Olivier Avoine

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· min-1·kg-1 in order to ensure PaCO2 below 55 mmHg. From a clinicians 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.

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 patients respiratory parameters during total liquid ventilation treatment.

Effects of postnatal smoke exposure on laryngeal chemoreflexes in newborn lambs.

Laryngeal chemoreflexes (LCR), which are elicited by the contact of liquids such as gastric refluxate with laryngeal mucosa, may trigger some cases of sudden infant death syndrome. Indeed, while LCR in mature mammals consist of protective responses, previous animal data have shown that LCR in immature newborns can include laryngospasm, apnea, bradycardia, and desaturation. The present study was aimed at testing the hypothesis that postnatal exposure to cigarette smoke is responsible for enhancing cardiorespiratory inhibition observed with LCR. Eight lambs were exposed to cigarette smoke (20 cigarettes/day) over 16 days and compared with seven control lambs. Urinary cotinine/creatinine ratio was measured at a level relevant to previously published levels in infants. On days 15 and 16, 0.5 ml of HCl (pH 2), milk, distilled water, or saline was injected onto the larynx via a chronic supraglottal catheter during sleep. Results showed that exposure to cigarette smoke enhanced respiratory inhibition (P < 0.05) and tended to enhance cardiac inhibition and decrease swallowing and arousal during LCR (P < 0.1). Overall, these results were observed independently of the state of alertness and the experimental solution tested. In conclusion, 16-day postnatal exposure to cigarette smoke increases cardiorespiratory inhibition and decreases protective mechanisms during LCR in nonsedated full-term lambs.

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.

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.

A Liquid Ventilator Prototype for Total Liquid Ventilation Preclinical Studies

1.1 Context Mechanical ventilation is a life-saving procedure used for treating acute respiratory distress, when the respiratory system is no longer capable of regulating blood gases via pulmonary gas exchange. While conventional mechanical ventilation (CMV) is often sufficient to transiently replace lung function until recovery, the most severe respiratory distress syndromes must be treated either by non conventional mechanical ventilation such as high frequency ventilation or even non ventilator strategies such as extracorporeal gas exchange (Raoof et al., 2010). Large literature data suggest a radical change in ventilator support by replacing the traditional gas mixture with a breathable liquid. This method, called liquid assisted ventilation, leads to the replacement of the air-liquid interface in the alveoli by a liquidliquid interface. Since the 70s, perfluorocarbon liquids (PFC) have been identified as the best candidates to be used in liquid ventilation due to their high oxygen and carbon dioxide solubility (Wolfson & Shaffer, 2005). In addition, they are biochemically stable and bio-inert molecules, available as medical grade products including for respiratory use. Liquid assisted ventilation can be performed either as partial or total liquid ventilation. During partial liquid ventilation, only a fraction of the lungs are filled with perfluorocarbon liquid and a conventional mechanical gas ventilator ensures lung ventilation. In contrast, during total liquid ventilation (TLV), the lungs are completely filled with perfluorocarbon liquid while a dedicated device, called a liquid ventilator, must be used to periodically renew a liquid tidal volume in the lungs. A large number of preclinical studies involving various animal models of acute respiratory distress syndrome have demonstrated clear benefits from total liquid ventilation as compared to all other tested ventilation strategies, including partial liquid ventilation, conventional and high frequency gas ventilation (Hirschl et al., 1996; Wolfson et al., 2008). Among its several theoretical advantages over CMV, TLV is considered less aggressive for the lungs, due to lower positive inspiratory pressures and lower respiratory rates. This is felt to be beneficial in both pediatric and adult respiratory distress syndromes, where repeated alveolar overdistension during CMV contributes to

Lumped Thermal Model of a Newborn Lamb and a Liquid Ventilator in Total Liquid Ventilation

Total liquid ventilation (TLV) is an emerging and promising mechanical ventilation method in which the lungs are filled with a breathable liquid. Perfluorocarbon (PFC) is the predominant liquid of choice due to its high O2 and CO2 solubility. In TLV, a dedicated liquid ventilator ensures gas exchange by renewing a tidal volume of PFC, which is temperature-controlled, oxygenated and free of CO2. A fundamental difference between TLV and conventional mechanical ventilation relates to the fact that PFCs are approximately 1500 times denser than air. This high density provides PFCs with a large heat capacity, turning the lungs into an efficient heat exchanger with circulating blood. The originality of this study is the development of a lumped thermal model of the body as a heat exchanger coupled to a liquid ventilator. The model was validated with an animal experimentation on a newborn lamb with the Inolivent-5.0 liquid ventilator prototype. TLV was initiated with a fast hypothermia induction, followed successively by a slow posthypothermic rewarming, a fast rewarming and finally a second fast hypothermia induction. Results demonstrate that the model was able to aptly predict, in every phase, the temperature of the lungs, the eardrum, the rectum as well as the various compartments of the liquid ventilator.Copyright

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.

Alveolar pressure estimation in total liquid ventilation during pauses impeded by tube resonance

Total liquid ventilation 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 (PFC) by using a dedicated liquid ventilator. The positive end-inspiratory and end-expiratory pressures (PEIP and PEEP) are static pressure measurements that are critic to the safe and efficient control of the ventilation. However, their measurement is impeded by large oscillations of pressure caused by the propagation of pressure waves along the flexible tubes carrying the PFC to the patient. The aim of this paper is to describe a method to accurately estimate the PEEP and the PEIP from noisy data hindered by flexible tubing resonance during short respiratory pauses. The method developped makes use of the least squares technique to estimate the steady state pressure. Preliminary in vivo validation of the algorithm shows that the method gives accurate estimations with respiratory pauses as short as 0.3 second.

Virtual Airway Pressure and Lung Temperature Sensors in a Total Liquid Ventilation Connector

Total liquid ventilation (TLV) is an experimental mechanical ventilation technique where the lungs are completely filled with a perfluorocarbon liquid (PFC). It can be used to implement moderate therapeutic hypothermia (MTH) and treat severe respiratory problems. During TLV, the airway pressure must be monitored adequately to avoid overpressure and airway collapses. On the thermodynamic level, rectal, esophageal or tympanic temperature measurements are not suitable (long time constant) to avoid lowering the heart below 30°C. The objective was to design a Y connector positioned at the mouth which integrates the virtual sensors, used by controllers. The first estimates the airway pressure and the second provides the core body temperature. Pressure and RTD sensors were installed in the connector to implement the virtual measurements. In-vitro experiments were done to validate the virtual sensors. In-vivo experiments (on newborn lambs) confirm the accuracy of the airway pressure estimation and of the systemic arterial temperature.Copyright