About a third of women receiving pethidine for labour pain subsequently require an epidural, which provides effective pain relief but increases the risk of instrumental vaginal delivery. Remifentanil ...patient-controlled analgesia (PCA) in labour is an alternative to pethidine, but is not widely used. We aimed to evaluate epidural analgesia progression among women using remifentanil PCA compared with pethidine.
We did an open-label, multicentre, randomised controlled trial in 14 UK maternity units. We included women aged 16 years or older, beyond 37 weeks' gestation, in labour with a singleton cephalic presentation, and who requested opioid pain relief. We randomly assigned eligible participants (1:1) to either the intravenous remifentanil PCA group (40 μg bolus on demand with a 2 min lockout) or the intramuscular pethidine group (100 mg every 4 h, up to 400 mg in 24 h), using a web-based or telephone randomisation service with a minimisation algorithm for parity, maternal age, ethnicity, and mode of labour onset. Because of the differences in routes of drug administration, study participants and health-care providers were not masked to the group allocation. The primary outcome was the proportion of women who received epidural analgesia after enrolment for pain relief in labour. Primary analyses were unadjusted and analysed by the intention-to-treat principle. This study is registered with the ISRCTN registry, number ISRCTN29654603.
Between May 13, 2014, and Sept 2, 2016, 201 women were randomly assigned to the remifentanil PCA group and 200 to the pethidine group. One participant in the pethidine group withdrew consent, leaving 199 for analyses. The proportions of epidural conversion were 19% (39 of 201) in the remifentanil PCA group and 41% (81 of 199) in the pethidine group (risk ratio 0·48, 95% CI 0·34–0·66; p<0·0001). There were no serious adverse events or drug reactions directly attributable to either analgesic during the study.
Intravenous remifentanil PCA halved the proportion of epidural conversions compared with intramuscular pethidine. This finding challenges routine pethidine use as standard of care in labour.
National Institute for Health Research Clinician Scientist Award.
OBJECTIVE:To undertake a randomized comparison of the Biodesign Surgisis anal fistula plug against surgeonʼs preference in treating cryptoglandular transsphincteric fistula-in-ano.
SUMMARY BACKGROUND ...DATA:The efficacy of the Biodesign Surgisis anal fistula plug in healing anal fistulae is uncertain.
METHODS:Participants were randomized to the fistula plug with surgeonʼs preference (advancement flap, cutting seton, fistulotomy, Ligation of the Intersphincteric Fistula Tract procedure). The primary outcome was faecal incontinence quality of life (FIQoL) at 12-months. Secondary outcomes were fistula healing, incontinence rates, and complication and reintervention rates.
RESULTS:Between May 2011 and March 2016, 304 participants were randomized to fistula plug or surgeonʼs preference. No differences were seen in FIQoL between the 2 groups at 12 months. Clinical fistula healing was reported in 66/122 (54%) of the fistula plug and 66/119 (55%) of the surgeonʼs preference groups at 12 months. Fecal incontinence rates improved marginally in both the groups. Complications and reinterventions were frequent, with significantly more complications in the fistula plug group at 6-weeks (49/142, 35% vs 25/137, 18%; P=0.002). The mean total costs were £2738 (s.d. £1151) for the fistula plug and £2308 (s.d. £1228) for the surgeonʼs preference group (mean difference +£430, P=0.0174). The average total quality adjusted life years (QALYs) gained was marginally higher in the fistula plug group. The fistula plug was 35% to 45% likely to be cost-effective across a willingness to pay threshold of £20,000 to £30,000 / QALY.
CONCLUSIONS:The Biodesign Surgisis anal fistula plug is associated with similar FIQoL and healing rates to surgeonʼs preference at 12 months. Higher costs and highly uncertain gains in QALYs mean that the fistula plug may not be considered as a cost-effective treatment in the UK NHS.
The aim of fistula surgery is to eradicate the disease while preserving anal sphincter function. The efficacy of the Surgisis
anal fistula plug (Cook Medical, Bloomington, IN, USA) in the treatment ...of trans-sphincteric fistula-in-ano has been variably reported.
To undertake a randomised comparison of the safety and efficacy of the Surgisis anal fistula plug in comparison with surgeon's preference for the treatment of trans-sphincteric anal fistulas.
A randomised, unblinded, parallel-arm, prospective, multicentre clinical trial.
Hospitals in the UK NHS involving colorectal surgeons accredited by the Association of Coloproctology of Great Britain and Ireland.
