In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear.
We randomly assigned adults with an ...intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia).
We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03).
In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).
Summary Background The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO ...recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis. Methods We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study BIDS). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation SpO2 <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428. Findings Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference −1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly. Interpretation Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce. Funding National Institute for Health Research, Health Technology Assessment programme.
Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well ...understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes.
We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m2 or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30–39 vs ≥40 kg/m2). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843.
Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference −0·029, 95% CI −0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74–17·50; p=0·11).
Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.
The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.
Summary Background Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related ...to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. Methods We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270 ). Findings Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13–0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20–0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12–0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (13/101) and shorter modified (9/100) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20–1·83); however, the proportion was higher with ondansetron (16/100) than with placebo (6/101; 3·30, 1·01–10·72; p=0·024). Interpretation In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. Funding Chief Scientist Office of the Scottish Government.
Background/Aims
There are increasing pressures for anonymised datasets from clinical trials to be shared across the scientific community, and differing recommendations exist on how to perform ...anonymisation prior to sharing. We aimed to systematically identify, describe and synthesise existing recommendations for anonymising clinical trial datasets to prepare for data sharing.
Methods
We systematically searched MEDLINE®, EMBASE and Web of Science from inception to 8 February 2021. We also searched other resources to ensure the comprehensiveness of our search. Any publication reporting recommendations on anonymisation to enable data sharing from clinical trials was included. Two reviewers independently screened titles, abstracts and full text for eligibility. One reviewer extracted data from included papers using thematic synthesis, which then was sense-checked by a second reviewer. Results were summarised by narrative analysis.
Results
Fifty-nine articles (from 43 studies) were eligible for inclusion. Three distinct themes are emerging: anonymisation, de-identification and pseudonymisation. The most commonly used anonymisation techniques are: removal of direct patient identifiers; and careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymised datasets joined with controlled access was the preferred method for data sharing.
Conclusions
There is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, this systematic review shows a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect patient privacy, and they need to be paired with controlled access.
Introduction
There is increasing application of robots and other artificial intelligence-driven technologies in the management of retinal disease. These technologies have the potential to meet ...increasing demands for retinal diseases. However, there is currently a lack of understanding of patients’ attitudes towards use of robots in ophthalmology. This study investigates patients’ attitudes towards robot-led management of retinal disease.
Methods
Paper questionnaires were distributed to 177 patients attending intravitreal treatment (IVT) at the Princess Alexandra Eye Pavilion between 1 October 2022 and 31 January 2023. The questionnaire collected information on age, sex, diagnosis and postcode. In the questionnaire, patients responded to questions about their attitudes towards robot-led diagnosis, treatment decisions and IVT injections. Responses were collected using a 5-category Likert scale which was analysed using ordinal logistic regression with adjustments for age, sex and deprivation status.
Results
Those from affluent socioeconomic backgrounds were significantly (
p
< 0.001) more accepting of robots diagnosing and deciding on treatment, although the total number of patients who were accepting was only 26 (14.7%). Furthermore, there was an increased proportion of patients who would accept robots if the robot made fewer mistakes than doctors, if the robot reduced waiting or appointment time and if the robot was able to communicate well and have empathy; the same association with socioeconomic background remains (
p
< 0.001). Lastly, 116 patients (65.5%) would not be happy if IVT injections were performed by a robot; this was more likely the case if the patient was female (
p
= 0.04) or from a more deprived socioeconomic background (
p
< 0.001).
Conclusion
Attitudes towards robot involvement in diagnosis and management of retinal disease are significantly associated with socioeconomic backgrounds and sex. Additional studies are required to further investigate these determinants of robot receptiveness to ensure acceptance and compliance with treatment with these new technologies.
There are no randomised trials of peripheral capillary oxygen saturation (SpO2) targets in acute respiratory infection. Two national guidelines recommended different targets for the management of ...acute viral bronchiolitis.
To compare the American Academy of Pediatrics guideline target of SpO2 ≥ 90% with the Scottish Intercollegiate Guidelines Network target of SpO2 ≥ 94%.
A multicentre, parallel-group, double-blind, randomised controlled, equivalence trial with economic evaluation.
Eight paediatric hospital departments in the UK.
