Impact of arginine-vasopressin on regional perfusions in a porcine model of post-resuscitation syndrome.

Background: Post-cardiac arrest (CA) shock is associated with multiple organ failure, including acute kidney injury, and is the leading cause of early death among patient successfully resuscitated from CA. Arginine-vasopressin (AVP) may be an interesting therapeutic alternative or complement to noradrenaline (NAD) to both control shock and preserve regional, especially renal, organ perfusions. Methods: 18 swine (24-39 kg) were submitted to 14 min of ventricular fibrillation and cardio-pulmonary resuscitation. After return of spontaneous circulation (ROSC), animals randomly received either AVP, NAD or AVP-NAD combination for maintaining a targeted mean arterial pressure of 70 ± 5 mmHg for 6 h. Haemodynamic and biological parameters, including kidney function biomarkers and diuresis, were monitored throughout the follow-up. Results: Targeted mean arterial pressure was successfully obtained in the NAD (n = 6) and the AVP-NAD (n = 6) groups, but not in the AVP group (n = 6), where 4 animals died. As compared to NAD alone, renal blood flow (2.9 ± 1.15 vs 4.36 ± 0.64 mL//kg/min in NAD and AVP-NAD groups) and diuresis were higher in the AVP-NAD group. This was associated with a reduction of carotid blood flow and a more severe metabolic acidosis during the first 3 h of follow-up in the AVP-NAD group as compared to NAD group. Conclusion: Combination of AVP and NAD improved renal perfusion and diuresis but reduced carotid blood flow as compared to NAD alone in a porcine model of post-resuscitation syndrome. AVP alone failed to manage shock and led to mortality.

High-Mobility Group Box 1-Signaling Inhibition With Glycyrrhizin Prevents Cerebral T-Cell Infiltration After Cardiac Arrest.

Background High-mobility group box 1 (HMGB1) is a major promotor of ischemic injuries and aseptic inflammatory responses. We tested its inhibition on neurological outcome and systemic immune response after cardiac arrest (CA) in rabbits. Methods and Results After 10 minutes of ventricular fibrillation, rabbits were resuscitated and received saline (control) or the HMGB1 inhibitor glycyrrhizin. A sham group underwent a similar procedure without CA. After resuscitation, glycyrrhizin blunted the successive rises in HMGB1, interleukin-6, and interleukin-10 blood levels as compared with control. Blood counts of the different immune cell populations were not different in glycyrrhizin versus control. After animal awakening, neurological outcome was improved by glycyrrhizin versus control, regarding both clinical recovery and histopathological damages. This was associated with reduced cerebral CD4+ and CD8+ T-cell infiltration beginning 2 hours after CA. Conversely, granulocytes' attraction or loss of microglial cells or cerebral monocytes were not modified by glycyrrhizin after CA. These modifications were not related to the blood-brain barrier preservation with glycyrrhizin versus control. Interestingly, the specific blockade of the HMGB1 receptor for advanced glycation end products by FPS-ZM1 recapitulated the neuroprotective effects of glycyrrhizin. Conclusions Our findings support that the early inhibition of HMGB1-signaling pathway prevents cerebral chemoattraction of T cells and neurological sequelae after CA. Glycyrrhizin could become a clinically relevant therapeutic target in this situation.

A novel capnogram analysis to guide ventilation during cardiopulmonary resuscitation: clinical and experimental observations.

