Measuring Oxygenation in Newborn Infants with Targeted Oxygen Ranges (MONITOR): a randomised crossover pilot study.

OBJECTIVE: The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration showed that high (91-95%) versus low (85-89%) SpO2 targets reduced mortality. Trials of higher targets are needed to determine whether any more survival advantage may be gained. This pilot study explored the achieved oxygenation patterns observed when targeting SpO2 92-97% to facilitate the design of future trials. DESIGN: Single-centre prospective randomised crossover pilot study. Manual FiO2 adjustment. Study time 12 hours per infant. 6 hours targeting SpO2 90-95% and 6 hours targeting SpO2 92-97%. PATIENTS: Twenty preterm infants born <29 weeks' gestation, greater than 48 hours old, receiving supplemental oxygen. OUTCOMES: Primary outcome was percentage time with SpO2 above 97% and below 90%. Pre-defined secondary outcomes included percentage time spent within, above or below transcutaneous PO2 (TcPO2) 6.7-10.7 kPa (50-80 mm Hg). Comparisons were made using paired-samples t-test (2-tailed). RESULTS: With SpO2 target 92-97% versus 90-95%, the mean (IQR) percentage time above SpO2 97% was 11.3% (2.7-20.9) versus 7.8% (1.7-13.9), p=0.02. Percentage time with SpO2 <90% was 13.1% (6.7-19.1) versus 17.9% (11.1-22.4), p=0.003. Percentage time with SpO2 <80% was 1% (0.1-1.4) versus 1.6% (0.4-2.6), p=0.119. Percentage time with TcPO2 <6.7 kPa (50 mm Hg) was 49.6% (30.2-66.0) versus 55% (34.3-73.5), p=0.63. Percentage time above TcPO2 10.7 kPa (80 mm Hg) was 1.4% (0-1.4) versus 1.8% (0-0), p=0.746. CONCLUSIONS: Targeting SpO2 92-97% produced a right shift in SpO2 and TcPO2 distribution, with reduced time at SpO2 <90% and increased time at SpO2 >97%, without increasing time with TcPO2 >10.7 kPa (80 mm Hg). Clinical trials targeting this higher SpO2 range could be conducted without significant hyperoxic exposure. TRIAL REGISTRATION NUMBER: NCT03360292.

Economic evaluation alongside the Speed of Increasing milk Feeds Trial (SIFT).

OBJECTIVE: To evaluate the cost-effectiveness of two rates of enteral feed advancement (18 vs 30 mL/kg/day) in very preterm and very low birth weight infants. DESIGN: Within-trial economic evaluation alongside a multicentre, two-arm parallel group, randomised controlled trial (Speed of Increasing milk Feeds Trial). SETTING: 55 UK neonatal units from May 2013 to June 2015. PATIENTS: Infants born <32 weeks' gestation or <1500 g, receiving less than 30 mL/kg/day of milk at trial enrolment. Infants with a known severe congenital anomaly, no realistic chance of survival, or unlikely to be traceable for follow-up, were ineligible. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, infants were randomised to receive daily increments in feed volume of 30 mL/kg (intervention) or 18 mL/kg (control). MAIN OUTCOME MEASURE: Cost per additional survivor without moderate to severe neurodevelopmental disability at 24 months of age corrected for prematurity. RESULTS: Average costs per infant were slightly higher for faster feeds compared with slower feeds (mean difference £267, 95% CI -6928 to 8117). Fewer infants achieved the principal outcome of survival without moderate to severe neurodevelopmental disability at 24 months in the faster feeds arm (802/1224 vs 848/1246). The stochastic cost-effectiveness analysis showed a likelihood of worse outcomes for faster feeds compared with slower feeds. CONCLUSIONS: The stochastic cost-effectiveness analysis shows faster feeds are broadly equivalent on cost grounds. However, in terms of outcomes at 24 months age (corrected for prematurity), faster feeds are harmful. Faster feeds should not be recommended on either cost or effectiveness grounds to achieve the primary outcome.

Dose-dependent relationship between acidosis at birth and likelihood of death or cerebral palsy.

BACKGROUND: The acid-base status of infants around birth can provide information about their past, current and future condition. Although umbilical cord blood pH <7.0 or base deficit ≥12 mmol/L is associated with increased risk of adverse outcome, there is uncertainty about the prognostic value of degree of acidosis as previous studies have used different variables, thresholds, outcomes and populations. METHODS: Retrospective review of routinely collected clinical data in all live-born inborn infants of 35 weeks gestation or more delivered between January 2005 and December 2013 at the Simpson Centre for Reproductive Health, Edinburgh, UK. Infants were included if their lowest recorded pH was <7 and/or highest base deficit ≥12 mmol/L on either umbilical cord blood and/or neonatal blood gas within 1 hour of birth. Neurodevelopmental outcome of the infants with encephalopathy was collected from the targeted follow-up database. RESULTS: 56 574 infants were eligible. 506 infants (0.9%) met inclusion criteria. Poor condition at birth and all adverse outcomes increased with worsening acidosis. Combined outcome of death or cerebral palsy was 3%, 10% and 40% at lowest pH of 6.9-6.99, 6.8-6.89 and <6.8, respectively, and 8%, 14% and 59% at a base deficit of 12-15.9, 16-19.9 and 20 mmol/L or more, respectively. CONCLUSIONS: There is a dose-dependent relationship between the degree of acidosis within an hour of delivery, and the likelihood of adverse neonatal and later neurodevelopmental outcome in infants born at 35 weeks gestation or more.

