Pharmacological interventions for the prevention of bleeding in people undergoing elective hip or knee surgery: a systematic review and network meta-analysis.

BACKGROUND: Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care. OBJECTIVES: To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology. SEARCH METHODS: We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants. DATA COLLECTION AND ANALYSIS: We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received. MAIN RESULTS: We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials). AUTHORS' CONCLUSIONS: We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review.

Pharmacological interventions for the prevention of bleeding in people undergoing definitive fixation or joint replacement for hip, pelvic and long bone fractures.

BACKGROUND: Pelvic, hip, and long bone fractures can result in significant bleeding at the time of injury, with further blood loss if they are treated with surgical fixation. People undergoing surgery are therefore at risk of requiring a blood transfusion and may be at risk of peri-operative anaemia. Pharmacological interventions for blood conservation may reduce the risk of requiring an allogeneic blood transfusion and associated complications. OBJECTIVES: To assess the effectiveness of different pharmacological interventions for reducing blood loss in definitive surgical fixation of the hip, pelvic, and long bones. SEARCH METHODS: We used a predefined search strategy to search CENTRAL, MEDLINE, PubMed, Embase, CINAHL, Transfusion Evidence Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) from inception to 7 April 2022, without restrictions on language, year, or publication status. We handsearched reference lists of included trials to identify further relevant trials. We contacted authors of ongoing trials to acquire any unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people who underwent trauma (non-elective) surgery for definitive fixation of hip, pelvic, and long bone (pelvis, tibia, femur, humerus, radius, ulna and clavicle) fractures only. There were no restrictions on gender, ethnicity, or age. We excluded planned (elective) procedures (e.g. scheduled total hip arthroplasty), and studies published since 2010 that had not been prospectively registered. Eligible interventions included: antifibrinolytics (tranexamic acid, aprotinin, epsilon-aminocaproic acid), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. We did not perform a network meta-analysis due to lack of data. MAIN RESULTS: We included 13 RCTs (929 participants), published between 2005 and 2021. Three trials did not report any of our predefined outcomes and so were not included in quantitative analyses (all were tranexamic acid versus placebo). We identified three comparisons of interest: intravenous tranexamic acid versus placebo; topical tranexamic acid versus placebo; and recombinant factor VIIa versus placebo. We rated the certainty of evidence as very low to low across all outcomes. Comparison 1. Intravenous tranexamic acid versus placebo Intravenous tranexamic acid compared to placebo may reduce the risk of requiring an allogeneic blood transfusion up to 30 days (RR 0.48, 95% CI 0.34 to 0.69; 6 RCTs, 457 participants; low-certainty evidence) and may result in little to no difference in all-cause mortality (Peto odds ratio (Peto OR) 0.38, 95% CI 0.05 to 2.77; 2 RCTs, 147 participants; low-certainty evidence).  It may result in little to no difference in risk of participants experiencing myocardial infarction (risk difference (RD) 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 199 participants; low-certainty evidence), and cerebrovascular accident/stroke (RD 0.00, 95% CI -0.02 to 0.02; 3 RCTs, 324 participants; low-certainty evidence).  We are uncertain if there is a difference between groups for risk of deep vein thrombosis (Peto OR 2.15, 95% CI 0.22 to 21.35; 4 RCTs, 329 participants, very low-certainty evidence), pulmonary embolism (Peto OR 1.08, 95% CI 0.07 to 17.66; 4 RCTs, 329 participants; very low-certainty evidence), and suspected serious drug reactions (RD 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 185 participants; very low-certainty evidence). No data were available for number of red blood cell units transfused, reoperation, or acute transfusion reaction. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures), and upgraded the evidence for transfusion requirement for a large effect.  Comparison 2. Topical tranexamic acid versus placebo We are uncertain if there is a difference between topical tranexamic acid and placebo for risk of requiring an allogeneic blood transfusion (RR 0.31, 95% CI 0.08 to 1.22; 2 RCTs, 101 participants), all-cause mortality (RD 0.00, 95% CI -0.10 to 0.10; 1 RCT, 36 participants), risk of participants experiencing myocardial infarction (Peto OR 0.15, 95% CI 0.00 to 7.62; 1 RCT, 36 participants), cerebrovascular accident/stroke (RD 0.00, 95% CI -0.06 to 0.06; 1 RCT, 65 participants); and deep vein thrombosis (Peto OR 1.11, 95% CI 0.07 to 17.77; 2 RCTs, 101 participants).  All outcomes reported were very low-certainty evidence. No data were available for number of red blood cell units transfused, reoperation, incidence of pulmonary embolism, acute transfusion reaction, or suspected serious drug reactions. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), inconsistency (moderate heterogeneity), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures, and high risk of attrition and reporting biases in one trial). Comparison 3. Recombinant factor VIIa versus placebo   Only one RCT of 48 participants reported data for recombinant factor VIIa versus placebo, so we have not presented the results here. AUTHORS' CONCLUSIONS: We cannot draw conclusions from the current evidence due to lack of data. Most published studies included in our analyses assessed the use of tranexamic acid (compared to placebo, or using different routes of administration).  We identified 27 prospectively registered ongoing RCTs (total target recruitment of 4177 participants by end of 2023). The ongoing trials create six new comparisons: tranexamic acid (tablet + injection) versus placebo; intravenous tranexamic acid versus oral tranexamic acid; topical tranexamic acid versus oral tranexamic acid; different intravenous tranexamic acid dosing regimes; topical tranexamic acid versus topical fibrin glue; and fibrinogen (injection) versus placebo.

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women.

BACKGROUND: Ovarian cancer (OC) has the highest case fatality rate of all gynaecological cancers. Diagnostic delays are caused by non-specific symptoms. Existing systematic reviews have not comprehensively covered tests in current practice, not estimated accuracy separately in pre- and postmenopausal women, or used inappropriate meta-analytic methods. OBJECTIVES: To establish the accuracy of combinations of menopausal status, ultrasound scan (USS) and biomarkers for the diagnosis of ovarian cancer in pre- and postmenopausal women and compare the accuracy of different test combinations. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), five other databases and three trial registries from 1991 to 2015 and MEDLINE (Ovid) and Embase (Ovid) form June 2015 to June 2019. We also searched conference proceedings from the European Society of Gynaecological Oncology, International Gynecologic Cancer Society, American Society of Clinical Oncology and Society of Gynecologic Oncology, ZETOC and Conference Proceedings Citation Index (Web of Knowledge). We searched reference lists of included studies and published systematic reviews. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies evaluating single tests or comparing two or more tests, randomised trials comparing two or more tests, and studies validating multivariable models for the diagnosis of OC investigating test combinations, compared with a reference standard of histological confirmation or clinical follow-up in women with a pelvic mass (detected clinically or through USS) suspicious for OC. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using QUADAS-2. We used the bivariate hierarchical model to indirectly compare tests at commonly reported thresholds in pre- and postmenopausal women separately. We indirectly compared tests across all thresholds and estimated sensitivity at fixed specificities of 80% and 90% by fitting hierarchical summary receiver operating characteristic (HSROC) models in pre- and postmenopausal women separately. MAIN RESULTS: We included 59 studies (32,059 women, 9545 cases of OC). Two tests evaluated the accuracy of a combination of menopausal status and USS findings (IOTA Logistic Regression Model 2 (LR2) and the Assessment of Different NEoplasias in the adneXa model (ADNEX)); one test evaluated the accuracy of a combination of menopausal status, USS findings and serum biomarker CA125 (Risk of Malignancy Index (RMI)); and one test evaluated the accuracy of a combination of menopausal status and two serum biomarkers (CA125 and HE4) (Risk of Ovarian Malignancy Algorithm (ROMA)). Most studies were at high or unclear risk of bias in participant, reference standard, and flow and timing domains. All studies were in hospital settings. Prevalence was 16% (RMI, ROMA), 22% (LR2) and 27% (ADNEX) in premenopausal women and 38% (RMI), 45% (ROMA), 52% (LR2) and 55% (ADNEX) in postmenopausal women. The prevalence of OC in the studies was considerably higher than would be expected in symptomatic women presenting in community-based settings, or in women referred from the community to hospital with a suspicion of OC. Studies were at high or unclear applicability because presenting features were not reported, or USS was performed by experienced ultrasonographers for RMI, LR2 and ADNEX. The higher sensitivity and lower specificity observed in postmenopausal compared to premenopausal women across all index tests and at all thresholds may reflect highly selected patient cohorts in the included studies. In premenopausal women, ROMA at a threshold of 13.1 (± 2), LR2 at a threshold to achieve a post-test probability of OC of 10% and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 77.4%, 95% CI 72.7% to 81.5%; LR2: 83.3%, 95% CI 74.7% to 89.5%; ADNEX: 95.5%, 95% CI 91.0% to 97.8%) compared to RMI (57.2%, 95% CI 50.3% to 63.8%). The specificity of ROMA and ADNEX were lower in premenopausal women (ROMA: 84.3%, 95% CI 81.2% to 87.0%; ADNEX: 77.8%, 95% CI 67.4% to 85.5%) compared to RMI 92.5% (95% CI 90.3% to 94.2%). The specificity of LR2 was comparable to RMI (90.4%, 95% CI 84.6% to 94.1%). In postmenopausal women, ROMA at a threshold of 27.7 (± 2), LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 90.3%, 95% CI 87.5% to 92.6%; LR2: 94.8%, 95% CI 92.3% to 96.6%; ADNEX: 97.6%, 95% CI 95.6% to 98.7%) compared to RMI (78.4%, 95% CI 74.6% to 81.7%). Specificity of ROMA at a threshold of 27.7 (± 2) (81.5, 95% CI 76.5% to 85.5%) was comparable to RMI (85.4%, 95% CI 82.0% to 88.2%), whereas for LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) specificity was lower (LR2: 60.6%, 95% CI 50.5% to 69.9%; ADNEX: 55.0%, 95% CI 42.8% to 66.6%). AUTHORS' CONCLUSIONS: In specialist healthcare settings in both premenopausal and postmenopausal women, RMI has poor sensitivity. In premenopausal women, ROMA, LR2 and ADNEX offer better sensitivity (fewer missed cancers), but for ROMA and ADNEX this is off-set by a decrease in specificity and increase in false positives. In postmenopausal women, ROMA demonstrates a higher sensitivity and comparable specificity to RMI. ADNEX has the highest sensitivity in postmenopausal women, but reduced specificity. The prevalence of OC in included studies is representative of a highly selected referred population, rather than a population in whom referral is being considered. The comparative accuracy of tests observed here may not be transferable to non-specialist settings. Ultimately health systems need to balance accuracy and resource implications to identify the most suitable test.

Effect of regional versus general anaesthesia on postoperative delirium in elderly patients undergoing surgery for hip fracture: a systematic review.

OBJECTIVE: Older patients with hip fractures who are undergoing surgery are at high risk of significant mortality and morbidity including postoperative delirium. It is unclear whether different types of anaesthesia may reduce the incidence of postoperative delirium. This systematic review will investigate the impact of anaesthetic technique on postoperative delirium. Other outcomes included mortality, length of stay, complications and functional outcomes. DESIGN: Systematic review of randomised controlled trials and non-randomised controlled studies. DATA SOURCES: Bibliographic databases were searched from inception to June 2018. Web of Science and ZETOC databases were searched for conference proceedings. Reference lists of relevant articles were checked, and clinical trial registers were searched to identify ongoing trials. ELIGIBILITY CRITERIA: Studies were eligible if general and regional anaesthesia were compared in patients (aged 60 and over) undergoing hip fracture surgery, reporting primary outcome of postoperative delirium and secondary outcomes of mortality, length of hospital stay, adverse events, functional outcomes, discharge location and quality of life. Exclusion criteria were anaesthetic technique or drug not considered current standard practice; patients undergoing hip fracture surgery alongside other surgery and uncontrolled studies. RESULTS: One hundred and four studies were included. There was no evidence to suggest that anaesthesia type influences postoperative delirium or mortality. Some studies suggested a small reduction in length of hospital stay with regional anaesthesia. There was some evidence to suggest that respiratory complications and intraoperative hypotension were more common with general anaesthesia. Heterogeneity precluded meta-analysis. All findings were described narratively and data were presented where possible in forest plots for illustrative purposes. CONCLUSIONS: While there was no evidence to suggest that anaesthesia types influence postoperative delirium, the evidence base is lacking. There is a need to ascertain the impact of type of anaesthesia on outcomes with an adequately powered, methodologically rigorous study. PROSPERO REGISTRATION NUMBER: CRD42015020166.

Refining Ovarian Cancer Test accuracy Scores (ROCkeTS): protocol for a prospective longitudinal test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

INTRODUCTION: Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III). METHODS AND ANALYSIS: ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios.

Effectiveness of Embolization or Sclerotherapy of Pelvic Veins for Reducing Chronic Pelvic Pain: A Systematic Review.

PURPOSE: Chronic pelvic pain (CPP) in the presence of dilated and refluxing pelvic veins is often described as pelvic congestion syndrome (PCS), although the causal relationship between pelvic vein incompetence and CPP has not been established. Percutaneous embolization is the principal treatment for PCS, with high success rates cited. This study was undertaken to systematically and critically review the effectiveness of embolization of incompetent pelvic veins. MATERIALS AND METHODS: A comprehensive search strategy encompassing various terms for pelvic congestion, pelvic pain, and embolization was deployed in 17 bibliographic databases, with no restriction on study design. Methodologic quality was assessed. The quality and heterogeneity generally precluded meta-analysis. Results were tabulated and described narratively. RESULTS: Twenty-one prospective case series and one poor-quality randomized trial of embolization (involving a total of 1,308 women) were identified. Early substantial relief from pain was observed in approximately 75% of women undergoing embolization, and generally increased over time and was sustained. Significant pain reductions following treatment were observed in all studies that measured pain on a visual analog scale. Repeat intervention rates were generally low. There were few data on the impact on menstruation, ovarian reserve, or fertility, but no concerns were noted. Transient pain was common following foam embolization, and there was a < 2% risk of coil migration. CONCLUSIONS: Embolization appears to provide symptomatic relief of CPP in the majority of women and is safe, although the quality of the evidence is low.

Regional versus general anaesthesia in elderly patients undergoing surgery for hip fracture: protocol for a systematic review.

BACKGROUND: With an ageing population, the incidence of hip fractures requiring surgery is increasing. Post-operative delirium is common following hip fracture surgery. Delirium is associated with high mortality and morbidity, poor long-term functional outcomes and institutionalisation. There is some evidence to suggest that perioperative intervention, specifically the anaesthetic technique employed, may reduce the incidence of delirium in this population. The aim of this systematic review is to investigate the impact of anaesthesia type on post-operative delirium. METHOD: We will conduct a systematic literature review using Embase, MEDLINE, CINAHL and the Cochrane Library (CENTRAL) bibliographic databases and the ZETOC and Web of Science websites. Authors of these trials will be invited to contribute unpublished data. PROSPERO register and clinical trial registers will also be searched to identify any ongoing reviews and trials. Eligible studies will assess the incidence of post-operative delirium in patients having regional or general anaesthesia for hip fracture surgery. The primary outcome of interest will be post-operative delirium; secondary outcomes will include mortality, measures of functional outcome, quality of life, length of hospital stay, discharge location and adverse events. Two reviewers will independently screen references identified by electronic literature searches. Two independent reviewers will extract data from studies fulfilling our inclusion criteria using a piloted data extraction form. Methodological quality and bias of included randomised controlled trials will be assessed using the 'Cochrane Collaborations tool for assessing risk of bias'; for non-randomised studies, this will be assessed using the Newcastle-Ottawa scale. Data on similar outcomes will be pooled when possible. Where possible, meta-analysis will be undertaken using Review Manager (RevMan version 5.3) software. DISCUSSION: This systematic review will provide an updated evidence base with which to guide clinical practice and research for this group of challenging patients. If the anaesthetic technique employed is shown to reduce the incidence of post-operative cognition dysfunction, then this may lead to a change in evidence-based practice, influence future guidelines and support further randomised controlled trial research. There is no known effective treatment for delirium, creating the urgent need for research into delirium prevention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015020166.

Graphical displays for effective reporting of evidence quality tables in research syntheses.

BACKGROUND: When generating guidelines, quality of the evidence is tabulated to capture its several domains, often using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We developed a graphic display to capture deficiencies, outliers and similarities across comparisons contained in GRADE tables. METHODS: Based on a systematic literature review capturing the effects of 32 different therapeutic comparisons on dysmenorrhoea, we synthesised evidence quality in tables and graphs. We evaluated time taken to accurately assess evident quality and preference for tables vs. graphs. RESULTS: The plots provided visually striking displays of strengths and weaknesses of the evidence across the spectrum of comparisons on a single page. Equivalent tabulated information spread over 4 pages. Participants preferred and interpreted graphs quicker and more accurately than tables. CONCLUSIONS: The graphic approach we developed makes interpreting evidence easier. Large tables are dry and cumbersome to read and assimilate. When guideline statements are accompanied by these plots, they have the scope for improving the credibility of the recommendations made, as the strength of the evidence used can be clearly seen. Further empirical research will establish the place for graphic displays.

Obstetric anal sphincter injuries after episiotomy: systematic review and meta-analysis.

INTRODUCTION: There is conflicting evidence on whether mediolateral episiotomy (MLE) reduces the risk of obstetric anal sphincter injuries (OASI) in spontaneous vaginal deliveries (SVD). OBJECTIVES: A systematic review was undertaken to compare rates of OASI amongst women who had undergone mediolateral episiotomy versus those who did not. METHODS: ᅟ SEARCH STRATEGY: Electronic searches were performed in literature databases: CINAHL, Cochrane, EMBASE, Medline and MIDIRS from database inception to July 2015. Studies were eligible if MLE was compared to spontaneous tears and if OASI was the outcome of interest. Two reviewers independently selected and extracted data on study characteristics, quality and results. We computed events of OASI in those who did and did not have an episiotomy from individual studies and pooled these results in a meta-analysis where possible. MAIN RESULTS: Of the 2090 citations, 16 were included in the review. All were non-randomised, population based or retrospective cohort studies. There was great variation in quality amongst these studies. Data from 7 studies was used for meta-analysis. On collating data from these studies where the majority of women (636755/651114) were nulliparous, MLE reduced the risk of OASI (RR 0.67 95 % CI 0.49-0.92) in vaginal delivery. CONCLUSION: The pooled analysis of a large number of women undergoing vaginal birth, most of who were nulliparous, indicates that MLE has a beneficial effect in prevention of OASI. An accurately given MLE might have a role in reducing OASI and should not be withheld, especially in nulliparous women. Caution is advised as the data is from non-randomised studies.

The relationship between pelvic vein incompetence and chronic pelvic pain in women: systematic reviews of diagnosis and treatment effectiveness.