BACKGROUND: Cardiopulmonary resuscitation (CPR) decreases lung volume below the functional residual capacity and can generate intrathoracic airway closure. Conversely, large insufflations can induce thoracic distension and jeopardize circulation. The capnogram (CO2 signal) obtained during continuous chest compressions can reflect intrathoracic airway closure, and we hypothesized here that it can also indicate thoracic distension. OBJECTIVES: To test whether a specific capnogram may identify thoracic distension during CPR and to assess the impact of thoracic distension on gas exchange and hemodynamics. METHODS: (1) In out-of-hospital cardiac arrest patients, we identified on capnograms three patterns: intrathoracic airway closure, thoracic distension or regular pattern. An algorithm was designed to identify them automatically. (2) To link CO2 patterns with ventilation, we conducted three experiments: (i) reproducing the CO2 patterns in human cadavers, (ii) assessing the influence of tidal volume and respiratory mechanics on thoracic distension using a mechanical lung model and (iii) exploring the impact of thoracic distension patterns on different circulation parameters during CPR on a pig model. MEASUREMENTS AND MAIN RESULTS: (1) Clinical data: 202 capnograms were collected. Intrathoracic airway closure was present in 35%, thoracic distension in 22% and regular pattern in 43%. (2) Experiments: (i) Higher insufflated volumes reproduced thoracic distension CO2 patterns in 5 cadavers. (ii) In the mechanical lung model, thoracic distension patterns were associated with higher volumes and longer time constants. (iii) In six pigs during CPR with various tidal volumes, a CO2 pattern of thoracic distension, but not tidal volume per se, was associated with a significant decrease in blood pressure and cerebral perfusion. CONCLUSIONS: During CPR, capnograms reflecting intrathoracic airway closure, thoracic distension or regular pattern can be identified. In the animal experiment, a thoracic distension pattern on the capnogram is associated with a negative impact of ventilation on blood pressure and cerebral perfusion during CPR, not predicted by tidal volume per se.

HEAD AND THORAX ELEVATION PREVENTS THE RISE OF INTRACRANIAL PRESSURE DURING EXTRACORPOREAL RESUSCITATION IN SWINE.

Aim: Head and thorax elevation during cardiopulmonary resuscitation improves cerebral hemodynamics and ultimate neurological outcome after cardiac arrest. Its effect during extracorporeal cardiopulmonary resuscitation (E-CPR) is unknown. We tested whether this procedure could improve hemodynamics in swine treated by E-CPR. Methods and Results: Pigs were anesthetized and submitted to 15 minutes of untreated ventricular fibrillation followed by E-CPR. Animals randomly remained in flat position (flat group) or underwent head and thorax elevation since E-CPR institution (head-up group). Electric shocks were delivered after 30 minutes until the return of spontaneous circulation (ROSC). They were followed during 120 minutes after ROSC. After 30 minutes of E-CPR, ROSC was achieved in all animals, with no difference regarding blood pressure, heart rate, and extracorporeal membrane of oxygenation flow among groups. The head-up group had an attenuated increase in ICP as compared with the flat group after cardiac arrest (13 ± 1 vs. 26 ± 2 mm Hg at the end of the follow-up, respectively). Cerebral perfusion pressure tended to be higher in the head-up versus flat group despite not achieving statistical difference (66 ± 1 vs 46 ± 1 mm Hg at the end of the follow-up). Carotid blood flow and cerebral oxygen saturation were not significantly different among groups. Conclusion: During E-CPR, head and thorax elevation prevents ICP increase. Whether it could improve the ultimate neurological outcome in this situation deserves further investigation.

Targeted high mean arterial pressure aggravates cerebral hemodynamics after extracorporeal resuscitation in swine.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (E-CPR) is used for the treatment of refractory cardiac arrest. However, the optimal target to reach for mean arterial pressure (MAP) remains to be determined. We hypothesized that MAP levels critically modify cerebral hemodynamics during E-CPR and tested two distinct targets (65-75 vs 80-90 mmHg) in a porcine model. METHODS: Pigs were submitted to 15 min of untreated ventricular fibrillation followed by 30 min of E-CPR. Defibrillations were then delivered until return of spontaneous circulation (ROSC). Extracorporeal circulation was initially set to an average flow of 40 ml/kg/min. The dose of epinephrine was set to reach a standard or a high MAP target level (65-75 vs 80-90 mmHg, respectively). Animals were followed during 120-min after ROSC. RESULTS: Six animals were included in both groups. During E-CPR, high MAP improved carotid blood flow as compared to standard MAP. After ROSC, this was conversely decreased in high versus standard MAP, while intra-cranial pressure was superior. The pressure reactivity index (PRx), which is the correlation coefficient between arterial blood pressure and intracranial pressure, also demonstrated inverted patterns of alteration according to MAP levels during E-CPR and after ROSC. In standard-MAP, PRx was transiently positive during E-CPR before returning to negative values after ROSC, demonstrating a reversible alteration of cerebral autoregulation during E-CPR. In high-MAP, PRx was negative during E-CPR but became sustainably positive after ROSC, demonstrating a prolonged alteration in cerebral autoregulation after ROSC. It was associated with a significant decrease in cerebral oxygen consumption in high- versus standard-MAP after ROSC. CONCLUSIONS: During early E-CPR, MAP target above 80 mmHg is associated with higher carotid blood flow and improved cerebral autoregulation. This pattern is inverted after ROSC with a better hemodynamic status with standard versus high-MAP.

