Ventilatory response and stability of oxygen saturation during a hypoxic challenge in very preterm infants.

BACKGROUND: Preterm infants have immature control of breathing and impaired pulmonary gas exchange. We hypothesized that infants with bronchopulmonary dysplasia (BPD) have a blunted ventilatory response and peripheral oxygen saturation (SpO2 ) instability during a hypoxic challenge. METHODS: We evaluated the response to hypoxia in 57 very preterm infants (38 no BPD, 10 mild BPD, 9 moderate-to-severe BPD) at 36 weeks' postmenstrual age. The fraction of inspired oxygen (FI O2 ) was reduced stepwise at 5-min intervals to achieve peripheral SpO2 between 86% and 95%. The lowest permissible FI O2 and SpO2 were 0.14% and 86%. We recorded SpO2 , FI O2 , and the respiratory signal (respiratory inductive plethysmography). We calculated respiratory rate (RR), tidal volume (VT ), minute ventilation (VE ), and respiratory drive (ratio between VT and inspiratory time, VT /TI ). SpO2 variability was expressed as the interquartile range (IQR). RESULTS: FI O2 was reduced from a median (Q1, Q3) of 0.21 (0.21, 0.21) to 0.17 (0.17, 0.18). We observed a marked individual variability in the ventilatory response to the hypoxic challenge, regardless of BPD severity. At the lowest permissible FI O2 , 37 (65%) infants reduced their VE , and 20 (35%) increased minute ventilation; 20 infants (35%) developed periodic breathing associated with increased SpO2 IQR and lower SpO2 minima, and 16 (28%) exhibited an oscillatory pattern in VE and SpO2 without end-expiratory pauses, regardless of BPD severity. CONCLUSION: In very preterm infants, a mild hypoxic challenge reduced ventilation, increased SpO2 variability and periodic breathing regardless of BPD severity.

Aerosol drug delivery to spontaneously-breathing preterm neonates: lessons learned.

Delivery of medications to preterm neonates receiving non-invasive ventilation (NIV) represents one of the most challenging scenarios for aerosol medicine. This challenge is highlighted by the undersized anatomy and the complex (patho)physiological characteristics of the lungs in such infants. Key physiological restraints include low lung volumes, low compliance, and irregular respiratory rates, which significantly reduce lung deposition. Such factors are inherent to premature birth and thus can be regarded to as the intrinsic factors that affect lung deposition. However, there are a number of extrinsic factors that also impact lung deposition: such factors include the choice of aerosol generator and its configuration within the ventilation circuit, the drug formulation, the aerosol particle size distribution, the choice of NIV type, and the patient interface between the delivery system and the patient. Together, these extrinsic factors provide an opportunity to optimize the lung deposition of therapeutic aerosols and, ultimately, the efficacy of the therapy.In this review, we first provide a comprehensive characterization of both the intrinsic and extrinsic factors affecting lung deposition in premature infants, followed by a revision of the clinical attempts to deliver therapeutic aerosols to premature neonates during NIV, which are almost exclusively related to the non-invasive delivery of surfactant aerosols. In this review, we provide clues to the interpretation of existing experimental and clinical data on neonatal aerosol delivery and we also describe a frame of measurable variables and available tools, including in vitro and in vivo models, that should be considered when developing a drug for inhalation in this important but under-served patient population.

Simplified bedside assessment of pulmonary gas exchange in very preterm infants at 36 weeks' postmenstrual age.

INTRODUCTION: We aimed to develop and validate a prediction table for a simplified measure of rightward shift of the fetal oxyhaemoglobin saturation (SpO2) versus inspired oxygen pressure (PIO2) curve as an objective marker of lung disease severity in very preterm infants, independent of unit altitude or oxygen prescribing policies. METHODS: Very preterm infants (n=219) had an oxygen reduction test at median (IQR) test age of 354 (345-360) weeks' postmenstrual age (PMA). Shift was derived from at least three paired SpO2 versus PIO2 measurements using a computer algorithm, using the fetal oxyhaemoglobin dissociation curve as the reference. Linear regression of resultant shift values enabled construction of a table to predict shift using a single paired SpO2 versus PIO2 measurement, validated subsequently in a separate infant cohort using Bland-Altman analysis. Receiver operating curve analysis provided threshold values equating to a clinical diagnosis of mild bronchopulmonary dysplasia (BPD) or moderate to severe BPD. RESULTS: The median (IQR) age of 63 infants in the validation cohort was 360 (356-362) weeks' PMA. Mean difference (95% CI) between predicted and measured shift was 2.1 (-0.8% to 4.9%) with wide limits of agreement (-20.7% to 24.8%). Predicted shift >10.1 kPa identified mild BPD with 71% sensitivity and 88% specificity while values>13.0 kPa identified moderate to severe BPD with 81% sensitivity and 100% specificity. DISCUSSION: Shift predicted from a single paired SpO2 versus PIO2 measurement using our validated table enables objective bedside screening of lung disease severity in very preterm infant cohorts at 36 weeks' PMA.

