Aeration strategy at birth does not impact carotid haemodynamics in preterm lambs.

BACKGROUND: The impact of different respiratory strategies at birth on the preterm lung is well understood; however, concerns have been raised that lung recruitment may impede cerebral haemodynamics. This study aims to examine the effect of three different ventilation strategies on carotid blood flow, carotid artery oxygen content and carotid oxygen delivery. METHODS: 124-127-day gestation apnoeic intubated preterm lambs studied as part of a larger programme primarily assessing lung injury were randomised to positive pressure ventilation with positive end-expiratory pressure (PEEP) 8 cmH2O (No-RM; n = 12), sustained inflation (SI; n = 15) or dynamic PEEP strategy (DynPEEP; maximum PEEP 14 or 20 cmH2O, n = 41) at birth, followed by 90 min of standardised ventilation. Haemodynamic data were continuously recorded, with intermittent arterial blood gas analysis. RESULTS: Overall carotid blood flow measures were comparable between strategies. Except for mean carotid blood flow that was significantly lower for the SI group compared to the No-RM and DynPEEP groups over the first 3 min (p < 0.0001, mixed effects model). Carotid oxygen content and oxygen delivery were similar between strategies. Maximum PEEP level did not alter cerebral haemodynamic measures. CONCLUSIONS: Although there were some short-term variations in cerebral haemodynamics between different PEEP strategies and SI, these were not sustained. IMPACT: Different pressure strategies to facilitate lung aeration at birth in preterm infants have been proposed. There is minimal information on the effect of lung recruitment on cerebral haemodynamics. This is the first study that compares the effect of sustained lung inflation and dynamic and static positive end-expiratory pressure on cerebral haemodynamics. We found that the different ventilation strategies did not alter carotid blood flow, carotid oxygen content or carotid oxygen delivery. This preclinical study provides some reassurance that respiratory strategies designed to focus on lung aeration at birth may not impact cerebral haemodynamics in preterm neonates.

Dynamic positive end-expiratory pressure strategies using time and pressure recruitment at birth reduce early expression of lung injury in preterm lambs.

Positive end-expiratory pressure (PEEP) is critical to the preterm lung at birth, but the optimal PEEP level remains uncertain. The objective of this study was to determine the effect of maximum PEEP levels at birth on the physiological and injury response in preterm lambs. Steroid-exposed preterm lambs (124-127 days gestation; n = 65) were randomly assigned from birth to either 1) positive pressure ventilation (PPV) at 8 cmH2O PEEP or 3-min dynamic stepwise PEEP strategy (DynPEEP), with either 2) 20 cmH2O maximum PEEP (10 PEEP second steps) or 3) 14 cmH2O maximum PEEP (20-s steps), all followed by standardized PPV for 90 min. Lung mechanics, gas exchange, regional ventilation and aeration (electrical impedance tomography), and histological and molecular measures of lung injury were compared between groups. Dynamic compliance was greatest using a maximum 20 cmH2O (DynPEEP). There were no differences in gas exchange, end-expiratory volume, and ventilator requirements. Regional ventilation became more uniform with time following all PEEP strategies. For all groups, gene expression of markers of early lung injury was greater in the gravity nondependent lung, and inversely related to the magnitude of PEEP, being lowest in the 20 cmH2O DynPEEP group overall. PEEP levels had no impact on lung injury in the dependent lung. Transient high maximum PEEP levels using dynamic PEEP strategies may confer more lung protection at birth.

Respiratory mechanics during initial lung aeration at birth in the preterm lamb.

Despite recent insights into the dynamic processes during lung aeration at birth, several aspects remain poorly understood. We aimed to characterize changes in lung mechanics during the first inflation at birth and their relationship to changes in lung volume. Intubated preterm lambs (gestational age, 124-127 days; n = 17) were studied at birth. Lung volume changes were measured by electrical impedance tomography (VLEIT). Respiratory system resistance (R5) and oscillatory compliance (Cx5) were monitored with the forced oscillation technique at 5 Hz. Lambs received 3-7 s of 8 cmH2O of continuous distending pressure (CDP) before delivery of a sustained inflation (SI) of 40 cmH2O. The SI was then applied until either Cx5 or the VLEIT or the airway opening volume was stable. CDP was resumed for 3-7 s before commencement of mechanical ventilation. The exponential increases with time of Cx5 and VLEIT from commencement of the SI were characterized by estimating their time constants (τCx5 and τVLEIT, respectively). During SI, a fast decrease in R5 and an exponential increase in Cx5 and VLEIT were observed. Cx5 and VLEIT provided comparable information on the dynamics of lung aeration in all lambs, with τCx5 and τVLEIT being highly linearly correlated (r2 = 0.87, P < 0.001). Cx5 and VLEIT decreased immediately after SI. Despite the standardization of the animal model, changes in Cx5 and R5 both during and after SI were highly variable. Lung aeration at birth is characterized by a fast reduction in resistance and a slower increase in oscillatory compliance, the latter being a direct reflection of the amount of lung aeration.

