Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study).

PURPOSE: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. METHODS: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. RESULTS: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. CONCLUSION: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population.

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).

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.

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.

International aircraft ECMO transportation: first French pediatric experience.

Refractory severe hemodynamic or respiratory failure may require extracorporeal membrane oxygenation (ECMO). Since some patients are too sick to be transported safely to a referral ECMO center on conventional transportation, mobile ECMO transport teams have been developed. The experiences of some ECMO transport teams have already been reported, including air and international transport. We report the first French pediatric international ECMO transport by aircraft. This case shows that a long distance intervention of the pediatric ECMO transport team is feasible, even in an international setting. Long distance ECMO transportations are widely carried out for adults, but remain rare in neonates and children.

Effect of ultra-fast mild hypothermia using total liquid ventilation on hemodynamics and respiratory mechanics.

Ultra-fast cooling for mild therapeutic hypothermia (MTH) has several potential applications, including prevention of post-cardiac arrest syndrome. Ultra-fast MTH by total liquid ventilation (TLV) entails the sudden filling of the lungs with a cold perfluorocarbon liquid and its subsequent use to perform TLV. The present physiological study was aimed at assessing whether pulmonary and systemic hemodynamics as well as lung mechanics are significantly altered during this procedure. Pulmonary and systemic arterial pressures, cardiac output as well as airway resistance and respiratory system compliance were measured during ultra-fast MTH by TLV followed by rewarming and normothermia in six healthy juvenile lambs. Results show that none of the studied variables were altered upon varying the perfluorocarbon temperature from 12 to 41 °C. It is concluded that ultra-fast MTH by TLV does not have any deleterious effect on hemodynamics or lung mechanics in healthy juvenile lambs.

Thermal Dynamics in Newborn and Juvenile Models Cooled by Total Liquid Ventilation.

BACKGROUND: Total liquid ventilation (TLV) consists in filling the lungs with a perfluorocarbon (PFC) and using a liquid ventilator to ensure a tidal volume of oxygenated, CO 2 -free and temperature-controlled PFC. Having a much higher thermal capacity than air, liquid PFCs assume that the filled lungs become an efficient heat exchanger with pulmonary circulation. OBJECTIVE: The objective of the present study was the development and validation of a parametric lumped thermal model of a subject in TLV. METHODS: The lungs were modeled as one compartment in which the control volume varied as a function of the tidal volume. The heat transfer in the body was modeled as seven parallel compartments representing organs and tissues. The thermal model of the lungs and body was validated with two groups of lambs of different ages and weights (newborn and juvenile) undergoing an ultrafast mild therapeutic hypothermia induction by TLV. RESULTS: The model error on all animals yielded a small mean error of -0.1 ±0.4  (°)C for the femoral artery and 0.0 ±0.1   (°)C for the pulmonary artery. CONCLUSION: The resulting experimental validation attests that the model provided an accurate estimation of the systemic arterial temperature and the venous return temperature. SIGNIFICANCE: This comprehensive thermal model of the lungs and body has the advantage of closely modeling the rapid thermal dynamics in TLV. The model can explain how the time to achieve mild hypothermia between newborn and juvenile lambs remained similar despite of highly different physiological and ventilatory parameters. The strength of the model is its strong relationship with the physiological parameters of the subjects, which suggests its suitability for projection to humans.

Optimal control of inspired perfluorocarbon temperature for induction of hypothermia by total liquid ventilation in juvenile lamb model.

Mild hypothermia is well known for its therapeutic value in cardio- and neuroprotection. Many recent experimental studies have shown that the swiftness of the cooling offered by total liquid ventilation (TLV) holds great promise in achieving maximal therapeutic effect. TLV is an emerging ventilation technique in which the lungs are filled with breathable liquids, namely perfluorocarbons (PFCs). A liquid ventilator ensures subject ventilation by periodically renewing a volume of oxygenated, CO2-free and temperature-controlled breathable PFC. The substantial difference between breathing air and liquid is related to the fact that PFCs have over 500 times the volumetric thermal capacity of air 100% relative humidity. The PFC-filled lungs thus turn into an efficient heat exchanger with pulmonary circulation. The objective of the present study was to compute a posteriori the optimal inspired PFC temperature for ultrafast induction of mild hypothermia by TLV in a juvenile lamb experimentation using direct optimal control. The continuous time model and the discretized cycle-by-cycle model are presented. The control objectives of the direct optimal control are also presented and the results are compared with experimental data in order to validate the improved control performances. The computed direct optimal control showed that the inspired PFC temperature command can be improved to avoid temperature undershoots without altering the cooling performances.

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.

Liquid ventilator for ultrafast hypothermia induction in juvenile lambs: Preliminary results.

