Abstract: RATIONALE: Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support. OBJECTIVES: To evaluate the injury response to a brief period of large tidal volume (Vt) ventilation, simulating neonatal resuscitation in preterm neonates. METHODS: Preterm lambs (129 d gestation; term is150 d) were ventilated (Vt = 15 ml/kg, no positive end-expiratory pressure) for 15 minutes to simulate delivery room resuscitation, either with the placental circulation intact (fetal resuscitation [ FR]) or after delivery (neonatal resuscitation [NR]). After the initial 15 minutes, lambs received surfactant and were maintained with either ventilatory support (FR-VS and NR-VS) or placental support (FR-PS) for 2 hours, 45 minutes. A control group received no resuscitation and was maintained with placental support. Samples of bronchoalveolar lavage fluid, lung, and liver were analyzed. MEASUREMENTS AND MAIN RESULTS: Inflammatory cells and protein in bronchoalveolar lavage fluid, heat shock protein-70 immunostaining, IL-1beta, IL-6, IL-8, monocyte chemotactic protein-1, serum amyloid A (SAA)-3, Toll-like receptor (TLR)-2, and TLR4 mRNA in the lungs were increased in the FR-PS group compared with control animals. There were further elevations in neutrophils, IL-6, and IL-8 mRNA in the FR-VS and NR-VS groups compared with FR-PS. SAA3, TLR2, and TLR4 mRNA increased in the liver in all resuscitation groups relative to control animals. CONCLUSIONS: Ventilation for 15 minutes with a Vt of 15 ml/kg initiates an injurious process in the preterm lung and a hepatic acute-phase response. Subsequent ventilatory support causes further increases in some injury indicators.
Abstract: RATIONALE: The technique used to provide continuous positive airway pressure (CPAP) to the newborn may influence lung function and breathing efficiency. OBJECTIVES: To compare differences in gas exchange physiology and lung injury resulting from treatment of respiratory distress with either bubble or constant pressure CPAP and to determine if the applied flow influences short-term outcomes. METHODS: Lambs (133 d gestation; term is 150 d) born via cesarean section were weighed, intubated, and treated with CPAP for 3 hours. Two groups were treated with 8 L/minute applied flow using the bubble (n = 12) or the constant pressure (n = 12) technique. A third group (n = 10) received the bubble method with 12 L/minute bias flow. Measurements at study completion included arterial blood gases, oxygraphy, capnography, tidal flow, multiple breath washout, lung mechanics, static pressure-volume curves, and bronchoalveolar lavage fluid protein. MEASUREMENTS AND MAIN RESULTS: Birth weight and arterial gas variables at 15 minutes were comparable. Flow (8 or 12 L/min) did not influence the 3-hour outcomes in the bubble group. Bubble technique was associated with a higher pH, Pa(O2), oxygen uptake, and area under the flow-volume curve, and a decreased alveolar protein, respiratory quotient, Pa(CO2), and ventilation inhomogeneity compared with the constant pressure group. CONCLUSIONS: Compared with constant pressure technique, bubble CPAP promotes enhanced airway patency during treatment of acute postnatal respiratory disease in preterm lambs and may offer protection against lung injury.
Abstract: This review considers measurement of global and regional ventilation inhomogeneity (VI) in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy (CLDI). We focus primarily on multiple-breath inert gas washout (MBW) and electrical impedance tomography (EIT). The literature is critically reviewed and the relevant methods, equipment, and studies are summarized, including the limitations and strengths of individual techniques, together with the availability and appropriateness of any reference data. There has been a recent resurgence of interest in using MBW to monitor lung function within individuals and between different groups. In the mechanically ventilated, sedated, and paralyzed patient, VI indices can identify serial changes occurring following exogenous surfactant. Similarly, global VI indices appear to be increased in infants with CLDI and to differentiate between infants without lung disease and those with mild, moderate, and severe lung disease following preterm birth. While EIT is a relatively new technique, recent studies suggest that it is feasible in newborn infants, and can quantitatively identify changes in regional lung ventilation following alterations to ventilator settings, positive end expiratory pressure (PEEP), and administration of treatments such as surfactant. As such, EIT represents one of the more exciting prospects for continuous bedside pulmonary monitoring. For both techniques, there is an urgent need to establish guidelines regarding data collection, analysis, and interpretation in infants both with and without CLDI.
