly higher in the positive pressure ventilation compared with the no assisted ventilation group (117 +/- 29 and 41 +/- 21 vs. 40 +/- 24 and 10.8 +/- 7; p = .01 for both). Paco2 was significantly lower in the positive pressure ventilation group (48 +/- 10 vs. 77 +/- 26, p = .01). After 24 hrs, four of nine no assisted ventilation pigs were alive with a mean cerebral performance category score of 3 +/- 0 vs. five of seven alive and neurologically intact positive pressure ventilation pigs with a cerebral performance category score of 1 +/- 0.3 (p < .001 for cerebral performance category score). CONCLUSIONS: No assisted ventilation cardiopulmonary resuscitation results in profound hypoxemia, respiratory acidosis, and significantly worse 24-hr neurologic outcomes compared with positive pressure ventilation cardiopulmonary resuscitation in pigs.

Subcutaneous bioimpedance recording: assessment of a method for hemodynamic monitoring by implanted devices.

BACKGROUND: Diagnostic evaluation of patients with suspected symptomatic arrhythmias is limited by inability to assess the hemodynamic impact of a detected rhythm. OBJECTIVE: To address this limitation, we utilized closely spaced subcutaneous electrodes, small enough to incorporate within an implantable monitor, to detect blood flow-induced pectoral muscle bioimpedance (Z) changes in a swine model of hemorrhage-induced hypotension. METHODS: In seven anesthetized and ventilated adult pigs, small ring electrodes (current electrodes 5 cm apart; voltage electrodes 3.5 cm apart) were positioned on the left pectoral muscle. Z signals (Biopac system) and invasive arterial blood pressures were recorded. Hypotension was induced by hemorrhage (50% blood volume reduction). Mean arterial pressure (MAP) and pulse pressure (PP) with corresponding pulse Z (DeltaZ) and base Z (Z(o)) were measured. A longitudinal mixed model with a first-order autoregressive error structure was used to test for associations (change in DeltaZ vs change in MAP and change in DeltaZ vs change in PP) taking into account within pig correlation. RESULTS: During bleeding-induced hypotension, Z(o) increased. Changes of DeltaZ correlated with both a change in MAP (coefficient = 1.17, P < 0.0001) and change in PP (coefficient = 0.98, P < 0.0001). A change in DeltaZ of 1-2 orders of magnitude corresponded to an approximate 40-70% drop in MAP and PP in a porcine model in which the baseline MAP was 69-70 mmHg. CONCLUSION: Our findings suggest that closely spaced subcutaneous electrodes identify changes in local tissue/vascular bioimpedance that correlate well with direct invasive measures of induced hypotension in a porcine model.

From laboratory science to six emergency medical services systems: New understanding of the physiology of cardiopulmonary resuscitation increases survival rates after cardiac arrest.

OBJECTIVE: The purpose of this study is to: 1) describe a newly mechanism of blood flow to the brain during cardiopulmonary resuscitation using the impedance threshold device in a piglet model of cardiac arrest, and 2) describe the survival benefits in humans of applying all of the highly recommended changes in the 2005 guidelines related to increasing circulation during cardiopulmonary resuscitation, including use of the impedance threshold device, from six emergency medical services systems in the United States. DESIGN: Animal studies prospective trial with each piglet serving as its own control. Historical controls were used for the human studies. SUBJECTS: Piglets and patients with out-of-hospital cardiac arrest. INTERVENTIONS: Piglets (10-12 kg) were treated with an active (n = 9) or sham (n = 9) impedance threshold device after 6 mins of ventricular fibrillation. Humans were treated with cardiopulmonary resuscitation per the American Heart Association 2005 guidelines and the impedance threshold device. ANIMALS: The primary endpoint in the piglet study was carotid blood flow which increased from 59 mL/min without an impedance threshold device to 91 mL/min (p = 0.017) with impedance threshold device use. Airway pressures during the chest recoil phase decreased from -0.46 mm Hg to -2.59 mm Hg (p = 0.0006) with the active impedance threshold device. Intracranial pressure decreased more rapidly and to a greater degree during the decompression phase of cardiopulmonary resuscitation with the active impedance threshold device. Humans: Conglomerate quality assurance data were analyzed from six emergency medical services systems in the United States serving a population of approximately 3 million people. There were 920 patients treated for cardiac arrest after implementation of the 2005 American Heart Association guidelines, including impedance threshold device use, and 1750 patients in the control group during the year before implementation. Demographics were similar between the two groups. Survival to hospital discharge was 9.3% in the control group versus 13.6% in the intervention group. The odds ratio, 95% confidence interval, and p value were 1.54 (1.19-1.99) and p = 0.0008, respectively. This survival advantage was conferred to patients with a presenting cardiac arrest rhythm of ventricular fibrillation (28.5% vs. 18.0%, p = 0.0008). CONCLUSIONS: Use of the impedance threshold device in piglets increased carotid blood flow and coronary and cerebral perfusion pressures and reduced intracranial pressure during the decompression phase of cardiopulmonary resuscitation at a faster rate than controls, resulting in a longer duration of time when intracranial pressures are at their nadir. Patients in six emergency medical services systems treated with the impedance threshold device together with the renewed emphasis on more compressions, fewer ventilations, and complete chest wall recoil had a nearly 50% increase in survival rates after out-of-hospital cardiac arrest compared with historical controls.

