Management of Respiratory Distress Syndrome in Preterm Infants In Wales: A Full Audit Cycle of a Quality Improvement Project

Respiratory Distress Syndrome (RDS) is the commonest diagnosis after premature birth. We aimed to audit clinical practices before and after introduction of a national guideline in Wales on RDS management. Anonymised, prospective data on all infants born at <34 weeks of gestation and cared for at one of the participating neonatal units in Wales were collected in two six-month time periods in 2015 and 2018. A national guideline was introduced in 2016 by the Wales Neonatal Network. Data collection included areas of antenatal management, delivery room stabilisation, invasive and non-invasive respiratory support, surfactant treatment and elements of supportive care. Univariate and multivariate methods were used to compare data between the two epochs. Comparing care before and after introduction of the national guideline, areas of significant improvement include use of targeted tidal volume ventilation, use of caffeine therapy, oxygen therapy post-surfactant and increasing early use of parenteral nutrition. Areas of poorer management included levels of positive end expiratory pressures and timing of introduction of enteral feeds. Little variation was seen between level two and three units, although gestational age was a significant independent variable for several practices, including delayed cord clamping, stabilisation with intubation, early enteral feeding and caffeine administration. A national guideline for management of RDS in Wales has significantly improved practice in several areas. However, despite a large volume of high-quality evidence and robust guidance, there remains a significant variation in some elements of best practice for RDS management. Further work should focus on education and training, especially for elements requiring cross-departmental work.


Methods
Prospective, anonymised audits of the management of RDS in all preterm infants born at <34 weeks gestational age and cared for in a participating neonatal unit in Wales were undertaken. The first round of data collection was undertaken over a six-month period between September 2014 and March 2015. Following the first round of data collection, a Wales Neonatal Network Guideline on the Management of RDS, based on the European Consensus Guideline, was introduced in July 2016 and disseminated throughout all Welsh neonatal units 10 . This represented the best-practice document for the management of RDS in infants born at <34 weeks gestational age, concentrating on areas which were supported by Grade A evidence (http://www.gradeworkinggroup.org/). A second round of data collection was undertaken between March 2018 and September 2018, aiming to assess changes in practice by comparing the two cohorts.
Patient recruitment and data collection was undertaken through the Welsh Research and Education Network (WREN; www.wrenpaediatrics.com) 11 . All infants who were born at <34 weeks gestational age and were cared for in a Welsh neonatal unit were eligible for the study and all units were approached to participate.
The audit proforma was based upon the recommendations in the European Consensus Guideline on the Management of RDS in Preterm Infants 2013, and concentrated on management areas which were supported by Grade A evidence 9 . An update on the Consensus Guideline was released in 2016 12 , which did not alter the main recommendations, therefore the same proforma was used for both data collection cycles. The proforma (Supplementary Table 1) collected data on 26 items in six domains including infant demographics, antenatal management, delivery room stabilisation, surfactant management, non-invasive ventilation management, mechanical ventilation strategies and other supportive care used (Supplementary Table 1 Descriptive statistics for all variables were produced. For variables with a known eligibility denominator, univariate statistical comparisons between cohorts were made using Chi-squared and T-tests where appropriate. Unadjusted and adjusted odds ratios (OR and aOR) with 95% confidence intervals (CI) were estimated between the cohorts by logistic regression analysis using 2015 data as baseline, adjusting for level of unit of delivery (either level two or three, categorical variable) and gestational age at delivery (continuous variable). Two post-hoc subgroup analyses were performed between the two cohorts comparing infants born at below and above 28 weeks' gestation, and for those born in level 2 or level 3 units. Statistical significance for all analyses was set at p < 0.05. The study was designed as a quality improvement project and implemented as local audits in all participating hospitals. Local audit and governance departments of all hospitals approved the collection of routine clinical data. Individual consent was not requested from parents for the collection of routine clinical data. Anonymised data from each hospital were combined at the end of the study period for analysis; the authors had no access to any identifiable data.  Table 1). Demographic details for infants in both cohorts are presented in Table 1, with no significant difference being found between cohorts. The spread of gestational ages for both cohorts can be seen in the Supplementary Fig. 1

Subgroup analyses.
The results from the post-hoc subgroup analyses were broadly similar to the regression analyses. All results are presented in Supplementary Tables 2 and 3.
In the <28-week gestation subgroup, a significant decrease was seen in the number of infants stabilised in FiO 2 21-30% (72.1 vs 22.2% p =< 0.001). A significant decrease was also seen in DCC (9.8% vs 0% p = 0.04). A significant increase in the number receiving TTV (67.5 vs 92.3% p = 0.006) was observed. In the ≥28-weeks subgroup a significant decrease was seen in stabilisation in  www.nature.com/scientificreports www.nature.com/scientificreports/