Brain and Myocardial Mitochondria Follow Different Patterns of Dysfunction After Cardiac Arrest.

ABSTRACT: Mitochondria is often considered as the common nexus of cardiac and cerebral dysfunction after cardiac arrest. Here, our goal was to determine whether the time course of cardiac and cerebral mitochondrial dysfunction is similar after shockable versus non-shockable cardiac arrest in rabbits. Anesthetized rabbits were submitted to 10 min of no-flow by ventricular fibrillation (VF group) or asphyxia (non-shockable group). They were euthanized at the end of the no-flow period or 30 min, 120 min, or 24 h after resuscitation for in vitro evaluation of oxygen consumption and calcium retention capacity. In the brain (cortex and hippocampus), moderate mitochondrial dysfunction was evidenced at the end of the no-flow period after both causes of cardiac arrest versus baseline. It partly recovered at 30 and 120 min after cardiac arrest, with lower calcium retention capacity and higher substrate-dependant oxygen consumption after VF versus non-shockable cardiac arrest. However, after 24 h of follow-up, mitochondrial dysfunction dramatically increased after both VF and non-shockable cardiac arrest, despite greater neurological dysfunction after the latter one. In the heart, mitochondrial dysfunction was also maximal after 24 h following resuscitation, with no significant difference among the causes of the cardiac arrest. During the earlier timing of evaluation, calcium retention capacity and ADP-dependant oxygen consumption were lower and higher, respectively, after non-shockable cardiac arrest versus VF. In conclusion, the kinetics of cardiac and cerebral mitochondrial dysfunction suggests that mitochondrial function does not play a major role in the early phase of the post-resuscitation process but is only involved in the longer pathophysiological events.

Resuscitative endovascular balloon occlusion of the aorta vs epinephrine in the treatment of non-traumatic cardiac arrest in swine.

BACKGROUND: The administration of epinephrine in the management of non-traumatic cardiac arrest remains recommended despite controversial effects on neurologic outcome. The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an interesting alternative. The aim of this study was to compare the effects of these 2 strategies on return of spontaneous circulation (ROSC) and cerebral hemodynamics during cardiopulmonary resuscitation (CPR) in a swine model of non-traumatic cardiac arrest. RESULTS: Anesthetized pigs were instrumented and submitted to ventricular fibrillation. After 4 min of no-flow and 18 min of basic life support (BLS) using a mechanical CPR device, animals were randomly submitted to either REBOA or epinephrine administration before defibrillation attempts. Six animals were included in each experimental group (Epinephrine or REBOA). Hemodynamic parameters were similar in both groups during BLS, i.e., before randomization. After epinephrine administration or REBOA, mean arterial pressure, coronary and cerebral perfusion pressures similarly increased in both groups. However, carotid blood flow (CBF) and cerebral regional oxygenation saturation were significantly higher with REBOA as compared to epinephrine administration (+ 125% and + 40%, respectively). ROSC was obtained in 5 animals in both groups. After resuscitation, CBF remained lower in the epinephrine group as compared to REBOA, but it did not achieve statistical significance. CONCLUSIONS: During CPR, REBOA is as efficient as epinephrine to facilitate ROSC. Unlike epinephrine, REBOA transitorily increases cerebral blood flow and could avoid its cerebral detrimental effects during CPR. These experimental findings suggest that the use of REBOA could be beneficial in the treatment of non-traumatic cardiac arrest.

Argon Attenuates Multiorgan Failure in Relation with HMGB1 Inhibition.

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups (n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.

Ultrafast Hypothermia Selectively Mitigates the Early Humoral Response After Cardiac Arrest.