Comparison of a 10-breaths-per-minute versus a 2-breaths-per-minute strategy during cardiopulmonary resuscitation in a porcine model of cardiac arrest.

BACKGROUND: Hyperventilation during cardiopulmonary resuscitation (CPR) is harmful. METHODS: We tested the hypotheses that, during CPR, 2 breaths/min would result in higher cerebral perfusion pressure and brain-tissue oxygen tension than 10 breaths/min, and an impedance threshold device (known to increase circulation) would further enhance cerebral perfusion and brain-tissue oxygen tension, especially with 2 breaths/min. RESULTS: Female pigs (30.4 +/- 1.3 kg) anesthetized with propofol were subjected to 6 min of untreated ventricular fibrillation, followed by 5 min of CPR (100 compressions/min, compression depth of 25% of the anterior-posterior chest diameter), and ventilated with either 10 breaths/min or 2 breaths/min, while receiving 100% oxygen and a tidal volume of 12 mL/kg. Brain-tissue oxygen tension was measured with a probe in the parietal lobe. The impedance threshold device was then used during an 5 additional min of CPR. During CPR the mean +/- SD calculated coronary and cerebral perfusion pressures with 10 breaths/min versus 2 breaths/min, respectively, were 17.6 +/- 9.3 mm Hg versus 14.3 +/- 6.5 mm Hg (p = 0.20) and 16.0 +/- 9.5 mm Hg versus 9.3 +/- 12.5 mm Hg (p = 0.25). Carotid artery blood flow, which was prospectively designated as the primary end point, was 65.0 +/- 49.6 mL/min in the 10-breaths/min group, versus 34.0 +/- 17.1 mL/min in the 2-breaths/min group (p = 0.037). Brain-tissue oxygen tension was 3.0 +/- 3.3 mm Hg in the 10-breaths/min group, versus 0.5 +/- 0.5 mm Hg in the 2-breaths/min group (p = 0.036). After 5 min of CPR there were no significant differences in arterial pH, PO2, or PCO2 between the groups. During CPR with the impedance threshold device, the mean carotid blood flow and brain-tissue oxygen tension in the 10-breaths/min group and the 2-breaths/min group, respectively, were 102.5 +/- 67.9 mm Hg versus 38.8 +/- 23.7 mm Hg (p = 0.006) and 4.5 +/- 6.0 mm Hg versus 0.7 +/- 0.7 mm Hg (p = 0.032). CONCLUSIONS: Contrary to our initial hypothesis, during the first 5 min of CPR, 2 breaths/min resulted in significantly lower carotid blood flow and brain-tissue oxygen tension than did 10 breaths/min. Subsequent addition of an impedance threshold device significantly enhanced carotid flow and brain-tissue oxygen tension, especially in the 10-breaths/min group.

Inspiratory impedance threshold device effects on hypotension in heat-stroked swine.

INTRODUCTION: Heat stroke is still an epidemiologically relevant disease with overall mortality rates as high as 15-33%. In heat stroke, hypotension is caused by relative central hypovolemia. We performed a feasibility study to determine if an inspiratory impedance threshold valve (ITDTM) set to open at -12 cm H2O would reverse systemic hypotension by enhancing venous return in hyperthermic, hypotensive, but spontaneously breathing animals. METHODS: Seven anesthetized pigs weighing 30 +/- 2 kg were warmed with a heating device until a mean rectal temperature of 44 degrees C was reached, and mean arterial blood pressure (MAP) was < or = 60 mmHg. The animals were then treated with the ITD. An intravenous bolus of 200 cc of 4 degrees C normal saline was delivered 20 min after the ITD was placed, and external cooling was started. RESULTS: Heat stroke criteria were achieved within 105 +/- 15 min. MAP had decreased from 105 +/- 5 to 57 +/- 5 mmHg, and respiratory rates had increased from 33 +/- 2 to 101 +/- 13 breaths/min. Addition of the ITD significantly improved MAP to 85 +/- 4 mmHg, and reduced respiratory rate to 54 +/- 6 breaths/min within 2 min. The effect was sustained until fluid replacement and external cooling were delivered 20 min later. At that point, MAP returned to baseline within 30 min, and 6/7 animals survived for an additional 30 min. CONCLUSIONS: Use of an inspiratory impedance threshold device resulted in an immediate rise in blood pressure in animals in heat stroke and preserved blood pressure for at least 20 min prior to cooling and fluid replacement.

