Bronchopulmonary dysplasia: Pathophysiology and potential anti-inflammatory therapies.

Inflammation of the preterm lungs is key to the pathogenesis of bronchopulmonary dysplasia (BPD), whether it arises as a consequence of intrauterine inflammation or postnatal respiratory management. This review explores steroidal and non-steroidal therapies for reducing neonatal pulmonary inflammation, aimed at treating or preventing BPD.

Association of prematurity, lung disease and body size with lung volume and ventilation inhomogeneity in unsedated neonates: a multicentre study.

BACKGROUND: Previous studies have suggested that preterm birth with or without subsequent chronic lung disease is associated with reduced functional residual capacity (FRC) and increased ventilation inhomogeneity in the neonatal period. We aimed to establish whether such findings are associated with the degree of prematurity, neonatal respiratory illness and disproportionate somatic growth. METHODS: Multiple breath washout measurements using an ultrasonic flowmeter were obtained from 219 infants on 306 test occasions during the first few months of life, at three neonatal units in the UK and Australia. Tests were performed during unsedated sleep in clinically stable infants (assigned to four exclusive diagnostic categories: term controls, preterm controls, respiratory distress syndrome and chronic lung disease). The determinants of neonatal lung function were assessed using multivariable, multilevel modelling. RESULTS: After adjustment for age and body proportions, the factors gestation, intrauterine growth restriction and days of supplemental oxygen were all significantly associated with a reduced FRC. In contrast, increased ventilation inhomogeneity (elevated lung clearance index) was only significantly associated with duration of supplemental oxygen. After adjusting for continuous variables, diagnostic category made no further contribution to the models. Despite using identical techniques, unexpected inter-centre differences occurred, associated with the equipment used; these did not alter the negative association of preterm delivery and disease severity with lung function outcomes. CONCLUSION: Reduction in FRC is independently associated with prematurity, intrauterine growth restriction and severity of neonatal lung disease. Determinants of lung function shortly after birth are highly complex in different disease groups.

Effect of I/E ratio on mean alveolar pressure during high-frequency oscillatory ventilation.

This study investigated factors contributing to differences between mean alveolar pressure (PA) and mean pressure at the airway opening (Pao) during high-frequency oscillatory ventilation (HFOV). The effect of the inspiratory-to-expiratory time (I/E) ratio and amplitude of oscillation on the magnitude of - Pao (Pdiff) was examined by using the alveolar capsule technique in normal rabbit lungs (n = 4) and an in vitro lung model. The effect of ventilator frequency and endotracheal tube (ETT) diameter on Pdiff was further examined in the in vitro lung model at an I/E ratio of 1:2. In both lung models, fell below Pao during HFOV when inspiratory time was shorter than expiratory time. Under these conditions, differences between inspiratory and expiratory flows, combined with the nonlinear relationship between resistive pressure drop and flow in the ETT, are the principal determinants of Pdiff. In our experiments, the magnitude of Pdiff at each combination of I/E, frequency, lung compliance, and ETT resistance could be predicted from the difference between the mean squared inspiratory and expiratory velocities in the ETT. These observations provide an explanation for the measured differences in mean pressure between the airway opening and the alveoli during HFOV and will assist in the development of optimal strategies for the clinical application of this technique.

Overexpression of TGF-alpha increases lung tissue hysteresivity in transgenic mice.

Increased transforming growth factor (TGF)-alpha has been observed in neonatal chronic lung disease. Lungs of transgenic mice that overexpress TGF-alpha develop enlarged air spaces and pulmonary fibrosis compared with wild-type mice. We hypothesized that these pathological changes may alter the mechanical coupling of viscous and elastic forces within lung parenchyma. Respiratory impedance was measured in open-chested, tracheostomized adult wild-type and TGF-alpha mice by using the forced oscillation technique (0.25-19.63 Hz) delivered by flexiVent (Scireq, Montreal, PQ). Estimates of airway resistance (Raw), inertance (I), and the coefficients of tissue damping (G(L)) and tissue elastance (H(L)) were obtained by fitting a model to each impedance spectrum. Hysteresivity (eta) was calculated as G(L)/H(L). There was a significant increase in eta (P < 0.01) and a trend to a decrease in H(L) (P = 0.07) of TGF-alpha mice compared with the wild-type group. There was no significant change in Raw, I, or G(L). Structural abnormality present in the lungs of adult TGF-alpha mice alters viscoelastic coupling of the tissues, as evidenced by a change in eta.

Effect of sighs on breathing memory and dynamics in healthy infants.

