Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs

BACKGROUND: Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF), cysteine rich-61 (CYR61) and early growth response 1 (EGR1), were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. METHODS: To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term approximately 147 d) were resuscitated with an injurious ventilation strategy (V(T) 20 mL/kg for 15 min) then gently ventilated (5 mL/kg) for 15, 30, 60 or 120 min (n = 4 in each). To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each) were ventilated from birth with a V(T) of 5 (VG5) or 10 mL/kg (VG10) for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. RESULTS: CTGF, CYR61 and EGR1 lung mRNA levels were increased approximately 25, 50 and 120-fold respectively (p < 0.05), within 30 minutes of injurious ventilation. VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1- , IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance. CONCLUSION: CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes

Elective high-frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: an individual patient data meta-analysis

<p>Abstract</p> <p>Background</p> <p>Despite the considerable amount of evidence from randomized controlled trials and meta-analyses, uncertainty remains regarding the efficacy and safety of high-frequency oscillatory ventilation as compared to conventional ventilation in the early treatment of respiratory distress syndrome in preterm infants. This results in a wide variation in the clinical use of high-frequency oscillatory ventilation for this indication throughout the world. The reasons are an unexplained heterogeneity between trial results and a number of unanswered, clinically important questions. Do infants with different risk profiles respond differently to high-frequency oscillatory ventilation? How does the ventilation strategy affect outcomes? Does the delay – either from birth or from the moment of intubation – to the start of high-frequency oscillation modify the effect of the intervention? Instead of doing new trials, those questions can be addressed by re-analyzing the individual patient data from the existing randomized controlled trials.</p> <p>Methods/Design</p> <p>A systematic review with meta-analysis based on individual patient data. This involves the central collection, validation and re-analysis of the original individual data from each infant included in each randomized controlled trial addressing this question.</p> <p>The study objective is to estimate the effect of high-frequency oscillatory ventilation on the risk for the combined outcome of death or bronchopulmonary dysplasia or a severe adverse neurological event. In addition, it will explore whether the effect of high-frequency oscillatory ventilation differs by the infant's risk profile, defined by gestational age, intrauterine growth restriction, severity of lung disease at birth and whether or not corticosteroids were given to the mother prior to delivery. Finally, it will explore the importance of effect modifying factors such as the ventilator device, ventilation strategy and the delay to the start of high-frequency ventilation.</p> <p>Discussion</p> <p>An international collaborative group, the PreVILIG Collaboration (Prevention of Ventilator Induced Lung Injury Group), has been formed with the investigators of the original randomized trials to conduct this systematic review. In the field of neonatology, individual patient data meta-analysis has not been used previously. Final results are expected to be available by the end of 2009.</p

Late Outcomes of a Randomized Trial of High-Frequency Oscillation in Neonates

BACKGROUND: Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding. METHODS: We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF(75)). RESULTS: The HFOV group had superior results on a test of small-airway function (z score for FEF(75), −0.97 with HFOV vs. −1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes. CONCLUSIONS: In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.