Intrathoracic pressure regulation improves 24-hour survival in a porcine model of hypovolemic shock.

BACKGROUND: The intrathoracic pressure regulator (ITPR) plus positive pressure ventilation (PPV) has been shown to improve coronary and cerebral perfusion pressures during hypovolemia by improving mean arterial blood pressure and by decreasing right atrial and intracranial pressures. We hypothesized that application of intermittent negative intrathoracic pressure in a pig model of severe hypovolemic hypotension would increase 24-h neurological intact survival rates. METHODS: Eighteen isoflurane-anesthetized pigs were bled 55% of their estimated blood volume and were then prospectively randomized to either ITPR treatment with -8 mm Hg endotracheal pressure plus PPV or only PPV alone for 90 min. All survivors were reinfused with their own blood. Arterial blood gases, end-tidal CO2, and aortic pressures were monitored for the 90 min and neurological evaluation was performed at 12 and 24 h after reinfusion. RESULTS: ITPR plus PPV treatment for 90 min prevented the progression of metabolic acidosis and significantly improved mean arterial blood pressure (mean over 90 min, 55 +/- 3 vs 35 +/- 2.4 mm Hg, P < 0.001) when compared with controls. Twenty-four hour survival significantly improved with use of the ITPR when compared with untreated controls: 9/9 (100%) vs 1/9 (11%), P < 0.01. CONCLUSIONS: Use of the ITPR plus PPV for 90 min significantly increased arterial blood pressure and 24 h neurologically intact survival rates compared with controls treated with PPV alone.

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.

Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest.

BACKGROUND: A novel device, the intrathoracic pressure regulator (ITPR), combines an inspiratory impedance threshold device (ITD) with a vacuum source for the generation of controlled -10 mm Hg vacuum in the trachea during cardiopulmonary resuscitation (CPR) while allowing positive pressure ventilation. Compared with standard (STD) CPR, ITPR-CPR will enhance venous return, systemic arterial pressure, and vital organ perfusion in both porcine models of ventricular fibrillation and hypovolemic cardiac arrest. METHODS AND RESULTS: In protocol 1, 20 pigs (weight, 30+/-0.5 kg) were randomized to STD-CPR or ITPR-CPR. After 8 minutes of untreated ventricular fibrillation, CPR was performed for 6 minutes at 100 compressions per minute and positive pressure ventilation (100% O2) with a compression-to-ventilation ratio of 15:2. In protocol 2, 6 animals were bled 50% of their blood volume. After 4 minutes of untreated ventricular fibrillation, interventions were performed for 2 minutes with STD-CPR and 2 minutes of ITPR-CPR. This sequence was repeated. In protocol 3, 6 animals after 8 minutes of untreated VF were treated with ITPR-CPR for 15 minutes, and arterial and venous blood gases were collected at baseline and minutes 5, 10, and 15 of CPR. A newer, leak-proof ITPR device was used. Aortic, right atrial, endotracheal pressure, intracranial pressure, and end-tidal CO2 values were measured (mm Hg); common carotid arterial flow also was measured (mL/min). Coronary perfusion pressure (diastolic; aortic minus right atrial pressure) and cerebral perfusion pressure (mean arterial minus mean intracranial pressure) were calculated. Unpaired Student t test and Friedman's repeated-measures ANOVA of ranks were used in protocols 1 and 3. A 2-tailed Wilcoxon signed-rank test was used for analysis in protocol 2. Fischer's exact test was used for survival. Significance was set at P<0.05. Vital organ perfusion pressures and end-tidal CO2 were significantly improved with ITPR-CPR in both protocols. In protocol 1, 1-hour survival was 100% with ITPR-CPR and 10% with STD-CPR (P=0.001). Arterial blood pH was significantly lower and Paco2 was significantly higher with ITPR-CPR in protocol 1. Arterial oxygen saturation was 100% throughout the study in both protocols. Paco2 and Pao2 remained stable, but metabolic acidosis progressed, as expected, throughout the 15 minutes of CPR in protocol 3. CONCLUSIONS: Compared with STD-CPR, use of ITPR-CPR improved hemodynamics and short-term survival rates after cardiac arrest.