Adult patients suffering from trans-sphincteric fistula-in-ano of cryptoglandular origin.
Patients were randomised on a 1 : 1 basis to either the fistula plug or the surgeon's preference e.g. fistulotomy, cutting seton, advancement flap or ligation of intersphincteric fistula tract (LIFT) procedure.
The primary outcome measure was quality of life as measured by the Faecal Incontinence Quality of Life (FIQoL) questionnaire at 12-month follow-up. Secondary outcome measures included clinical and radiological fistula healing rates, faecal incontinence rates, complications rates, reintervention rates and cost-effectiveness.
Between May 2011 and March 2016, 304 participants were recruited (152 fistula plug vs. 152 surgeon's preference). No difference in FIQoL score between the two trial groups was seen at the 6-week, 6-month or 12-month follow-up. Clinical evidence of fistula healing was reported in 66 of 122 (54%) participants in the fistula plug group and in 66 of 119 (55%) participants in the surgeon's preference group at 12 months. Magnetic resonance imaging (MRI) showed fistula healing in 54 of 110 (49%) participants in the fistula plug group and in 63 of 112 (56%) participants in the surgeon's preference group. Variation in 12-month clinical healing rates was observed: 55%, 64%, 75%, 53% and 42% for fistula plug, cutting seton, fistulotomy, advancement flap and LIFT procedure, respectively. Faecal incontinence rates were low at baseline, with small improvement in both groups post treatment. Complications and reinterventions were frequent. The mean total costs were £2738 standard deviation (SD) £1151 in the fistula plug group and £2308 (SD £1228) in the surgeon's preference group. The average total quality-adjusted life-years (QALYs) gain was much smaller in the fistula plug group (0.829, SD 0.174) than in the surgeon's preference group (0.790, SD 0.212). Using multiple imputation and probabilistic sensitivity analysis, and adjusting for differences in baseline EuroQol-5 Dimensions, three-level version utility, there was a 35-45% chance that the fistula plug was as cost-effective as surgeon's preference over a range of thresholds of willingness to pay for a single QALY of £20,000-30,000.
Limitations include a smaller sample size than originally calculated, a lack of blinding that perhaps biased patient-reported outcomes and a lower compliance rate with MRI at 12-month follow-up.
The Surgisis anal fistula plug is associated with similar FIQoL score to surgeon's preference at 12-month follow-up. The higher costs and highly uncertain and small gains in QALYs associated with the fistula plug mean that this technology is unlikely to be considered a cost-effective use of resources in the UK NHS.
Further in-depth analysis should consider the clinical and MRI characteristics of fistula-in-ano in an attempt to identify predictors of fistula response to treatment.
Current Controlled Trials ISRCTN78352529.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 21. See the NIHR Journals Library website for further project information.
AbstractObjectiveTo evaluate the effectiveness of telephone health coaching delivered by a nurse to support self management in a primary care population with mild symptoms of chronic obstructive ...pulmonary disease (COPD).DesignMulticentre randomised controlled trial.Setting71 general practices in four areas of England.Participants577 patients with Medical Research Council dyspnoea scale scores of 1 or 2, recruited from primary care COPD registers with spirometry confirmed diagnosis. Patients were randomised to telephone health coaching (n=289) or usual care (n=288).InterventionsTelephone health coaching intervention delivered by nurses, underpinned by Social Cognitive Theory. The coaching promoted accessing smoking cessation services, increasing physical activity, medication management, and action planning (4 sessions over 11 weeks; postal information at weeks 16 and 24). The nurses received two days of training. The usual care group received a leaflet about COPD.Main outcome measuresThe primary outcome was health related quality of life at 12 months using the short version of the St George’s Respiratory Questionnaire (SGRQ-C).ResultsThe intervention was delivered with good fidelity: 86% of scheduled calls were delivered; 75% of patients received all four calls. 92% of patients were followed-up at six months and 89% at 12 months. There was no difference in SGRQ-C total score at 12 months (mean difference −1.3, 95% confidence interval −3.6 to 0.9, P=0.23). Compared with patients in the usual care group, at six months follow-up, the intervention group reported greater physical activity, more had received a care plan (44% v 30%), rescue packs of antibiotics (37% v 29%), and inhaler use technique check (68% v 55%).ConclusionsA new telephone health coaching intervention to promote behaviour change in primary care patients with mild symptoms of dyspnoea did lead to changes in self management activities, but did not improve health related quality of life.Trial registrationCurrent controlled trials ISRCTN 06710391
The reports from cohort studies comparing outcomes after revascularisation for chronic limb threatening ischaemia (CLTI) between men and women remain controversial. Anatomical and clinical disease ...severity is often heterogeneous, and treatment choice influenced by a variety of clinician and patient factors. The aim was to compare outcomes in men and women entered into the only randomised study comparing bypass and angioplasty for infra-inguinal disease causing severe limb ischaemia.
