ASEPTIC: primary antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis-study protocol for an interventional randomised controlled trial.

BACKGROUND: Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites. METHODS: The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients' health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events. DISCUSSION: This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT043955365 . Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central - Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA).

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial.

RATIONALE: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. AIM: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. METHODS AND DESIGN: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. STUDY OUTCOMES: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. SAMPLE SIZE TARGET: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. DISCUSSION: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke.Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.

Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson's disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The 'Exenatide-PD3' study.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. METHODS AND ANALYSIS: This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. ETHICS AND DISSEMINATION: This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. TRIAL REGISTRATION NUMBERS: NCT04232969, ISRCTN14552789.

Preoperative intravenous iron for anaemia in elective major open abdominal surgery: the PREVENTT RCT.

BACKGROUND: Anaemia affects 30-50% of patients before they undergo major surgery. Preoperative anaemia is associated with increased need for blood transfusion, postoperative complications and worse patient outcomes after surgery. International guidelines support the use of intravenous iron to correct anaemia in patients before surgery. However, the use of preoperative intravenous iron for patient benefit has not been assessed in the setting of a formal clinical trial. OBJECTIVES: To assess if intravenous iron given to patients with anaemia before major abdominal surgery is beneficial by reducing transfusion rates, postoperative complications, hospital stay and re-admission to hospital, and improving quality of life outcomes. DESIGN: A multicentre, double-blinded, randomised, controlled, Phase III clinical trial, with 1 : 1 randomisation comparing placebo (normal saline) with intravenous iron (intravenous ferric carboxymaltose 1000 mg). Randomisation and treatment allocation were by a secure web-based service. SETTING: The study was conducted across 46 hospitals in England, Scotland and Wales between September 2013 and September 2018. PARTICIPANTS: Patients aged > 18 years, undergoing elective major open abdominal surgery, with anaemia [Hb level of > 90 g/l and < 120 g/l (female patients) and < 130 g/l (male patients)] who could undergo randomisation and treatment 10-42 days before their operation. INTERVENTION: Double-blinded study comparing placebo of normal saline with 1000 mg of ferric carboxymaltose administered 10-42 days prior to surgery. MAIN OUTCOME MEASURES: Co-primary end points were risk of blood transfusion or death at 30 days postoperatively, and rate of blood transfusions at 30 days post operation. RESULTS: A total of 487 patients were randomised (243 given placebo and 244 given intravenous iron), of whom 474 completed the trial and provided data for the analysis of the co-primary end points. The use of intravenous iron increased preoperative Hb levels (mean difference 4.7 g/l, 95% confidence interval 2.7 to 6.8 g/l; p < 0.0001), but had no effect compared with placebo on risk of blood transfusion or death (risk ratio 1.03, 95% confidence interval 0.78 to 1.37; p = 0.84; absolute risk difference +0.8%, 95% confidence interval -7.3% to 9.0%), or rates of blood transfusion (rate ratio 0.98, 95% confidence interval 0.68 to 1.43; p = 0.93; absolute rate difference 0.00, 95% confidence interval -0.14 to 0.15). There was no difference in postoperative complications or hospital stay. The intravenous iron group had higher Hb levels at the 8-week follow-up (difference in mean 10.7 g/l, 95% confidence interval 7.8 to 13.7 g/l; p < 0.0001). There were a total of 71 re-admissions to hospital for postoperative complications in the placebo group, compared with 38 re-admissions in the intravenous iron group (rate ratio 0.54, 95% confidence interval 0.34 to 0.85; p = 0.009). There were no differences between the groups in terms of mortality (two per group at 30 days post operation) or in any of the prespecified safety end points or serious adverse events. CONCLUSIONS: In patients with anaemia prior to elective major abdominal surgery, there was no benefit from giving intravenous iron before the operation. FUTURE WORK: The impact of iron repletion on recovery from postoperative anaemia, and the association with reduced re-admission to hospital for complications, should be investigated. LIMITATIONS: In the preoperative intravenous iron to treat anaemia in major surgery (PREVENTT) trial, all patients included had anaemia and only 20% had their anaemia corrected before surgery. The definition and causality of iron deficiency in this setting is not clear. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67322816 and ClinicalTrials.gov NCT01692418. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25 No. 11. See the NIHR Journals Library website for further project information.