Hemodynamic and respiratory effects of negative tracheal pressure during CPR in pigs.

BACKGROUND: A new device, the intrathoracic pressure regulator (ITPR), was developed to generate continuous negative intrathoracic pressure during cardiopulmonary resuscitation (CPR) and allow for intermittent positive pressure ventilation. Use of the ITPR has been shown to increase vital organ perfusion and short-term survival rates in pigs. The purpose of this study was to investigate the hemodynamic and blood gas effects of more prolonged (15 min) use of the ITPR during CPR in a porcine model of cardiac arrest. METHODS: After 8 min of untreated ventricular fibrillation (VF), 16 female pigs were anaesthetized with propofol, intubated, and randomized prospectively to 15 min of either ITPR-CPR or standard (STD) CPR. Compressions were delivered at a rate of 100/min with a compression to ventilation ratio of 15:2. Ventilations were delivered with a resuscitator bag. Tracheal, aortic, right atrial, intracranial pressures (ICP), common carotid blood flow and respiratory variables were recorded continuously. Arterial and venous blood gases were collected at baseline, and after 5, 10, and 15 min of CPR. Coronary perfusion pressure (CPP) was calculated as diastolic aortic pressure-right atrial pressure. Cerebral perfusion pressure (CerPP) was calculated as mean arterial pressure (MAP)-intracranial pressure. Statistical analysis was performed with unpaired t-test and Friedman's Repeated Measures Analysis. RESULTS: ITPR-CPR when compared to STD-CPR resulted in a significant decrease in mean decompression phase (diastolic) tracheal pressure (-9+/-0.6 mmHg versus -3+/-0.3 mmHg, p<0.001), diastolic right atrial pressure (DRAP) (-0.1+/-0.2 mmHg versus 2.3+/-0.2 mmHg, p<0.001) and intracranial pressure (20.8+/-0.6 mmHg versus 23+/-0.5 mmHg, respectively, p=0.04) and a significant increase in total mean aortic pressure, coronary and cerebral perfusion pressures and end tidal carbon dioxide (ETCO(2)), (p<0.001). Common carotid artery blood flow was increased by an average of 70%, p<0.001. ABGs showed progressive metabolic acidosis in the ITPR-CPR group, but PaCO(2) remained stable at 34 mmHg for 15 min. In the STD-CPR group, pseudorespiratory alkalosis was observed with PaCO(2) values remaining <20 mmHg (p<0.001). PaO(2) was not different between groups. Following 23 min of cardiac arrest (15 min of CPR) ROSC was achieved in 5/8 ITPR-CPR animals versus 2/8 STD-CPR animals p=0.3. CONCLUSION: ITPR-CPR significantly improved hemodynamics, vital organ perfusion pressures and common carotid blood flow compared to STD-CPR in a porcine model of prolonged cardiac arrest and basic life support. The beneficial hemodynamic effects of ITPR-CPR were sustained at least 15 min without any compromise in oxygenation.

Effects of an inspiratory impedance threshold device on blood pressure and short term survival in spontaneously breathing hypovolemic pigs.

BACKGROUND: The inspiratory impedance threshold device (ITD) has been shown to improve hemodynamic variables and survival outcomes during cardiopulmonary resuscitation in animals and humans. We hypothesized that use of an ITD, with a resistance of -10 cm H2O, will improve hemodynamics and short-term survival rates during hypovolemic hypotension in spontaneously breathing pigs. METHODS: Female farm pigs ( approximately 26 kg) were intubated and anesthetized with propofol with the dose adjusted to permit spontaneous respirations. They were bled to 50% of calculated blood volume through an arterial catheter and then prospectively randomized to either treatment with an ITD or observation alone. Arterial and intratracheal pressures as well as arterial blood gases were measured. After 90 min the ITD was removed, normal saline was administered to all surviving animals, the anesthetic was discontinued, and animals were allowed to recover. Statistical analysis was performed with one-way repeated ANOVA and survival rates were calculated with Kaplan-Meier analysis. RESULTS: Treatment with the ITD resulted in lower intratracheal inspiratory pressure in the treatment group (-11+/-0.4 mmHg versus -4+/-0.7 mmHg, respectively, P<0.005). Mean arterial pressure after 30 min of treatment with the ITD was higher in the treatment group (61.1+/-5.5 mmHg versus 37.4+/-2.1 mmHg, respectively, P<0.005). All pigs in the control group died within 65 min of the initial bleed, whereas 7/8 (87%) treated with an ITD survived for >90 min (P<0.001). During the recovery phase, 6/8 (75%) in the ITD group survived for >3h and awoke without neurological deficit; one surviving animal in the ITD group never woke up. Arterial oxygenation was not compromised in the ITD group. CONCLUSIONS: Use of an ITD improved blood pressure and short-term survival rates in a spontaneously breathing porcine model of hypovolemic hypotension.