Total liquid ventilation (TLV) is an emerging mechanical ventilation technique. In this technique, the lungs are filled with liquid perfluorocarbons (PFC) and a liquid ventilator assures ventilation by periodically renewing a volume of oxygenated, CO2 freed and temperature controlled PFC. A huge difference between conventional mechanical ventilation and TLV relates to the fact that PFCs are about 1500 times denser than air. Thus, the PFCs filled lungs turn into an efficient heat exchanger with the circulating blood. One of the most appealing utilization of the lungs as a heat exchanger in TLV is for ultrafast induction of mild therapeutic hypothermia (MTH) for neuroprotection and cardioprotection after ischemia-reperfusion injuries. This study aimed to perform ultrafast MTH induction by TLV in animals up to 25 kg, then perform a fast post-hypothermic rewarming while maintaining proper ventilation. A thermal model of the lamb and liquid ventilator was developed to predict the dynamic and the control strategy to adopt for MTH induction. Two juvenile lambs were instrumented with temperature sensors in the femoral artery, pulmonary artery, oesophagus, right eardrum and rectum. After stabilization in conventional mechanical ventilation, TLV was initiated with ultrafast MTH induction, followed by posthypothermic rewarming. Preliminary results in the two juvenile lambs reveal that the liquid ventilator Inolivent-6.0 can induce MTH by TLV in less than 2.5 min for systemic arterial blood and in less than 10 min for venous return, esophagus and eardrum. Rectal temperature reached MTH in respectively 19.4 and 17.0 min for both lambs. Experimental results were consistent with the model predictions. Moreover, blood gas analysis exhibited that the gas exchange in the lungs was maintained adequately for the entire experiments.

Core body temperature control by total liquid ventilation using a virtual lung temperature sensor.

In total liquid ventilation (TLV), the lungs are filled with a breathable liquid perfluorocarbon (PFC) while a liquid ventilator ensures proper gas exchange by renewal of a tidal volume of oxygenated and temperature-controlled PFC. Given the rapid changes in core body temperature generated by TLV using the lung has a heat exchanger, it is crucial to have accurate and reliable core body temperature monitoring and control. This study presents the design of a virtual lung temperature sensor to control core temperature. In the first step, the virtual sensor, using expired PFC to estimate lung temperature noninvasively, was validated both in vitro and in vivo. The virtual lung temperature was then used to rapidly and automatically control core temperature. Experimentations were performed using the Inolivent-5.0 liquid ventilator with a feedback controller to modulate inspired PFC temperature thereby controlling lung temperature. The in vivo experimental protocol was conducted on seven newborn lambs instrumented with temperature sensors at the femoral artery, pulmonary artery, oesophagus, right ear drum, and rectum. After stabilization in conventional mechanical ventilation, TLV was initiated with fast hypothermia induction, followed by slow posthypothermic rewarming for 1 h, then by fast rewarming to normothermia and finally a second fast hypothermia induction phase. Results showed that the virtual lung temperature was able to provide an accurate estimation of systemic arterial temperature. Results also demonstrate that TLV can precisely control core body temperature and can be favorably compared to extracorporeal circulation in terms of speed.

Control of rapid hypothermia induction by total liquid ventilation: preliminary results.

Mild therapeutic hypothermia (MTH) consists in cooling the body temperature of a patient to between 32 and 34 °C. This technique helps to preserve tissues and neurological functions in multi-organ failure by preventing ischemic injury. Total liquid ventilation (TLV) ensures gas exchange in the lungs with a liquid, typically perfluorocarbon (PFC). A liquid ventilator is responsible for ensuring cyclic renewal of tidal volume of oxygenated and temperature-controlled PFC. Hence, TLV using the lung as a heat exchanger and PFC as a heat carrier allows ultra fast cooling of the whole body which can help improve outcome after ischemic injuries. The present study was aimed to evaluate the control performance and safety of automated ultrarapid MTH induction by TLV. Experimentation was conducted using the Inolivent-5.0 liquid ventilator equipped with a PFC treatment unit that allows PFC cooling and heating from the flow of energy carrier water inside a double wall installed on an oxygenator. A water circulating bath is used to manage water temperature. A feedback controller was developed to modulate inspired PFC temperature and control body temperature. Such a controller is important since, with MTH induction, heart temperature should not reach 28 °C because of a high risk of fibrillation. The in vivo experimental protocol was conducted on a male newborn lamb of 4.7 kg which, after anesthetization, was submitted to conventional gas ventilation and instrumented with temperature sensors at the femoral artery, oesophagus, right ear drum and rectum. After stabilization, TLV was initiated with fast automated MTH induction to 33.5 °C until stabilization of all temperatures. MTH could be reached safely in 3 minutes at the femoral artery, in 3.6 minutes at the esophagus, in 7.7 minutes at the eardrum and in 15 minutes at the rectum. All temperatures were stable at 33.5 ± 0.5 °C within 15 minutes. The present results reveal that ultra-fast MTH induction by TLV with Inolivent-5.0 is safe for the heart while maintaining esophageal and arterial temperature over 32.6 °C.