In patients undergoing major surgery, anaemia (low blood count) is a common problem. Anaemia is often a consequence of the disease necessitating surgery and can make people feel tired and unwell. Anaemia increases the need for a blood transfusion at the time of surgery, and patients with anaemia have more complications from surgery, prolonged hospital stay and delayed recovery. Iron deficiency is the most common cause of anaemia. An iron infusion has been shown to be effective to rapidly treat anaemia, but it is not known if this is effective in treating anaemia in the presurgical setting, and whether or not this may benefit patients. The main aim of this study was to assess if intravenous iron can treat anaemia in patients before major surgery and if this will reduce the need for blood transfusion, make patients feel better and, consequently, help them do better during and after surgery. A total of 487 patients with anaemia were recruited from 46 UK hospitals before major abdominal surgery. Patients were randomly allocated to receive an infusion of iron or placebo 10 days to 6 weeks before their surgery. Patients were followed up at 8 weeks and 6 months after their surgery. Intravenous iron increased the blood count in patients before surgery. There was no difference in blood transfusion rates or patient deaths between those who received intravenous iron and those who received placebo. Similarly, there was no difference in the patients' postoperative complications or length of hospital stay. Patients who received iron had a higher blood count at 8 weeks and 6 months post operation and there were fewer re-admissions to hospital for complications. In conclusion, for patients undergoing major surgery, giving intravenous iron to treat anaemia before the operation did not reduce the need for blood transfusion. Further work is needed to evaluate whether or not there is any benefit after discharge from hospital.

Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.

BACKGROUND: Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes. METHODS: In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants. FINDINGS: Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints. INTERPRETATION: Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery. FUNDING: UK National Institute of Health Research Health Technology Assessment Program.

Preoperative intravenous iron before cardiac surgery: a prospective multicentre feasibility study.

BACKGROUND: Preoperative anaemia affects one third of patients undergoing cardiac surgery and is associated with increased mortality and morbidity. Although it is recommended that perioperative teams should identify and treat patients with preoperative anaemia before surgery, introducing new treatment protocols can be challenging in surgical pathways. The aim of this study was to assess the feasibility and effectiveness of introducing a preoperative intravenous iron service as a national initiative in cardiac surgery. METHODS: We performed a multicentre, stepped, observational study using the UK Association of Cardiothoracic Anaesthesia and Critical Care Research Network. The primary feasibility outcome was the ability to set up an anaemia and intravenous iron clinic at each site. The primary efficacy outcome was change in haemoglobin (Hb) concentration between intervention and operation. Secondary outcomes included blood transfusion and hospital stay. Patients with anaemia were compared with non-anaemic patients and with those who received intravenous iron as part of their routine treatment protocol. RESULTS: Seven out of 11 NHS hospitals successfully set up iron clinics over 2 yr, and 228 patients were recruited into this study. Patients with anaemia who received intravenous iron were at higher surgical risk, were more likely to have a known previous history of iron deficiency or anaemia, had a higher rate of chronic kidney disease, and were slightly more anaemic than the non-treated group. Intravenous iron was administered a median (inter-quartile range, IQR [range]) of 33 (15-53 [4-303]) days before surgery. Preoperative intravenous iron increased [Hb] from baseline to pre-surgery; mean (95% confidence interval) change was +8.4 (5.0-11.8) g L-1 (P<0.001). Overall, anaemic compared with non-anaemic patients were more likely to be transfused (49% [59/136] vs 27% (22/92), P=0.001) and stayed longer in hospital (median days [IQR], 9 [7-15] vs 8 [6-11]; P=0.014). The number of days alive and at home was lower in the anaemic group (median days [IQR], 20 [14-22] vs 21 [17-23]; P=0.033). CONCLUSION: The development of an intravenous iron pathway is feasible but appears limited to selected high-risk cardiac patients in routine NHS practise. Although intravenous iron increased [Hb], there is a need for an appropriately powered clinical trial to assess the clinical effect of intravenous iron on patient-centred outcomes.

Perioperative Anemia Management.

Anemia is increasingly recognized as an interventional hematological target in patients before major surgery. Preoperative anemia increases the need for perioperative blood transfusion, and there is now a well-recognized association with increased patient complications, length of hospital stay, and worse outcomes. Patient Blood Management (PBM) is a World Health Organization endorsed, evidence-based management bundle of care in transfusion hemostasis that focuses on three main aspects: anemia management, prevention of blood loss, and appropriate transfusion practice. Implementation of PBM guidelines has been accompanied by reduced transfusion needs and improved patient outcomes. In a patient presenting with preoperative anemia or at risk of transfusion, this should initiate a program of PBM that manages the patient through the entire operative period. We review the current evidence on the three pillars of PBM and highlight those aspects with the strongest evidence in support of their impact.

Development and feasibility of a Patient Blood Management implementation programme in vascular surgery.