Infants > 6 weeks and ≤ 12 months of age (corrected for prematurity) with physician-diagnosed bronchiolitis admitted to hospital from a paediatric emergency assessment area. Follow-up for 6 months by standardised telephone contacts.
Infants were randomised to a target oxygen saturation of ≥ 94% (standard care) or ≥ 90% (modified care) displayed by a pulse saturation oximeter (Masimo Corporation Limited, CA, USA).
All infants received routine care in addition to the study intervention. Infants were eligible for discharge when they exhibited a SpO2 of ≥ 94% in room air for 4 hours including a period of sleep and were also feeding adequately (≥ 75% usual volume).
A total of 615 infants were recruited, of whom 308 were allocated to the standard care group and 307 to the modified care group. The primary outcome was time to cough resolution. There was equivalence at the prespecified variance of ± 2 days time to cough resolution: standard care group, 15 days; modified care group, 15 days; median difference 1 day (benefit modified), 95% confidence interval (CI) -1 to 2 days.
Return to adequate feeding occurred sooner in infants in the modified care group than in those in the standard care group (19.5 vs. 24.1 hours). This difference was non-equivalent median difference 2.7 hours (95% CI -0.3 to 7.0 hours) versus prespecified ± 4 hours; post-hoc hazard ratio 1.22 (95% CI 1.04 to 1.44 (p-value = 0.015). Parent perspective of the time taken to return to normal was not equivalent, being 12 days in the standard care group compared with 11 days in the modified care group median difference 1.0 day (95% CI 0.0 to 3.0 days) versus prespecified ± 2 days; post-hoc hazard ratio 1.19 (95% CI 1.00 to 1.41); p-value = 0.043. At 28 days, SpO2 was equivalent mean difference 0.11% (95% CI -0.35% to 0.57%), within the 1% prespecified. The modified care group (55.6%) required oxygen less than the standard care group (73.1%), and for a shorter period (5.7 hours vs. 27.6 hours). Infants in the modified care group were fit for discharge (30.2 hours vs. 44.2 hours, hazard ratio 1.46, 95% CI 1.23 to 1.73; p-value < 0.001) and were discharged (40.9 hours vs. 50.9 hours; hazard ratio 1.28, 95% CI 1.06 to 1.50; p-value < 0.003) sooner than those in the standard care group. There were 35 serious adverse events in the standard care group, compared with 25 in the modified care group. Eight infants in the standard care group and 12 in the modified care group were admitted to a high-dependency unit. By 28 days, 23 infants had been readmitted to hospital in the standard care group and 12 infants in the modified care group. Parents of infants in the modified care group did not experience higher levels of anxiety and, by 14 days, had lost 28% fewer hours to usual activities. NHS costs were £290 lower in the modified care group than in the standard care group, with additional societal costs also being lower in the modified care group.
Management of infants to a SpO2 target of ≥ 90% is as clinically effective as ≥ 94%, gives rise to no additional safety concerns, and appears to be cost-effective. Future work could focus on the safety and effectiveness of using intermittent oxygen saturation monitoring in secondary care, and to consider what are safe and effective oxygen saturation targets for children with bronchiolitis managed in primary care.
This trial is registered as ISRCTN28405428.
This project was funded by the NIHR Health Technology Assessment programme. Masimo Corporation Limited, CA, USA, kindly provided oxygen saturation monitors with standard and altered algorithms.
Traumatic brain injury (TBI) is a major cause of disability and death in young adults worldwide. It results in around 1 million hospital admissions annually in the European Union (EU), causes a ...majority of the 50,000 deaths from road traffic accidents and leaves a further ≈10,000 people severely disabled.
The Eurotherm3235 Trial was a pragmatic trial examining the effectiveness of hypothermia (32-35 °C) to reduce raised intracranial pressure (ICP) following severe TBI and reduce morbidity and mortality 6 months after TBI.
An international, multicentre, randomised controlled trial.
Specialist neurological critical care units.
