Safety and efficacy of 2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheter insertion in preterm neonates:The ARCTIC randomised-controlled feasibility trial protocol

Introduction Catheter-related sepsis is one of the most dangerous complications of neonatal intensive care and is associated with significant morbidity and mortality. Use of catheter-care € bundles' has reduced the incidence of catheter-related sepsis, although individual components have not been well studied. Better evidence is needed to guide selection of the most appropriate antiseptic solution for skin disinfection in preterm neonates. This study will inform the feasibility and design of the first randomised controlled trial to examine the safety and efficacy of alcohol-based versus aqueous-based chlorhexidine antiseptic formulations for skin disinfection prior to percutaneous central venous catheterisation in preterm neonates. The antiseptics to be compared are 2% chlorhexidine gluconate (CHG) aqueous and 2% CHG in 70% isopropyl alcohol. Methods and analysis The Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) is a two-centre randomised-controlled feasibility trial. At least 100 preterm infants born at <34 weeks' gestation and due to undergo percutaneous insertion of a central venous catheter will be randomly allocated to receive prior skin disinfection with one of the two antiseptic solutions. Outcomes include: i) recruitment and retention rates; ii) completeness of data collection; iii) numbers of enrolled infants meeting case definitions for definite catheter-related sepsis, catheter-associated sepsis and catheter colonisation and iv) safety outcomes of skin morbidity scores recorded daily from catheter insertion until 48 hours post removal. The key feasibility metrics will be reported as proportions with 95% CIs. Estimated prevalence of catheter colonisation will allow calculation of sample size for the large-scale trial. The data will inform whether it will be feasible to progress to a large-scale trial. Ethics and dissemination ARCTIC has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge South) (IRAS ID 163868), was adopted onto the National Institute of Health Research Clinical Research Network portfolio (CPMS ID 19899) and is registered with an International Standard Randomised Control Trials Number (ISRCTN: 82571474; Pre-results) and European Clinical Trials Database number 2015-000874-36. Dissemination plans include presentations at scientific conferences, scientific publications and sharing of the findings with parents via the support of Bliss baby charity

Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology

Distinct electrophysiological phenotypes are exhibited 1 by biological cells that have differentiated into particular cell types. The usual approach when simulating the cardiac electrophysiology of tissue that includes different cell types is to model the different cell types as occupying spatially distinct yet coupled regions. Instead, we model the electrophysiology of well-mixed cells by using homogenisation to derive an extension to the commonly used monodomain or bidomain equations. These new equations permit spatial variations in the distribution of the different subtypes of cells and will reduce the computational demands of solving the governing equations. We validate the homogenisation computationally, and then use the new model to explain some experimental observations from stem cell-derived cardiomyocyte monolayers

Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology

Distinct electrophysiological phenotypes are exhibited 1 by biological cells that have differentiated into particular cell types. The usual approach when simulating the cardiac electrophysiology of tissue that includes different cell types is to model the different cell types as occupying spatially distinct yet coupled regions. Instead, we model the electrophysiology of well-mixed cells by using homogenisation to derive an extension to the commonly used monodomain or bidomain equations. These new equations permit spatial variations in the distribution of the different subtypes of cells and will reduce the computational demands of solving the governing equations. We validate the homogenisation computationally, and then use the new model to explain some experimental observations from stem cell-derived cardiomyocyte monolayers

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

Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT

Background Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50–60%). Standard technique includes lying infants on their side and removing the stylet ‘late’, that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet ‘early’, that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives The aim of the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of ‘early’ rather than ‘late’ stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations This trial predominantly recruited term-born infants who were 2.5 kg. The impact of practitioners’ seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators’ previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information

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.)

Planned delivery or expectant management for late preterm pre-eclampsia:study protocol for a randomised controlled trial (PHOENIX trial)

Abstract Background Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks’ gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. Trial registration ISRCTN01879376. Registered on 25 November 2013

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

Ursodeoxycholic acid versus placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP) to improve perinatal outcomes:protocol for a randomised controlled trial (PITCHES)

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. Methods The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks’ gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks’ gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks’ gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. Discussion Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. Trial registration ISRCTN registry, ID: ISRCTN91918806. Prospectively registered on 27 August 2015