Oxygen targeting in preterm infants using the Masimo SET Radical pulse oximeter

Background A pretrial clinical improvement project for the BOOST-II UK trial of oxygen saturation targeting revealed an artefact affecting saturation profiles obtained from the Masimo Set Radical pulse oximeter.Methods Saturation was recorded every 10 s for up to 2 weeks in 176 oxygen dependent preterm infants in 35 UK and Irish neonatal units between August 2006 and April 2009 using Masimo SET Radical pulse oximeters. Frequency distributions of % time at each saturation were plotted. An artefact affecting the saturation distribution was found to be attributable to the oximeter's internal calibration algorithm. Revised software was installed and saturation distributions obtained were compared with four other current oximeters in paired studies.Results There was a reduction in saturation values of 87-90%. Values above 87% were elevated by up to 2%, giving a relative excess of higher values. The software revision eliminated this, improving the distribution of saturation values. In paired comparisons with four current commercially available oximeters, Masimo oximeters with the revised software returned similar saturation distributions.Conclusions A characteristic of the software algorithm reduces the frequency of saturations of 87-90% and increases the frequency of higher values returned by the Masimo SET Radical pulse oximeter. This effect, which remains within the recommended standards for accuracy, is removed by installing revised software (board firmware V4.8 or higher). Because this observation is likely to influence oxygen targeting, it should be considered in the analysis of the oxygen trial results to maximise their generalisability

Persistence of the immune response induced by BCG vaccination.

BACKGROUND: Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. METHODS: A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-gamma) response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD) in a whole blood assay before, 3 months, 12 months (n = 148) and 3 years (n = 19) after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16). RESULTS: A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13%) failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13%) or 3 (3/19; 16%) years. IFN-gamma response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81%) made a detectable IFN-gamma response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38%) matched unvaccinated controls (p = 0.012); teenagers vaccinated in infancy were 19 times more likely to make an IFN-gamma response of > 500 pg/ml than unvaccinated teenagers. CONCLUSION: BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the majority of vaccinees, although the magnitude of the peripheral blood response wanes from 3 months to 12 months and from 12 months to 3 years post vaccination. The data presented here suggest that because of such waning in the response there may be scope for boosting anti-tuberculous immunity in BCG vaccinated children anytime from 3 months post-vaccination. This supports the prime boost strategies being employed for some new TB vaccines currently under development

Challenges In The Simultaneous Development And Deployment Of A Large Integrated Modelling System

Many of our natural resource management issues cannot be adequately informed by a single discipline or sub-discipline, and require an integration of information from multiple natural and human systems. As we are unable to observe and monitor more than a few important indicators there is a strong reliance on supplementing observed information with modelled information. Following a period of record drought in the 1990’s, the Australian government recognised the need for better quality, more integrated, and nationally consistent water information. The Australian Water Resources Assessment system (AWRA) is an integrated hydrological modelling system developed by CSIRO and Australian Bureau of Meteorology (the Bureau) as part of the Water Information Research and Development Alliance (WIRADA) to support the development of two new water information products produced by the Bureau. This paper outlines the informatics, systems implementation and integration challenges in the development and deployment of the proto-operational AWRA system. A key challenge of model integration is how you access and repurpose data, how you reconcile semantic differences between both models and disparate input data sources, how you translate terms when passing between often conceptually different modelling components and how you ensure consistent identity between real world objects. The rapid development of AWRA and simultaneous transfer to an operational environment also raised many additional challenges, such as supporting multiple technologies and differing development rates of each model component, while still maintaining a working system. Additionally the continentally sized model extent, combined with techniques relatively new to the hydrologic domain, such as data assimilation and continental calibration, have introduced significant computational overheads. While an in-house fit for purpose operational build of AWRA is currently under development within the Bureau, the research challenges undertaken early in AWRA’s development still hold many valuable lessons. We have found that the use of file standards such as NetCDF, services-based modelling, and scientific workflow technologies such as ‘The WorkBench’ combined with strong model governance has mostly reduced the burden of system development and deployment and exposes some important lessons for future integrated modelling and systems integration efforts

An Application Of Services Based Modelling Paradigm To The Hydrologic Domain Using Ewater Source

The traditional paradigm for the deployment of hydrological models involves the capturing and testing of model concepts and numerical consistency for robustness and accuracy, which is then distributed as binary files with or without source code. The model software is then populated with data and parameters and run locally within the modeller’s organisation, often on their own desktop. This modelling workflow is used by many organisations; however, there are several limitations and potential issues. Once the software is outside the developer’s organisation they rely on the modeller to apply updates and bug fixes in a timely manner, and to correctly describe the model version used for reporting. The developer also loses control of the quality and suitability of the input data for a particular application of the model. With more prevalent access to high bandwidth internet and flexible computing infrastructure there is an increased opportunity to better control model access through the exposure of modelling functionality through web services. As well as giving the developer tighter control over model versioning and IP, it also allows closer coupling of the model to both data sources and computational resources, which is especially beneficial to multi-run use cases such as uncertainty analysis and calibration, where the ability to easily scale to many model instances is of most value. The eWater Source modelling system is an important use case for Australia’s hydrologic community, and provides a rich array of functionality. Source is especially suited to the services modelling paradigm as it has project load times much greater than simulation runtimes, the services based approach allows the hiding of these load times by keeping the project in memory for each instance of a Source Server. This paper investigates the use of a Source service interface for providing hydrological modelling web services

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

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.)

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 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 95% (44.0 (27.8-66.2) % vs 30.8 (22.6-44.5) %; p 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

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

Two speeds of increasing milk feeds for very preterm or very low-birthweight infants : the SIFT RCT

BACKGROUND: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. OBJECTIVE: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. DESIGN: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. SETTING: The setting was 55 UK neonatal units, from May 2013 to June 2015. PARTICIPANTS: The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. MAIN OUTCOME MEASURES: The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. RESULTS: The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. LIMITATIONS: The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. CONCLUSIONS: No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76463425. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information