Title: NeoCLEAR: Neonatal Champagne Lumbar punctures Every time - An RCT. A multicentre, randomised controlled 2x2 factorial trial to investigate techniques to increase lumbar puncture success
Funder: Department of Health and Social Care

Abstract: DESIGN: Multicentre 2x2 factorial RCT. SETTING: Level 2 & 3 UK neonatal units & their maternity wards. POPULATION: Newborn babies (corrected gestational age 27 weeks or more, working weight over 1,000g) requiring lumbar puncture (LP) to obtain cerebrospinal fluid (CSF). Babies must be able to be held sitting and lying. HEALTH TECHNOLOGIES: Two modifications to the 'traditional' LP technique, for which there is scientific rationale and observational evidence of benefit: (1) sitting position; (2) ‘Early Stylet Removal’ (ESR, which involves removing the stylet after skin puncture but before advancing into CSF, to avoid a blood-stained sample through overshooting). These will be compared with traditional lying position and Late Stylet Removal (LSR) in a 2x2 design, creating 4 groups: (i) Lying & LSR; (ii) Lying & ESR; (iii) Sitting & LSR; (iv) Sitting & ESR. Other aspects of LP will be standardised, including analgesia and needle type. PRIMARY OUTCOME: Percentage of babies with CSF Red Cell count (RCC) <10,000/mm3 on microscopy, on first LP. This has been chosen as: (i) important to parents as a measure of successful LPs that do NOT need repeating; (ii) a clinically effective and objective diagnostic for meningitis; (iii) since CSFs with higher RCCs are more difficult to interpret. SECONDARY OUTCOMES: Number of LPs; duration of LPs; total RCC in CSF; percentage of samples unsuitable for microscopy ('uninterpretable'); duration of antibiotic therapy; length of hospital stay; proportion of infants diagnosed with meningitis; parental anxiety; and safety (e.g. cardiovascular instability). SAMPLE SIZE: A minimum of 483 per main comparison (e.g. sitting vs lying) to detect a 10% absolute difference (59 to 69%) in the primary outcome, with 90% power and significance level of 5% (two sided). Allowing for up to 5% attrition, the required overall sample size target is 1020 (255 in each of the 4 groups). Baseline data are derived from a local prospective cohort study, corroborated by published UK data. PROJECT TIMETABLES & RECRUITMENT: The expected timeline and uptake rate (50%) are based on previous national and local neonatal trial experience. From local prospective cohort data and a survey of other units, we expect each centre to recruit, on average, 62 babies per year. We will collaborate with other neonatal units, predicting the recruitment of ~1100 babies in 24 months. Timeline (in months): Trial Set-up & Ethics (6); LP Training & Internal Pilot (8); Further Recruitment (16); Analysis & Dissemination (6). Total (36)

Lay abstract: AIM: To determine the best technique for performing lumbar puncture in newborn babies. BACKGROUND: Meningitis is an infection of the lining around the brain and spinal cord. In newborns it can be fatal, or have lifelong complications. A lumbar puncture (LP) is an essential test for diagnosing meningitis. It involves taking a small amount of spinal fluid from the lower back using a small needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. LPs are performed on up to 30,000 UK babies each year, but are technically difficult. In 50-60%, either no fluid is obtained, or the sample is mixed with blood, making analysis less reliable. Uncertain results often lead to babies having repeated attempts, and/or receiving 14-21 days' intravenous antibiotics in hospital (instead of 2-5 days), because meningitis could not be excluded. No one knows which is the best LP technique, so practice varies. Firstly, the baby can be held lying on their side or sitting. Secondly, the ‘stylet’, which sits inside (and aids initial insertion of) the needle can be removed either soon after piercing the skin (‘early stylet removal’), or 'late' - once the tip is thought to have reached the spinal fluid. Previous studies suggest that sitting position or early stylet removal could increase the chances of a successful LP. However, these studies have been too small or not designed well enough to provide convincing evidence for the superiority of any particular technique. This study is the first large, well-designed trial to examine the best LP technique in newborns. DESIGN & METHODS: We will simultaneously compare (1) lying vs sitting positions, (2) ‘early’ vs ‘late stylet removal’. The trial will be conducted in newborn care units in England, in babies who would be having an LP anyway. If parents consent to their baby taking part in the trial, we will randomly select which technique is to be used. We will collect data about the procedure itself, whether it was successful, or needed repeating, and what effect it had on the baby’s treatment, including the length of hospital stay. We will then compare success rates of the different techniques and determine the optimal procedure. This should benefit babies and their families in the future, by ensuring that: 1) The number of LPs required to get a clear sample is minimised 2) Babies who do NOT have meningitis are not unnecessarily treated with long courses of antibiotics 3) Cases of meningitis are not missed. PATIENT & PUBLIC INVOLVEMENT: Parents, patient representatives and the public have been integral in designing this trial, including parent representatives as part of the study team. We have sought and received input via online and face-to-face surveys, focus groups, through the NIHR and a newborn care charity, Support for the sick newborn and their parents (SSNAP). DISSEMINATION & IMPLICATIONS: Our results will be presented at international conferences and published in freely-accessible journals. Our clinical trials unit and local newborn charity will inform parents and the public about the trial results and coordinate press releases, website promotion, social and other media interest. If we find a superior LP technique, it would cost nothing to implement it nationally. As a result, thousands of babies each year would have fewer procedures, receive less antibiotics and go home sooner after birth. This would improve care for babies and families, protect against the spread of antibiotic-resistant bacteria, and save costs for the NHS.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH