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.

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).

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.

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.

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.

Intrathoracic pressure regulation for intracranial pressure management in normovolemic and hypovolemic pigs.

OBJECTIVE: To evaluate the potential to use subatmospheric intrathoracic pressure to regulate intracranial pressure (ICP) in normovolemic and hypovolemic animals, we tested the hypothesis that mechanical devices designed to reduce intrathoracic pressure will decrease ICP in a dose-related manner. An inspiratory impedance threshold device was used in spontaneously breathing animals and an intrathoracic pressure regulator was attached to a positive pressure ventilator and used in apneic animals: both devices lower intrathoracic pressure. DESIGN: Prospective, randomized animal study. SETTING: Animal laboratory facilities. SUBJECTS: A total of 36 female farm pigs in four different protocols (n = 12, 6, 12, and 6, respectively). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: In all protocols, endotracheal, right atrial, central aortic, and ICP were measured continuously. In protocol 1, spontaneously breathing animals were randomized to breath for 15 mins through an impedance threshold device with a cracking pressure of -10 or -15 mm Hg. In protocol 2, after untreated ventricular fibrillation for 4 mins and successful defibrillation to a normal rhythm, spontaneously breathing pigs were used to evaluate the effect of two different impedance threshold device cracking pressures (-10 and -15 mm Hg) on increased ICP. In protocol 3, the acute effects of an intrathoracic pressure regulator on ICP were evaluated in combination with a positive pressure mechanical ventilator in apneic hypovolemic hypotensive pigs after 35% or 50% blood loss. In protocol 4, after 40% blood loss, an intrathoracic pressure regulator was applied for 120 mins and ICP was recorded to determine whether the intrathoracic pressure regulator effects were sustained over time. Inspiratory impedance successfully decreased ICP in spontaneously breathing pigs in a dose-dependent manner and decreased elevated ICP immediately after cardiac arrest and successful resuscitation. The same effect was seen in apneic animals with the use of the intrathoracic pressure regulator. The effect was more pronounced in hypovolemia, and it was sustained for >/=2 hrs. CONCLUSIONS: Reduction of intrathoracic pressure to subatmospheric levels resulted in an instantaneous and sustained reduction in ICP in spontaneously breathing and apneic animals. The effect was most pronounced in the hypovolemic animals.

Clinical and hemodynamic comparison of 15:2 and 30:2 compression-to-ventilation ratios for cardiopulmonary resuscitation.

OBJECTIVE: To compare cardiopulmonary resuscitation (CPR) with a compression to ventilation (C:V) ratio of 15:2 vs. 30:2, with and without use of an impedance threshold device (ITD). DESIGN: Prospective randomized animal and manikin study. SETTING: Animal laboratory and emergency medical technician training facilities. SUBJECTS: Twenty female pigs and 20 Basic Life Support (BLS)-certified rescuers. ANIMALS: Acid-base status, cerebral, and cardiovascular hemodynamics were evaluated in 18 pigs in cardiac arrest randomized to a C:V ratio of 15:2 or 30:2. After 6 mins of cardiac arrest and 6 mins of CPR, an ITD was added. Compared to 15:2, 30:2 significantly increased diastolic blood pressure (20 +/- 1 to 26 +/- 1; p < .01); coronary perfusion pressure (18 +/- 1 to 25 +/- 2; p = .04); cerebral perfusion pressure (16 +/- 3 to 18 +/- 3; p = .07); common carotid blood flow (48 +/- 5 to 82 +/- 5 mL/min; p < .001); end-tidal CO2 (7.7 +/- 0.9 to 15.7 +/- 2.4; p < .0001); and mixed venous oxygen saturation (26 +/- 5 to 36 +/- 5, p < .05). Hemodynamics improved further with the ITD. Oxygenation and arterial pH were similar. Only one of nine pigs had return of spontaneous circulation with 15:2, vs. six of nine with 30:2 (p < 0.03). HUMANS: Fatigue and quality of CPR performance were evaluated in 20 BLS-certified rescuers randomized to perform CPR for 5 mins at 15:2 or 30:2 on a recording CPR manikin. There were no significant differences in the quality of CPR performance or measurement of fatigue. Significantly more compressions per minute were delivered with 30:2 in both the animal and human studies. CONCLUSIONS: These data strongly support the contention that a ratio of 30:2 is superior to 15:2 during manual CPR and that the ITD further enhances circulation with both C:V ratios.

Rapid induction of cerebral hypothermia is enhanced with active compression-decompression plus inspiratory impedance threshold device cardiopulmonary resusitation in a porcine model of cardiac arrest.