We included adult participants following TBI. Eligible patients had ICP monitoring in place with an ICP of > 20 mmHg despite first-line treatments. Participants were randomised to receive standard care with the addition of hypothermia (32-35 °C) or standard care alone. Online randomisation and the use of an electronic case report form (CRF) ensured concealment of random treatment allocation. It was not possible to blind local investigators to allocation as it was obvious which participants were receiving hypothermia. We collected information on how well the participant had recovered 6 months after injury. This information was provided either by the participant themself (if they were able) and/or a person close to them by completing the Glasgow Outcome Scale - Extended (GOSE) questionnaire. Telephone follow-up was carried out by a blinded independent clinician.
The primary intervention to reduce ICP in the hypothermia group after randomisation was induction of hypothermia. Core temperature was initially reduced to 35 °C and decreased incrementally to a lower limit of 32 °C if necessary to maintain ICP at < 20 mmHg. Rewarming began after 48 hours if ICP remained controlled. Participants in the standard-care group received usual care at that centre, but without hypothermia.
The primary outcome measure was the GOSE range 1 (dead) to 8 (upper good recovery) at 6 months after the injury as assessed by an independent collaborator, blind to the intervention. A priori subgroup analysis tested the relationship between minimisation factors including being aged < 45 years, having a post-resuscitation Glasgow Coma Scale (GCS) motor score of < 2 on admission, having a time from injury of < 12 hours and patient outcome.
We enrolled 387 patients from 47 centres in 18 countries. The trial was closed to recruitment following concerns raised by the Data and Safety Monitoring Committee in October 2014. On an intention-to-treat basis, 195 participants were randomised to hypothermia treatment and 192 to standard care. Regarding participant outcome, there was a higher mortality rate and poorer functional recovery at 6 months in the hypothermia group. The adjusted common odds ratio (OR) for the primary statistical analysis of the GOSE was 1.54 95% confidence interval (CI) 1.03 to 2.31; when the GOSE was dichotomised the OR was 1.74 (95% CI 1.09 to 2.77). Both results favoured standard care alone. In this pragmatic study, we did not collect data on adverse events. Data on serious adverse events (SAEs) were collected but were subject to reporting bias, with most SAEs being reported in the hypothermia group.
In participants following TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced ICP but led to a higher mortality rate and worse functional outcome.
Inability to blind treatment allocation as it was obvious which participants were randomised to the hypothermia group; there was biased recording of SAEs in the hypothermia group. We now believe that more adequately powered clinical trials of common therapies used to reduce ICP, such as hypertonic therapy, barbiturates and hyperventilation, are required to assess their potential benefits and risks to patients.
Current Controlled Trials ISRCTN34555414.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 22, No. 45. See the NIHR Journals Library website for further project information. The European Society of Intensive Care Medicine supported the pilot phase of this trial.
Purpose Pain is suboptimally managed in patients with cancer. We aimed to compare the effect of a policy of adding a clinician-delivered bedside pain assessment and management tool (Edinburgh Pain ...Assessment and management Tool EPAT) to usual care (UC) versus UC alone on pain outcomes. Patients and Methods In a two-arm, parallel group, cluster randomized (1:1) trial, we observed pain outcomes in 19 cancer centers in the United Kingdom and then randomly assigned the centers to either implement EPAT or to continue UC. The primary outcome was change in the percentage of study participants in each center with a clinically significant (≥ 2 point) improvement in worst pain (using the Brief Pain Inventory Short Form) from admission to 3 to 5 days after admission. Secondary outcomes included quality of analgesic prescribing and opioid-related adverse effects. Results Ten centers were randomly assigned to EPAT, and nine were assigned to UC. We enrolled 1,921 patients and obtained outcome data from 93% (n = 1,795). Participants (mean age, 60 years; 49% women) had a variety of cancer types. For centers randomly assigned to EPAT, the percentage of participants with a clinically significant improvement in worst pain increased from 47.7% to 54.1%, and for those randomly assigned to continue UC, this percentage decreased from 50.6% to 46.4%. The absolute difference was 10.7% (95% CI, 0.2% to 21.1%; P = .046) and it increased to 15.4% (95% CI, 5.8% to 25.0%; P = .004) when two centers that failed to implement EPAT were excluded. EPAT centers had greater improvements in prescribing practice and in the Brief Pain Inventory Short Form pain subscale score. Other pain and distress outcomes and opioid adverse effects did not differ between EPAT and UC. Conclusion A systematic integrated approach improves pain outcomes for inpatients in cancer centers without increasing opioid adverse effects.
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