Intrathoracic pressure regulation improves vital organ perfusion pressures in normovolemic and hypovolemic pigs.

BACKGROUND: The intrathoracic pressure regulator (ITPR) was created to improve hemodynamics by generating continuous negative airway pressure between positive pressure ventilations to enhance cardiac preload in apnoeic animals. In normovolemic and hypovolemic pigs, we tested the hypothesis that continuous negative intrathoracic pressure set at -5 or -10mmHg, interrupted only for intermittent positive pressure ventilations, would decrease intracranial (ICP) and right atrial (RAP) pressure, and increase mean arterial pressure (MAP). METHODS: Twelve pigs were anesthetized with propofol and ventilated with a bag. The ITPR was used to vary baseline endotracheal pressures (ETPs) for 5min periods in the following sequence: 0, -5, 0, -10, 0mmHg under normovolemic conditions. Six pigs were bled 50% (32.5+/-mL/kg) of their estimated blood volume and the airway pressure sequence was repeated. Six other pigs were bled 35% (22.75+/-mL/kg) of their estimated blood volume and the same airway pressure sequence was repeated. Intracranial, aortic, right atrial pressures, arterial blood gases, end tidal CO(2) (ETCO(2)), were measured. ANOVA was used for statistical analysis. Linear regression analysis was performed for ETP and ICP. RESULTS: Mean arterial and vital organ perfusion pressures were significantly improved and RA pressure significantly decreased with the use of the ITPR; the effect was greater with the more negative ETPs and lower circulating blood volume. The change of ICP was linearly related to the ETP and blood loss: DeltaICP=[1.22-0.84(1-%blood loss/100)]xETP, r(2)=0.88 (in mmHg), p<0.001. There were no adverse device effects and there was a significant increase of ETCO(2) with the use of ITPR. CONCLUSION: The ITPR decreased RAP and ICP significantly and improved mean arterial and cerebral and coronary perfusion pressures without affecting acid base balance severely. The decrease in ICP was directly proportional to the reduction in intrathoracic pressure. The effects were more pronounced in severe hypovolemic and hypotensive states with more negative ETP pressure.

Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation.

INTRODUCTION: Spontaneous gasping is associated with increased survival in animal models of cardiac arrest and in observational studies of humans. The potential beneficial effect of gasping on cerebral perfusion may underlie the observed survival benefit, but mechanisms remain unknown. HYPOTHESIS: We hypothesized that spontaneous gasping in a pig model of ventricular fibrillation (VF) decreases intracranial pressure (ICP) and increases cerebral perfusion pressure (CePP) during VF in a pig model. METHODS: The 13 female farm pigs, weighing between 16 and 33 kg, were anesthetized with propofol and intubated, and then had VF induced for 8 min without intervention. Intrathoracic pressure (ITP), aortic pressure (AoP), and ICP were measured continuously. CePP and ITP were recorded simultaneously during three maximal gasps and correlated with gasping by Spearman rank correlation. RESULTS: Gasping during VF occurred in 13/13 pigs and followed a crescendo-decrescendo pattern. Each gasp was associated with a biphasic AoP (initial fall, then rise) and ICP (initial rise, then fall) morphology. Time to first gasp (r(2)=0.06), time to maximal gasp (r(2)=0.02), duration of gasping (r(2)=0.11) and frequency of gasping (r(2)=0.32) did not correlate significantly with CePP during gasping while depth of gasping exhibited a weak but significant correlation with CePP (r(2)=0.35, p=0.05). Maximal gasping occurred at 202+/-34 s from onset of VF and resulted in an average decrease in ICP from 27.4+/-5.8 to 20+/-6.7 mmHg, p<0.01 along with an increase in CePP from -0.05+/-10.9 to 11.5+/-12.6 mmHg, p<0.05. CONCLUSIONS: Spontaneous gasping during cardiac arrest decreased intra-cranial pressure and increased cerebral perfusion pressure significantly. These results may help explain why gasping is associated with improved cardiac arrest survival rates. Based upon this new understanding of the physiology of gasping, we speculate that investigation of devices that can enhance the physiological effects of gasping on intracranial pressure and cerebral perfusion should be prioritized.

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.