An in vitro investigation of the inflammatory response to the strain amplitudes which occur during high frequency oscillation ventilation and conventional mechanical ventilation

The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College Londo

Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births.

BACKGROUND: Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. METHODS: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. FINDINGS: Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. CONCLUSIONS: We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions

P07 Interleukin response to cyclical mechanical stretch with models of different neonatal ventilation modes

Aims: A follow-up study of a randomised trial, the United Kingdom Oscillation Study (UKOS) comparing conventional ventilation (CMV) to high frequency oscillation ventilation (HFOV) immediately after birth,(1) demonstrated lung function was significantly better at age 11–14 years in the HFOV group.(2) During CMV, the inflation volumes are approximately two to three times larger than those during HFOV. Cyclical mechanical stretch (CMS) applied to A549 cells (type II alveolar cell analogues) has been shown to result in interleukin-8 release which increases with increasing basement membrane stretch.(3) We, therefore, hypothesised that during ‘CMV’ there would be greater interleukin release compared with ‘HFOV’, from type II alveolar cells. Methods: A549 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) on flexible collagen based plates. Adherent cells were subjected to CMS conditions modelling CMV or HFOV using a Flexcell 4000T machine. Conditioned medium was analysed by ELISA to determine IL-6 and IL-8 levels following CMS for two and four hours. The results were compared with levels measured from control A549 cells that were unstretched or constantly stretched to 5% and 20% over the same time course. Results: The mean fold increase of IL-8 release compared with the un-stretched control samples was higher in the ‘CMV’ compared with the ‘HFOV’ model at two hours (1.59, standard deviation (SD) 0.17 versus 0.91, SD 0.31, p<0.001) and four hours (2.55, SD 0.82 versus 1.45 SD 0.16, p=0.001). The mean fold increase of IL-6 release compared with the un-stretched control samples were higher at four hours in the ‘CMV’ compared with the ‘HFOV’ model (1.36, SD 0.13 versus 1.15, SD 0.06, p<0.001). Conclusion: Conditions modelling CMV resulted in greater interleukin release in lung epithelial cells relative to those modelling HFOV. We propose that this may disrupt lung development in neonates supported by CMV rather than HFOV resulting in inferior lung function at follow-up