Background Total liquid ventilation (TLV) has been shown to prevent neurological damage though ultrafast cooling in animal models of cardiac arrest. We investigated whether its neuroprotective effect could be explained by mitigation of early inflammatory events. Methods and Results Rabbits were submitted to 10 minutes of ventricular fibrillation. After resuscitation, they underwent normothermic follow-up (control) or ultrafast cooling by TLV and hypothermia maintenance for 3 hours (TLV). Immune response, survival, and neurological dysfunction were assessed for 3 days. TLV improved neurological recovery and reduced cerebral lesions and leukocyte infiltration as compared with control (eg, neurological dysfunction score=34±6 versus 66±6% at day 1, respectively). TLV also significantly reduced interleukin-6 blood levels during the hypothermic episode (298±303 versus 991±471 pg/mL in TLV versus control at 3 hours after resuscitation, respectively), but not after rewarming (752±563 versus 741±219 pg/mL in TLV versus control at 6 hours after resuscitation, respectively). In vitro assays confirmed the high temperature sensitivity of interleukin-6 secretion. Conversely, TLV did not modify circulating high-mobility group box 1 levels or immune cell recruitment into the peripheral circulation. The link between interleukin-6 early transcripts (<8 hours) and neurological outcome in a subpopulation of the previously described Epo-ACR-02 (High Dose of Erythropoietin Analogue After Cardiac Arrest) trial confirmed the importance of this cytokine at the early stages as compared with delayed stages (>8 hours). Conclusions The neuroprotective effect of hypothermic TLV was associated with a mitigation of humoral interleukin-6 response. A temperature-dependent attenuation of immune cell reactivity during the early phase of the post-cardiac arrest syndrome could explain the potent effect of rapid hypothermia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00999583.

A new paradigm for lung-conservative total liquid ventilation.

BACKGROUND: Total liquid ventilation (TLV) of the lungs could provide radically new benefits in critically ill patients requiring lung lavage or ultra-fast cooling after cardiac arrest. It consists in an initial filling of the lungs with perfluorocarbons and subsequent tidal ventilation using a dedicated liquid ventilator. Here, we propose a new paradigm for a lung-conservative TLV using pulmonary volumes of perfluorocarbons below functional residual capacity (FRC). METHODS AND FINDINGS: Using a dedicated technology, we showed that perfluorocarbon end-expiratory volumes could be maintained below expected FRC and lead to better respiratory recovery, preserved lung structure and accelerated evaporation of liquid residues as compared to complete lung filling in piglets. Such TLV below FRC prevented volutrauma through preservation of alveolar recruitment reserve. When used with temperature-controlled perfluorocarbons, this lung-conservative approach provided neuroprotective ultra-fast cooling in a model of hypoxic-ischemic encephalopathy. The scale-up and automating of the technology confirmed that incomplete initial lung filling during TLV was beneficial in human adult-sized pigs, despite larger size and maturity of the lungs. Our results were confirmed in aged non-human primates, confirming the safety of this lung-conservative approach. INTERPRETATION: This study demonstrated that TLV with an accurate control of perfluorocarbon volume below FRC could provide the full potential of TLV in an innovative and safe manner. This constitutes a new paradigm through the tidal liquid ventilation of incompletely filled lungs, which strongly differs from the previously known TLV approach, opening promising perspectives for a safer clinical translation. FUND: ANR (COOLIVENT), FRM (DBS20140930781), SATT IdfInnov (project 273).

Multi-parametric functional ultrasound imaging of cerebral hemodynamics in a cardiopulmonary resuscitation model.

Patient mortality at one year reaches 90% after out-of-hospital cardiac arrest and resuscitation. Temperature management is one of the main strategies proposed to improve patient outcome after resuscitation and preclinical studies have shown neuroprotective effects when hypothermia is achieved rapidly, although the underlying mechanisms have not yet been elucidated. State-of-the-art brain imaging technologies can bring new insights into the early cerebral events taking place post cardiac arrest and resuscitation. In this paper, we characterized cerebral hemodynamics in a post-cardiac arrest rabbit model using functional ultrasound imaging. Ultrasound datasets were processed to map the dynamic changes in cerebral blood flow and cerebral vascular resistivity with a 10 second repetition rate while animals underwent cardiac arrest and a cardiopulmonary resuscitation. We report that a severe transient hyperemia takes place in the brain within the first twenty minutes post resuscitation, emphasizing the need for fast post-cardiac arrest care. Furthermore, we observed that this early hyperemic event is not spatially homogeneous and that maximal cerebral hyperemia happens in the hippocampus. Finally, we show that rapid cooling induced by total liquid ventilation reduces early cerebral hyperemia, which could explain the improved neurological outcome reported in preclinical studies.

