Biophysical function of pulmonary surfactant in liquid ventilation.

Liquid ventilation is a mechanical ventilation technique in which the entire or part of the lung is filled with oxygenated perfluorocarbon (PFC) liquids rather than air in conventional mechanical ventilation. Despite its many ideal biophysicochemical properties for assisting liquid breathing, a general misconception about PFC is to use it as a replacement for pulmonary surfactant. Because of the high PFC-water interfacial tension (59 mN/m), pulmonary surfactant is indispensable in liquid ventilation to increase lung compliance. However, the biophysical function of pulmonary surfactant in liquid ventilation is still unknown. Here, we have studied the adsorption and dynamic surface activity of a natural surfactant preparation, Infasurf, at the PFC-water interface using constrained drop surfactometry. The constrained drop surfactometry is capable of simulating the intra-alveolar microenvironment of liquid ventilation under physiologically relevant conditions. It was found that Infasurf adsorbed to the PFC-water interface reduces the PFC-water interfacial tension from 59 mN/m to an equilibrium value of 9 mN/m within seconds. Atomic force microscopy revealed that after de novo adsorption, Infasurf forms multilayered structures at the PFC-water interface with an average thickness of 10-20 nm, depending on the adsorbing surfactant concentration. It was found that the adsorbed Infasurf film is capable of regulating the interfacial tension of the PFC-water interface within a narrow range, between ∼12 and ∼1 mN/m, during dynamic compression-expansion cycles that mimic liquid ventilation. These findings have novel implications in understanding the physiological and biophysical functions of the pulmonary surfactant film at the PFC-water interface, and may offer new translational insights into the development of liquid ventilation and liquid breathing techniques.

Liquid Ventilation Reconditions Isolated Rat Lungs Following Ischemia-Reperfusion Injury.

Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Lung ischemia-reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate lungs before transplant but has failed to provide significant improvements after IRI. We hypothesized that liquid ventilation (LV) could be utilized for ex vivo lung reconditioning in a rat IRI model. We compared EVLP with LV in an isolated ex vivo rat lung with an aqueous ventilant using quantitative physiological and immunological parameters. We observed improved physiological parameters and mechanical clearance of alveolar macrophages and cytokines halting the propagation of the inflammatory response in IRI. While the wide applicability to large animal or human transplantation have yet to be explored, these findings represent a method for lung reconditioning in the setting of significant IRI that could widen the lung organ donation pool and limit morbidity and mortality associated with ischemia-induced primary graft dysfunction.

Conventional vs high-frequency ventilation for weaning from total liquid ventilation in lambs.

OBJECTIVE: To compare conventional gas ventilation (GV) and high-frequency oscillatory ventilation (HFOV) for weaning from total liquid ventilation (TLV). METHODS: Sixteen lambs were anesthetized. After 1 h of TLV with perflubron (PFOB), they were assigned to either GV or HFOV for 2 h. Oxygen requirements, electrical impedance tomography and videofluoroscopic sequences, and respiratory system compliance were recorded. RESULTS: The lambs under GV needed less oxygen at 20 min following TLV (40 [25, 45] and 83 [63, 98]%, p = 0.001 under GV and HFOV, respectively). During weaning, tidal volume distribution was increased in the nondependent regions in the GV group compared to baseline (p = 0.046). Furthermore, residual PFOB was observed in the most dependent region. No air was detected by fluoroscopy in that region at the end of expiration in the GV group. CONCLUSION: GV offers a transient advantage over HFOV with regards to oxygenation for TLV weaning.

Oxygen transport during liquid ventilation: an in vitro study.

An in vitro experiment on the dissolved oxygen transport during liquid ventilation by means of measuring global oxygen concentration fields is presented within this work. We consider the flow in an idealized four generation model of the human airways in a range of peak Reynolds numbers of [Formula: see text]-3400 and Womersley numbers of [Formula: see text]-5. Fluorescence quenching measurements were employed in order to visualize and quantify the oxygen distribution with high temporal and spatial resolution during the breathing cycle. Measurements with varying tidal volumes and oscillating frequencies reveal short living times of characteristic concentration patterns for all parameter variations. Similarities to typical velocity patterns in similar lung models persist only in early phases during each cycle. Concentration gradients are quickly homogenized by secondary motions within the lung model. A strong dependency of peak oxygen concentration on tidal volume is observed with considerably higher relative concentrations for higher tidal volumes.

Extracorporeal Membrane Oxygenation and Perfluorocarbon in a Therapy Refractory Case of Acute Respiratory Distress Syndrome.