Gradual Aeration at Birth Is More Lung Protective Than a Sustained Inflation in Preterm Lambs.

Rationale: The preterm lung is susceptible to injury during transition to air breathing at birth. It remains unclear whether rapid or gradual lung aeration at birth causes less lung injury.Objectives: To examine the effect of gradual and rapid aeration at birth on: 1) the spatiotemporal volume conditions of the lung; and 2) resultant regional lung injury.Methods: Preterm lambs (125 ± 1 d gestation) were randomized at birth to receive: 1) tidal ventilation without an intentional recruitment (no-recruitment maneuver [No-RM]; n = 19); 2) sustained inflation (SI) until full aeration (n = 26); or 3) tidal ventilation with an initial escalating/de-escalating (dynamic) positive end-expiratory pressure (DynPEEP; n = 26). Ventilation thereafter continued for 90 minutes at standardized settings, including PEEP of 8 cm H2O. Lung mechanics and regional aeration and ventilation (electrical impedance tomography) were measured throughout and correlated with histological and gene markers of early lung injury.Measurements and Main Results: DynPEEP significantly improved dynamic compliance (P < 0.0001). An SI, but not DynPEEP or No-RM, resulted in preferential nondependent lung aeration that became less uniform with time (P = 0.0006). The nondependent lung was preferential ventilated by 5 minutes in all groups, with ventilation only becoming uniform with time in the No-RM and DynPEEP groups. All strategies generated similar nondependent lung injury patterns. Only an SI caused greater upregulation of dependent lung gene markers compared with unventilated fetal controls (P < 0.05).Conclusions: Rapidly aerating the preterm lung at birth creates heterogeneous volume states, producing distinct regional injury patterns that affect subsequent tidal ventilation. Gradual aeration with tidal ventilation and PEEP produced the least lung injury.

Time to lung aeration during a sustained inflation at birth is influenced by gestation in lambs.

BackgroundCurrent sustained lung inflation (SI) approaches use uniform pressures and durations. We hypothesized that gestational-age-related mechanical and developmental differences would affect the time required to achieve optimal lung aeration, and resultant lung volumes, during SI delivery at birth in lambs.Methods49 lambs, in five cohorts between 118 and 139 days of gestation (term 142 d), received a standardized 40 cmH2O SI, which was delivered until 10 s after lung volume stability (optimal aeration) was visualized on real-time electrical impedance tomography (EIT), or to a maximum duration of 180 s. Time to stable lung aeration (Tstable) within the whole lung, gravity-dependent, and non-gravity-dependent regions, was determined from EIT recordings.ResultsTstable was inversely related to gestation (P<0.0001, Kruskal-Wallis test), with the median (range) being 229 (85,306) s and 72 (50,162) s in the 118-d and 139-d cohorts, respectively. Lung volume at Tstable increased with gestation from a mean (SD) of 20 (17) ml/kg at 118 d to 56 (13) ml/kg at 139 d (P=0.002, one-way ANOVA). There were no gravity-dependent regional differences in Tstable or aeration.ConclusionsThe trajectory of aeration during an SI at birth is influenced by gestational age in lambs. An understanding of this may assist in developing SI protocols that optimize lung aeration for all infants.

Electrical impedance tomography identifies a distinct change in regional phase angle delay pattern in ventilation filling immediately prior to a spontaneous pneumothorax.

