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.

Effects of Nasal Respiratory Support on Laryngeal and Esophageal Reflexes in Preterm Lambs.

BACKGROUND: Significant cardiorespiratory events can be triggered in preterm infants as part of laryngeal chemoreflexes (LCRs) and esophageal reflexes (ERs). We previously showed that nasal continuous positive airway pressure (nCPAP) blunted the cardiorespiratory inhibition induced with LCRs. Therefore, we aimed to compare the effects of nCPAP and high-flow nasal cannulas (HFNC) on the cardiorespiratory events induced during LCRs and ERs. The hypothesis is that nCPAP but not HFNC decreases the cardiorespiratory inhibition observed during LCRs and ERs. METHODS: Eleven preterm lambs were instrumented to record respiration, ECG, oxygenation, and states of alertness. LCRs and ERs were induced during non-rapid eye movement sleep in a random order under these conditions: nCPAP 6 cmH2O, HFNC 7 L/min, high-flow nasal cannulas 7 L/min at a tracheal pressure of 6 cmH2O, and no respiratory support. RESULTS: nCPAP 6 cmH2O decreased the cardiorespiratory inhibition induced with LCRs, but not with ERs in preterm lambs. This blunting effect was less marked with HFNC 7 L/min, even when the tracheal pressure was maintained at 6 cmH2O. CONCLUSIONS: nCPAP might be a treatment for cardiorespiratory events related to LCRs in newborns, either in the context of laryngopharyngeal refluxes or swallowing immaturity. Our preclinical results merit to be confirmed through clinical studies. IMPACT: Laryngeal chemoreflexes can be responsible for significant cardiorespiratory inhibition in newborns, especially preterm. Nasal continuous positive airway pressure at 6 cmH2O significantly decreased this cardiorespiratory inhibition. High-flow nasal cannulas at 7 L/min had a lesser effect than nasal continuous positive airway pressure. Esophageal stimulation was responsible for a smaller cardiorespiratory inhibition, which was not significantly modified by nasal continuous positive airway pressure or high-flow nasal cannulas. Nasal continuous positive airway pressure should be tested for its beneficial effect on cardiorespiratory events related to laryngeal chemoreflexes in preterm newborns.

Hemodynamic impacts of apelin-13 in a neonatal lamb model of septic peritonitis.

BACKGROUND: Apelins are potential candidate therapeutic molecules for hemodynamic support. The objective of this study was to assess the hemodynamic impacts of apelin-13 in a neonatal lamb model of septic shock. METHODS: Lambs were randomized to receive apelin-13 or normal saline. Septic shock was induced by injecting a fecal slurry into the peritoneal cavity. Lambs underwent volume repletion (30 mL/kg over 1 h) followed by intravenous administration of 5 incremental doses (D) of apelin-13 (D1 = 0.039 to D5 = 19.5 µg/kg/h) or normal saline. RESULTS: Following fecal injection, mean arterial pressure (MAP) and cardiac index (CI) dropped in both groups (p < 0.05). The MAP decreased non-significantly from D1 to D5 (p = 0.12) in the saline group, while increasing significantly (p = 0.02) in the apelin group (-12 (-17; 12) vs. +15 (6; 23) % (p = 0.012)). Systemic vascular resistances were higher in the apelin-13 group at D5 compared to the saline group (4337 (3239, 5144) vs. 2532 (2286, 3966) mmHg/min/mL, respectively, p = 0.046). The CI increased non-significantly in the apelin-13 group. CONCLUSION: Apelin-13 increased MAP in a neonatal lamb septic shock model. IMPACT: Administration of apelin-13 stabilized hemodynamics during the progression of the sepsis induced in this neonatal lamb model. Systemic vascular resistances were higher in the apelin-13 group than in the placebo group. This suggests ontogenic differences in vascular response to apelin-13 and warrants further investigation. This study suggests that apelin-13 could eventually become a candidate for the treatment of neonatal septic shock.

Corrigendum: Safety of Bottle-Feeding Under Nasal Respiratory Support in Preterm Lambs With and Without Tachypnoea.

[This corrects the article DOI: 10.3389/fphys.2021.785086.].