Perfluorocarbons are oxygen-carrying, dense liquids initially intended for the use in partial or total liquid ventilation of patients with severe acute respiratory distress syndrome but which did not show beneficial effects in clinical studies. However, perfluorocarbons may be used for lung lavage in severe alveolar proteinosis. In acute respiratory distress syndrome, oxygenation may be so severely compromised that the use of nonoxygenated perfluorocarbons may not be possible. We report a case of severe, nonresolving acute respiratory distress syndrome treated with extracorporeal membrane oxygenation to secure oxygenation, using perfluorocarbon in a single instillation to aid the clearance of debris and proteinacous edema.

Air distribution within the lungs after total liquid ventilation in a neonatal ovine model.

OBJECTIVE: To gain insight into the total and regional lung aeration dynamics at the transition from total liquid ventilation (TLV) to conventional mechanical ventilation (GV). METHODS: Neonatal lambs received either TLV for 4 h followed by GV (n = 15) or GV only (n = 11, controls). Monitoring was performed in the prone position with both videofluoroscopy and electrical impedance tomography (EIT) for the first 10 min of the transition. RESULTS: Total and regional end-expiratory lung volumes were stable throughout the transition (p < 0.05). The percentage of tidal volume, liquid and/or gaseous, distributed to the different regions was stable (p < 0.05). Radiopacity of the nondependent regions markedly decreased at end-expiration (p < 0.01), reflecting the progressive transition to a gaseous end-expiratory lung volume. CONCLUSION: Weaning to GV did not increase total or regional lung volumes, suggesting that the risk of overdistention was not increased. Residual perfluorocarbon in the dependent lung regions might account for the high O2 needs we observed in the first minutes of GV after TLV.

Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: A physio-pathological theory.

The Corona Virus Disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) requires a rapid solution and global collaborative efforts in order to define preventive and treatment strategies. One of the major challenges of this disease is the high number of patients needing advanced respiratory support due to the Acute Respiratory Distress Syndrome (ARDS) as the lung is the major - although not exclusive - target of the virus. The molecular mechanisms, pathogenic drivers and the target cell type(s) in SARS-CoV-2 infection are still poorly understood, but the development of a "hyperactive" immune response is proposed to play a role in the evolution of the disease and it is envisioned as a major cause of morbidity and mortality. Here we propose a theory by which the main targets for SARS-CoV-2 are the Type II Alveolar Epithelial Cells and the clinical manifestations of the syndrome are a direct consequence of their involvement. We propose the existence of a vicious cycle by which once alveolar damage starts in AEC II cells, the inflammatory state is supported by macrophage pro-inflammatory polarization (M1), cytokines release and by the activation of the NF-κB pathway. If this theory is confirmed, future therapeutic efforts can be directed to target Type 2 alveolar cells and the molecular pathogenic drivers associated with their dysfunction with currently available therapeutic strategies.

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.

Effect of perfluorocarbon partial liquid ventilation-induced hypothermia on dogs with acute lung injury.

BACKGROUND: Acute lung injury (ALI) is the damage of alveolar epithelial cells and capillary endothelial cells caused by various direct and indirect injury factors, resulting in diffuse pulmonary interstitial and alveolar edema, resulting in acute hypoxic respiratory insufficiency. This study aimed to investigate the effects of hypothermia induced by partial fluid ventilation on dogs with ALI. METHODS: The experimental dogs were randomly divided into a conventional mechanical ventilation group (CMV) group, a normal temperature perfluorocarbon liquid ventilation group (NPLV) group, and a hypothermic perfluorocarbon liquid ventilation group (HPLV) group. After induction of ALI, the dogs of the CMV group was treated with CMV for respiratory support, the HPLV group was given a 15 °C low-temperature perfluorocarbon partial liquid ventilation (PLV), and the NPLV group was given partial fluid permeation of perfluorocarbon (PFC) at a room temperature of 37 °C. Anesthesia was stable at 0.5 h (T0), and successful modeling (T1), at 1 h (T2), 2 h (T3), 3 h (T4) and 4 h (T5) was completed. Blood gas analysis was performed, and rectum temperature, peak airway pressure (PIP), and lung compliance were measured. We performed enzyme-linked immunosorbent assay (ELISA) for peripheral blood and postoperative bronchoalveolar lavage fluid (BALF), calculation of lung tissue wet weight/dry weight ratio, and Western blot detection of NF-κB p65. RESULTS: In the HPLV group, the blood gas index of dogs with ALI was close to normal. In T2¬-T5, the rectal temperature of the HPLV group was significantly lower than that of the NPLV group and the CMV group the lung compliance in the HPLV group and the NPLV group was lower than that in the CMV group at the T2-T5 time point, while the CLst value was significantly increased. The detection of peripheral blood and BALF in dogs showed that interleukin-10 (IL-10) was significantly increased and TNF-α was significantly decreased in the HPLV group compared with the CMV group and NPLV group. Compared with CMV group, the wet/dry ratio of lung tissue in the BALF of HPLV group was decreased. CONCLUSIONS: The results indicate that mild hypothermia caused by partial fluid ventilation can increase oxygenation capacity, oxygen partial pressure, the expression of anti-inflammatory factor IL-10 and improve lung compliance in dogs with ALI.