Discussion
Early management of RDS can have a significant impact on later morbidity, especially on the development of CLD 13 . An extensive evidence base has grown over the past two decades on optimal management for these vulnerable infants 8,9,12 . We present for the first time the assessment of RDS management across several Welsh neonatal units before and after the implementation of a national guideline. To our knowledge, this is the first time RDS management has been reported in a relatively large cohort over time against the same recommendations in the UK.  www.nature.com/scientificreports www.nature.com/scientificreports/ There were several notable improvements in management, the most significant of which are use of TTV-mode, FiO2 management post-surfactant administration, increased caffeine prescribing, and increasing use of parenteral nutrition on day one of life. However, there are two areas which appear to have deteriorated: stabilising infants in the delivery room with an FiO2 21-30% and use of CPAP pressures of ≥ 6cmH2O. Both of these practices showed some variation depending on the unit level and GA, with the tertiary units being more likely to use higher CPAP pressures, but less mature infants being more likely to be stabilised with a higher inspired oxygen fraction. Owing to the data collection methodology, this could be secondary to documentation; however, it is important to emphasise the importance of not exposing premature infants to unnecessarily high FiO2 during stabilisation.
Immediate management of an infant being born prematurely is a multi-disciplinary process in the delivery room. Despite evidence supporting the efficacy of DCC in premature infants 14 , rates remained low in both cohorts, with no significant improvement. However, there was significant evidence of a move towards DCC for more mature infants.
Additionally, minimal enteral feeding commencing on day one of life remains low and unimproved. This may be secondary to clinical concerns with the infant but may also be due to a lack of maternal expressed breast milk. This often requires support from the midwifery team in the first hours of life. This highlights the need for robust training and complementary guidance between departments to ensure optimal practice. The recently published SIFT trial 15 has demonstrated the safety of establishing full enteral feeding early in preterm and very-low-birthweight infants, and this evidence will hopefully aid clinician's confidence in initiating early enteral feeding in practice.
We observed variation in management in several areas based upon GA. More mature infants were more likely to be stabilised on non-invasive respiratory support. This may be due to the experience of those in attendance and general confidence within unit culture in managing more vulnerable infants with non-invasive ventilation. Extremely preterm infants born in level two units may need intubation before transfer to a tertiary unit for further care. However, no variation in intubation was observed based on unit of delivery, although only a small proportion of these infants were delivered in level two units. Further evidence on LISA in extreme preterm infants 16 may improve the success of non-invasive respiratory support in this population. In addition, several local quality improvement projects are ongoing in many of the neonatal units in Wales, and we hope to see improved practice in the next round of data collection.
Our findings are in keeping with the limited amount of published data on RDS management against consensus guidance. A UK-based survey from 2018 found a significant number of units reluctant to use CPAP as the primary ventilation mode for extremely premature infants, but TTV-mode use was increasingly popular for mechanically ventilated infants 17 . Single-centre retrospective audits have been published on adherence to aspects of previous consensus guidelines. Retrospective audits have found variable use of prophylactic surfactant with less use in more mature infants 18 , and good adherence on early management in a cohort of twenty infants <28 weeks' gestation 19 . Both audits examined much more limited aspects of older European Consensus guidelines highlighting the need for robust training and education, but none published follow-up data to document changes.
Our study has several strengths. By capturing prospective data across multiple sites during the same time points, we have achieved a highly representative, contemporaneous impression of current practice across two epochs. This is the first report we are aware of describing changes of practice in RDS management within a defined population over time in the UK, which demonstrates the impact of a unified national guideline on RDS management. Our data collection was restricted mainly to areas of practice supported by Grade A evidence, and we used robust statistical methods to analyse reliable data. We believe this framework can be used in any neonatal network in the UK to document quality improvement in the management of RDS in preterm infants.
There are several limitations of our work. As with any multi-centre audit project there were missing data for variables, and this varied by cohort and data item ( Supplementary Figs. 2 and 3). The effect of incomplete participation of level-two units was partly mitigated as the majority of preterm infants were delivered in tertiary units. However, some Welsh preterm infants born in non-participating units did not have their management audited, and there may be more variation in practice than appreciated. It was difficult to determine the number of eligible infants (denominator) for some interventions through the data collection process, although the majority of these were based on grade B and C evidence. We also did not collect data on other relevant clinical indicators like admission temperature, which may have an effect on the severity of RDS; this will be added in future rounds of data collection. Finally, since our study examined practice against an established guideline, data on the outcome of these infants were not collected; this remains an objective in future rounds of data-collection.
Our analysis demonstrates that certain desirable Grade A evidence-based interventions are still yet to come into clinical practice. The 2013 edition of the European consensus guideline recommended a change in practice towards stabilising preterm infants on non-invasive respiratory support at delivery rather than elective intubation 9 . Additionally, it also recommended delayed cord clamping of at least sixty-seconds is practised where possible. Our data demonstrates that intubation rates at delivery have remained unchanged despite introduction of the Wales guideline, and the number of infants receiving delayed cord clamping remains low. There are quality improvement and training initiatives targeting these practices currently underway in Welsh neonatal units, and this will form a major focus in the next cycle of data collection in this quality improvement project.
In conclusion, this study highlights the successes and challenges with improving management and reducing the variation in practice of RDS in Wales. Interestingly, our data suggests relatively limited variation between level two and three units. Some important areas of practice have shown substantial improvement, but there remain areas of practice that are not in keeping with current best evidence, most importantly the low rates of extremely preterm infants being stabilised on non-invasive respiratory support. Unified, national guidelines are a potentially powerful tool to effect change and reduce variation in practice. They are feasible to implement and can be established in other neonatal networks and nations of the UK. Moving forward, an update to the European