Deep inspirations (sighs) play a significant role in altering lung mechanical and airway wall function; however, their role in respiratory control remains unclear. We examined whether sighs act via a resetting mechanism to improve control of the respiratory regulatory system. Effects of sighs on system variability, short- and long-range memory, and stability were assessed in 25 healthy full-term infants at 1 mo of age [mean 36 (range 28-57) days] during quiet sleep. Variability was examined using moving-window coefficient of variation, short-range memory using autocorrelation function, and long-range memory using detrended fluctuation analysis. Stability was examined by studying the behavior of the attractor with use of phase-space plots. Variability of tidal volume (VT) and minute ventilation (VE) increased during the initial 15 breaths after a sigh. Short-range memory of VT decreased during the 50 breaths preceding a sigh, becoming uncorrelated (random) during the 10-breath presigh window. Short-range memory increased after a sigh for the entire 50 breaths compared with the randomized data set and for 20 breaths compared with the presigh window. Similar, but shorter duration, changes were noted in VE. No change in long-range memory was seen after a sigh. Coefficient of variation and range of points located within a defined attractor segment increased after a sigh. Thus control of breathing in healthy infants shows long-range stability and improvement in short-range memory and variability after a sigh. These results add new evidence that the role of sighs is not purely mechanical.

Developmental changes in diaphragm muscle function in the preterm and postnatal lamb.

RATIONALE: The preterm diaphragm is structurally and functionally immature, potentially contributing to an increased risk of respiratory distress and failure. We investigated developmental changes in contractile function and susceptibility to fatigue of the costal diaphragm in the fetal lamb to understand factors contributing to the risk of developing diaphragm dysfunction and respiratory disorders. We hypothesized that the functional capacity of the diaphragm will vary with maturational stage as will its susceptibility to fatigue. METHODS: Lambs were studied at 75, 100, 125, 145, 154, 168, and 200 days postconceptional age (term = 147 days). Lambs were euthanized (sodium pentobarbitone, 100 mg/kg) either at delivery or immediately prior to post-mortem for postnatal lambs. Contractile function was assessed on longitudinal strips of intact muscle fibers and the remaining tissue frozen in liquid nitrogen for analysis of myosin heavy chain (MHC) mRNA expression and protein content. RESULTS: Fetal development of diaphragm function was characterized by a significant increase in maximum specific force, increased susceptibility to fatigue, reduced twitch contraction times, and a progressive increase in MHCI and MHCII protein content. Postnatally, there was a progressive decrease in the susceptibility to fatigue that coincided with an increase in the MHC I:II protein ratio. CONCLUSION: These data indicate that the functional capacity of the diaphragm varies with maturational age and may be an important determinant of the susceptibility to preterm respiratory failure.

Antenatal exposure to chorioamnionitis affects lipid metabolism in 7-week-old sheep.

Antenatal exposure of the fetus to inflammation may alter postnatal organ development. In our previous work, we demonstrated that the fetal liver is involved in the systemic inflammation associated with chorioamnionitis, leading to metabolic changes. On the basis of these findings, we hypothesized that chorioamnionitis can lead to postnatal inflammation-related liver injury and disturbed lipid metabolism. Chorioamnionitis was induced in sheep by intra-amniotic injection of lipopolysaccharide (LPS) or saline at 90, 100 and 110 days of gestation. Liver homeostasis and lipid metabolism were analyzed at term and at 7 weeks of age. At term, hepatic T-lymphocytes and apoptotic hepatocytes were increased. In addition, hepatic cholesterol and triglyceride levels were decreased in LPS-exposed animals compared with controls. At 7 weeks of age, no hepatic inflammation could be detected. However, liver triglycerides and plasma cholesterol levels were increased in LPS-exposed animals relative to controls. The changes in lipid levels at 7 weeks of age were associated with increased leptin receptor mRNA levels, increased lipid peroxidation, increased expression of cytochrome c oxidase subunit 4 as a marker for mitochondrial function and increased circulating ceramide levels. These findings demonstrate that chorioamnionitis-mediated antenatal inflammation-related liver disturbances have long-lasting postnatal effects on lipid metabolism.

The cerebral critical oxygen threshold of ventilated preterm lambs and the influence of antenatal inflammation.