Pulmonary stretch receptor activity during partial liquid ventilation with different pressure waveforms.

BACKGROUND: The aim of the present study was to investigate pulmonary stretch receptor activity (PSR) under different peak inspiratory pressures (PIPs) and inspiratory pressure waveforms during partial liquid (PLV) and gas ventilation (GV). METHODS: PSR instantaneous impulse frequency (PSRfimp) was recorded from single fibers in the vagal nerve during PLV and GV in young cats. PIPs were set at 1.2/1.8/2.2/2.7 kPa, and square and sinusoidal pressure waveforms were applied. RESULTS: PSRfimp at the start of inspiration increased with increasing PIPs, and was steeper and higher with square than with sinusoidal waveforms (p < 0.05). Total number of impulses, peak and mean PSRfimp were lower during PLV than GV at the lowest and highest PIPs (p < 0.025). Time to peak PSRfimp was shorter with square than with sinusoidal waveforms at all pressures and ventilations (p < 0.005). Irrespective of waveform, lower PIPs yielded lower ventilation during PLV. CONCLUSION: As assessed by PSRfimp, increased PIPs do not expose the lungs to more stretching during PLV than during GV, with only minor differences between square and sinusoidal waveforms.

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).

Pharmacological and non-pharmacological interventions to promote sleep in intensive care units: a critical review.

PURPOSE: Although it is generally recognized that poor sleep is common in the intensive care unit (ICU), it is still unclear which interventions can effectively improve sleep in this setting. In this review, we critically analyze the various pharmacological and non-pharmacological measures that have been proposed to tackle this problem. METHODS: A search of MEDLINE/PubMed, SciELO, and the Brazilian Virtual Library in Health (LILACS and BNDEF) databases was performed. Results were reviewed and 41 articles on pharmacological and non-pharmacological interventions to promote sleep in ICU were analyzed. RESULTS: Non-pharmacological interventions including eye mask and earplugs, bundles to reduce noise and lighting, and organization of patient care were shown to improve subjective and objective sleep quality, although the level of evidence was considered low. Assist-control ventilation was associated with a greater objective sleep quality than spontaneous modes, such as pressure support ventilation and proportional assist ventilation. Among pharmacological interventions, a moderate level of evidence was found for oral melatonin, with increases in both objective and subjective sleep quality. Continuous nocturnal infusion of dexmedetomidine was reported to increase sleep efficiency and favorably modify the sleep pattern, although evidence level was moderate to low. CONCLUSIONS: Several non-pharmacological and pharmacological measures can be helpful to improve sleep in critical patients. Further high-quality studies are needed to strengthen the evidence base.

Partial liquid ventilation-induced mild hypothermia improves the lung function and alleviates the inflammatory response during acute respiratory distress syndrome in canines.