Data were obtained from BASIL-1 trial case record forms. Baseline demographics were compared, and Cox proportional hazard models were used to examine the relationship between sex and amputation free survival (AFS), overall survival (OS), and freedom from major adverse limb events (FF-MALE) using a per-protocol analysis. Data were analysed using a per-protocol analysis.
A total of 452 patients were randomised into the BASIL-1 trial from 1999 to 2004. At randomisation, women were older and less likely to be smokers, to have diabetes, or to be on recommended best medical therapy. Men were more likely to present with gangrene. Ankle brachial pressure index (ABPI), post-revascularisation length of hospital stay, and 30 day morbidity and mortality were similar for men and women. At three years, female sex was associated with significantly better AFS (HR 0.65, 95% CI 0.47–0.89, p < .01), OS (HR 0.66 95% CI 0.46–0.95, p = .02) and FF-MALE (HR 0.74, 95% CI 0.57–0.96, p = .02).
In the BASIL-1 trial, women had similar short term but better long term outcomes after revascularisation. Sex is an important consideration when developing early, evidence based treatment pathway and revascularisation strategies for CLTI, and is an independent risk factor for outcomes following revascularisation as well as development of symptomatic PAD.
Abstract
Objective
Patients with ANCA-associated vasculitis (AAV) experience high levels of fatigue, despite disease remission. This study assessed the feasibility and acceptability of a definitive ...randomized controlled trial of a behavioural-based physical activity intervention to support fatigue self-management in AAV patients.
Methods
AAV patients in disease remission with fatigue (Multidimensional Fatigue Inventory-20 general fatigue domain ≥14) were randomly allocated to intervention or standard care in this single-centre open-label randomized controlled feasibility study. The intervention lasted 12 weeks and comprised eight face-to-face physical activity sessions with a facilitator and 12 weekly telephone calls. Participants were encouraged to monitor their physical activity using a tracker device (Fitbit). Standard care involved sign-posting to fatigue websites. The primary outcome was feasibility of a phase III trial assessed against three stop/go traffic light criteria, (recruitment, intervention adherence and study withdrawal). A qualitative study assessed participant views about the intervention.
Results
A total of 248 patients were screened and 134 were eligible to participate (54%). Stop/go criteria were amber for recruitment; 43/134 (32%, 95% CI: 24, 40) eligible participants randomized, amber for adherence; 73% of participants attended all eight physical activity sessions, but only 11/22 (50%, 95% CI: 29, 71%) completed the intervention as per the intended schedule, and green for study withdrawal; 2/43 participants withdrew before 24 weeks (5%, 95% CI: 0, 11). Qualitative results suggested the intervention was acceptable.
Conclusion
This study suggests a behavioural-based physical activity intervention targeting fatigue self-management was acceptable to patients with AAV, although recruitment and protocol adherence will need modification prior to a definitive trial.
Clinical Trial Registration Number
ISRCTN11929227.
Abstract
Background
Preterm birth is associated with significant mortality and morbidity for mothers and babies. Women are identified as high risk for preterm birth based on either previous ...medical/pregnancy history or on ultrasound assessment of the cervix. Women identified as high risk can be offered a cervical cerclage (a purse string stitch) around the cervix (neck of the womb) to reduce the risk of preterm birth. In women who have a cervical cerclage, the procedure can be performed using either a monofilament (single-stranded) or braided (woven) suture material. Both suture materials are routinely used for cervical cerclage and there is uncertainty as to which is superior.
Methods
A multicentre, open, randomised controlled superiority trial of 2050 women presenting at obstetric units, deemed to be at risk of preterm birth and already scheduled to have a cervical cerclage as part of their standard care. Inclusion criteria include singleton pregnancies and an indication for cervical cerclage for either a history of three or more previous mid-trimester losses or premature births (≤ 28 weeks), insertion of cervical sutures in previous pregnancies, a history of mid trimester loss or premature birth with a (current) shortened (≤ 25 mm) cervix, or women whom clinicians deem to be at risk of preterm birth either by history or the results of an ultrasound scan. Exclusion criteria include women who have taken part in C-STICH previously, are aged less than 18 years old at the time of presentation, require a rescue cerclage, and are unwilling or unable to give informed consent and in whom a cerclage will be placed by any route other than vaginally (e.g. via an abdominal route). Following informed consent, women are randomised on a 1:1 basis to either monofilament or braided suture, by minimisation. The primary outcome is pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life), and secondary outcomes include the core outcome set for preterm birth trials.
