Total liquid ventilation in an ovine model of extreme prematurity: a randomized study.

BACKGROUND: This study aimed at comparing cardiorespiratory stability during total liquid ventilation (TLV)-prior to lung aeration-with conventional mechanical ventilation (CMV) in extremely preterm lambs during the first 6 h of life. METHODS: 23 lambs (11 females) were born by c-section at 118-120 days of gestational age (term = 147 days) to receive 6 h of TLV or CMV from birth. Lung samples were collected for RNA and histology analyses. RESULTS: The lambs under TLV had higher and more stable arterial oxygen saturation (p = 0.001) and cerebral tissue oxygenation (p = 0.02) than the lambs in the CMV group in the first 10 min of transition to extrauterine life. Although histological assessment of the lungs was similar between the groups, a significant upregulation of IL-1a, IL-6 and IL-8 RNA in the lungs was observed after TLV. CONCLUSIONS: Total liquid ventilation allowed for remarkably stable transition to extrauterine life in an extremely preterm lamb model. Refinement of our TLV prototype and ventilation algorithms is underway to address specific challenges in this population, such as minimizing tracheal deformation during the active expiration. IMPACT: Total liquid ventilation allows for remarkably stable transition to extrauterine life in an extremely preterm lamb model. Total liquid ventilation is systematically achievable over the first 6 h of life in the extremely premature lamb model. This study provides additional incentive to pursue further investigation of total liquid ventilation as a transition tool for the most extreme preterm neonates.

Mechanical ventilation causes diaphragm dysfunction in newborn lambs.

BACKGROUND: Diaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined. Furthermore, it is unknown whether co-existent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). We investigated the impact of MV (mean duration = 7.65 h), either with or without co-existent respiratory failure caused by surfactant deficiency, on the development of VIDD in newborn lambs. METHODS: Newborn lambs (1-4 days) were assigned to control (CTL, non-ventilated), mechanically ventilated (MV), and MV + experimentally induced surfactant deficiency (MV+SD) groups. Immunoblotting and quantitative PCR assessed inflammatory signaling, the ubiquitin-proteasome system, autophagy, and oxidative stress. Immunostaining for myosin heavy chain (MyHC) isoforms and quantitative morphometry evaluated diaphragm atrophy. Contractile function of the diaphragm was determined in isolated myofibrils ex vivo. RESULTS: Equal decreases (25-30%) in myofibrillar force generation were found in MV and MV+SD diaphragms compared to CTL. In comparison to CTL, both MV and MV+SD diaphragms also demonstrated increased STAT3 transcription factor phosphorylation. Ubiquitin-proteasome system (Atrogin1 and MuRF1) transcripts and autophagy indices (Gabarapl1 transcripts and the ratio of LC3B-II/LC3B-I protein) were greater in MV+SD relative to MV alone, but fiber type atrophy was not observed in any group. Protein carbonylation and 4-hydroxynonenal levels (indices of oxidative stress) also did not differ among groups. CONCLUSIONS: In newborn lambs undergoing controlled MV, there is a rapid onset of diaphragm dysfunction consistent with VIDD. Superimposed lung injury caused by surfactant deficiency did not influence the severity of early diaphragm weakness.

Nasal continuous positive airway pressure influences bottle-feeding in preterm lambs.

BackgroundIn preterm infants, the time from initiation to full oral feeding can take weeks, which represents a very worrisome problem in neonatal medicine. Although current knowledge suggests that oral feeding should be introduced early, this is often delayed due to the need for prolonged nasal continuous positive airway pressure (nCPAP). Indeed, most caregivers fear that nCPAP could disrupt sucking-swallowing-breathing coordination and induce tracheal aspiration. The goal of the present study was to assess the impact of nCPAP delivered by the Infant Flow System on the physiology of sucking-swallowing-breathing coordination during bottle-feeding in preterm lambs over 24 h.MethodsSeventeen lambs (8 control, 9 nCPAP of 6 cmH2O) born 14 days prematurely were instrumented to record sucking, swallowing, respiration, ECG, and oxygenation. They were fed via a nasogastric tube for the first 5 days of life until introduction of bottle-feeding every 4 h for 24 h.ResultsnCPAP increased the feeding efficiency while maintaining higher oxygenation without any deleterious cardiorespiratory events. However, coughs were observed in lambs under nCPAP immediately following bottle-feeding and may be related to the high milk flow in preterm lambs.ConclusionFurther studies documenting tracheal aspirations are needed, especially in preterm lambs under nCPAP for moderate respiratory difficulties, to further inform future clinical studies.