OBJECTIVES: A rapid, ice-cold saline flush combined with active compression-decompression (ACD) plus an inspiratory impedance threshold device (ITD) cardiopulmonary resusitation (CPR) will cool brain tissue more effectively than with standard CPR (S-CPR) during cardiac arrest (CA). BACKGROUND: Early institution of hypothermia after CPR and return of spontaneous circulation improves survival and outcomes after CA in humans. METHODS: Ventricular fibrillation (VF) was induced for 8 min in anesthetized and tracheally intubated pigs. Pigs were randomized to receive either ACD + ITD CPR (n = 8) or S-CPR (n = 8). After 2 min of CPR, 30 ml/kg ice-cold saline (3 degrees C) was infused over the next 3 min of CPR via femoral vein followed by up to three defibrillation attempts (150 J, biphasic). If VF persisted, epinephrine (40 microg/kg) and vasopressin (0.3 U/kg) were administered followed by three additional defibrillation attempts. Hemodynamic variables and temperatures were continuously recorded. RESULTS: All ACD + ITD CPR pigs (8 of 8) survived (defined as 15 min of return of spontaneous circulation [ROSC]) versus 3 of 8 pigs with S-CPR (p < 0.05). In survivors, brain temperature (degrees C) measured at 2-cm depth in brain cortex 1 min after ROSC decreased from 37.6 +/- 0.2 to 35.8 +/- 0.3 in ACD + ITD CPR versus 37.8 +/- 0.2 to 37.3 +/- 0.3 in S-CPR (p < 0.005). Immediately before defibrillation: 1) right atrial systolic/diastolic pressures (mm Hg) were lower (85 +/- 19, 4 +/- 1) in ACD + ITD CPR than S-CPR pigs (141 +/- 12, 8 +/- 3, p < 0.01); and 2) coronary perfusion pressures (mm Hg) were higher in ACD + ITD CPR (28.3 +/- 2) than S-CPR pigs (17.4 +/- 3, p < 0.01). CONCLUSIONS: A rapid ice-cold saline infusion combined with ACD + ITD CPR during cardiac arrest induces cerebral hypothermia more rapidly immediately after ROSC than with S-CPR.

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.

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 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.

Treatment of hypotension in pigs with an inspiratory impedance threshold device: a feasibility study.

OBJECTIVE: An inspiratory impedance threshold device was evaluated in spontaneously breathing animals with hypotension to determine whether it could help improve systemic arterial pressures when fluid replacement was not immediately available. DESIGN: Prospective, randomized. SETTING: Animal laboratory. SUBJECTS: Thirty-nine female farm pigs (weight, 28-33 kg). INTERVENTIONS: A total of 39 anesthetized spontaneously breathing pigs were treated with an impedance threshold device, with cracking pressures from 0 to -20 cm H2O. Four separate experimental protocols were performed: protocol A, in which the hemodynamics of seven pigs were examined during application of an impedance threshold device at various levels of inspiratory impedance (-5, -10, -15, and -20 cm H(2)O), both before and after a severe, controlled hemorrhage to a systolic blood pressure of 50 - 55 mm Hg; protocol B, in which nine pigs bled to systolic blood pressure of 50 -55 mm Hg were treated with an impedance threshold device set at -12 cm H2O and were compared with nine others treated with a sham device; protocol C, in which the effects of the impedance threshold device on mixed venous gases were measured in seven hemorrhaged pigs; and protocol D, in which the effects of the impedance threshold device on cardiac output in seven hemorrhaged pigs were measured. METHODS AND MAIN RESULTS: During initial studies with both normovolemic and hypovolemic pigs, sequential increases in inspiratory impedance resulted in a significant increase in systolic blood pressure, whereas diastolic left ventricular and right atrial pressures decreased significantly and proportionally to the level of impedance. When comparing the sham vs. active impedance threshold device (-12 cm H(2)O) in hypotensive pigs, systolic blood pressure (mean +/- sem) with active impedance threshold device treatment increased from 70 +/- 2 mm Hg to 105 +/- 4 mm Hg (p <.01). Pressures in the control group remained at 70 +/- 4 mm Hg (p <.01). Cardiac output increased by nearly 25% (p <.01) with the active impedance threshold device when calculated using the mixed gas equation and when determined by thermodilution. CONCLUSIONS: These studies demonstrate that it is feasible to use a device that creates inspiratory impedance in spontaneously breathing normotensive and hypotensive pigs to increase blood pressure and enhance cardiopulmonary circulation in the absence of immediate fluid resuscitation. Further studies are needed to evaluate the potential long-term effects and limitations of this new approach to treat hypovolemic hypotension.

Cardiorespiratory interactions and blood flow generation during cardiac arrest and other states of low blood flow.