Discussion
Optimising established interventions to prevent preterm birth is important in reducing perinatal mortality rates.
Trial registration
ISRCTN 15373349
. Registered before recruitment on 03 December 2014 prior to first recruit.
Abstract
Background
Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured ...membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach.
Methods
C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis.
Inclusion criteria are ≥16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0–27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy.
Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat.
Discussion
To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (
n
= 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies.
Trial registration
ISRCTN Registry
ISRCTN12981869
. Registered on 13th June 2018.
Introduction
Cesarean sections are the most common major operation worldwide. One in 10 women develops a surgical‐site infection after cesarean section. The PREPS pilot trial was developed to assess ...the feasibility of a randomized controlled trial of vaginal cleansing with chlorhexidine before cesarean section, to reduce infectious morbidity.
Material and methods
A multi‐center, open‐label, parallel‐group pilot randomized controlled trial across 4 UK maternity units. Women aged ≥16 years, undergoing elective or emergency cesarean section, ≥34 weeks of gestation, and able to give informed consent were eligible. Women were randomized 1:1 to chlorhexidine 0.05% or no cleansing and were followed up until 6 weeks after cesarean section. The feasibility of a larger randomized controlled trial was assessed by the pilot trial’s recruitment, ability to use verbal consent in an emergency, adherence, follow‐up and withdrawal rates. The main clinical outcome collected was Center for Disease Control and Prevention (CDC) classification of endometritis at 30 days. Trial registration number is ISRCTN33435996.
Results
A total of 320 women (128% of target) were randomized. Of these, 93% (95% CI 89%‐95%) received their allocated intervention. Of the 88 women who had an emergency cesarean section, verbal consent was initially given by 32 (36%) women, with the remainder having sufficient time to give written consent. Endometritis (CDC definition) was collected from medical notes of 96% of women, 68% (95% CI 63%‐73%) were followed up at both 14 and 30 days by telephone, and we were able to collect patient‐reported outcomes. In the vaginal cleansing arm 2/152 (1.3%) women had endometritis compared with 1/155 (0.7%) in the no cleansing arm (RR 2.08, 95% CI 0.19‐22.31).
Conclusions
It is possible to perform a randomized controlled trial in women undergoing an elective or emergency cesarean section, using a verbal‐followed‐by‐written consent process, while maintaining high adherence and retaining women in the trial.
The in vitro micronucleus assay is a globally significant method for DNA damage quantification used for regulatory compound safety testing in addition to inter-individual monitoring of environmental, ...lifestyle and occupational factors. However, it relies on time-consuming and user-subjective manual scoring. Here we show that imaging flow cytometry and deep learning image classification represents a capable platform for automated, inter-laboratory operation. Images were captured for the cytokinesis-block micronucleus (CBMN) assay across three laboratories using methyl methanesulphonate (1.25–5.0 μg/mL) and/or carbendazim (0.8–1.6 μg/mL) exposures to TK6 cells. Human-scored image sets were assembled and used to train and test the classification abilities of the “DeepFlow” neural network in both intra- and inter-laboratory contexts. Harnessing image diversity across laboratories yielded a network able to score unseen data from an entirely new laboratory without any user configuration. Image classification accuracies of 98%, 95%, 82% and 85% were achieved for ‘mononucleates’, ‘binucleates’, ‘mononucleates with MN’ and ‘binucleates with MN’, respectively. Successful classifications of ‘trinucleates’ (90%) and ‘tetranucleates’ (88%) in addition to ‘other or unscorable’ phenotypes (96%) were also achieved. Attempts to classify extremely rare, tri- and tetranucleated cells with micronuclei into their own categories were less successful (≤ 57%). Benchmark dose analyses of human or automatically scored micronucleus frequency data yielded quantitation of the same equipotent concentration regardless of scoring method. We conclude that this automated approach offers significant potential to broaden the practical utility of the CBMN method across industry, research and clinical domains. We share our strategy using openly-accessible frameworks.
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