Measurement of fractional order model parameters of respiratory mechanical impedance in total liquid ventilation.

This study presents a methodology for applying the forced-oscillation technique in total liquid ventilation. It mainly consists of applying sinusoidal volumetric excitation to the respiratory system, and determining the transfer function between the delivered flow rate and resulting airway pressure. The investigated frequency range was f ∈ [0.05, 4] Hz at a constant flow amplitude of 7.5 mL/s. The five parameters of a fractional order lung model, the existing "5-parameter constant-phase model," were identified based on measured impedance spectra. The identification method was validated in silico on computer-generated datasets and the overall process was validated in vitro on a simplified single-compartment mechanical lung model. In vivo data on ten newborn lambs suggested the appropriateness of a fractional-order compliance term to the mechanical impedance to describe the low-frequency behavior of the lung, but did not demonstrate the relevance of a fractional-order inertance term. Typical respiratory system frequency response is presented together with statistical data of the measured in vivo impedance model parameters. This information will be useful for both the design of a robust pressure controller for total liquid ventilators and the monitoring of the patient's respiratory parameters during total liquid ventilation treatment.

Total liquid ventilation efficacy in an ovine model of severe meconium aspiration syndrome.

OBJECTIVE: To test the hypothesis that total liquid ventilation enables a more effective and better tolerated lavage than a bronchoalveolar lavage performed with diluted surfactant in a newborn ovine model of severe acute meconium aspiration syndrome. DESIGN: Prospective, randomized, interventional study. SETTING: Animal research laboratory at the Faculté de médecine et des sciences de la santé de l'université de Sherbrooke, Sherbrooke, Canada. SUBJECTS: Twenty-three newborn lambs, <4 days, 2.5-4.0 kg in weight. INTERVENTIONS: Animals were intubated, anesthetized, and paralyzed. Catheters were placed in the femoral artery and jugular vein. Severe meconium aspiration syndrome was obtained by instillation of a 25% dilution of human meconium in saline (1 mL/kg × 2). Lambs were then randomized in 12 total liquid ventilation-bronchoalveolar lavage (minute ventilation of 160 mL/kg/min with perfluorodecalin) vs. 11 bronchoalveolar lavage performed with diluted surfactant (conventional ventilation + 30 mL/kg in two aliquots bronchoalveolar lavage with 5 mg/mL BLES surfactant). Surviving lambs were ventilated for a total of 4 hrs and euthanized. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases, systemic and pulmonary hemodynamic parameters using the thermodilution method, percentage of recovered meconium, and lung histologic scores. Total liquid ventilation bronchoalveolar lavage enabled a significantly higher PaO2 throughout the experiment. PaCO2, pH, and hemodynamic parameters were comparable for both groups except for an increase in mean pulmonary arterial pressure during total liquid ventilation. Total liquid ventilation bronchoalveolar lavage allowed for 43 ± 14% of the instilled meconium to be removed vs. 28 ± 10% for bronchoalveolar lavage performed with diluted surfactant (p = .022). Lung histologic analysis showed no difference between total scores. CONCLUSIONS: Total liquid ventilation bronchoalveolar lavage is well tolerated and more effective in terms of meconium washout and gas exchange than bronchoalveolar lavage performed with diluted surfactant in this experimental model of severe meconium aspiration syndrome. These positive results open the way to further experiments in our ovine model, ultimately aiming at a clinical trial with total liquid ventilation bronchoalveolar lavage to treat severe meconium aspiration syndrome.

Neonatal total liquid ventilation: is low-frequency forced oscillation technique suitable for respiratory mechanics assessment?

This study aimed to implement low-frequency forced oscillation technique (LFFOT) in neonatal total liquid ventilation (TLV) and to provide the first insight into respiratory impedance under this new modality of ventilation. Thirteen newborn lambs, weighing 2.5 + or - 0.4 kg (mean + or - SD), were premedicated, intubated, anesthetized, and then placed under TLV using a specially design liquid ventilator and a perfluorocarbon. The respiratory mechanics measurements protocol was started immediately after TLV initiation. Three blocks of measurements were first performed: one during initial respiratory system adaptation to TLV, followed by two other series during steady-state conditions. Lambs were then divided into two groups before undergoing another three blocks of measurements: the first group received a 10-min intravenous infusion of salbutamol (1.5 microg x kg(-1) x min(-1)) after continuous infusion of methacholine (9 microg x kg(-1) x min(-1)), while the second group of lambs was chest strapped. Respiratory impedance was measured using serial single-frequency tests at frequencies ranging between 0.05 and 2 Hz and then fitted with a constant-phase model. Harmonic test signals of 0.2 Hz were also launched every 10 min throughout the measurement protocol. Airway resistance and inertance were starkly increased in TLV compared with gas ventilation, with a resonant frequency < or = 1.2 Hz. Resistance of 0.2 Hz and reactance were sensitive to bronchoconstriction and dilation, as well as during compliance reduction. We report successful implementation of LFFOT to neonatal TLV and present the first insight into respiratory impedance under this new modality of ventilation. We show that LFFOT is an effective tool to track respiratory mechanics under TLV.