Abstract: This is the second paper in a review series that will summarize available data and discuss the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses the expansive subject of measurements of lung volume using plethysmography and gas dilution/washout techniques. Following orientation of the reader to the subject area, we focus our comments on areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. Measurements of lung volume are important both for assessing growth and development of lungs in health and disease, and for interpreting volume-dependent lung function parameters such as respiratory compliance, resistance, forced expiratory flows, and indices of gas-mixing efficiency. Acute neonatal lung disease is characterized by severely reduced functional residual capacity (FRC), with treatments aimed at securing optimal lung recruitment. While FRC may remain reduced in established chronic lung disease of infancy, more commonly it becomes normalized or even elevated due to hyperinflation, with or without gas-trapping, secondary to airway obstruction. Ideally, accurate and reliable bedside measurements of FRC would be feasible from birth, throughout all phases of postnatal care (including assisted ventilation), and during subsequent long-term follow-up. Although lung volume measurements in extremely preterm infants were described in a research environment, resolution of several issues is required before such investigations can be translated into routine clinical monitoring.
Abstract: This is the fifth paper in a review series that summarizes available data and critically discusses the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy (CLDI). This review focuses on respiratory mechanics, including chest-wall and tissue mechanics, obtained in the intensive care setting and in infants during unassisted breathing. Following orientation of the reader to the subject area, we focused comments on areas of enquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically with respect to relevant methods, equipment and study design, limitations and strengths of different techniques, and availability and appropriateness of reference data. Recommendations to guide future investigations in this field are provided. Numerous different methods have been used to assess respiratory mechanics with the aims of describing pulmonary status in preterm infants and assessing the effect of therapeutic interventions such as surfactant treatment, antenatal or postnatal steroids, or bronchodilator treatment. Interpretation of many of these studies is limited because lung volume was not measured simultaneously. In addition, populations are not comparable, and the number of infants studied has generally been small. Nevertheless, results appear to support the pathophysiological concept that immaturity of the lung leads to impaired lung function, which may improve with growth and development, irrespective of the diagnosis of chronic lung disease. To fully understand the impact of immaturity on the developing lung, it is unlikely that a single parameter such as respiratory compliance or resistance will accurately describe underlying changes. Assessment of respiratory mechanics will have to be supplemented by assessment of lung volume and airway function. New methods such as the low-frequency forced oscillation technique, which differentiate the tissue and airway components of respiratory mechanics, are likely to require further development before they can be of clinical significance.
Abstract: This paper is the fourth in a series of reviews that will summarize available data and critically discuss the potential role of lung-function testing in infants with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses information derived from tidal breathing measurements within the framework outlined in the introductory paper of this series, with particular reference to how these measurements inform on control of breathing. Infants with acute and chronic respiratory illness demonstrate differences in tidal breathing and its control that are of clinical consequence and can be measured objectively. The increased incidence of significant apnea in preterm infants and infants with chronic lung disease, together with the reportedly increased risk of sudden unexplained death within the latter group, suggests that control of breathing is affected by both maturation and disease. Clinical observations are supported by formal comparison of tidal breathing parameters and control of breathing indices in the research setting.
Abstract: Continuous positive airway pressure (CPAP) is often used to provide noninvasive respiratory support in infants with Respiratory distress syndrome. The recruitment of atelectatic lung and appropriate lung volume maintenance are vital to the success of CPAP treatment. The noisy pressure waveform of bubble CPAP superimposed on pressure fluctuations as a result of spontaneous breathing may promote airway opening events as a result of stochastic resonance. The magnitude and the frequency of the superimposed noise are critical to this process. We hypothesized that the applied bias flow and mechanical properties of the lung would influence the magnitude and the frequency content of the noise transmitted to the lung. The effect of varying bias flow (6-10 L/min) and lung compliance (0.1-1.5 mL/cm H(2)O) on the mean, range, and frequency content of the pressure fluctuations at the airway opening and within the lung was evaluated in an in vitro model lung. Increasing bias flow increased the mean and the magnitude of pressure oscillations at the airway opening and in the lung model. Decreasing compliance of the lung model increased the magnitude and the frequency content of pressure oscillations in the model lung. Lung mechanics and applied flow influence the magnitude of the noise superimposed on the transmitted pressure waveform and may influence lung volume recruitment in bubble CPAP.