Targeted Temperature Management With Total Liquid Ventilation After Ischemic Spinal Cord Injury.

BACKGROUND: Ischemic spinal cord injury is a devastating condition after aortic surgery. We determined whether ultrafast and short whole-body hypothermia provided by total liquid ventilation (TLV) attenuated lower limb paralysis after aortic cross-clamping with a targeted temperature management at 33°C versus 36°C. METHODS: Anesthetized rabbits were submitted to infrarenal aortic cross-clamping during 15 min. A control group (n = 7) was maintained at normothermia (38°C to 38.5°C) with conventional mechanical ventilation. In TLV groups, TLV was started after reperfusion and maintained during 30 min with a target temperature at either 33°C or 36°C (TLV-33°C and TLV-36°C, respectively; n = 7 in each condition). After TLV, animals were resumed to conventional ventilation. Hypothermia was maintained during 120 min, before rewarming and awakening. Hind limb motor function was assessed with modified Tarlov score at day 2 and infarct size in the spinal cord was determined using triphenyltetrazolium chloride staining. RESULTS: Target temperature was achieved within 20 minutes in the two TLV groups. At day 2, the modified Tarlov score was significantly lower in the control group, as compared with TLV-33°C and TLV-36°C groups (0.0 ± 0.0 versus 3.1 ± 0.7 and 2.6 ± 0.6, respectively). The infarct size of the spinal cord was also significantly higher in the control group compared with TLV-33°C and TLV-36°C groups (75% ± 10% versus 32% ± 7% and 28% ± 10%, respectively). Neither motor function nor infarct size differed significantly between TLV-33°C and TLV-36°C groups. CONCLUSIONS: Ultrafast hypothermic TLV attenuates spinal cord injury when applied after ischemic insult. Neurological outcome was similar with targeted temperature management at either 33°C or 36°C.

Hypothermic total liquid ventilation after experimental aspiration-associated acute respiratory distress syndrome.

BACKGROUND: Ultrafast cooling by total liquid ventilation (TLV) provides potent cardio- and neuroprotection after experimental cardiac arrest. However, this was evaluated in animals with no initial lung injury, whereas out-of-hospital cardiac arrest is frequently associated with early-onset pneumonia, which may lead to acute respiratory distress syndrome (ARDS). Here, our objective was to determine whether hypothermic TLV could be safe or even beneficial in an aspiration-associated ARDS animal model. METHODS: ARDS was induced in anesthetized rabbits through a two-hits model including the intra-tracheal administration of a pH = 1 solution mimicking gastric content and subsequent gaseous non-protective ventilation during 90 min (tidal volume [Vt] = 10 ml/kg with positive end-expiration pressure [PEEP] = 0 cmH2O). After this initial period, animals either received lung protective gas ventilation (LPV; Vt = 8 ml/kg and PEEP = 5 cmH2O) under normothermic conditions, or hypothermic TLV (TLV; Vt = 8 ml/kg and end-expiratory volume = 15 ml/kg). Both strategies were applied for 120 min with a continuous monitoring of respiratory and cardiovascular parameters. Animals were then euthanized for pulmonary histological analyses. RESULTS: Eight rabbits were included in each group. Before randomization, all animals elicited ARDS with arterial oxygen partial pressure over inhaled oxygen fraction ratios (PaO2/FiO2) below 100 mmHg, as well as decreased lung compliance. After randomization, body temperature rapidly decreased in TLV versus LPV group (32.6 ± 0.6 vs. 38.2 ± 0.4 °C after 15 min). Static lung compliance and gas exchanges were not significantly different in the TLV versus LPV group (PaO2/FiO2 = 62 ± 4 vs. 52 ± 8 mmHg at the end of the procedure, respectively). Mean arterial pressure and arterial bicarbonates levels were significantly higher in TLV versus LPV. Histological analysis also showed significantly lower inflammation in TLV versus LPV group (median histological score = 3 vs. 4.5/5, respectively; p = 0.03). CONCLUSION: Hypothermic TLV can be safely induced in rabbits during aspiration-associated ARDS. It modified neither gas exchanges nor respiratory mechanics but reduced lung inflammation and hemodynamic failure in comparison with LPV. Since hypothermic TLV was previously shown to provide neuro- and cardio protective effects after cardiac arrest, these findings suggest a possible use of TLV in the settings of cardiac arrest-associated ARDS.