Use of Temperature Sensors to Determine Exclusivity of Improved Stove Use and Associated Household Air Pollution Reductions in Kenya.

Household air pollution (HAP) contributes to 3.5-4 million annual deaths globally. Recent interventions using improved cookstoves (ICS) to reduce HAP have incorporated temperature sensors as stove use monitors (SUMs) to assess stove use. We deployed SUMs in an effectiveness study of 6 ICSs in 45 Kenyan rural homes. Stove were installed sequentially for 2 weeks and kitchen air monitoring was conducted for 48 h during each 2-week period. We placed SUMs on the ICSs and traditional cookstoves (TCS), and the continuous temperature data were analyzed using an algorithm to examine the number of cooking events, days of exclusive use of ICS, and how stove use patterns affect HAP. Stacking, defined as using both a TCS and an ICS in the same day, occurred on 40% of the study days, and exclusive use of the ICS occurred on 25% of study days. When researchers were not present, ICS use declined, which can have implications for long-term stove adoption in these communities. Continued use of TCSs was also associated with higher HAP levels. SUMs are a valuable tool for characterizing stove use and provide additional information to interpret HAP levels measured during ICS intervention studies.

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.

The design and evaluation of a system for improved surveillance and prevention programmes in resource-limited settings using a hospital-based burn injury questionnaire.

BACKGROUND: Limited and fragmented data collection systems exist for burn injury. A global registry may lead to better injury estimates and identify risk factors. A collaborative effort involving the WHO, the Global Alliance for Clean Cookstoves, the CDC and the International Society for Burn Injuries was undertaken to simplify and standardise inpatient burn data collection. An expert panel of epidemiologists and burn care practitioners advised on the development of a new Global Burn Registry (GBR) form and online data entry system that can be expected to be used in resource-abundant or resource-limited settings. METHODS: International burn organisations, the CDC and the WHO solicited burn centre participation to pilot test the GBR system. The WHO and the CDC led a webinar tutorial for system implementation. RESULTS: During an 8-month period, 52 hospitals in 30 countries enrolled in the pilot and were provided the GBR instrument, guidance and a data visualisation tool. Evaluations were received from 29 hospitals (56%). KEY FINDINGS: Median time to upload completed forms was <10 min; physicians most commonly entered data (64%), followed by nurses (25%); layout, clarity, accuracy and relevance were all rated high; and a vast majority (85%) considered the GBR 'highly valuable' for prioritising, developing and monitoring burn prevention programmes. CONCLUSIONS: The GBR was shown to be simple, flexible and acceptable to users. Enhanced regional and global understanding of burn epidemiology may help prioritise the selection, development and testing of primary prevention interventions for burns in resource-limited settings.

The role of mixed methods in improved cookstove research.

The challenge of promoting access to clean and efficient household energy for cooking and heating is a critical issue facing low- and middle-income countries today. Along with clean fuels, improved cookstoves (ICSs) continue to play an important part in efforts to reduce the 4 million annual premature deaths attributed to household air pollution. Although a range of ICSs are available, there is little empirical evidence on appropriate behavior change approaches to inform adoption and sustained used at scale. Specifically, evaluations using either quantitative or qualitative methods provide an incomplete picture of the challenges in facilitating ICS adoption. This article examines how studies that use the strengths of both these approaches can offer important insights into behavior change in relation to ICS uptake and scale-up. Epistemological approaches, study design frameworks, methods of data collection, analytical approaches, and issues of validity and reliability in the context of mixed methods ICS research are examined, and the article presents an example study design from an evaluation study in Kenya incorporating a nested approach and a convergent case oriented design. The authors discuss the benefits and methodological challenges of mixed-methods approaches in the context of researching behavior change and ICS use recognizing that such methods represent relatively uncharted territory. The authors propose that more published examples are needed to provide frameworks for other researchers seeking to apply mixed methods in this context and suggest a comprehensive research agenda is required that incorporates integrated mixed-methods approaches, to provide best evidence for future scale-up.

Validity of rating of perceived exertion ranges in individuals in the subacute stage of stroke recovery.