Effect of a smaller target range on the compliance in targeting and distribution of oxygen saturation in preterm infants.

BACKGROUND: Following recent recommendations, the oxygen saturation (SpO2) target range for preterm infants in our nursery was narrowed towards the higher end from 85%-95% to 90%-95%. We determined the effect of narrowing the SpO2 target range on the compliance in target range and distribution of SpO2 in preterm infants. METHODS: Before and after changing the target range from 85%-95% to 90%-95%, infants <30 weeks of gestation receiving oxygen were compared during their admission on the neonatal intensive care unit. For each infant, distribution of SpO2 was noted by collecting SpO2 samples each minute, and the percentage of time spent with SpO2 within 90%-95% was calculated. Oxygen was manually adjusted. Hypoxaemic events (SpO2 <80%) where oxygen was titrated were analysed. RESULTS: Data were analysed for 104 infants (57 before and 47 after the range was narrowed). The narrower range was associated with an increase in the median (IQR) SpO2 (93% (91%-96%) vs 94% (92%-97%), p=0.01), but no increase in median time SpO2 within 90%-95% (49.2% (39.6%-59.7%) vs (46.9% (27.1%-57.9%), p=0.72). The distribution of SpO2 shifted to the right with a significant decrease in SpO2 <90%, but not <80%. The count of minute values for Sp02 <80% decreased, while the frequency and duration of hypoxaemic events and oxygen titration were not different. CONCLUSION: Narrowing the target range from 85%-95% to 90%-95% in preterm infants was associated with an increase in median SpO2 and a rightward shift in the distribution, but no change in time spent between 90% and 95%.

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome.

OBJECTIVE: CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. DESIGN: Multicentre cohort study. PATIENTS: Forty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. OUTCOME MEASURES: Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue. RESULTS: Rapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. CONCLUSIONS: Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01651637.

Improving manual oxygen titration in preterm infants by training and guideline implementation.

To study oxygen saturation (SpO2) targeting before and after training and guideline implementation of manual oxygen titration, two cohorts of preterm infants <30 weeks of gestation needing respiratory support and oxygen therapy were compared. The percentage of the time spent with SpO2 within the target range (85-95%) was calculated (%SpO2-wtr). SpO2 was collected every minute when oxygen is >21%. ABCs where oxygen therapy was given were identified and analyzed. After training and guideline implementation the %SpO2-wtr increased (median interquartile range (IQR)) 48.0 (19.6-63.9) % vs 61.9 (48.5-72.3) %; p < 0.005, with a decrease in the %SpO2 > 95% (44.0 (27.8-66.2) % vs 30.8 (22.6-44.5) %; p < 0.05). There was no effect on the %SpO2 < 85% (5.9 (2.8-7.9) % vs 6.2 (2.5-8) %; ns) and %SpO2 < 80% (1.9 (1.0-3.0) % vs 1.7 (0.8-2.6) %; ns). In total, 186 ABCs with oxygen therapy before and 168 ABCs after training and guideline implementation occurred. The duration of SpO2 < 80% reduced (2 (1-2) vs 1 (1-2) minutes; p < 0.05), the occurrence of SpO2 > 95% did not decrease (73% vs 64%; ns) but lasted shorter (2 (0-7) vs 1 (1-3) minute; p < 0.004). CONCLUSION: Training and guideline implementation in manual oxygen titration improved SpO2 targeting in preterm infants with more time spent within the target range and less frequent hyperoxaemia. The durations of hypoxaemia and hyperoxaemia during ABCs were shorter. What is Known: • Oxygen saturation targeting in preterm infants can be challenging and the compliance is low when oxygen is titrated manually. • Hyperoxaemia often occurs after oxygen therapy for oxygen desaturation during apnoeas. What is New: • Training and implementing guidelines improved oxygen saturation targeting and reduced hyperoxaemia. • Training and implementing guidelines improved manual oxygen titration during ABC.

Oxygen Saturation Targets for Extremely Preterm Infants after the NeOProM Trials.