Pneumothoraxes are common in preterm infants and are a major cause of morbidity. Early detection and treatment of pneumothoraxes are vital to minimize further respiratory compromise. Electrical impedance tomography (EIT) has been suggested as a method of rapidly detecting pneumothoraxes at the bedside. Our objective was to define the EIT-derived regional phase angle differences in filling characteristics before and during spontaneous pneumothoraxes in preterm lambs. Preterm lambs (124-127-day gestation) were ventilated with high-frequency oscillatory ventilation for 120 min. EIT data and cardiorespiratory parameters were monitored continuously and recorded for 3 min every 15 min. Six animals spontaneously developed a pneumothorax within a gravity-nondependent quadrant of the lung and were included for this analysis. Changes in end-expiratory lung impedance (EELI), ventilation, and phase angle delay were calculated in the four lung quadrants at the onset of the pneumothorax and 15 and 30 min prior. At the onset of the pneumothorax, all animals showed a clear increase in EELI in the affected lung quadrant. Fifteen and thirty minutes before the pneumothorax there was a significant phase angle delay between the nondependent and dependent lung. At 1 min before pneumothorax this phase angle delay was isolated just to the affected quadrant (nondependent). These findings are the first description of the events within the lung at initiation of a pneumothorax, demonstrating distinct predictive changes in air-filling characteristics before the occurrence of pneumothorax. This suggests that EIT may be able to accurately identify the onset of a pneumothorax.NEW & NOTEWORTHY In this article we describe for the first time predictive changes in electrical impedance tomography-based regional filling characteristics of the lung before the onset of a one-sided pneumothorax in six preterm lambs ventilated with high-frequency oscillatory ventilation. This can give clinicians bedside information to change treatment of preterm infants and prevent pneumothorax as life-threatening event from happening.

Gestational Age Influences the Early Microarchitectural Changes in Response to Mechanical Ventilation in the Preterm Lamb Lung.

Background: Preterm birth is associated with abnormal lung architecture, and a reduction in pulmonary function related to the degree of prematurity. A thorough understanding of the impact of gestational age on lung microarchitecture requires reproducible quantitative analysis of lung structure abnormalities. The objectives of this study were (1) to use quantitative histological software (ImageJ) to map morphological patterns of injury resulting from delivery of an identical ventilation strategy to the lung at varying gestational ages and (2) to identify associations between gestational age-specific morphological alterations and key functional outcomes. Method: Lung morphology was compared after 60 min of a standardized ventilation protocol (40 cm H2O sustained inflation and then volume-targeted positive pressure ventilation with positive end-expiratory pressure 8 cm H2O) in lambs at different gestations (119, 124, 128, 133, 140d) representing the spectrum of premature developmental lung states and the term lung. Age-matched controls were compared at 124 and 128d gestation. Automated and manual functions of Image J were used to measure key histological features. Correlation analysis compared morphological and functional outcomes in lambs aged ≤128 and >128d. Results: In initial studies, unventilated lung was indistinguishable at 124 and 128d. Ventilated lung from lambs aged 124d gestation exhibited increased numbers of detached epithelial cells and lung tissue compared with 128d lambs. Comparing results from saccular to alveolar development (120-140d), lambs aged ≤124d exhibited increased lung tissue, average alveolar area, and increased numbers of detached epithelial cells. Alveolar septal width was increased in lambs aged ≤128d. These findings were mirrored in the measures of gas exchange, lung mechanics, and molecular markers of lung injury. Correlation analysis confirmed the gestation-specific relationships between the histological assessments and functional measures in ventilated lambs at gestation ≤128 vs. >128d. Conclusion: Image J allowed rapid, quantitative assessment of alveolar morphology, and lung injury in the preterm lamb model. Gestational age-specific patterns of injury in response to delivery of an identical ventilation strategy were identified, with 128d being a transition point for associations between morphological alterations and functional outcomes. These results further support the need to develop individualized respiratory support approaches tailored to both the gestational age of the infant and their underlying injury response.

Aeration strategy at birth influences the physiological response to surfactant in preterm lambs.

BACKGROUND: The influence of pressure strategies to promote lung aeration at birth on the subsequent physiological response to exogenous surfactant therapy has not been investigated. OBJECTIVES: To compare the effect of sustained inflation (SI) and a dynamic positive end-expiratory pressure (PEEP) manoeuvre at birth on the subsequent physiological response to exogenous surfactant therapy in preterm lambs. METHODS: Steroid-exposed preterm lambs (124-127 days' gestation; n=71) were randomly assigned from birth to either (1) positive-pressure ventilation (PPV) with no recruitment manoeuvre; (2) SI until stable aeration; or (3) 3 min dynamic stepwise PEEP strategy (maximum 14-20 cmH2O; dynamic PEEP (DynPEEP)), followed by PPV for 60 min using a standardised protocol. Surfactant (200 mg/kg poractant alfa) was administered at 10 min. Dynamic compliance, gas exchange and regional ventilation and aeration characteristics (electrical impedance tomography) were measured throughout and compared between groups, and with a historical group (n=38) managed using the same strategies without surfactant. RESULTS: Compliance increased after surfactant only in the DynPEEP group (p<0.0001, repeated measures analysis of variance), being 0.17 (0.10, 0.23) mL/kg/cmH2O higher at 60 min than the SI group. An SI resulted in the least uniform aeration, and unlike the no-recruitment and DynPEEP groups, the distribution of aeration and tidal ventilation did not improve with surfactant. All groups had similar improvements in oxygenation post-surfactant compared with the corresponding groups not treated with surfactant. CONCLUSIONS: A DynPEEP strategy at birth may improve the response to early surfactant therapy, whereas rapid lung inflation with SI creates non-uniform aeration that appears to inhibit surfactant efficacy.