Argon attenuates multiorgan failure following experimental aortic cross-clamping.

AIMS: Argon has been shown to prevent ischaemic injuries in several scenarios of regional ischaemia. We determined whether it could provide a systemic effect in a model of multiorgan failure (MOF) induced by aortic cross-clamping. METHODS: Anaesthetized rabbits were submitted to aortic cross-clamping (30 min) and subsequent reperfusion (300 min). They were either ventilated with oxygen-enriched air throughout the protocol [fraction of inspired oxygen (FiO2 ) = 30%; control group) or with a mixture of 30% oxygen and 70% argon (argon groups). In a first group treated with argon ('Argon-Total'), its administration was started 30 min before ischaemia and maintained throughout the protocol. In the two other groups, the administration was started either 30 min before ischaemia ('Argon-Pre') or at the onset of reperfusion ('Argon-Post'), for a total duration of 2 h. Cardiovascular, renal and inflammatory endpoints were assessed throughout protocol. RESULTS: Compared with control, shock was significantly attenuated in Argon-Total and Argon-Pre but not Argon-Post groups (e.g. cardiac output = 62±5 vs. 29 ± 5 ml min-1 kg-1 in Argon-Total and control groups at the end of the follow-up). Shock and renal failure were reduced in all argon vs. control groups. Histopathological examination of the gut showed attenuation of ischaemic lesions in all argon vs. control groups. Blood transcription levels of interleukin (IL) 1ß, IL-8, IL-10 and hypoxia-inducible factor 1α were not significantly different between groups. CONCLUSION: Argon attenuated clinical and biological modifications of cardiovascular, renal and intestinal systems, but not the inflammatory response, after aortic cross-clamping. The window of administration was crucial to optimize organ protection.

Early Coronary Reperfusion Facilitates Return of Spontaneous Circulation and Improves Cardiovascular Outcomes After Ischemic Cardiac Arrest and Extracorporeal Resuscitation in Pigs.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is widely proposed for the treatment of refractory cardiac arrest. It should be associated with coronary angiography if coronary artery disease is suspected. However, the prioritization of care remains unclear in this situation. Our goal was to determine whether coronary reperfusion should be instituted as soon as possible in such situations in a pig model. METHODS AND RESULTS: Anesthetized pigs were instrumented and submitted to coronary artery occlusion and ventricular fibrillation. After 5 minutes of untreated cardiac arrest, conventional cardiopulmonary resuscitation (CPR) was started. Fifteen minutes later, ECPR was initiated for a total duration of 240 minutes. Animals randomly underwent either early or late coronary reperfusion at 20 or 120 minutes of ECPR, respectively. This timing was adapted to the kinetic of infarct extension in pigs. Return of spontaneous circulation was determined as organized electrocardiogram rhythm with systolic arterial pressure above 80 mm Hg. During conventional CPR, hemodynamic parameters were not different between groups. Carotid blood flow then increased by 70% after the onset of ECPR in both groups. No animal (0 of 7) elicited return of spontaneous circulation after late reperfusion versus 4 of 7 after early reperfusion (P=0.025). The hemodynamic parameters, such as carotid blood flow, were also improved in early versus late reperfusion groups (113±20 vs 43±17 mL/min after 240 minutes of ECPR, respectively; P=0.030), along with infarct size decrease (71±4% vs 84±2% of the risk zone, respectively; P=0.013). CONCLUSIONS: Early reperfusion improved hemodynamic status and facilitated return of spontaneous circulation in a porcine model of ischemic cardiac arrest treated by ECPR.

A Brief Period of Hypothermia Induced by Total Liquid Ventilation Decreases End-Organ Damage and Multiorgan Failure Induced by Aortic Cross-Clamping.

