Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation.

BACKGROUND: We tested the hypothesis that routine MRI would improve the care and well-being of preterm infants and their families. DESIGN: Parallel-group randomised trial (1.1 allocation; intention-to-treat) with nested diagnostic and cost evaluations (EudraCT 2009-011602-42). SETTING: Participants from 14 London hospitals, imaged at a single centre. PATIENTS: 511 infants born before 33 weeks gestation underwent both MRI and ultrasound around term. 255 were randomly allocated (siblings together) to receive only MRI results and 255 only ultrasound from a paediatrician unaware of unallocated results; one withdrew before allocation. MAIN OUTCOME MEASURES: Maternal anxiety, measured by the State-Trait Anxiety inventory (STAI) assessed in 206/214 mothers receiving MRI and 217/220 receiving ultrasound. Secondary outcomes included: prediction of neurodevelopment, health-related costs and quality of life. RESULTS: After MRI, STAI fell from 36.81 (95% CI 35.18 to 38.44) to 32.77 (95% CI 31.54 to 34.01), 31.87 (95% CI 30.63 to 33.12) and 31.82 (95% CI 30.65 to 33.00) at 14 days, 12 and 20 months, respectively. STAI fell less after ultrasound: from 37.59 (95% CI 36.00 to 39.18) to 33.97 (95% CI 32.78 to 35.17), 33.43 (95% CI 32.22 to 34.63) and 33.63 (95% CI 32.49 to 34.77), p=0.02. There were no differences in health-related quality of life. MRI predicted moderate or severe functional motor impairment at 20 months slightly better than ultrasound (area under the receiver operator characteristic curve (CI) 0.74; 0.66 to 0.83 vs 0.64; 0.56 to 0.72, p=0.01) but cost £315 (CI £295-£336) more per infant. CONCLUSIONS: MRI increased costs and provided only modest benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT01049594 https://clinicaltrials.gov/ct2/show/NCT01049594.EudraCT: EudraCT: 2009-011602-42 (https://www.clinicaltrialsregister.eu/)

Tranexamic acid for spontaneous intracerebral hemorrhage: a randomized controlled pilot trial (ISRCTN50867461)

Background: Spontaneous intracerebral hemorrhage (ICH) can be devastating, particularly if hematoma expansion (HE) occurs. Tranexamic acid (TA), an antifibrinolytic drug, significantly reduced mortality in bleeding patients after trauma in the large CRASH-2 trial. The CRASH-2 ICH substudy found that TA nonsignificantly reduced mortality and dependency in traumatic ICH. The aim of this study was to assess the feasibility of performing a randomized controlled trial of tranexamic acid in spontaneous ICH, ahead of a definitive study. Methods: We performed a single-center, prospective, randomized (2:1), double-blind, placebo-controlled blinded endpoint trial of TA (intravenous 1 g bolus, 1 g infusion/8 h) in acute (<24 hours) spontaneous ICH. The primary objective was to test the feasibility of recruiting to the trial. Other objectives included tolerability (adverse events) and the effect of TA on HE and death and dependency. Results: The trial was feasible, with 24 patients enrolled (TA, n 5 16; placebo, n 5 8) between March 2011 and March 2012, and acceptable—only 3 patients declined to participate. All patients received the correct randomized treatment; 1 patient in the TA group did not complete the infusion because of neurologic deterioration. There were no significant differences in secondary outcomes including adverse events, HE, death, and dependency. One patient in the TA group had a deep vein thrombosis. Conclusions: This, the first randomized controlled trial of TAin ICH, found that the protocol could be delivered on schedule (2 patients/mo) and was feasible. Larger studies are needed to assess safety and efficacy of TA in ICH

Nutritional Evaluation and Optimisation in Neonates (NEON) trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition: a randomised double-blind controlled trial

Background Parenteral nutrition (PN) is central to the care of very immature infants. Early intakes of higher amounts of amino acids and the use of lipid emulsions containing fish oils are recommended by current international recommendations. Objective To confirm the safety and demonstrate efficacy of the immediate introduction of the recommended daily intake of amino acids (Imm-RDI) and soya bean oil, medium-chain triglycerides, olive oil and fish oil lipid in PN to increase non-adipose (lean) body mass and decrease intrahepatocellular lipid (IHCL) content. Design Multicentre, double-blind, 2 × 2 factorial and randomised controlled trial (RCT). Setting Neonatal units in London and south-east England, UK. Participants Extremely preterm infants born before 31 weeks of gestation without major congenital or life-threatening abnormalities who could to be randomised to receive PN within 24 hours of birth. Interventions Infants were randomised within 24 hours of birth to receive PN containing either high [RDI of amino acids (Imm-RDI)] or low [incremental amino acids (Inc-AA) control] levels of amino acids. In addition, infants were randomised to receive either 20% SMOFlipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) or 20% Intralipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) (control). This resulted in four groups: (1) Inc-AA/Intralipid, (2) Inc-AA/SMOFlipid, (3) Imm-RDI/Intralipid and (4) Imm-RDI/SMOFlipid. The intervention was continued until infants were receiving 150 ml/kg/day of enteral feeds for 24 hours. Primary outcome measure For the amino acid intervention, this was non-adipose or lean body mass measured by magnetic resonance imaging. For the lipid composition intervention, this was IHCL content as measured by hepatic magnetic resonance spectroscopy. Primary outcomes were measured at term age equivalent, between 37 and 44 weeks postmenstrual age. Results We randomised 168 infants born before 31 weeks of gestation. We evaluated outcomes, at term, in 133 infants. There were no significant differences in non-adipose mass between the Imm-RDI and Inc-AA groups [adjusted mean difference 1.0 g, 95% confidence interval (CI) –108 to 111 g] or in levels of IHCLs between the SMOFlipid and Intralipid groups (adjusted mean SMOFlipid to Intralipid ratio 1.1, 95% CI 0.8 to 1.6). Infants receiving the Imm-RDI were more likely than Inc-AA infants to have blood urea nitrogen levels > 7 mmol/l [75% vs. 49% (p  10 mmol/l [49% vs. 18% (p < 0.01)]. Furthermore, head circumference at term was smaller in the Imm-RDI group (mean difference –0.8 cm, 95% CI –1.5 to –0.1 cm; p = 0.02). There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, weight, length and mortality. Limitations Not all eligible babies were available for recruitment, as pharmacy staff trained in clinical trial procedures were unavailable at weekends in three of the four centres. We were able to assess brain volumes in only one-third of participants, as imaging was carried out while the participants were sleeping naturally and we measured primary outcomes first and continued to brain imaging only if the infant remained asleep. Conclusions Immediate delivery of the recommended daily intake of parenteral amino acids does not benefit body composition or growth to term and may be harmful; SMOFlipid does not affect IHCL content. Future work The long-term functional outcomes of early administration of RDI of amino acids and the use of SMOFlipid, including neurodevelopment, body composition and metabolic health, should be evaluated. Trial registration Current Controlled Trials ISRCTN29665319 and EudraCT 2009-016731-34. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

Prevention of haematoma progression by tranexamic acid in intracerebral haemorrhage patients with and without spot sign on admission scan: a statistical analysis plan of a pre-specified sub-study of the TICH-2 trial

Objective We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status. Results Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients

European research priorities for intracerebral haemorrhage

Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH. Copyright (C) 2011 S. Karger AG, Base

Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: protocol for a randomized, placebo-controlled trial

Rationale: Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. Aim: This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Design: Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. Sample size estimates: A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. Study outcomes: The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. Discussion: This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013; as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214