Regional distribution of chest wall displacements in infants during high-frequency ventilation.

The distribution of ventilation during high-frequency ventilation (HFV) is asynchronous, nonhomogeneous, and frequency dependent. We hypothesized that differences in the regional distribution of ventilation at different oscillatory frequencies may affect gas exchange efficiency. We studied 15 newborn infants with a median gestational age of 28.9 (26.4-30.3) wk and body weight of 1.0 (0.8-1.4) kg. Five ventilation frequencies (5, 8, 10, 12, and 15 Hz) were tested, keeping carbon dioxide diffusion coefficient constant. The displacements of 24 passive markers placed on the infant's chest wall were measured by optoelectronic plethysmography. We evaluated the amplitude and phase shift of displacements of single markers placed along the midline and the regional displacements of the chest wall surface. Blood gases were unaffected by frequency. Chest wall volume changes decreased from 1.6 (0.4) ml/kg at 5 Hz to 0.7 ml/kg at 15 Hz. At all frequencies, the abdomen (AB) oscillated more markedly than the ribcage (RC). The mean (SD) AB/RC ratio was 1. 95 (0.7) at 5 Hz, increased to 2.1 (1.3) at 10 Hz, and then decreased to 1.1 (0.5) at 15 Hz ( P < 0.05 vs. 10 Hz). Volume changes in the AB lagged the RC and this phase shift increased with frequency. The AB oscillated more than the RC at all frequencies. Regional oscillations were highly inhomogeneous up to 10 Hz, and they became progressively more asynchronous with increasing frequency. When the carbon dioxide diffusion coefficient is held constant, such differences in regional chest wall expansion do not affect gas exchange. NEW & NOTEWORTHY We characterized the regional distribution of chest wall displacements in infants receiving high-frequency oscillatory ventilation at different frequencies. When carbon dioxide diffusion coefficient is held constant, there is no combination of frequency and tidal volume that optimizes gas exchange. The relative displacement between different chest wall compartments is not affected by frequency. However, at high frequencies, chest wall displacements are lower, with the potential to reduce total and regional overdistension without affecting gas exchange.

Effect of frequency on pressure cost of ventilation and gas exchange in newborns receiving high-frequency oscillatory ventilation.

BackgroundWe hypothesized that ventilating at the resonant frequency of the respiratory system optimizes gas exchange while limiting the mechanical stress to the lung in newborns receiving high-frequency oscillatory ventilation (HFOV). We characterized the frequency dependence of oscillatory mechanics, gas exchange, and pressure transmission during HFOV.MethodsWe studied 13 newborn infants with a median (interquartile range) gestational age of 29.3 (26.4-30.4) weeks and body weight of 1.00 (0.84-1.43) kg. Different frequencies (5, 8, 10, 12, and 15 Hz) were tested, keeping carbon dioxide diffusion coefficient (DCO2) constant. Oscillatory mechanics and transcutaneous blood gas were measured at each frequency. The attenuation of pressure swings (ΔP) from the airways opening to the distal end of the tracheal tube (TT) and to the alveolar compartment was mathematically estimated.ResultsBlood gases were unaffected by frequency. The mean (SD) resonant frequency was 16.6 (3.5) Hz. Damping of ΔP increased with frequency and with lung compliance. ΔP at the distal end of the TT was insensitive to frequency, whereas ΔP at the peripheral level decreased with frequency.ConclusionThere is no optimal frequency for gas exchange when DCO2 is held constant. Greater attenuation of oscillatory pressure at higher frequencies offers more protection from barotrauma, especially in patients with poor compliance.

Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs.