PURPOSE OF REVIEW: Recent advances in cardiopulmonary resuscitation have shed light on the importance of cardiorespiratory interactions during shock and cardiac arrest. This review focuses on recently published studies that evaluate factors that determine preload during chest compression, methods that can augment preload, and the detrimental effects of hyperventilation and interrupting chest compressions. RECENT FINDINGS: Refilling of the ventricles, so-called ventricular preload, is diminished during cardiovascular collapse and resuscitation from cardiac arrest. In light of the potential detrimental effects and challenges of large-volume fluid resuscitations, other methods have increasing importance. During cardiac arrest, active decompression of the chest and impedance of inspiratory airflow during the recoil of the chest work by increasing negative intrathoracic pressure and, hence, increase refilling of the ventricles and increase cardiac preload, with improvement in survival. Conversely, increased frequency of ventilation has detrimental effects on coronary perfusion pressure and survival rates in cardiac arrest and severe shock. Prolonged interruption of chest compressions for delivering single-rescuer ventilation or analyzing rhythm before shock delivery is associated with decreased survival rate. SUMMARY: Cardiorespiratory interactions are of profound importance in states of cardiovascular collapse in which increased negative intrathoracic pressure during decompression of the chest has a favorable effect and increased intrathoracic pressure with ventilation has a detrimental effect on survival rate.

Evaluation of a prototypic inspiratory impedance threshold valve designed to enhance the efficiency of cardiopulmonary resuscitation.

OBJECTIVE: Assess a prototype inspiratory impedance threshold valve (ITV) designed to enhance vital organ circulation during standard and active compression/decompression cardiopulmonary resuscitation (CPR). BACKGROUND: The ITV attaches to commonly used airway assist devices and decreases intrathoracic pressure during the decompression (chest recoil) phase of CPR by creating a vacuum within the thorax, which increases venous blood flow to the heart and thus increases coronary perfusion pressure and blood flow to the brain. METHODS: The evaluation included laboratory bench testing, according to American Society for Testing and Materials (ASTM) and International Standards Organization (ISO) guidelines, and performance testing with pigs in cardiac arrest. A vacuum pull test was developed to determine the inspiratory impedance under various inspiratory flow conditions. RESULTS: The valve passed all minimum ASTM and ISO performance tests. During cardiac arrest in pigs the ITV decreased intrathoracic pressures by 6-8 mm Hg during the decompression phase. The vacuum pull test demonstrated that the prototype ITV functioned as intended. CONCLUSIONS: The prototype ITV passed all performance testing recommended by international guidelines and functioned effectively as intended for use. The animal study results, when combined with recent clinical data, suggest that an ITV inspiratory cracking pressure of 12 cm H(2)O should be sufficient to decrease intrathoracic pressure during the decompression phase of standard CPR. Clinical studies are now underway.

Combination drug therapy with vasopressin, adrenaline (epinephrine) and nitroglycerin improves vital organ blood flow in a porcine model of ventricular fibrillation.

There is increasing evidence that the combination of epinephrine (adrenaline) with vasopressin may be superior to either epinephrine or vasopressin alone for treatment of cardiac arrest. However, the optimal combination, and dosage of cardiovascular drugs to minimize side effects, and to improve outcome has yet to be found. We therefore evaluated whether the combination of vasopressin plus epinephrine plus nitroglycerin (EVN), would improve vital organ blood flow during cardiopulmonary resuscitation (CPR) when compared with epinephrine (EPI) alone. After 4 min of ventricular fibrillation (VF) and 4 min of standard CPR, pigs were randomized to the combination of epinephrine (45 microg/kg) plus vasopressin (0.4 U/kg) plus nitroglycerin (7.5 microg/kg; n=12), or epinephrine (40 microg/kg; n=12) alone. Cerebral and myocardial blood flow was measured with radiolabeled microspheres. Defibrillation was attempted after 19 min of VF including 15 min of CPR. Mean+/-SEM coronary perfusion pressures were significantly (P < 0.01) higher 5 min after EVN vs. EPI alone (34+/-3 vs. 24+/-3 mmHg, respectively). At the same time, mean+/-SEM left ventricular, and global cerebral blood flow was also significantly (P < 0.05) higher after EVN vs. EPI alone (0.78+/-0.11 vs. 0.48+/-0.08 ml/min/g; and 0.37+/-0.05 vs. 0.22+/-0.0 3 ml/min/g, respectively). Spontaneous circulation was restored in 11 of 12 animals in the EVN group vs. 6 of 12 swine after EPI alone (P = N.S.). In conclusion, the combination of EVN significantly improved vital organ blood flow during CPR compared with EPI alone. Addition of nitroglycerin to the combination of low dose epinephrine with vasopressin during cardiac arrest may be beneficial.