Abstract: OBJECTIVE: Overview of the mechanisms governing gas transport, mechanical factors influencing the transmission of pressure and flow to the lung, and the measurement of lung mechanics during high-frequency oscillatory ventilation (HFOV) in acute respiratory distress syndrome. DATA SOURCES AND STUDY SELECTION: Studies indexed in PubMed illustrating key concepts relevant to the manuscript objectives. Pressure transmission during HFOV in the adult lung was simulated using a published theoretical model. DATA SYNTHESIS: Gas transport during HFOV is complex and involves a range of different mechanisms, including bulk convection, turbulence, asymmetric velocity profiles, pendelluft, cardiogenic mixing, laminar flow with Taylor dispersion, collateral ventilation, and molecular diffusion. Except for molecular diffusion, each mechanism involves generation of convective fluid motion, and is influenced by the mechanical characteristics of the intubated respiratory system and the ventilatory settings. These factors have important consequences for the damping of the oscillatory pressure waveform and the drop in mean pressure from the airway opening to the lung. New techniques enabling partitioning of airway and tissue properties are being developed for measurement of lung mechanics during HFOV. CONCLUSIONS: Awareness of the different mechanisms governing gas transport and the prevailing lung mechanics during HFOV represents essential background for the physician planning to use this mode of ventilation in the adult patient. Monitoring of lung volume, respiratory mechanics, and ventilation homogeneity may facilitate individual optimization of HFOV ventilatory settings in the future.
Abstract: The recent trend toward development of noninvasive methods that can accurately evaluate the lung periphery has particular relevance for the predominantly parenchymal nature of neonatal respiratory disease. Concerns regarding the safety of sedating newborn (especially preterm) infants have also stimulated a drive toward measurements obtained during natural sleep. This study aimed to adapt existing methodology for the low-frequency forced oscillation technique to obtain partitioned measurements of airway and parenchymal mechanics during unsedated, quiet sleep in newborn infants without a history of previous respiratory disease. A face mask was positioned over the infant's mouth and nose and a brief (4-5 s) breathing pause was induced by evoking the Hering-Breuer reflex via end-inspiratory occlusion at raised lung volume (airway opening occluded at 2 kPa). Airway opening pressure and flow were measured while a pseudorandom noise (2-14 Hz) was applied to the airway. Acceptable pulmonary impedance data were collected in 11 of the 12 infants studied (34.1-42.6 wk postmenstrual age, 1.9-3.9 kg body weight) on 17 (total of 20) occasions. Airway parameters (resistance and inertance) and respiratory tissue parameters were calculated from the resultant impedance spectra. Tissue resistance and tissue elastance decreased with increasing body length albeit at different rates such that hysteresivity (tissue resistance/tissue elastance) also decreased. There was a trend toward reduction in airway resistance with increasing length. Measurements of lung function are feasible in the unsedated newborn infant using low-frequency forced oscillations and confirm the important contribution of tissue resistance to lung mechanics in the developing lung.
Abstract: 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.
Abstract: OBJECTIVES: To determine whether the low-frequency forced oscillation technique (LFOT) can track changes in lung mechanics resulting from prophylactic intratracheal surfactant and a volume recruitment-derecruitment maneuver during high-frequency oscillatory ventilation (HFOV) and how this relates to the damping of the tracheal pressure waveform (P(tr)). DESIGN: Interventional laboratory study. SETTING: Rural animal research facility in Western Australia. SUBJECTS: Sedated newborn preterm lambs. INTERVENTIONS: Two separate studies were performed. Study 1 involved a volume recruitment-derecruitment maneuver during HFOV using stepwise changes (4 cm H(2)O) in mean airway opening pressure (P(ao), n = 5). Study 2 involved instillation of 4 mL/kg fetal lung fluid (n = 5) or exogenous surfactant (n = 8) at birth and subsequent intermittent mandatory ventilation for 40 mins. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were recorded every 10 mins and ventilation was appropriately adjusted to achieve moderate hypercarbia (Paco(2), 50-60 mm Hg). Lung mechanics were measured using LFOT 10 mins following each adjustment in P(ao) in parallel with measurements of P(tr) and tidal volume (study 1) or after 40 mins (study 2). Both the recruitment-derecruitment maneuver and prophylactic surfactant administration achieved similar improvements (decrease) in tissue impedance (Z(ti)). The coefficient of tissue resistance (G) decreased more than the coefficient of tissue elastance (H), consistent with improved homogeneity of the lung tissue compartment as lung volume was recruited. Minimum Z(ti) coincided with minimum tracheal pressure amplitude (DeltaP(tr)) on the deflation limb of the volume recruitment-derecruitment maneuver during HFOV. There was a linear relationship between DeltaP(tr) and H. CONCLUSIONS: In the preterm lamb, the LFOT can successfully detect changes in lung mechanics resulting from volume recruitment maneuvers during both HFOV and ventilation at conventional rates and may provide information on ventilation inhomogeneity. Minimization of Z(ti) is crucial to damping of P(tr) and may limit potential barotrauma to proximal alveolar units during establishment of HFOV.