Preterm infants often require mechanical ventilation due to lung immaturity including reduced or abnormal surfactant. Since cyclic stretch with cycle-by-cycle variability is known to augment surfactant release by epithelial cells, we hypothesized that such in vivo mechanotransduction improves surfactant maturation and hence lung physiology in preterm subjects. We thus tested whether breath-by-breath variability in tidal volume (VT) in variable ventilation (VV) can be tuned for optimal performance in a preterm lamb model. Preterm lambs were ventilated for 3 h with conventional ventilation (CV) or two variants of VV that used a maximum VT of 1.5 (VV1) or 2.25 (VV2) times the mean VT. VT was adjusted during ventilation to a permissive pCO2 target range. Respiratory mechanics were monitored continuously using the forced oscillation technique, followed by postmortem bronchoalveolar lavage and tissue collection. Both VVs outperformed CV in blood gas parameters (pH, SaO2, cerebral O2 saturation). However, only VV2 lowered PaCO2 and had a higher specific respiratory compliance than CV. VV2 also increased surfactant protein (SP)-B release compared to VV1 and stimulated its production compared to CV. The production and release of proSP-C however, was increased with CV compared to both VVs. There was more SP-A in both VVs than CV in the lung, but VV2 downregulated SP-A in the lavage, whereas SP-D significantly increased in CV in both the lavage and lung. Compared to CV, the cytokines IL-1ß, and TNFα decreased with both VVs with less inflammation during VV2. Additionally, VV2 lungs showed the most homogeneous alveolar structure and least inflammatory cell infiltration assessed by histology. CV lungs exhibited over-distension mixed with collapsed and interstitial edematous regions with occasional hemorrhage. Following VV1, some lambs had normal alveolar structure while others were similar to CV. The IgG serum proteins in the lavage, a marker of leakage, were the highest in CV. An overall combined index of performance that included physiological, biochemical and histological markers was the best in VV2 followed by VV1. Thus, VV2 outperformed VV1 by enhancing SP-B metabolism resulting in open alveolar airspaces, less leakage and inflammation and hence better respiratory mechanics.

The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity.

Acute respiratory distress syndrome (ARDS) is undefined in neonates, despite the long-standing existing formal recognition of ARDS syndrome in later life. We describe the Neonatal ARDS Project: an international, collaborative, multicentre, and multidisciplinary project which aimed to produce an ARDS consensus definition for neonates that is applicable from the perinatal period. The definition was created through discussions between five expert members of the European Society for Paediatric and Neonatal Intensive Care; four experts of the European Society for Paediatric Research; two independent experts from the USA and two from Australia. This Position Paper provides the first consensus definition for neonatal ARDS (called the Montreux definition). We also provide expert consensus that mechanisms causing ARDS in adults and older children-namely complex surfactant dysfunction, lung tissue inflammation, loss of lung volume, increased shunt, and diffuse alveolar damage-are also present in several critical neonatal respiratory disorders.

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. METHODS/DESIGN: In this study, 206 spontaneously breathing infants born at 24(+0)-27(+6) weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. DISCUSSION: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02482766 . Registered on 1 June 2015.

Influence of gestational age on dead space and alveolar ventilation in preterm infants ventilated with volume guarantee.

BACKGROUND: Ventilated preterm infant lungs are vulnerable to overdistension and underinflation. The optimal ventilator-delivered tidal volume (VT) in these infants is unknown and may depend on the extent of alveolarisation at birth. OBJECTIVES: We aimed to calculate respiratory dead space (VD) from the molar mass (MM) signal of an ultrasonic flowmeter (VD,MM) in very preterm infants on volume-targeted ventilation (VT target, 4-5 ml/kg) and to study the association between gestational age (GA) and VD,MM-to-VT ratio (VD,MM/VT), alveolar tidal volume (VA) and alveolar minute volume (AMV). METHODS: This was a single-centre, prospective, observational, cohort study in a neonatal intensive care unit. Tidal breathing analysis was performed in ventilated very preterm infants (GA range 23-32 weeks) on day 1 of life. RESULTS: Valid measurements were obtained in 43/51 (87%) infants. Tidal breathing variables were analysed using multivariable linear regression. VD,MM/VT was negatively associated with GA after adjusting for birth weight Z score (p < 0.001, R(2) = 0.26). This association was primarily influenced by the appliance dead space. Despite similar VT/kg and VA/kg across all studied infants, respiratory rate and AMV/kg increased with GA. CONCLUSIONS: VD,app rather than anatomical VD is the major factor influencing increased VD,MM/VT at a younger GA. A volume guarantee setting of 4-5 ml/kg in the Dräger Babylog® 8000 plus ventilator may be inappropriate as a universal target across the GA range of 23-32 weeks. Differences between measured and set VT and the dependence of this difference on GA require further investigation.