Background Acute respiratory distress syndrome (ARDS), which is the severest form of pulmonary injury, is the leading cause of death in critical care. At present, the mortality remains high in ARDS. Partial liquid ventilation (PLV) using perfluorocarbon (PFC) has been proven to improve gas exchange and respiratory dynamics of the lungs during ARDS. However, PLV has not been shown to reduce the mortality of ARDS. Some studies have shown that mild hypothermia therapy can reduce lung injuries in animal models of ARDS by reducing inflammatory cytokine levels in lung tissues. However, hypothermia cannot produce a lung protection effect alone, and it may have a synergistic effect with other protective measures. To explore the possible role of PLV combined with mild hypothermia in the treatment of ARDS, in this study, we used PFC liquid ventilation to induce mild hypothermia in dogs suffering from ARDS and analyzed the effects of PFC liquid ventilation-induced mild hypothermia on the levels of inflammatory factors and lung histopathology in dogs with ARDS. The experimental dogs were randomly divided into conventional mechanical ventilation (CMV), normal temperature PFC liquid ventilation (NPLV), hypothermic PFC liquid ventilation (HPLV), and mechanical ventilation (MV) groups. After induction of ARDS, the CMV group was treated with CMV for respiratory support, the HPLV group was treated with PLV-induced mild hypothermia using 15 °C PFC and maintained the rectal temperature at 34-36 °C, the NPLV group was treated with PLV using 36 °C PFC and maintained the rectal temperature at 36-38 °C. The MV group served as the control group. Analyses of the pulmonary pathology, partial pressure of oxygen in the blood, and lung wet-dry weight ratio (W/T) of each dog revealed that PLV-induced mild hypothermia significantly increased the PaO2 values and attenuated lung injury, and there were no adverse effects on hemodynamics. Furthermore, treatment with PLV-induced mild hypothermia significantly increased the expression of the anti-inflammatory factor IL-10 in bronchoalveolar lavage fluid (BALF) and attenuated the expression of interleukin (IL-6) and tumor necrosis factor-α (TNF-α) in peripheral blood and in lung BALF. Moreover, the results showed that the expression of myeloperoxidase (MPO) and NF-κB p65 in lung tissues was significantly decreased by PLV-induced mild hypothermia compared with NPLV and CMV. Our results indicated that PLV combined with mild hypothermia can provide protection against oleic acid-induced ARDS in dogs.

Imaging Assessment of Partial Liquid Ventilation in Bronchopulmonary Dysplasia.

Partial liquid ventilation is proposed as an alternative ventilation strategy to reduce surface tension, increase alveolar recruitment, and decrease inflammation. Studied in acute respiratory distress and other indications, liquid ventilation is being revisited for infants with bronchopulmonary dysplasia. Perfluorooctyl bromide used for liquid ventilation is radiopaque, allowing radiographic visualization of lung liquid ventilation patterns that may provide additional insight into pulmonary pathophysiology. Current protocols utilize reduced liquid dosing, resulting in unique imaging features. We discuss optimal radiographic technique and report initial ultrasound evaluation results. With renewed interest in partial liquid ventilation, it may be helpful for pediatric radiologists to familiarize themselves with the clinical use and radiographic appearance of liquid ventilation material.

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.

Experimental and Numerical Modeling of Aerosol Delivery for Preterm Infants.

Respiratory distress syndrome (RDS) represents one of the major causes of mortality among preterm infants, and the best approach to treat it is an open research issue. The use of perfluorocarbons (PFC) along with non-invasive respiratory support techniques has proven the usefulness of PFC as a complementary substance to achieve a more homogeneous surfactant distribution. The aim of this work was to study the inhaled particles generated by means of an intracorporeal inhalation catheter, evaluating the size and mass distribution of different PFC aerosols. In this article, we discuss different experiments with the PFC perfluorodecalin (PFD) and FC75 with a driving pressure of 4-5 bar, evaluating properties such as the aerodynamic diameter (Da), since its value is directly linked to particle deposition in the lung. Furthermore, we develop a numerical model with computational fluid dynamics (CFD) techniques. The computational results showed an accurate prediction of the airflow axial velocity at different downstream positions when compared with the data gathered from the real experiments. The numerical validation of the cumulative mass distribution for PFD particles also confirmed a closer match with the experimental data measured at the optimal distance of 60 mm from the catheter tip. In the case of FC75, the cumulative mass fraction for particles above 10 µm was considerable higher with a driving pressure of 5 bar. These numerical models could be a helpful tool to assist parametric studies of new non-invasive devices for the treatment of RDS in preterm infants.

Assessing the impacts of total liquid ventilation on left ventricular diastolic function in a model of neonatal respiratory distress syndrome.