Determining the pattern and prevalence of alcohol consumption in pregnancy by measuring biomarkers in meconium.

OBJECTIVE: To investigate the feasibility of determining the pattern and prevalence of alcohol consumption in pregnancy by measuring ethanol biomarkers in meconium. DESIGN: Population-based observational study. SETTING: Inner-city maternity unit in Scotland, UK. POPULATION: Random sample of singleton infants delivered after 36 completed weeks' gestation. METHODS: Fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG) in meconium were measured by liquid chromatography-mass spectroscopy. Samples were frozen at -20°C before analysis. Results were compared anonymously with demographic data including maternal age, parity, smoking, ethnicity and postcode and with infant gestation, birth weight and head circumference. Written informed consent was obtained from all subjects. RESULTS: 235 samples of meconium were analysed (70% of eligible babies). Only four (1%) of mothers declined to participate. FAAEs were detected in all, including four samples below the limit of quantification (10 ng/g). 98 (42%) samples had FAEE concentrations >600 ng/g. EtG was detectable in 93 (40%) samples; in 35 (15%) EtG concentration was >30 ng/g. No mother reported heavy alcohol consumption in pregnancy. FAAE concentration correlated with EtG (Pearson's coefficient; p<0.001). There was no association between either biomarker and maternal age, parity, smoking, ethnicity or postcode, or infant gestation, birth weight or head circumference. CONCLUSION: Measurement of ethanol biomarkers in meconium is a feasible tool for determining the pattern and prevalence of alcohol consumption in pregnancy. Data suggest that at least 15% of pregnant women in the west of Scotland are consuming significant quantities of alcohol during latter pregnancy.

Plasma proteomics reveals gestational age-specific responses to mechanical ventilation and identifies the mechanistic pathways that initiate preterm lung injury.

The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states; the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma samples taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of individualized respiratory support approaches tailored to both the developmental and pathological state of the lung.

Lung Recruitment Strategies During High Frequency Oscillatory Ventilation in Preterm Lambs.

Background: High frequency oscillatory ventilation (HFOV) is considered a lung protective ventilation mode in preterm infants only if lung volume is optimized. However, whilst a "high lung volume strategy" is advocated for HFOV in preterm infants this strategy is not precisely defined. It is not known to what extent lung recruitment should be pursued to provide lung protection. In this study we aimed to determine the relationship between the magnitude of lung volume optimization and its effect on gas exchange and lung injury in preterm lambs. Methods: 36 surfactant-deficient 124-127 d lambs commenced HFOV immediately following a sustained inflation at birth and were allocated to either (1) no recruitment (low lung volume; LLV), (2) medium- (MLV), or (3) high lung volume (HLV) recruitment strategy. Gas exchange and lung volume changes over time were measured. Lung injury was analyzed by post mortem pressure-volume curves, alveolar protein leakage, gene expression, and histological injury score. Results: More animals in the LLV developed a pneumothorax compared to both recruitment groups. Gas exchange was superior in both recruitment groups compared to LLV. Total lung capacity tended to be lower in the LLV group. Other parameters of lung injury were not different. Conclusions: Lung recruitment during HFOV optimizes gas exchange but has only modest effects on lung injury in a preterm animal model. In the HLV group aiming at a more extensive lung recruitment gas exchange was better without affecting lung injury.

Sustained lung inflation at birth: what do we know, and what do we need to know?

A sustained inflation has been advocated as a potential method of augmenting lung aeration at birth. Clinical trials have suggested that a sustained inflation may lead to a reduced need for intubation and ventilation in the first few days of life, without cardiovascular compromise or increased lung injury. Despite this, a sustained inflation is not currently a standard of practice, mainly due to a lack of clarity regarding the optimal delivery method. Animal trials have sought to refine delivery techniques. This review will outline current recommendations regarding a sustained inflation, discuss potential strategies for its optimal delivery and suggest priorities for future research.