Perinatal inflammation is associated with adverse neurodevelopmental outcomes, which may be partly due to changes in the cerebral oxygen delivery/consumption relationship. We aimed to determine the critical oxygen delivery threshold of the brain of preterm, ventilated lambs and to determine whether the critical threshold is affected by exposure to inflammation in utero. Pregnant ewes received intra-amniotic injection of lipopolysaccharide or saline at 125 or 127 days of gestation. Pulmonary and systemic flow probes and catheters were surgically positioned in the fetus immediately before delivery at 129 days of gestation. After delivery, lambs were ventilated for 90 min using a positive end-expiratory pressure recruitment strategy. Cardio-respiratory variables and blood gases were measured regularly. Systemic and cerebral oxygen delivery, consumption (Fick), and extraction were calculated, and the relationship between cerebral delivery and consumption analyzed. Linear regression was used to define the transition or "critical" oxygen threshold as the point at which the slope of the oxygen delivery/consumption curve changed to be > 10°. Four subgroups were defined according to the calculated critical threshold. A total of 150 measurements were recorded in 18 lambs. Fetal cerebral oxygen consumption was increased by antenatal lipopolysaccharide (P < 0.05). The postnatal critical oxygen threshold was 3.6 ml·kg⁻¹·min⁻¹, corresponding to cerebral oxygen consumption of 0.73 ml·kg⁻¹·min⁻¹. High oxygen delivery and consumption were associated with increased pulmonary and carotid blood flow and systemic extraction compared with low oxygen delivery and consumption. No postnatal effect of antenatal inflammation was observed. Inflammation in utero increases fetal, but not postnatal, cerebral oxygen consumption. Adverse alterations to pulmonary blood flow can result in reduced cerebral blood flow, oxygen delivery, and consumption. Regardless of exposure to inflammation, there is a consistent postnatal relationship between cerebral oxygen delivery and consumption.

Nasal versus face mask for multiple-breath washout technique in preterm infants.

The large dead space associated with face masks might impede the accuracy and feasibility of multiple-breath washout (MBW) measurements in small infants. We asked if a low dead space nasal mask would provide measurements of resting lung volume and ventilation inhomogeneity comparable to those obtained with a face mask, when using the MBW technique. Unsedated preterm infants breathing without mechanical assistance and weighing between 1.50 and 2.49 kg were studied. Paired MBW tests with nasal and face masks were obtained using sulphur hexafluoride (SF(6)) as the tracer gas. The order of mask application was quasi-randomized. Bland-Altman method and intraclass correlation coefficient were used to analyze outcomes. Measurements were obtained in 20 infants with a mean (SD) postmenstrual age of 36 (1.4) w and a test weight of 2.0 (0.3) kg. The mean difference (95% CI) for nasal vs. face mask was -3.2 breaths/min (-6.2, -0.1 breaths/min) for respiratory rate, -1.0 ml/kg (-2.3, 0.3 ml/kg) for lung volume, 0.6 (0.1, 1.1) for lung clearance index, 0.2 (0.1, 0.3) for first to zeroeth moment ratio and 1.33 (0.6, 2.4) for second to zeroeth moment ratio. Paired measurements of lung volume showed acceptable agreement and good correlation, but there was poor agreement and poor correlation between indices of ventilation inhomogeneity obtained with the two masks. Functional dead space of the nasal mask was similar to that of the face mask despite its smaller water displacement volume. During MBW in infants below 2.5 kg body weight, a nasal mask results in comparable lung volume measurements. Indices of ventilation inhomogeneity may not be directly comparable using masks with different dead space.

High frequency ventilation.

The 1990s have seen a dramatic resurgence of interest in high frequency ventilation (HFV). The role of HFV in the rescue of infants failing conventional mechanical ventilation (CMV) is now relatively well established. However, the wider role of HFV in the routine management of respiratory failure in the newborn is more contentious. Recent trials in small numbers of infants suggest that HFV may be associated with significantly less chronic lung disease than CMV when used under optimal conditions (i.e. with a 'high-volume' strategy, from early in the disease and continued to the point of weaning). Further, clinical trials are now required to define the role of HFV more clearly.

Vitamin D deficiency in infants and young children born to migrant parents.

OBJECTIVE: To determine the current modes of presentation for the development of nutritional vitamin D deficiency in Melbourne children. METHODOLOGY: A retrospective descriptive review was undertaken of the case records of children less than 5 years of age discharged from three Melbourne hospitals with a diagnosis of vitamin D deficiency or hypocalcaemia from January 1992 to January 1994. RESULTS: The study identified 13 infants and young children whose hospital admission was related to nutritional vitamin D deficiency. Significant morbidity and a broad spectrum of biochemical and clinical features were noted at presentation. All children had migrant parents and were either exclusively or predominantly breast fed. Ten infants (77%) were less than 1 year at presentation. Associated deficiencies of iron and B12 were present in five cases. Of the five mothers tested, serum 25-hydroxy vitamin D3 was low in four. CONCLUSIONS: Nutritional vitamin D deficiency is a continuing health problem in infants and young children born to migrant parents living in Melbourne. Paediatricians, obstetricians and general practitioners, particularly those managing women and infants from migrant communities, should be aware of this condition. Vitamin D supplementation to high-risk women during pregnancy and to their infants should be considered.