BACKGROUND: In animal models, whole-body cooling reduces end-organ injury after cardiac arrest and other hypoperfusion states. The benefits of cooling in humans, however, are uncertain, possibly because detrimental effects of prolonged cooling may offset any potential benefit. Total liquid ventilation (TLV) provides both ultrafast cooling and rewarming. In previous reports, ultrafast cooling with TLV potently reduced neurological injury after experimental cardiac arrest in animals. We hypothesized that a brief period of rapid cooling and rewarming via TLV could also mitigate multiorgan failure (MOF) after ischemia-reperfusion induced by aortic cross-clamping. METHODS: Anesthetized rabbits were submitted to 30 minutes of supraceliac aortic cross-clamping followed by 300 minutes of reperfusion. They were allocated either to a normothermic procedure with conventional ventilation (control group) or to hypothermic TLV (33°C) before, during, and after cross-clamping (pre-clamp, per-clamp, and post-clamp groups, respectively). In all TLV groups, hypothermia was maintained for 75 minutes and switched to a rewarming mode before resumption to conventional mechanical ventilation. End points included cardiovascular, renal, liver, and inflammatory parameters measured 300 minutes after reperfusion. RESULTS: In the normothermic (control) group, ischemia-reperfusion injury produced evidence of MOF including severe vasoplegia, low cardiac output, acute kidney injury, and liver failure. In the TLV group, we observed gradual improvements in cardiac output in post-clamp, per-clamp, and pre-clamp groups versus control (53 ± 8, 64 ± 12, and 90 ± 24 vs 36 ± 23 mL/min/kg after 300 minutes of reperfusion, respectively). Liver biomarker levels were also lower in pre-clamp and per-clamp groups versus control. However, acute kidney injury was prevented in pre-clamp, and to a limited extent in per-clamp groups, but not in the post-clamp group. For instance, creatinine clearance was 4.8 ± 3.1 and 0.5 ± 0.6 mL/kg/min at the end of the follow-up in pre-clamp versus control animals (P = .0004). Histological examinations of the heart, kidney, liver, and jejunum in TLV and control groups also demonstrated reduced injury with TLV. CONCLUSIONS: A brief period of ultrafast cooling with TLV followed by rapid rewarming attenuated biochemical and histological markers of MOF after aortic cross-clamping. Cardiovascular and liver dysfunctions were limited by a brief period of hypothermic TLV, even when started after reperfusion. Conversely, acute kidney injury was limited only when hypothermia was started before reperfusion. Further work is needed to determine the clinical significance of our results and to identify the optimal duration and timing of TLV-induced hypothermia for end-organ protection in hypoperfusion states.

Total liquid ventilation offers ultra-fast and whole-body cooling in large animals in physiological conditions and during cardiac arrest.

INTRODUCTION: Total liquid ventilation (TLV) can cool down the entire body within 10-15 min in small animals. Our goal was to determine whether it could also induce ultra-fast and whole-body cooling in large animals using a specifically dedicated liquid ventilator. Cooling efficiency was evaluated under physiological conditions (beating-heart) and during cardiac arrest with automated chest compressions (CC, intra-arrest). METHODS: In a first set of experiments, beating-heart pigs were randomly submitted to conventional mechanical ventilation or hypothermic TLV with perfluoro-N-octane (between 15 and 32 °C). In a second set of experiments, pigs were submitted to ventricular fibrillation and CC. One group underwent continuous CC with asynchronous conventional ventilation (Control group). The other group was switched to TLV while pursuing CC for the investigation of cooling capacities and potential effects on cardiac massage efficiency. RESULTS: Under physiological conditions, TLV significantly decreased the entire body temperatures below 34 °C within only 10 min. As examples, cooling rates averaged 0.54 and 0.94 °C/min in rectum and esophageous, respectively. During cardiac arrest, TLV did not alter CC efficiency and cooled the entire body below 34 °C within 20 min, the low-flow period slowing cooling during CC. CONCLUSION: Using a specifically designed liquid ventilator, TLV induced a very rapid cooling of the entire body in large animals. This was confirmed in both physiological conditions and during cardiac arrest with CC. TLV could be relevant for ultra-rapid cooling independently of body weight.

Hypothermic Total Liquid Ventilation Is Highly Protective Through Cerebral Hemodynamic Preservation and Sepsis-Like Mitigation After Asphyxial Cardiac Arrest.