Five randomized controlled trials comparing lower (85-89%) versus higher (91-95%) pulse oximeter saturation (SpO2) targets for extremely preterm infants have now been reported from the United States of America, Canada, the United Kingdom, Australia and New Zealand. These trials included more than 4,800 infants, and they provide robust evidence to permit comparison of these target ranges and consider the next steps for clinicians and researchers. The lower SpO2 range was associated with a significant increase in the risk of death. There was no significant difference between the two target ranges in the rate of disability at 18-24 months, including blindness. A significant difference between groups in the risk of the composite primary outcome of death or disability in favour of the higher SpO2 range was mainly attributable to the difference between groups in the risk of death. The lower target range did not reduce bronchopulmonary dysplasia or severe visual impairment, but it did increase the risk of necrotizing enterocolitis requiring surgery or causing death. The trials provide no reason to prefer SpO2 targets below 90% and indicate the importance of more trials to see if a further survival advantage can be identified. The safety of targets above 95% has not been evaluated. The five trials were designed to be similar to facilitate an individual patient data meta-analysis, and this Neonatal Oxygen Prospective Meta-Analysis (NeOProM) may provide further insights.

Prediction of severe retinopathy of prematurity using the WINROP algorithm in a birth cohort in South East Scotland.

PURPOSE: We tested the ability of the 'Weight, IGF-1, Neonatal Retinopathy of Prematurity (WINROP)' clinical algorithm to detect preterm infants at risk of severe Retinopathy of Prematurity (ROP) in a birth cohort in the South East of Scotland. In particular, we asked the question: 'are weekly weight measurements essential when using the WINROP algorithm?' STUDY DESIGN: This was a retrospective cohort study. Anonymised clinical data were uploaded to the online WINROP site, and infants at risk of developing severe ROP were identified. The results using WINROP were compared with the actual ROP screening outcomes. Infants with incomplete weight data were included in the whole group, but were excluded from a subgroup analysis of infants with complete weight data. In addition, data were manipulated to test whether missing weight data points in the early neonatal period would lead to loss of sensitivity of the algorithm. RESULTS: The WINROP algorithm had 73% sensitivity for detecting infants at risk of severe ROP when all infants were included and 87% when the complete weight data subgroup was analysed. Manipulation of data from the complete weight data subgroup demonstrated that one or two missing weight data points in the early postnatal period lead to loss of sensitivity performance by WINROP. IMPLICATIONS: The WINROP program offers a non-invasive method of identifying infants at high risk of severe ROP and also identifying those not at risk. However, for WINROP to function optimally, it has to be used as recommended and designed, namely weekly body weight measurements are required.

Oxygen targets for preterm infants.

Retinopathy of prematurity (ROP) was first observed soon after the widespread introduction of oxygen therapy into neonatal care. Early trials suggested that restricting oxygen supplementation could reduce ROP without other consequences, but when oxygen restriction became widespread, increased mortality was observed. These observations were made before continuous monitoring of oxygenation was possible. New trial evidence from masked randomized controlled trials of different pulse oximeter oxygen saturation (SpO2) target ranges now shows that targeting lower SpO2 levels reduces ROP but is associated with significantly increased mortality. These results illustrate the importance of randomized trials because, prior to these recent studies, trends in practice based on observational data were favouring lower SpO2. Follow-up data may yet further inform clinical practice.

Oxygen saturation and outcomes in preterm infants.

BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

Retinopathy of prematurity and the oxygen conundrum: lessons learned from recent randomized trials.

Emerging data from randomised controlled trials of different pulse oximeter oxygen saturation (SpO(2)) target ranges shows that higher SpO(2) targets are associated with a higher risk of severe retinopathy of prematurity. However, the trials have also shown that higher SpO(2) targets are associated with improved survival. In the light of these results and pending the full results for long-term outcome, it is recommended that oxygen saturation targets for preterm infants of gestational age less than 28 weeks at birth should be maintained at or more than 90%.

Subspecialty neonatal trainees views on being prepared for the consultant role.

Higher specialist training offers an opportunity to focus on non-clinical skills as well as clinical issues. The authors wished to determine whether doctors who complete neonatal higher specialist training in the UK feel prepared for the consultant role with respect to management, research and teaching, as well as clinical activities. A questionnaire related to the preparedness of the consultant to carry out a range of activities was sent to all doctors who were appointed to the UK higher specialist training programme in neonatology from 2002 to 2008 who were currently working as consultants. Seventy-one of the 83 eligible participants completed the questionnaire. Roles that consultants felt extremely well prepared for related to clinical care, communication, team-working, prioritising tasks, teaching and audit. Trainees reported that roles that they had been not at all well prepared for were related to roles in management and service delivery, medicolegal issues and complaints, job planning and personal development, supporting doctors in difficulty and chairing meetings. Four key themes emerged from the analysis of free-text responses regarding specialty training: the influence of shift patterns/service provision, the lack of non-clinical preparation, learning on the job as a consultant later on and problems with grid training itself. This study showed that for neonatal paediatrics in the UK, new consultants feel confident about managing ill babies but are unprepared for other aspects of the consultant's role. Neonatal higher specialist training needs to allow opportunities for non-clinical training.