BACKGROUND: Rating of perceived exertion (RPE) is used to monitor or prescribe workload of exercise, but its utility among individuals with a stroke remains in question. OBJECTIVE: To examine the validity of RPE at multiple percentages of peak aerobic capacity (Vo2peak) in individuals in the subacute stage of stroke recovery. METHODS: Thirty-seven patients with stroke in the subacute stage of recovery from an inpatient rehabilitation institute completed a graded maximal exercise test on a semi-recumbent cycle ergometer. Respiratory gas exchange was monitored for analysis of Vo2, while heart rate and RPE (Borg CR10 Scale) were measured at the end of each minute. RPE was compared with expected ranges when at 60%, 70%, and 80% of Vo2peak. Post hoc analyses were performed to determine whether patient characteristics differed between participants who fell within and outside the expected RPE range at 80% of Vo2peak. RESULTS: Median (interquartile range) RPE at 60%, 70%, and 80% Vo2peak were 3.0 (3.0-3.5), 3.0 (3.0-5.0), and 4.75 (3.0-5.75), respectively; 76.2%, 69.0%, and 38.9% of participants fell into the expected RPE range at each intensity. Patient characteristics were similar between participants who fell within and outside the expected RPE range at 80% Vo2peak. CONCLUSION: RPE appears to be a reasonable indicator of exercise intensity after stroke at moderate (60%-70% Vo2peak) but not high-intensity exercise (80% Vo2peak). This conclusion is based on the high degree of between-subject variability in RPE at 80% Vo2peak. Future research should identify whether RPE can be adapted to accurately capture exertion during high-intensity exercise after stroke.

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.

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.

Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients.

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

A positive influence of vision on motor symptoms during sensory attention focused exercise for Parkinson's disease.

This study evaluated the effect of increased attention to sensory feedback during exercise. Two 12-week exercise programs that differed only in the presence (PD SAFEx) or absence (non-SAFE control group) of increased attention focused on sensory feedback were compared. Participants were assessed symptomatically using the Unified Parkinson's Disease Rating Scale (UPDRS) before the start of the exercise program, immediately following the 12-week program and after a 6-week nonexercise washout period. Secondary outcome measures included the Timed-Up-and-Go (TUG), Grooved Pegboard (GP) and velocity and step length of self-paced gait. Both groups significantly improved on the TUG, GP, velocity, and step length, and this was maintained after a 6-week washout period. Of additional interest, only the PD SAFEx program significantly improved motor symptoms (UPDRS). These gains were maintained in the PD SAFEx group 6 weeks after the exercise was stopped, while motor symptoms significantly worsened in the non-SAFE group. These results suggest that increasing awareness of sensory feedback may be a critical factor that specifically impacts motor symptoms. Future work should strive to uncover the underlying neurophysiological mechanism behind this effect.

Effectiveness of Gas and Chimney Biomass Stoves for Reducing Household Air Pollution Pregnancy Exposure in Guatemala: Sociodemographic Effect Modifiers.

Household air pollution (HAP) due to solid fuel use during pregnancy is associated with adverse birth outcomes. The real-life effectiveness of clean cooking interventions has been disappointing overall yet variable, but the sociodemographic determinants are not well described. We measured personal 24-h PM2.5 (particulate matter <2.5 µm in aerodynamic diameter) thrice in pregnant women (n = 218) gravimetrically with Teflon filter, impactor, and personal pump setups. To estimate the effectiveness of owning chimney and liquefied petroleum gas (LPG) stoves (i.e., proportion of PM2.5 exposure that would be prevented) and to predict subject-specific typical exposures, we used linear mixed-effects models with log (PM2.5) as dependent variable and random intercept for subject. Median (IQR) personal PM2.5 in µg/m3 was 148 (90-249) for open fire, 78 (51-125) for chimney stove, and 55 (34-79) for LPG stoves. Adjusted effectiveness of LPG stoves was greater in women with ≥6 years of education (49% (95% CI: 34, 60)) versus <6 years (26% (95% CI: 5, 42)). In contrast, chimney stove adjusted effectiveness was greater in women with <6 years of education (50% (95% CI: 38, 60)), rural residence (46% (95% CI: 34, 55)) and lowest SES (socio-economic status) quartile (59% (95% CI: 45, 70)) than ≥6 years education (16% (95% CI: 22, 43)), urban (23% (95% CI: -164, 42)) and highest SES quartile (-44% (95% CI: -183, 27)), respectively. A minority of LPG stove owners (12%) and no chimney owner had typical exposure below World Health Organization Air Quality guidelines (35 µg/m3). Although having a cleaner stove alone typically does not lower exposure enough to protect health, understanding sociodemographic determinants of effectiveness may lead to better targeting, implementation, and adoption of interventions.

Effect of Low Versus High Tidal-Volume Total Liquid Ventilation on Pulmonary Inflammation.