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.

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.

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.

Safety of Bottle-Feeding Under Nasal Respiratory Support in Preterm Lambs With and Without Tachypnoea.

Aim: Convalescing preterm infants often require non-invasive respiratory support, such as nasal continuous positive airway pressure or high-flow nasal cannulas. One challenging milestone for preterm infants is achieving full oral feeding. Some teams fear nasal respiratory support might disrupt sucking-swallowing-breathing coordination and induce severe cardiorespiratory events. The main objective of this study was to assess the safety of oral feeding of preterm lambs on nasal respiratory support, with or without tachypnoea. Methods: Sucking, swallowing and breathing functions, as well as electrocardiogram, oxygen haemoglobin saturation, arterial blood gases and videofluoroscopic swallowing study were recorded in 15 preterm lambs during bottle-feeding. Four randomly ordered conditions were studied: control, nasal continuous positive airway pressure (6 cmH2O), high-flow nasal cannulas (7 L•min-1), and high-flow nasal cannulas at 7 L•min-1 at a tracheal pressure of 6 cmH2O. The recordings were repeated on days 7-8 and 13-14 to assess the effect of maturation. Results: None of the respiratory support impaired the safety or efficiency of oral feeding, even with tachypnoea. No respiratory support systematically impacted sucking-swallowing-breathing coordination, with or without tachypnoea. No effect of maturation was found. Conclusion: This translational physiology study, uniquely conducted in a relevant animal model of preterm infant with respiratory impairment, shows that nasal respiratory support does not impact the safety or efficiency of bottle-feeding or sucking-swallowing-breathing coordination. These results suggest that clinical studies on bottle-feeding in preterm infants under nasal continuous positive airway pressure and/or high-flow nasal cannulas can be safely undertaken.

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.

Effects of Early Myocardial Postnatal Maturation on Tolerance to Atrial Tachycardia With Altered Loading Conditions: An in vivo Swine Model.

Post-natal maturation of the myocardium starts shortly after birth and could affect how clinicians should provide hemodynamic support during this transition. Our aim was to assess the impact of post-natal maturation on tolerance to tachycardia with altered loading condition in a piglet model. Methods: We report three series of experimentations. Six groups of landrace cross neonatal piglets (NP) (1-3 days) and young piglets (YP) (14-17 days) were assigned to tachycardia (NP, YP), tachycardia and hypervolemia (NPV, YPV) or tachycardia and increased afterload (NPA, YPA) groups (n = 7/group). Under anesthesia, a pressure catheter was placed in the left ventricle and pacing wire in the right atrium. NPV and YPV groups had 60 ml/kg of normal saline infused over 20 min. NPA and YPA had balloon sub-occlusion of the descending aorta. Heart rate was increased by 10 bpm increments to 300 bpm. Left ventricular output was measured by echocardiography. Results: NP maintained left ventricular output throughout the pacing protocol but it decreased in the YP (p < 0.001). With volume loading both NPV and YPV maintained their output with tachycardia. Although increased afterload resulted in reduced output during tachycardia in NPA (p = 0.005), there was no added impact on output in YPA. Interestingly, 4 of 7 NPV had significant desaturation at 300 bpm (baseline 99.7% vs. 300 bpm 87.9%, p = 0.04), associated with a right to left shunt through the patent foramen ovale which resolved immediately on cessation of pacing. Conclusions: Early post-natal maturation is associated with improved myocardial tolerance to increased afterload and poor tolerance of tachycardia, the latter of which may be alleviated by increasing intravascular volume. These data could translate into the development of better strategies to optimize cardiac output at these early development ages.

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).

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.

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.

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.

Resection versus preservation of the middle turbinate in surgery for chronic rhinosinusitis with nasal polyposis: a randomized controlled trial.