Effect of maternal steroid on developing diaphragm integrity.

Antenatal steroids reduce the severity of initial respiratory distress of premature newborn babies but may have an adverse impact on other body organs. The study aimed to examine the effect of maternal steroids on postnatal respiratory muscle function during development and elucidate the mechanisms underlying the potential myopathy in newborn rats. Pregnant rats were treated with intramuscular injections of 0.5 mg/kg betamethasone 7 d and 3 d before birth. Newborn diaphragms were dissected for assessment of contractile function at 2 d, 7 d or 21 d postnatal age (PNA), compared with age-matched controls. The expression of myosin heavy chain (MHC) isoforms and atrophy-related genes and activity of intracellular molecular signalling were measured using quantitative PCR and/or Western blot. With advancing PNA, neonatal MHC gene expression decreased progressively while MHC IIb and IIx isoforms increased. Protein metabolic signalling showed high baseline activity at 2 d PNA, and significantly declined at 7 d and 21 d. Antenatal administration of betamethasone significantly decreased diaphragm force production, fatigue resistance, total fast fibre content and anabolic signalling activity (Akt and 4E-BP1) in 21 d diaphragm. These responses were not observed in 2 d or 7 d postnatal diaphragm. Results demonstrate that maternal betamethasone treatment causes postnatal diaphragmatic dysfunction at 21 d PNA, which is attributed to MHC II protein loss and impairment of the anabolic signalling pathway. Developmental modifications in MHC fibre composition and protein signalling account for the age-specific diaphragm dysfunction.

Pressure- versus volume-limited sustained inflations at resuscitation of premature newborn lambs.

BACKGROUND: Sustained inflations (SI) are advocated for the rapid establishment of FRC after birth in preterm and term infants requiring resuscitation. However, the most appropriate way to deliver a SI is poorly understood. We investigated whether a volume-limited SI improved the establishment of FRC and ventilation homogeneity and reduced lung inflammation/injury compared to a pressure-limited SI. METHODS: 131 d gestation lambs were resuscitated with either: i) pressure-limited SI (PressSI: 0-40 cmH2O over 5 s, maintained until 20 s); or ii) volume-limited SI (VolSI: 0-15 mL/kg over 5 s, maintained until 20 s). Following the SI, all lambs were ventilated using volume-controlled ventilation (7 mL/kg tidal volume) for 15 min. Lung mechanics, regional ventilation distribution (electrical impedance tomography), cerebral tissue oxygenation index (near infrared spectroscopy), arterial pressures and blood gas values were recorded regularly. Pressure-volume curves were performed in-situ post-mortem and early markers of lung injury were assessed. RESULTS: Compared to a pressure-limited SI, a volume-limited SI had increased pressure variability but reduced volume variability. Each SI strategy achieved similar end-inflation lung volumes and regional ventilation homogeneity. Volume-limited SI increased heart-rate and arterial pressure faster than pressure-limited SI lambs, but no differences were observed after 30 s. Volume-limited SI had increased arterial-alveolar oxygen difference due to higher FiO2 at 15 min (p = 0.01 and p = 0.02 respectively). No other inter-group differences in arterial or cerebral oxygenation, blood pressures or early markers of lung injury were evident. CONCLUSION: With the exception of inferior oxygenation, a sustained inflation targeting delivery to preterm lambs of 15 mL/kg volume by 5 s did not influence physiological variables or early markers of lung inflammation and injury at 15 min compared to a standard pressure-limited sustained inflation.

Lipopolysaccharide-induced weakness in the preterm diaphragm is associated with mitochondrial electron transport chain dysfunction and oxidative stress.