Vascular surgery is the largest (non-cardiac) user of blood transfusion which is associated with increased risk to patients. Patient Blood Management (PBM) is a quality improvement programme in transfusion medicine involving educational change and recommendations through preoperative, operative, and postoperative surgery. We wished to assess the feasibility to implement a PBM programme in vascular surgery. A multidisciplinary programme was developed at a vascular unit by PBM experts. The PBM programme involved a series of educational lectures, consultations, and discussions with doctors, nurses, and theatre staff. A one-page PBM checklist of recommendations was developed for all patients undergoing vascular surgery. Prospective audits were conducted before (October 2014 to March 2015) and after (November 2015 to February 2016) PBM implementation. Outcomes were blood transfusion and haemoglobin concentration (Hb) trigger threshold. A total of 211 patients were admitted under vascular surgery: 127 for Audit 1 and 84 for Audit 2. Overall, 30% of patients were transfused, with 193 units transfused in Audit 1 and 85 in Audit 2. PBM implementation was associated with a reduction in patients receiving a blood transfusion (37% to 20%; p = 0.01). However, there was no difference in Hb trigger threshold (76 g/L vs 72 g/L, p = 0.051). A PBM programme is feasible and can be implemented in vascular surgery. PBM was associated with an improvement in transfusion use and length of patient stay that merits further investigation.

Management of the patient presenting with anaemia in the preoperative setting.

Preoperative anaemia is common, seen in a third of patients before major surgery. Both preoperative anaemia and blood transfusion are associated with increased patient risk and adverse outcome. Patient Blood Management (PBM) is the multidisciplinary, multimodal approach to optimising the care of patients who may require blood transfusion. Guidelines exist with many recommendations throughout the perioperative pathway. However, the efficacy of individual recommendations as an intervention in terms of clinical outcome can be confusing. In the UK the first national audit of PBM in surgery was carried out in 2015. This reviewed the use and impact of PBM recommendations in hospitals throughout the UK where major surgery was undertaken. The current evidence base for these PBM recommendations was reviewed and the patient outcome in terms of blood transfusion use and length of hospital stay assessed in those where PBM interventions were followed. For the patient who presents with preoperative anaemia, 'quick wins' were identified that reduced blood transfusion use and reduced length of stay in hospital; preoperative discontinuation of anticoagulation or antiplatelet therapy, and intraoperative use of tranexamic acid and cell salvage.

Evaluation of a targeted, theory-informed implementation intervention designed to increase uptake of emergency management recommendations regarding adult patients with mild traumatic brain injury: results of the NET cluster randomised trial.

BACKGROUND: Evidence-based guidelines for management of mild traumatic brain injury (mTBI) in the emergency department (ED) are now widely available; however, clinical practice remains inconsistent with these guidelines. A targeted, theory-informed implementation intervention (Neurotrauma Evidence Translation (NET) intervention) was designed to increase the uptake of three clinical practice recommendations regarding the management of patients who present to Australian EDs with mild head injuries. The intervention involved local stakeholder meetings, identification and training of nursing and medical local opinion leaders, train-the-trainer workshops and standardised education materials and interactive workshops delivered by the opinion leaders to others within their EDs during a 3 month period. This paper reports on the effects of this intervention. METHODS: EDs (clusters) were allocated to receive either access to a clinical practice guideline (control) or the implementation intervention, using minimisation, a method that allocates clusters to groups using an algorithm to minimise differences in predefined factors between the groups. We measured clinical practice outcomes at the patient level using chart audit. The primary outcome was appropriate screening for post-traumatic amnesia (PTA) using a validated tool until a perfect score was achieved (indicating absence of acute cognitive impairment) before the patient was discharged home. Secondary outcomes included appropriate CT scanning and the provision of written patient information upon discharge. Patient health outcomes (anxiety, primary outcome: Hospital Anxiety and Depression Scale) were also assessed using follow-up telephone interviews. Outcomes were assessed by independent auditors and interviewers, blinded to group allocation. RESULTS: Fourteen EDs were allocated to the intervention and 17 to the control condition; 1943 patients were included in the chart audit. At 2 months follow-up, patients attending intervention EDs (n = 893) compared with control EDs (n = 1050) were more likely to have been appropriately assessed for PTA (adjusted odds ratio (OR) 20.1, 95%CI 6.8 to 59.3; adjusted absolute risk difference (ARD) 14%, 95%CI 8 to 19). The odds of compliance with recommendations for CT scanning and provision of written patient discharge information were small (OR 1.2, 95%CI 0.8 to 1.6; ARD 3.2, 95%CI - 3.7 to 10 and OR 1.2, 95%CI 0.8 to 1.8; ARD 3.1, 95%CI - 3.0 to 9.3 respectively). A total of 343 patients at ten interventions and 14 control sites participated in follow-up interviews at 4.3 to 10.7 months post-ED presentation. The intervention had a small effect on anxiety levels (adjusted mean difference - 0.52, 95%CI - 1.34 to 0.30; scale 0-21, with higher scores indicating greater anxiety). CONCLUSIONS: Our intervention was effective in improving the uptake of the PTA recommendation; however, it did not appreciably increase the uptake of the other two practice recommendations. Improved screening for PTA may be clinically important as it leads to appropriate periods of observation prior to safe discharge. The estimated intervention effect on anxiety was of limited clinical significance. We were not able to compare characteristics of EDs who declined trial participation with those of participating sites, which may limit the generalizability of the results. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12612001286831), date registered 12 December 2012.

Factors associated with persistent post-concussion symptoms following mild traumatic brain injury in adults.

OBJECTIVES: Debate regarding factors associated with persistent symptoms following mild traumatic brain injury continues. Nested within a trial aiming to change practice in emergency department management of mild traumatic brain injury, this study investigated the nature of persistent symptoms, work/study outcomes, anxiety and quality of life and factors associated with persistent symptoms following injury, including the impact of receiving information about mild traumatic brain injuries in the emergency department. METHODS: A total of 343 individuals with mild traumatic brain injury completed the Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety Depression Scale - Anxiety Scale, and Quality of Life - Short Form in average 7 months post-injury. RESULTS: Overall, 18.7% of participants reported 3 or more post-concussional symptoms, most commonly fatigue (17.2%) and forgetfulness (14.6%). Clinically significant anxiety was reported by 12.8%, and was significantly associated with symptom reporting, as were mental and physical quality of life scores. Significant predictors of post-concussional symptoms at follow-up were pre-injury psychological issues, experiencing loss of consciousness, and having no recall of receiving information about brain injury in the emergency department. CONCLUSION: This study confirms that loss of consciousness and pre-injury psychological issues are associated with persistent symptom reporting. Not receiving injury information in the emergency department may also negatively influence symptom reporting.

Economic evaluation of the NET intervention versus guideline dissemination for management of mild head injury in hospital emergency departments.

BACKGROUND: Evidence-based guidelines for the management of mild traumatic brain injury (mTBI) in the emergency department (ED) are now widely available, and yet, clinical practice remains inconsistent with the guidelines. The Neurotrauma Evidence Translation (NET) intervention was developed to increase the uptake of guideline recommendations and improve the management of minor head injury in Australian emergency departments (EDs). However, the adoption of this type of intervention typically entails an upfront investment that may or may not be fully offset by improvements in clinical practice, health outcomes and/or reductions in health service utilisation. The present study estimates the cost and cost-effectiveness of the NET intervention, as compared to the passive dissemination of the guideline, to evaluate whether any improvements in clinical practice or health outcomes due to the NET intervention can be obtained at an acceptable cost. METHODS AND FINDINGS: Study setting: The NET cluster randomised controlled trial [ACTRN12612001286831]. STUDY SAMPLE: Seventeen EDs were randomised to the control condition and 14 to the intervention. One thousand nine hundred forty-three patients were included in the analysis of clinical practice outcomes (NET sample). A total of 343 patients from 14 control and 10 intervention EDs participated in follow-up interviews and were included in the analysis of patient-reported health outcomes (NET-Plus sample). OUTCOME MEASURES: Appropriate post-traumatic amnesia (PTA) screening in the ED (primary outcome). Secondary clinical practice outcomes: provision of written information on discharge (INFO) and safe discharge (defined as CT scan appropriately provided plus PTA plus INFO). Secondary patient-reported, post-discharge health outcomes: anxiety (Hospital Anxiety and Depression Scale), post-concussive symptoms (Rivermead), and preference-based health-related quality of life (SF6D). METHODS: Trial-based economic evaluations from a health sector perspective, with time horizons set to coincide with the final follow-up for the NET sample (2 months post-intervention) and to 1-month post-discharge for the NET-Plus sample. RESULTS: Intervention and control groups were not significantly different in health service utilisation received in the ED/inpatient ward following the initial mTBI presentation (adjusted mean difference $23.86 per patient; 95%CI - $106, $153; p = 0.719) or over the longer follow-up in the NET-plus sample (adjusted mean difference $341.78 per patient; 95%CI - $58, $742; p = 0.094). Savings from lower health service utilisation are therefore unlikely to offset the significantly higher upfront cost of the intervention (mean difference $138.20 per patient; 95%CI $135, $141; p < 0.000). Estimates of the net effect of the intervention on total cost (intervention cost net of health service utilisation) suggest that the intervention entails significantly higher costs than the control condition (adjusted mean difference $169.89 per patient; 95%CI $43, $297, p = 0.009). This effect is larger in absolute magnitude over the longer follow-up in the NET-plus sample (adjusted mean difference $505.06; 95%CI $96, $915; p = 0.016), mostly due to additional health service utilisation. For the primary outcome, the NET intervention is more costly and more effective than passive dissemination; entailing an additional cost of $1246 per additional patient appropriately screened for PTA ($169.89/0.1363; Fieller's 95%CI $525, $2055). For NET to be considered cost-effective with 95% confidence, decision-makers would need to be willing to trade one quality-adjusted life year (QALY) for 25 additional patients appropriately screened for PTA. While these results reflect our best estimate of cost-effectiveness given the data, it is possible that a NET intervention that has been scaled and streamlined ready for wider roll-out may be more or less cost-effective than the NET intervention as delivered in the trial. CONCLUSIONS: While the NET intervention does improve the management of mTBI in the ED, it also entails a significant increase in cost and-as delivered in the trial-is unlikely to be cost-effective at currently accepted funding thresholds. There may be a scope for a scaled-up and streamlined NET intervention to achieve a better balance between costs and outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001286831 , date registered 12 December 2012.

Interventions for managing skeletal muscle spasticity following traumatic brain injury.

BACKGROUND: Skeletal muscle spasticity is a major physical complication resulting from traumatic brain injury (TBI), which can lead to muscle contracture, joint stiffness, reduced range of movement, broken skin and pain. Treatments for spasticity include a range of pharmacological and non-pharmacological interventions, often used in combination. Management of spasticity following TBI varies from other clinical populations because of the added complexity of behavioural and cognitive issues associated with TBI. OBJECTIVES: To assess the effects of interventions for managing skeletal muscle spasticity in people with TBI. SEARCH METHODS: In June 2017, we searched key databases including the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE (Ovid), Embase (Ovid) and others, in addition to clinical trials registries and the reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over RCTs evaluating any intervention for the management of spasticity in TBI. Only studies where at least 50% of participants had a TBI (or for whom separate data for participants with TBI were available) were included. The primary outcomes were spasticity and adverse effects. Secondary outcome measures were classified according to the World Health Organization International Classification of Functioning, Disability and Health including body functions (sensory, pain, neuromusculoskeletal and movement-related functions) and activities and participation (general tasks and demands; mobility; self-care; domestic life; major life areas; community, social and civic life). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Data were synthesised narratively; meta-analysis was precluded due to the paucity and heterogeneity of data. MAIN RESULTS: We included nine studies in this review which involved 134 participants with TBI. Only five studies reported between-group differences, yielding outcome data for 105 participants with TBI. These five studies assessed the effects of a range of pharmacological (baclofen, botulinum toxin A) and non-pharmacological (casting, physiotherapy, splints, tilt table standing and electrical stimulation) interventions, often in combination. The studies which tested the effect of baclofen and tizanidine did not report their results adequately. Where outcome data were available, spasticity and adverse events were reported, in addition to some secondary outcome measures.Of the five studies with results, three were funded by governments, charities or health services and two were funded by a pharmaceutical or medical technology company. The four studies without useable results were funded by pharmaceutical or medical technology companies.It was difficult to draw conclusions about the effectiveness of these interventions due to poor reporting, small study size and the fact that participants with TBI were usually only a proportion of the overall total. Meta-analysis was not feasible due to the paucity of data and heterogeneity of interventions and comparator groups. Some studies concluded that the intervention they tested had beneficial effects on spasticity, and others found no difference between certain treatments. The most common adverse event was minor skin damage in people who received casting. We believe it would be misleading to provide any further description of study results given the quality of the evidence was very low for all outcomes. AUTHORS' CONCLUSIONS: The very low quality and limited amount of evidence about the management of spasticity in people with TBI means that we are uncertain about the effectiveness or harms of these interventions. Well-designed and adequately powered studies using functional outcome measures to test the interventions used in clinical practice are needed.

The UK Cardiac and Vascular Surgery Interventional Anaemia Response (CAVIAR) Study: protocol for an observational cohort study to determine the impact and effect of preoperative anaemia management in cardiac and vascular surgical patients.

INTRODUCTION: Preoperative anaemia is linked to poor postsurgical outcome, longer hospital stays, greater risk of complications and mortality. Currently in the UK, some sites have developed anaemia clinics or pathways that use intravenous iron to correct iron deficiency anaemia prior to surgery as their standard of care. Although intravenous iron has been observed to be effective in a variety of patient settings, there is insufficient evidence in its use in cardiac and vascular patients. The aim of this study is to observe the impact and effect of anaemia and its management in patients undergoing cardiac and vascular surgery. In addition, the UK Cardiac and Vascular Surgery Interventional Anaemia Response (CAVIAR) Study is also a feasibility study with the aim to establish anaemia management pathways in the preoperative setting to inform the design of future randomised controlled trials. METHODS AND ANALYSIS: The UK CAVIAR Study is a multicentre, stepped, observational study, in patients awaiting major cardiac or vascular surgery. We will be examining different haematological variables (especially hepcidin), functional capacity and patient outcome. Patients will be compared based on their anaemia status, whether they received intravenous iron in accordance to their hospital's preoperative pathway, and their disease group. The primary outcomes are the change in haemoglobin levels from baseline (before treatment) to before surgery; and the number of successful patients recruited and consented (feasibility). The secondary outcomes will include changes in biomarkers of iron deficiency, length of stay, quality of life and postoperative recovery. ETHICS AND DISSEMINATION: The study protocol was approved by the London-Westminster Research Ethics Committee (15/LO/1569, 27 November 2015). NHS approval was also obtained with each hospital trust. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinical Trials registry (NCT02637102) and the ISRCTN registry (ISRCTN55032357).

Robotic Assisted Radical Cystectomy with Extracorporeal Urinary Diversion Does Not Show a Benefit over Open Radical Cystectomy: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: The number of robotic assisted radical cystectomy (RARC) procedures is increasing despite the lack of Level I evidence showing any advantages over open radical cystectomy (ORC). However, several systematic reviews with meta-analyses including non-randomised studies, suggest an overall benefit for RARC compared to ORC. We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) to evaluate the perioperative morbidity and efficacy of RARC compared to ORC in patients with bladder cancer. METHODS: Literature searches of Medline/Pubmed, Embase, Web of Science and clinicaltrials.gov databases up to 10th March 2016 were performed. The inclusion criteria for eligible studies were RCTs which compared perioperative outcomes of ORC and RARC for bladder cancer. Primary objective was perioperative and histopathological outcomes of RARC versus ORC while the secondary objective was quality of life assessment (QoL), oncological outcomes and cost analysis. RESULTS: Four RCTs (from 5 articles) met the inclusion criteria, with a total of 239 patients all with extracorporeal urinary diversion. Patient demographics and clinical characteristics of RARC and ORC patients were evenly matched. There was no significant difference between groups in perioperative morbidity, length of stay, positive surgical margin, lymph node yield and positive lymph node status. RARC group had significantly lower estimated blood loss (p<0.001) and wound complications (p = 0.03) but required significantly longer operating time (p<0.001). QoL was not measured uniformly across trials and cost analysis was reported in one RCTs. A test for heterogeneity did highlight differences across operating time of trials suggesting that surgeon experience may influence outcomes. CONCLUSIONS: This study does not provide evidence to support a benefit for RARC compared to ORC. These results may not have inference for RARC with intracorporeal urinary diversion. Well-designed trials with appropriate endpoints conducted by equally experienced ORC and RARC surgeons will be needed to address this.

Investigation of bias in meta-analyses due to selective inclusion of trial effect estimates: empirical study.

OBJECTIVE: To explore whether systematic reviewers selectively include trial effect estimates in meta-analyses when multiple are available, and what impact this may have on meta-analytic effects. DESIGN: Cross-sectional study. DATA SOURCES: We randomly selected systematic reviews of interventions from 2 clinical specialties published between January 2010 and 2012. The first presented meta-analysis of a continuous outcome in each review was selected (index meta-analysis), and all trial effect estimates that were eligible for inclusion in the meta-analysis (eg, from multiple scales or time points) were extracted from trial reports. ANALYSIS: We calculated a statistic (the Potential Bias Index (PBI)) to quantify and test for evidence of selective inclusion. The PBI ranges from 0 to 1; values above or below 0.5 are suggestive of selective inclusion of effect estimates more or less favourable to the intervention, respectively. The impact of any potential selective inclusion was investigated by comparing the index meta-analytic standardised mean difference (SMD) to the median of a randomly constructed distribution of meta-analytic SMDs (representing the meta-analytic SMD expected when there is no selective inclusion). RESULTS: 31 reviews (250 trials) were included. The estimated PBI was 0.57 (95% CI 0.50 to 0.63), suggesting that trial effect estimates that were more favourable to the intervention were included in meta-analyses slightly more often than expected under a process consistent with random selection; however, the 95% CI included the null hypothesis of no selective inclusion. Any potential selective inclusion did not have an important impact on the meta-analytic effects. CONCLUSION: There was no clear evidence that selective inclusion of trial effect estimates occurred in this sample of meta-analyses. Further research on selective inclusion in other clinical specialties is needed. To enable readers to assess the risk of selective inclusion bias, we recommend that systematic reviewers report the methods used to select effect estimates to include in meta-analyses.

Methods to select results to include in meta-analyses deserve more consideration in systematic reviews.

OBJECTIVES: To investigate how often systematic reviewers encounter multiple trial effect estimates that are available for inclusion in a particular meta-analysis (multiplicity of results) and the methods they use to select effect estimates. STUDY DESIGN AND SETTING: We randomly sampled Cochrane and MEDLINE-indexed non-Cochrane reviews published between January 2010 and January 2012. The first presented meta-analysis of an effect measure for a continuous outcome in each review was identified, and methods to select results to include in this meta-analysis were extracted from review protocols and reviews. All effect estimates that were available for inclusion in the meta-analyses were extracted from trial reports. RESULTS: We examined 44 reviews. Multiplicity of results was common, occurring in 49% of trial reports (n = 210). Prespecification of decision rules to select results from multiple measurement scales and intervention/control groups (in multi-arm trials) was uncommon (19% and 14% of 21 review protocols, respectively). Overall, 70% of reviews included at least one randomized controlled trial with multiplicity of results, but this occurred less frequently in reviews with a protocol (risk difference, -25%; 95% confidence interval: -52%, 1%). CONCLUSION: Systematic reviewers are likely to encounter multiplicity of results in the included trials. We recommend that systematic reviewers always consider predefining methods to select results to include in meta-analyses. Methods focusing on selection of measurement scales and how to deal with multi-arm trials would be most valuable.

Manual therapy and exercise for adhesive capsulitis (frozen shoulder).