OBJECTIVES: Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits. DESIGN: Randomized animal study. SETTING: Academic research laboratory. SUBJECTS: New Zealand Rabbits. INTERVENTIONS: Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12). MEASUREMENTS AND MAIN RESULTS: Ultrafast cooling with total liquid ventilation (32 °C within 5 min in the esophagus) dramatically attenuated the post-cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1ß, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32 °C within 90-120 min in the esophagus), providing none of the above-mentioned systemic or organ protection. CONCLUSIONS: Ultrafast cooling by total liquid ventilation limits the post-cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response.

Evaluation of lung recovery after static administration of three different perfluorocarbons in pigs.

BACKGROUND: The respiratory properties of perfluorocarbons (PFC) have been widely studied for liquid ventilation in humans and animals. Several PFC were tested but their tolerance may depend on the species. Here, the effects of a single administration of liquid PFC into pig lungs were assessed and compared. Three different PFC having distinct evaporative and spreading coefficient properties were evaluated (Perfluorooctyl bromide [PFOB], perfluorodecalin [PFD] and perfluoro-N-octane [PFOC]). METHODS: Pigs were anesthetized and submitted to mechanical ventilation. They randomly received an intra-tracheal administration of 15 ml/kg of either PFOB, PFD or PFOC with 12 h of mechanical ventilation before awakening and weaning from ventilation. A Control group was submitted to mechanical ventilation with no PFC administration. All animals were followed during 4 days after the initial PFC administration to investigate gas exchanges and clinical recovery. They were ultimately euthanized for histological analyses and assessment of PFC residual concentrations within the lungs using dual nuclei fluorine and hydrogen Magnetic Resonance Imaging (MRI). Sixteen animals were included (4/group). RESULTS: In the PFD group, animals tended to be hypoxemic after awakening. In PFOB and PFOC groups, blood gases were not significantly different from the Control group after awakening. The poor tolerance of PFD was likely related to a large amount of residual PFC, as observed using MRI in all lung samples (≈10% of lung volume). This percentage was lower in the PFOB group (≈1%) but remained significantly greater than in the Control group. In the PFOC group, the percentage of residual PFC was not significantly different from that of the Control group (≈0.1%). Histologically, the most striking feature was an alveolar infiltration with foam macrophages, especially in the groups treated by PFD or PFOB. CONCLUSIONS: Of the three tested perfluorocarbons, PFOC offered the best tolerance in terms of lung function, gas exchanges and residuum in the lung. PFOC was rapidly cleared from the lungs and virtually disappeared after 4 days whereas PFOB persisted at significant levels and led to foam macrophage infiltration. PFOC could be relevant for short term total liquid ventilation with a rapid weaning.

Comparative effect of hypothermia and adrenaline during cardiopulmonary resuscitation in rabbits.

BACKGROUND: Therapeutic hypothermia was shown to facilitate resumption of spontaneous circulation when instituted during cardiac arrest. Here, we investigated whether it directly improved the chance of successful resuscitation independently of adrenaline administration in rabbits. We further evaluated the direct effect of hypothermia on vascular function in vitro. METHODS: In a first set of experiments, four groups of anesthetized rabbits were submitted to 15 min of cardiac arrest and subsequent cardiopulmonary resuscitation (CPR). The "control" group underwent CPR with only cardiac massage and defibrillation attempts. Two other groups received cold or normothermic saline infusion during CPR (20 mL/kg of NaCl 0.9% at 4°C or 38°C, respectively). In a last group, the animals received adrenaline (15 µg/kg intravenously) during CPR. In a second set of experiments, we evaluated at 32°C vs. 38°C the vascular function of aortic rings withdrawn from healthy rabbits or after cardiac arrest. RESULTS: In the first set of experiments, cardiac massage efficiency was improved by adrenaline but neither by hypothermic nor normothermic saline administration. Resumption of spontaneous circulation was observed in five of eight animals after adrenaline as compared with none of eight in other groups. Defibrillation rates were conversely similar among groups (7/8 or 8/8). In the second set of experiments, in vitro hypothermia (32°C) was not able to prevent the dramatic alteration of vascular function observed after cardiac arrest. It also did not directly modify vasocontractile or the vasodilating functions in healthy conditions. CONCLUSION: In rabbits, hypothermia did not exert a direct hemodynamic or vascular effect that might explain its beneficial effect during CPR.