Animal experiments suggest that total liquid ventilation (TLV) induces less ventilator-induced lung injury (VILI) than conventional mechanical gas ventilation. However, TLV parameters that optimally minimize VILI in newborns remain unknown. Our objective was to compare lung inflammation between low (L-VT) and high (H-VT) liquid tidal volume and evaluate impacts on the weaning process. Sixteen anesthetized and paralyzed newborn lambs were randomized in an L-VT group (initial tidal volume of 10 mL/kg at 10/min) and an H-VT group (initial tidal volume of 20 mL/kg at 5/min). Five unventilated newborn lambs served as controls. After 4 h of TLV in the supine position, the lambs were weaned in the prone position for another 4 h. The levels of respiratory support needed during the 4 h post-TLV were compared. The anterior and posterior lung regions were assessed by a histological score and real-time quantitative PCR for IL1B, IL6, and TNF plus 12 other exploratory VILI-associated genes. All but one lamb were successfully extubated within 2 h post-TLV (72 ± 26 min vs. 63 ± 25 min, p = 0.5) with similar FiO2 at 4 h post-TLV (27 ± 6% vs. 33 ± 7%, p = 0.3) between the L-VT and H-VT lambs. No significant differences were measured in histological inflammation scores between L-VT and H-VT lambs, although lambs in both groups exhibited slightly higher scores than the control lambs. The L-VT group displayed higher IL1B mRNA expression than the H-VT group in both anterior (2.8 ± 1.5-fold increase vs. 1.3 ± 0.4-fold increase, p = 0.02) and posterior lung regions (3.0 ± 1.0-fold change increase vs. 1.1 ± 0.3-fold increase, p = 0.002), respectively. No significant differences were found in IL6 and TNF expression levels. Gene expression changes overall indicated that L-VT was associated with a qualitatively distinct inflammatory gene expression profiles compared to H-VT, which may indicate different clinical effects. In light of these findings, further mechanistic studies are warranted. In conclusion, we found no advantage of lower tidal volume use, which was in fact associated with a slightly unfavorable pattern of inflammatory gene expression.

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).

Symptom and gait changes after sensory attention focused exercise vs aerobic training in Parkinson's disease.

The current study compared lower-limb aerobic training and sensory attention focused exercise (PD SAFEx) to a non-exercise control group with the overall objective of determining which strategy would have a greater benefit for Parkinson's disease (PD) symptoms and gait. PD SAFEx was developed to focus on sensorimotor deficits identified in PD with the aim of increasing sensory feedback and body awareness, while the lower-limb aerobic training utilized a specially designed semi-recumbent elliptical device. Intervention groups (PD SAFEx, n = 18; aerobic, n = 13) exercised three times/week for 10-12 weeks, while nonexercise control participants (n = 15) maintained their regular activity level for 12 weeks. Outcome measures included the Unified Parkinson's disease rating scale motor section (UPDRS) administered by a blinded clinician; a posture and gait (PG) score (total of UPDRS items 27-31); the Timed-Up-and-Go (TUG); and spatiotemporal aspects of self-paced gait. PD SAFEx resulted in an improved UPDRS, PG score, and TUG (reached significance when participants with poor attendance were excluded) but not self-paced gait. The lower-limb aerobic training led to increased step length and velocity but had no change to disease severity. Since gait improvements were not combined with symptomatic changes, lower-limb aerobic exercise may not be optimal for individuals with PD. Conversely, sensory-based exercise (PD SAFEx) was beneficial, and led to improvement in symptoms and functional movement control.

Comparison of bolus- and filtering-based EIT measures of lung perfusion in an animal model.

OBJECTIVE: Two main functional imaging approaches have been used to measure regional lung perfusion using electrical impedance tomography (EIT): venous injection of a hypertonic saline contrast agent and imaging of its passage through the heart and lungs, and digital filtering of heart-frequency impedance changes over sequences of EIT images. This paper systematically compares filtering-based perfusion estimates and bolus injection methods to determine to which degree they are related. APPROACH: EIT data was recorded on seven mechanically ventilated newborn lambs in which ventilation distribution was varied through changes in posture between prone, supine, left- and right-lateral positions. Perfusion images were calculated using frequency filtering and ensemble averaging during both ventilation and apnoea time segments for each posture to compare against contrast agent-based methods using Jaccard distance score. MAIN RESULTS: Using bolus-based EIT measures of lung perfusion as the reference frequency filtering techniques performed better than ensemble averaging and both techniques performed equally well across apnoea and ventilation data segments. SIGNIFICANCE: Our results indicate the potential for use of filtering-based EIT measures of heart-frequency activity as a non-invasive proxy for contrast agent injection-based measures of lung perfusion.

Perflubron Distribution During Transition From Gas to Total Liquid Ventilation.

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume (p = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs (p = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% (p = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship (p = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography.

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.

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.