BACKGROUND: Filling the lung with dense liquid perfluorocarbons during total liquid ventilation (TLV) might compress the myocardium, a plausible explanation for the instability occasionally reported with this technique. Our objective is to assess the impacts of TLV on the cardiovascular system, particularly left ventricular diastolic function, in an ovine model of neonatal respiratory distress syndrome. METHOD: Eight newborns lambs, 3.0 ± 0.4 days (3.2 ± 0.3kg) were used in this crossover experimental study. Animals were intubated, anesthetized and paralyzed. Catheters were inserted in the femoral and pulmonary arteries. A high-fidelity pressure catheter was inserted into the left ventricle. Surfactant deficiency was induced by repeated lung lavages with normal saline. TLV was then conducted for 2 hours using a liquid ventilator prototype. Thoracic echocardiography and cardiac output assessment by thermodilution were performed before and during TLV. RESULTS: Left ventricular end diastolic pressure (LVEDP) (9.3 ± 2.1 vs. 9.2 ± 2.4mmHg, p = 0.89) and dimension (1.90 ± 0.09 vs. 1.86 ± 0.12cm, p = 0.72), negative dP/dt (-2589 ± 691 vs. -3115 ± 866mmHg/s, p = 0.50) and cardiac output (436 ± 28 vs. 481 ± 59ml/kg/min, p = 0.26) were not affected by TLV initiation. Left ventricular relaxation time constant (tau) slightly increased from 21.5 ± 3.3 to 24.9 ± 3.7ms (p = 0.03). Mean arterial systemic (48 ± 6 vs. 53 ± 7mmHg, p = 0.38) and pulmonary pressures (31.3 ± 2.5 vs. 30.4 ± 2.3mmHg, p = 0.61) were stable. As expected, the inspiratory phase of liquid cycling exhibited a small but significant effect on most variables (i.e. central venous pressure +2.6 ± 0.5mmHg, p = 0.001; LVEDP +1.18 ± 0.12mmHg, p<0.001). CONCLUSIONS: TLV was well tolerated in our neonatal lamb model of severe respiratory distress syndrome and had limited impact on left ventricle diastolic function when compared to conventional mechanical ventilation.

Optimal Control of Inspired Perfluorocarbon Temperature for Ultrafast Hypothermia Induction by Total Liquid Ventilation in an Adult Patient Model.

GOAL: Recent preclinical studies have shown that therapeutic hypothermia induced in less than 30 min by total liquid ventilation (TLV) strongly improves the survival rate after cardiac arrest. When the lung is ventilated with a breathable perfluorocarbon liquid, the inspired perfluorocarbon allows us to control efficiently the cooling process of the organs. While TLV can rapidly cool animals, the cooling speed in humans remains unknown. The objective is to predict the efficiency and safety of ultrafast cooling by TLV in adult humans. METHODS: It is based on a previously published thermal model of ovines in TLV and the design of a direct optimal controller to compute the inspired perfluorocarbon temperature profile. The experimental results in an adult sheep are presented. The thermal model of sheep is subsequently projected to a human model to simulate the optimal hypothermia induction and its sensitivity to physiological parameter uncertainties. RESULTS: The results in the sheep showed that the computed inspired perfluorocarbon temperature command can avoid arterial temperature undershoot. The projection to humans revealed that mild hypothermia should be ultrafast (reached in fewer than 3 min (-72 °C/h) for the brain and 20 min (-10 °C/h) for the entire body). CONCLUSION: The projection to human model allows concluding that therapeutic hypothermia induction by TLV can be ultrafast and safe. SIGNIFICANCE: This study is the first to simulate ultrafast cooling by TLV in a human model and is a strong motivation to translate TLV to humans to improve the quality of life of postcardiac arrest patients.

Low Tidal Volume Reduces Lung Inflammation Induced by Liquid Ventilation in Piglets With Severe Lung Injury.

Total liquid ventilation (TLV) is an alternative treatment for severe lung injury. High tidal volume is usually required for TLV to maintain adequate CO2 clearance. However, high tidal volume may cause alveolar barotrauma. We aim to investigate the effect of low tidal volume on pulmonary inflammation in piglets with lung injury and under TLV. After the establishment of acute lung injury model by infusing lipopolysaccharide, 12 piglets were randomly divided into two groups, TLV with high tidal volume (25 mL/kg) or with low tidal volume (6 mL/kg) for 240 min, respectively. Extracorporeal CO2 removal was applied in low tidal volume group to improve CO2 clearance and in high tidal volume group as sham control. Gas exchange and hemodynamic status were monitored every 30 min during TLV. At the end of the study, pulmonary mRNA expression and plasmatic concentration of interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured by collecting lung tissue and blood samples from piglets. Arterial blood pressure, PaO2 , and PaCO2 showed no remarkable difference between groups during the observation period. Compared with high tidal volume strategy, low tidal volume resulted in 76% reduction of minute volume and over 80% reduction in peak inspiratory pressure during TLV. In addition, low tidal volume significantly diminished pulmonary mRNA expression and plasmatic level of IL-6 and IL-8. We conclude that during TLV, low tidal volume reduces lung inflammation in piglets with acute lung injury without compromising gas exchange.