Experimental validation of cardiac index measurement using transpulmonary thermodilution technique in neonatal total liquid ventilation.

This study aimed to assess the precision and the interchangeability of cardiac index measurement by transpulmonary thermodilution (TPTD) and pulmonary thermodilution (PTD) devices on a neonatal animal model of acute respiratory distress syndrome under total liquid ventilation (TLV) and conventional mechanical ventilation (CMV). After acute respiratory distress induction by tracheal instillation of hydrochloric acid, transpulmonary (CI(TPTD)) and pulmonary (CI(PTD)) cardiac index were simultaneously measured every 30 minutes for a 240-minute experiment. Reproducibility of both thermodilution techniques was very good to excellent in both groups of ventilation with intrainstrument intraclass correlation coefficient >0.60. Disagreement was found between TPTD and PTD in TLV and CMV. Bland-Altman analysis revealed mean biases of 0.98 L/min/m² (22.8%) with limits of agreement of -1.33 to 3.25 L/min/m² in CMV and 1.28 L/min/m² (17.3%) with limits of agreement of -1.17 to 3.72 L/min/m² in TLV. Bias between TPTD and PTD was not statistically different in TLV than in CMV (p = 0.11). Transpulmonary thermodilution and PTD remained precise but not interchangeable techniques under TLV as well as CMV. Because TLV does not bring additional bias between both thermodilution techniques, we advocate the use of the less-invasive TPTD under TLV as currently recommended in CMV.

A regulator for pressure-controlled total-liquid ventilation.

Total-liquid ventilation (TLV) is an innovative experimental method of mechanical-assisted ventilation in which lungs are totally filled and then ventilated with a tidal volume of perfluorochemical liquid by using a dedicated liquid ventilator. Such a novel medical device must resemble other conventional ventilators: it must be able to conduct controlled-pressure ventilation. The objective was to design a robust controller to perform pressure-regulated expiratory flow and to implement it on our latest liquid-ventilator prototype (Inolivent-4). Numerical simulations, in vitro experiments, and in vivo experiments in five healthy term newborn lambs have demonstrated that it was efficient to generate expiratory flows while avoiding collapses. Moreover, the in vivo results have demonstrated that our liquid ventilator can maintain adequate gas exchange, normal acid-base equilibrium, and achieve greater minute ventilation, better oxygenation and CO2 extraction, while nearing flow limits. Hence, it is our suggestion to perform pressure-controlled ventilation during expiration with minute ventilation equal or superior to 140 mL x min(-1) x kg(-1) in order to ensure PaCO2 below 55 mmHg. From a clinician's point of view, pressure-controlled ventilation greatly simplifies the use of the liquid ventilator, which will certainly facilitate its introduction in intensive care units for clinical applications.

Optimal expiratory volume profile in tidal liquid ventilation under steady state conditions, based on a symmetrical lung model.

Liquid-assisted ventilation (LAV) using perfluorochemicals (PFC) offers clear theoretical advantages over gas ventilation. During tidal liquid ventilation (TLV) the residual capacity of the lungs is filled with PFC and a liquid ventilator is necessary to inhale and exhale the tidal volume of PFC. However, during the expiration phase, a flow limitation (choked flow) can be observed, which compromises minute ventilation and consequently the gas exchange. The hypothesis of the presented works is that the choked flow can be avoided by profiling the expiratory volume. To validate this concept, an elastic symmetrical lung numerical model, used to characterize forced expiration in gas ventilation, was transposed to TLV. The parameters of the developed numerical model were fitted from experimental data obtained on a newborn lamb. The results obtained demonstrate that general observations made with gas ventilation still hold, however, in TLV: flow limitation in the central airways is the result of a coupling between viscous pressure losses and airway compliance, and the flow limiting segment is located in the central airways. Using the model results, an optimal theoretical expiratory profile seems to be exponential as first approximation, and its time constant is dependent on the chocked flow mechanism and not on the product of resistance by compliance. This optimal profile is used to compute the maximal minute ventilation allowable with an acceptable risk of collapse. Also, the sensitivity of minute ventilation to different parameter variations were analyzed and practical recommendations are proposed.