Diaphragmatic contractility is reduced in preterm lambs after lipopolysaccharide (LPS) exposure in utero. The mechanism of impaired fetal diaphragm contractility after LPS exposure is unknown. We hypothesise that in utero exposure to LPS induces a deficiency of mitochondrial complex activity and oxidative damage in the fetal diaphragm. To test this hypothesis, we used a well-established preterm ovine model of chorioamnionitis: Pregnant ewes received intra-amniotic (IA) saline or 10 mg LPS, at 2 d or 7 d prior to surgical delivery at 121 d GA (term = 150 d). The fetus was killed humanely immediately after delivery for tissue sampling. Mitochondrial fractions were prepared from the isolated diaphragm and mitochondrial electron transfer chain activities were evaluated using enzymatic assays. Oxidative stress was investigated by quantifying mitochondrial oxidative protein levels and determining antioxidant gene and protein (catalase, superoxide dismutase 2 and glutathione peroxidase 1) expression. The activity of the erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signalling pathway was examined by quantifying the Nrf2 protein content of cell lysate and nuclear extract. A 2 d LPS exposure in utero significantly decreased electron transfer chain complex II and IV activity (p<0.05). A 7 d LPS exposure inhibited superoxide dismutase 2 and catalase expression at gene and protein levels, and Nrf2 pathway activity (p<0.05) compared with control and 2 d LPS groups, respectively. Diaphragm mitochondria accumulated oxidised protein after a 7 d LPS exposure. We conclude that intrauterine exposure to LPS induces mitochondrial oxidative stress and electron chain dysfunction in the fetal diaphragm, that is further exacerbated by impairment of the antioxidant signalling pathway and decreased antioxidant activity.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests.

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Flow-cycled versus time-cycled synchronized ventilation for neonates.

BACKGROUND: Synchronized ventilation of neonates is standard care in industrialized countries. Both flow-cycled and time-cycled modes of synchronized ventilation are in widespread use for assisted ventilation of neonates. OBJECTIVES: To determine the effect of flow-cycled versus time-cycled synchronized ventilation on the risk of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA) in neonates requiring assisted ventilation. SEARCH STRATEGY: We used the standard methods of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Issue 4, 2009, PubMed (January 1966 to October 2009), EMBASE (January 1974 to October 2009) and CINAHL (January 1982 to October 2009). We checked references and cross-references from identified studies. Abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to October 2009) were handsearched. We placed no restrictions on language. SELECTION CRITERIA: Randomized or quasi-randomized clinical trials comparing flow-cycled with time-cycled synchronized endotracheal ventilation in neonates, reporting on at least one outcome of interest were eligible for inclusion in the review. DATA COLLECTION AND ANALYSIS: One author (SMS) searched the literature as described above. Selection of studies and data extraction were done separately by two authors (SMS and SKP). Any disagreements were resolved by discussion involving all authors. MAIN RESULTS: Only two small, short-term, randomized, individual cross-over trials involving a total of 19 preterm neonates met the inclusion criteria of this review. Both trials reported on lung mechanics and short-term respiratory physiology outcomes but not on clinical morbidities or mortality. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the safety and efficacy of flow-cycled compared to time-cycled synchronized ventilation in neonates. Large randomized clinical trials using a parallel-group design and reporting on clinically important outcomes are warranted.

High and low body temperature during the initiation of ventilation for near-term lambs.

AIMS: Recent literature suggests hypothermia may protect against lung injury. We evaluated body temperature as a variable in lung inflammation due to oxygenation and mechanical ventilation following delivery of near-term lambs. METHODS: Twin fetuses were randomized prior to delivery at 140 d GA (term 150 d): unventilated controls, normothermic ventilated with room air, normothermic ventilated with 100% oxygen, low temperature ventilated (target 35 degrees C) with 100% oxygen, and high temperature (target 40 degrees C) with 100% oxygen. Lambs were intubated for gentle mechanical ventilation (tidal volume 7-8ml/kg). Temperature targeting was with radiant warmers and plastic wrap for normothermia, with heat lamps for hyperthermia, and with ice packs for hypothermia. Lambs were euthanized after 2h mechanical ventilation. Post-mortem, bronchoalveolar lavage fluid and lung tissue samples were evaluated for inflammatory responses by measuring inflammatory cell counts, protein, myeloperoxidase, protein carbonyl, and pro-inflammatory cytokine mRNA. RESULTS: Target temperatures were achieved by 30min of age and tightly maintained for the 2h study. There were no differences in physiologic variables among groups except those directly resulting from study protocol-PaO2 from air vs. 100% oxygen and body temperature. Indicators of inflammation increased similarly in all ventilated groups compared to unventilated controls. CONCLUSION: Moderate hyperthermia or hypothermia did not affect lung injury responses to the initiation of ventilation at birth in near-term lambs.

Injury and inflammation from resuscitation of the preterm infant.

We review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is amplified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.