BACKGROUND: Adhesive capsulitis (also termed frozen shoulder) is commonly treated by manual therapy and exercise, usually delivered together as components of a physical therapy intervention. This review is one of a series of reviews that form an update of the Cochrane review, 'Physiotherapy interventions for shoulder pain.' OBJECTIVES: To synthesise available evidence regarding the benefits and harms of manual therapy and exercise, alone or in combination, for the treatment of patients with adhesive capsulitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL Plus, ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to May 2013, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials, including adults with adhesive capsulitis, and comparing any manual therapy or exercise intervention versus placebo, no intervention, a different type of manual therapy or exercise or any other intervention. Interventions included mobilisation, manipulation and supervised or home exercise, delivered alone or in combination. Trials investigating the primary or adjunct effect of a combination of manual therapy and exercise were the main comparisons of interest. Main outcomes of interest were participant-reported pain relief of 30% or greater, overall pain (mean or mean change), function, global assessment of treatment success, active shoulder abduction, quality of life and the number of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: We included 32 trials (1836 participants). No trial compared a combination of manual therapy and exercise versus placebo or no intervention. Seven trials compared a combination of manual therapy and exercise versus other interventions but were clinically heterogeneous, so opportunities for meta-analysis were limited. The overall impression gained from these trials is that the few outcome differences between interventions that were clinically important were detected only up to seven weeks. Evidence of moderate quality shows that a combination of manual therapy and exercise for six weeks probably results in less improvement at seven weeks but a similar number of adverse events compared with glucocorticoid injection. The mean change in pain with glucocorticoid injection was 58 points on a 100-point scale, and 32 points with manual therapy and exercise (mean difference (MD) 26 points, 95% confidence interval (CI) 15 points to 37 points; one RCT, 107 participants), for an absolute difference of 26% (15% to 37%). Mean change in function with glucocorticoid injection was 39 points on a 100-point scale, and 14 points with manual therapy and exercise (MD 25 points, 95% CI 35 points to 15 points; one RCT, 107 participants), for an absolute difference of 25% (15% to 35%). Forty-six per cent (26/56) of participants reported treatment success with manual therapy and exercise compared with 77% (40/52) of participants receiving glucocorticoid injection (risk ratio (RR) 0.6, 95% CI 0.44 to 0.83; one RCT, 108 participants), with an absolute risk difference of 30% (13% to 48%). The number reporting adverse events did not differ between groups: 56% (32/57) reported events with manual therapy and exercise, and 53% (30/57) with glucocorticoid injection (RR 1.07, 95% CI 0.76 to 1.49; one RCT, 114 participants), with an absolute risk difference of 4% (-15% to 22%). Group differences in improvement in overall pain and function at six months and 12 months were not clinically important.We are uncertain of the effect of other combinations of manual therapy and exercise, as most evidence is of low quality. Meta-analysis of two trials (86 participants) suggested no clinically important differences between a combination of manual therapy, exercise, and electrotherapy for four weeks and placebo injection compared with glucocorticoid injection alone or placebo injection alone in terms of overall pain, function, active range of motion and quality of life at six weeks, six months and 12 months (though the 95% CI suggested function may be better with glucocorticoid injection at six weeks). The same two trials found that adding a combination of manual therapy, exercise and electrotherapy for four weeks to glucocorticoid injection did not confer clinically important benefits over glucocorticoid injection alone at each time point. Based on one high quality trial (148 participants), following arthrographic joint distension with glucocorticoid and saline, a combination of manual therapy and supervised exercise for six weeks conferred similar effects to those of sham ultrasound in terms of overall pain, function and quality of life at six weeks and at six months, but provided greater patient-reported treatment success and active shoulder abduction at six weeks. One trial (119 participants) found that a combination of manual therapy, exercise, electrotherapy and oral non-steroidal anti-inflammatory drug (NSAID) for three weeks did not confer clinically important benefits over oral NSAID alone in terms of function and patient-reported treatment success at three weeks.On the basis of 25 clinically heterogeneous trials, we are uncertain of the effect of manual therapy or exercise when not delivered together, or one type of manual therapy or exercise versus another, as most reported differences between groups were not clinically or statistically significant, and the evidence is mostly of low quality. AUTHORS' CONCLUSIONS: The best available data show that a combination of manual therapy and exercise may not be as effective as glucocorticoid injection in the short-term. It is unclear whether a combination of manual therapy, exercise and electrotherapy is an effective adjunct to glucocorticoid injection or oral NSAID. Following arthrographic joint distension with glucocorticoid and saline, manual therapy and exercise may confer effects similar to those of sham ultrasound in terms of overall pain, function and quality of life, but may provide greater patient-reported treatment success and active range of motion. High-quality RCTs are needed to establish the benefits and harms of manual therapy and exercise interventions that reflect actual practice, compared with placebo, no intervention and active interventions with evidence of benefit (e.g. glucocorticoid injection).

Safety and efficacy of pharmacologic thromboprophylaxis following blunt head injury: a systematic review.

BACKGROUND: Patients with blunt head injury are at high risk of venous thromboembolism. However, pharmacologic thromboprophylaxis (PTP) may cause progression of intracranial hemorrhage, and clinicians must often weigh up the risks and benefits. This review aimed to determine whether adding PTP to mechanical prophylaxis confers net benefit or harm and the optimal timing, dose, and agent for PTP in patients with blunt head injury. METHODS: We searched MEDLINE, EMBASE, The Cochrane Library Central Register of Controlled Trials (CENTRAL), and www.clinicaltrials.gov on April 24, 2013, to identify controlled studies and ongoing trials that assessed the efficacy or safety of thromboprophylaxis interventions in the early management of head-injured patients. Studies were classified based on types of interventions and comparisons, and the quality of included studies was assessed using Cochrane risk-of-bias tool and the Newcastle-Ottawa Quality Assessment Scale. We intended to undertake a meta-analysis if studies were sufficiently similar. RESULTS: Sixteen studies met the inclusion criteria, including four randomized controlled trials. At least two randomized controlled trials were at high risk of bias owing to inadequate randomization and concealment of allocation, and observational studies were potentially confounded by substantial differences between comparison groups. Heterogeneity of included studies precluded meta-analysis. Results were mixed, with some studies supporting and others refuting addition of PTP to mechanical interventions. Little evidence was available about dose or choice of agent. The safety and efficacy of early PTP in patients without early progression of hemorrhage is unclear. CONCLUSION: There is currently insufficient evidence to guide thromboprophylaxis in patients with blunt head injury. Standardized definitions and outcome measurements would facilitate comparison of outcomes across future studies. Studies in mixed populations should report head-injured specific subgroup data. Future randomized controlled trials should investigate the efficacy and safety of early pharmacologic prophylaxis in addition to mechanical intervention. LEVEL OF EVIDENCE: Systematic review, level IV.