Functional residual capacity measurements in healthy infants: ultrasonic flow meter versus a mass spectrometer.

Accurate, reproducible and portable bedside monitoring of lung volume could potentially facilitate the early recognition of both under and overinflation of the lungs in ventilated and nonventilated subjects. This study asked whether a prototype portable ultrasonic flow meter provided valid and reliable measurements of functional residual capacity (FRCUS) when compared to those obtained using a mass spectrometer (FRCMS) in nonventilated healthy infants. Paired, randomised measurements of FRCMS and FRCUS were obtained using the sulphur hexafluoride (SF6) multiple-breath washout technique in 23 healthy infants with a median (range) postnatal age of 34.6 (1.3-92.6) weeks and weight of 8.3 (3.9-11.7) kg. FRCUS was on average 5.7%, (95% CI: 1.0-10.4%) less than FRCMS equating to a difference of approximately 1 mL x kg(-1). The 95% limits of agreement (LA) between the two techniques were relatively wide (95% LA: -17.5% to 29%), although in keeping with previously reported within-patient variability for lung volume measurements. There was no significant difference between the within subject coefficient of variation for FRCMS (3.7%) and FRCUS (5.2%). The ultrasonic flow meter used in this study provides repeatable measurements of functional residual capacity in spontaneously breathing healthy infants that approximate those obtained during mass spectrometry.

Induction of procollagen processing in fibroblast cultures by neutral polymers.

In cultures of dermal fibroblasts, procollagen and the intermediates pC- and pN-collagen accumulated in the culture medium with little further processing to collagen. When polyethylene glycol (PEG) or other neutral polymers were added to fibroblast culture medium, no collagen or procollagen was found in the medium, but all the collagen was associated with the cell layer. The type I procollagen was fully processed to collagen with an initial transient accumulation of pN-collagen, and the processed collagen formed covalently cross-linked dimers. The presence of pepsin-sensitive COOH-terminal telopeptides and the accumulation of pN-collagen in PEG-treated cultures of dermatosparactic fibroblasts indicated that it was likely that processing occurred via the correct in vivo propeptidase activities. At the levels used in this study, PEG did not have any toxic effect during the incubation period on the fibroblasts in culture, since the amount of total protein synthesis was not altered by addition of PEG to cultures. However, the level of collagen production was reduced to about half, indicating that there was increased degradation or that the released collagen propeptides or the accumulation of processed collagen in association with the cells exerted a feedback regulation on collagen synthesis. Addition of neutral polymers to the culture medium provided a simple means of achieving complete and accurate processing of procollagen which more closely resembled the in vivo process.

In vitro performance characteristics of high-frequency oscillatory ventilators.

This study aimed to examine the performance characteristics of four high-frequency oscillatory-type ventilators, using an in vitro model of the intubated neonatal respiratory system. Each ventilator was examined across its operative range of settings and at varying model lung compliance (C) and resistance. The oscillatory pressure waveform was measured at the airway opening (Pao). Tidal volume (VT) and flow were determined from pressure changes within the model lung (DeltaPA). The spectral content of the Pao waveform differed between ventilators. The maximum ventilator VT ranged from 3.7 to 11.1 ml at 15 Hz and a mean airway pressure (Paw) of 12 cm H(2)O to oscillate a model lung (C = 0.4 ml/cm H(2)O) through a 3.0-mm internal diameter (i.d.) endotracheal tube (ETT). A small drop in C was associated with a decrease in VT and marked increase in DeltaPA from 0.1 to 0.8 ml/cm H(2)O. The influence of C on VT and DeltaPA and the pressure cost of ventilation (DeltaPA/f.VT(2)) was dependent on the oscillatory frequency, ETT inner diameter, and the specific ventilator used. Substantive differences exist between oscillatory ventilators that need to be considered in their clinical application. The rapid establishment of optimal lung volume and oscillatory frequency is important in minimizing barotrauma during high-frequency oscillatory ventilation.