BACKGROUND: Chronic rhinosinusitis (CRS) affects up to 16% of the population. When medical treatment fails, endoscopic sinus surgery (ESS) is considered. The value of resecting the middle turbinate to optimize surgical outcomes has been hypothesized but remains controversial and unproven. Whether the middle turbinate should be left in place or resected is controversial. Our objective is to determine if middle turbinectomy improves objective surgical outcomes after ESS. METHODS: Sixteen patients (15 men, 15 primary surgery) undergoing bilateral complete ESS for CRS with nasal polyposis were recruited. Nasal cavities were randomized so that middle turbinectomy was performed on one side while the middle turbinate was preserved on the other. Each participant acted as their own control. Nasal cavities were compared using Perioperative Sinus Endoscopy (POSE) and Lund-Kennedy (LKES) scores pre-operatively, and at 1, 3 and 6 months after ESS. Results were analyzed using Wilcoxon signed-rank test. RESULTS: Pre-operatively, the POSE (12.4 ± 2.9 vs 12.8 ± 2.6, p = 0.33, for the preserved side and the resected side, respectively) and LKES (5.0 ± 1.0 vs 4.8 ± 1.2, p = 0.33) scores were similar between sides. During follow up, resection was associated with more crusting at 1 month following ESS (1.0 ± 0.7 vs 0.4 ± 0.6, p = 0.02). There was a small, but statistically significant, difference between the nasal cavities at 3 months, where the resected side showed better endoscopic appearance (2.0 ± 2.2 vs 3.4 ± 2.8, p = 0.01). No difference was found at 6 months. Frontal sinus scores were similar between sides at 6 months (0.7 ± 0.5 vs 0.7 ± 0.5, p = 1.00). CONCLUSION: Our results show no sustained objective endoscopic benefit of routine middle turbinectomy, at least within the first six postoperative months, in patients undergoing primary ESS for CRS with polyposis. TRIAL REGISTRATION: NCT, NCT02855931 . Registered 16 August 2016.

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.

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.

The contribution of ovine models to perinatal respiratory physiology.

The dramatic transition to air breathing at birth represents a true challenge for the newborn infant mammal, a period in which neonatal respiratory diseases are common. Since the 1930s, fetal and newborn lambs have been the model of choice for whole-animal studies on neonatal respiration. The present review aims to illustrate the relevance of ovine models in studying the establishment of successful breathing at birth and its maintenance in the early postnatal period, as well as a number of abnormal conditions that can interfere with these processes.

Strain Rate in Children and Young Piglets Mirrors Changes in Contractility and Demonstrates a Force-Frequency Relationship.

BACKGROUND: In adult humans and pig models, strain rate (SR) correlates strongly with invasive measures of contractility but does not demonstrate a force-frequency relationship, which is a fundamental behavior of myocardial contraction. Given the considerable maturational changes of the myocardium from fetal stages to adulthood, extrapolation of adult findings to the young heart may not be appropriate. We sought to evaluate the SR response of the immature heart to increased heart rate (HR) and inotropic stimulation. METHODS: The study consisted of two parts. In part 1, children without obvious structural or functional cardiac abnormalities were evaluated following successful radiofrequency ablation. Echocardiography was performed at baseline HR and then with atrial pacing and isoprenaline infusion titrated to achieve 130% of baseline HR. Left ventricular (LV) speckle tracking-derived SR and tissue Doppler isovolumic acceleration (IVA, a load-independent marker of contractility) were measured. In part 2, young piglets were submitted to atrial pacing at 200, 230, and 260 bpm. Invasive LV dP/dt was assessed, and speckle tracking-derived SR was measured at all stages. Repeated measures analysis of variance was used for comparison with baseline values. RESULTS: In part 1, the LV SR and IVA (septal and lateral) in 23 children (ages 7.8-17.5 years) increased significantly with pacing and isoprenaline infusion (P < .001). In part 2, SR and invasive dP/dt increased significantly with increasing HR in young piglets (1-17 days; P < .01 and P < .001, respectively). Both LV SR and dP/dt plateaued at highest HRs concurrent with the decrease in LV end-diastolic dimension from baseline (73.0% ± 9.9% of the baseline value at 260 bpm; P < .001). CONCLUSIONS: SR in children is augmented with chronotropic and inotropic stimulation and in young infant piglets with chronotropic stimulation; in both children and piglets it has a force-frequency relationship, a behavior that is consistent with a measure of contractility.