BACKGROUND: Pelvic congestion syndrome (PCS) is described as chronic pelvic pain (CPP) arising from dilated and refluxing pelvic veins, although the causal relationship between pelvic vein incompetence (PVI) and CPP is not established. Non-invasive screening methods such as Doppler ultrasound and magnetic resonance venography are used before confirmation by venography. Percutaneous embolisation has become the principal treatment for PCS, with high success rates often cited. OBJECTIVES: Our proposal aimed to systematically and critically review the definitions and diagnostic criteria of PCS, the association between PVI and CPP, the accuracy of various non-invasive imaging techniques and the effectiveness of embolisation for PVI; and to identify factors associated with successful outcome. We also wished to survey clinicians and patients to assess awareness and management of PCS and gauge the enthusiasm for further research. DATA SOURCES: A comprehensive search strategy encompassing various terms for pelvic congestion, pain, imaging techniques and embolisation was deployed in 17 bibliographic databases, including MEDLINE, EMBASE and Web of Science. There was no restriction on study design. METHODS: Methodological quality was assessed using appropriate tools. Online surveys were sent to clinicians and patients. The quality and heterogeneity generally precluded meta-analysis and so results were tabulated and described narratively. RESULTS: We identified six association studies, 10 studies involving ultrasound, two studies involving magnetic resonance venography, 21 case series and one poor-quality randomised trial of embolisation. There were no consistent diagnostic criteria for PCS. We found that the associations between CPP and PVI were generally fairly similar, with three of five studies with sufficient data showing statistically significant associations (odds ratios of between 31 and 117). The prevalence of PVI ranged widely, although the majority of women with PVI had CPP. Transvaginal ultrasound with Doppler and magnetic resonance venography are both useful screening methods, although the data on accuracy are limited. Early substantial relief from pain symptoms was observed in approximately 75% of women undergoing embolisation, a figure which generally increased over time and was sustained. Reintervention rates were generally low. Transient pain was a common occurrence following foam embolisation, while there was a < 2% risk of coil migration. Confidence in the embolisation technique is reasonably high, although there is a desire to strengthen the evidence base. Even among women with CPP, fewer than half had any knowledge about PCS. CONCLUSIONS: The data supporting the diagnosis and treatment of PCS are limited and of variable methodological quality. There is some evidence to tentatively support a causative association, but it cannot be categorically stated that PVI is the cause of CPP in women with no other pathology, as the six most pertinent drew on clinically disparate populations and defined PVI inconsistently. Embolisation appears to provide symptomatic relief in the majority of women and is safe. However, the majority of included studies of embolism were relatively small case series and only the randomised controlled trial was considered at risk of potential biases. There is scope and demand for considerable further research. The question of the association of PVI and CPP requires a well-designed and well-powered case-control study, which will also provide data to derive a diagnostic standard. An adequately powered randomised trial is essential to provide evidence on the effectiveness of embolisation, but this faces methodological challenges. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002237 and CRD42012002238. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Hormonal contraception and pelvic floor function: a systematic review.

INTRODUCTION AND HYPOTHESIS: Hormonal contraceptive use is common practice worldwide. Although the effects of hormone treatments in the pelvic region are well established, there is no clear evidence regarding their effects on incontinence, bladder, bowel, vaginal and sexual symptoms in premenopausal women. We hypothesized that hormonal contraceptives affect pelvic floor function. We therefore performed a comprehensive systematic review of published studies to determine the influence of hormonal contraception on pelvic floor functions. METHODS: Electronic literature databases were searched from database inception to March 2015. Keywords and medical subject headings searched for included terms and word variations for 'contraception', and 'bowel', 'vaginal', 'sexual' and 'urinary' symptoms. Studies were eligible if they looked at these symptoms in women taking hormonal contraception. Two reviewers independently screened studies for inclusion, and extracted data on study characteristics, quality and results. Data were combined where possible. RESULTS: Of the 429 citations identified, 13 studies were included in the review. Data were meta-analysed where possible and presented as prevalence. The results indicate statistically significant links between interstitial cystitis and oral contraceptive use at any point (ever) (OR 2.31, 95 % CI 1.03 - 5.16; p = 0.04) and vulvar vestibulitis and current oral contraceptive use (OR 2.10, 95 % CI 1.26 - 3.49; p = 0.004). The evidence is unclear in other areas. CONCLUSIONS: Our results indicate that oral contraceptives may have an effect on pelvic floor function. They could increase the risk of painful bladder and vulvar vestibulitis, but their effect on dyspareunia is inconsistent. However, robustly collected prospective data to establish causal associations are needed.