Reliable tidal volume estimates at the airway opening with an infant monitor during high-frequency oscillatory ventilation.

OBJECTIVE: To assess the suitability of a hot-wire anemometer infant monitoring system (Florian, Acutronic Medical Systems AG, Hirzel, Switzerland) for measuring flow and tidal volume (Vt) proximal to the endotracheal tube during high-frequency oscillatory ventilation. DESIGN: In vitro model study. SETTING: Respiratory research laboratory. SUBJECT: In vitro lung model simulating moderate to severe respiratory distress. INTERVENTION: The lung model was ventilated with a SensorMedics 3100A ventilator. Vt was recorded from the monitor display (Vt-disp) and compared with the gold standard (Vt-adiab), which was calculated using the adiabatic gas equation from pressure changes inside the model. MEASUREMENTS AND MAIN RESULTS: A range of Vt (1-10 mL), frequencies (5-15 Hz), pressure amplitudes (10-90 cm H2O), inspiratory times (30% to 50%), and Fio2 (0.21-1.0) was used. Accuracy was determined by using modified Bland-Altman plots (95% limits of agreement). An exponential decrease in Vt was observed with increasing oscillatory frequency. Mean DeltaVt-disp was 0.6 mL (limits of agreement, -1.0 to 2.1) with a linear frequency dependence. Mean DeltaVt-disp was -0.2 mL (limits of agreement, -0.5 to 0.1) with increasing pressure amplitude and -0.2 mL (limits of agreement, -0.3 to -0.1) with increasing inspiratory time. Humidity and heating did not affect error, whereas increasing Fio2 from 0.21 to 1.0 increased mean error by 6.3% (+/-2.5%). CONCLUSIONS: The Florian infant hot-wire flowmeter and monitoring system provides reliable measurements of Vt at the airway opening during high-frequency oscillatory ventilation when employed at frequencies of 8-13 Hz. The bedside application could improve monitoring of patients receiving high-frequency oscillatory ventilation, favor a better understanding of the physiologic consequences of different high-frequency oscillatory ventilation strategies, and therefore optimize treatment.

Cell-layer-associated proteolytic cleavage of the telopeptides of type I collagen in fibroblast culture.

In human skin fibroblast cultures a fraction of the procollagen that was processed to collagen and remained in the cell layer was further proteolytically modified by removal of both N- and C-terminal telopeptides. The proteolytic activity was associated with the cell layer, since secreted collagens were found always to contain intact telopeptides. The inclusion of neutral polymers, which caused the accumulation of the collagen in the cell layer [Bateman, Cole, Pillow & Ramshaw (1986) J. Biol. Chem. 261, 4198-4203], made the telopeptide cleavage more apparent in those cells which expressed the proteolytic activity. The extent of this cleavage was variable from cell culture to cell culture and between experiments with the same fibroblast line. The proteolytic activity was pH-dependent; cleavage was greatest at a culture-medium pH of 7.5 and 8.0 and was completely inhibited at a culture-medium pH of 7.0 and 6.5. The activity was significantly inhibited by soybean trypsin inhibitor, an elastase-specific inhibitor (N-acetylalanylalanylprolylvalylchloromethane) and the thrombin inhibitor hirudin. This cell-associated proteolytic activity may play a role in collagen degradation by removing the telopeptides, which are the primary sites of collagen cross-linking, thus destabilizing the collagen matrix sufficiently to render it susceptible to further proteolytic breakdown.

Effects of gestation and antenatal steroid on airway and tissue mechanics in newborn lambs.

The aim of this study was to partition airway and parenchymal mechanics in newborn lambs at different gestations and following variable exposure to antenatal maternal betamethasone using the forced oscillation technique (FOT). Pulmonary impedance data were collected in 37 sedated and intubated apneic lambs with the FOT between 0.5 and 20 Hz and fitted by a model to estimate airway resistance (Raw) and inertance (Iaw) and the coefficients of tissue resistance (GL) and elastance (HL). Total respiratory resistance (Rrs) was also determined during tidal ventilation by using the multiple linear regression technique. Advancing gestation or increasing antenatal steroid exposure had no clinically significant effect on the values of Raw and Iaw, whereas Rrs and both GL and HL decreased markedly. There was a decrease in tissue hysteresivity (GL/HL) with repeated antenatal steroid exposure. Partitioning of lung mechanics highlights the dominant contribution of the tissues to the total respiratory resistance in the immature ovine lung. Clinically relevant changes in lung mechanics associated with structural and functional maturation of the immature ovine lung are primarily confined to the tissue compartment.