Abstract: 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.
Abstract: Antenatal exposure to intra-amniotic (i.a.) endotoxin initiates a complex series of events, including an inflammatory cascade, increased surfactant production, and alterations to lung structure. Using the low frequency forced oscillation technique as a sensitive tool for measurement of respiratory impedance, we aimed to determine which factors contributed most to measured changes in lung mechanics. Respiratory impedance data obtained from sedated preterm lambs exposed to either i.a. injection with saline or 20 mg of endotoxin 1, 2, 4, and 15 days before delivery at 125 days gestation were studied, and association with indexes of standard lung morphometry, inflammatory response, and alveolar surfactant-saturated phosphatidylcholine (Sat PC) pool size was demonstrated. Reduction in tissue impedance with increasing interval between exposure and delivery was evident as early as 4 days after i.a. endotoxin injection, coinciding with resolution of inflammatory reaction, increased alveolar surfactant pools, and contribution of alveolar ducts to the parenchymal fraction, and a later decrease in the tissue component of the parenchymal fraction. Decreases in tissue damping (resistance) were more marked than decreases in tissue elastance. Log alveolar Sat PC accounted for most variability in tissue damping (88.9%) and tissue elastance (73.4%), whereas tissue fraction contributed 2 and 6.4%, respectively. The alveolar Sat PC pool size was the sole factor contributing to change in tissue hysteresivity. No changes were observed in airway resistance. Despite the complex cascade of events initiated by antenatal endotoxin exposure, variability in lung tissue mechanics is associated primarily with changes in alveolar Sat PC pool and lung morphology.
Abstract: During the last 30 years, there has been an unexplained trend toward declining values for plethysmographic assessments of lung volume at functional residual capacity (FRC) in infants. The aim of this study was to compare data collected from healthy infants using contemporary equipment with published reference data and to explore reasons for discrepancies. Lung volumes were measured in 32 healthy infants (age, 4-93 weeks; weight, 3.9-12.4 kg) using a new, commercially available infant plethysmograph. Mean (SD) FRC was 19.6 (3.4) ml/kg (within subject coefficient of variation 3.4 [2.3%]), which was on average 7.0 [3.5] ml/kg and 2.3 [1.2] SD (Z) scores lower than the recently collated reference data from an American Thoracic Society task force. A total of 66% of these healthy infants had a FRC that was below the predicted normal range. Comparison of equipment, software, and protocols with those from previous reports revealed the importance of minimization of dead space and of adequate subtraction of all compressible occluded volume when calculating FRC in infants. These findings emphasize the need to establish reference data for lung function tests in infants that are appropriate for the equipment and protocols in current use.
Abstract: In the healthy animal lung, high-frequency oscillatory ventilation (HFOV) achieves effective ventilation at tidal volumes (V(T)) less than or equal to dead space while generating very small pressure fluctuations in the alveolar spaces (deltaP(A)). We hypothesized that the respiratory mechanical parameters influence the magnitude of the intrapulmonary pressure fluctuations during HFOV. A computer model of the neonatal respiratory system was used to examine the independent effects of altering the compliance, nonlinear and linear resistance, and inertance of the respiratory system on V(T), and cyclic intrapulmonary pressures under homogeneous and heterogeneous conditions. The impact of low compliance on the transmission of pressure from the airway opening to the trachea (deltaP(tr)/deltaP(ao)) and alveolar compartment (deltaP(A)/deltaP(ao)) during HFOV was determined in a preterm lamb lung model. In the computer model, an increase in flow-dependent resistance to simulate changing the internal diameter of the tracheal tube from 4.0 mm to 2.5 mm halved the transmission of the pressure waveform to both the carina and the alveolar compartment. Increased peripheral resistance was associated with an increased deltaP(tr)/deltaP(ao) but a reduction in deltaP(A)/deltaP(ao). The deltaP(A)/deltaP(ao) also decreased with increasing alveolar compartment compliance, a finding that was verified in the preterm lamb lung. There was an exponential decrease in the magnitude of deltaP(A1) compared with deltaP(A2) as the ratio of the time constants of the two parallel compartments (tau(1)/tau(2)) increased in the heterogeneous computer lung model. The transmission of driving pressure amplitude to both the proximal airways and lung tissue during HFOV is dependent on lung mechanics and may be greater in the poorly compliant lung than that observed previously in experiments on healthy animals.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