Complementary therapies for bladder pain syndrome: a systematic review.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome is a difficult condition to treat. The purpose of this systematic review is to assess the effectiveness of various complementary therapies available for treatment. METHODS: This review was conducted in adherence with Preferred Reporting Items for Systematic Reviews. Citations were retrieved using a comprehensive database search (from inception to July 2014: CINAHL, Cochrane, EMBASE, Medline and SIGEL and grey literature). Studies that fulfilled the inclusion criteria were selected. Eligibility consisted of women with bladder pain syndrome, an intervention of alternative/complementary therapies and an outcome of improvement of symptoms. Information regarding study characteristics and primary outcomes was collated. The Cochrane risk of bias scale was used to evaluate the quality of the studies included. RESULTS: A total of 1,454 citations were identified, 11 studies fulfilled the inclusion criteria (4 randomised control trials [RCTs] and 7 prospective studies). The key interventions studied were acupuncture, relaxation therapy, physical therapy, hydrogen-rich therapy, diet and nitric oxide synthetase. CONCLUSION: Therapies with the potential for benefit in patients with bladder pain syndrome are dietary management, acupuncture and physical therapy. These findings were obtained from small studies and hence caution is advised. Robustly designed multicentre RCTs on these complementary therapies are needed to guide patients and clinicians.

Dysmenorrhoea.

INTRODUCTION: Dysmenorrhoea may begin soon after the menarche, after which it often improves with age; or it may originate later in life, after the onset of an underlying causative condition. Dysmenorrhoea is common, and in up to 20% of women it may be severe enough to interfere with daily activities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of pharmacological treatments for primary dysmenorrhoea? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found eight studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: contraceptives (combined oral), non-steroidal anti-inflammatory drugs (NSAIDs), progestogens (intrauterine), and simple analgesics (aspirin, paracetamol) .

Comparison of embolic agents used in uterine artery embolisation: a systematic review and meta-analysis.

PURPOSE: This study was designed to undertake systematic review and meta-analysis of published comparative trials comparing embolic agents used in uterine artery embolisation (UAE) for uterine leiomyomata. METHODS: Systematic literature searches were performed in MEDLINE, Embase, PubMed, and Cochrane Central databases from database inception to July 2012. Randomised and nonrandomised trials comparing two or more embolic agents used in UAE were included. Assessment included five widely used embolic agents: nonspherical polyvinyl alcohol (PVA) (Contour PVA, Boston Scientific or PVA Cook Medical); spherical PVA (Contour SE, Boston Scientific); acrylamido PVA (Beadblock, Biocompatibles, Terumo); tris-acryl gelatin microspheres (TAGM) (Embospheres, Merit Medical Inc); and polyzene-F hydrogel microspheres (Embozenes, CeloNova Biosciences). Outcomes assessed included: quality of life (QOL), assessment, magnetic resonance imaging (MRI), uterine and fibroid volumes and degrees of MRI fibroid enhancement and devascularisation. A total of 262 citations were reviewed with 5 randomised, controlled trials involving 295 women and 5 non-RCTs involving 617 women included. RESULTS: No evidence of superiority of any embolic agent was demonstrated. Meta-analysis was performed between TAGM (Embospheres) and spherical PVA microspheres. Two RCTs found a trend toward greater uterine and dominant fibroid volume reductions with Embospheres but the combined differences were not statistically significant (p = 0.78 and p = 0.94 respectively). Embospheres demonstrated greater percentage fibroid devascularisation than spherical PVA (p = 0.039). CONCLUSIONS: This study confirms that the current evidence demonstrates superiority of Embospheres over spherical PVA but no reported differences in outcomes between any of the other agents. Comparison of embolic agents was limited by lack of RCT data and further research is warranted.

Analgesic effectiveness of transversus abdominis plane blocks after hysterectomy: a meta-analysis.

To determine the effectiveness of transversus abdominis plane blocks in gynecological surgery by systematic review and meta-analysis. Embase, MEDLINE and the Cochrane Library (CENTRAL) bibliographic databases were searched using a Cochrane Library search strategy modified for gynecological surgery. We included randomized controlled trials comparing transversus abdominis plane block with no block or placebo block. We retrieved 681 citations from which we included five published studies (225 randomized participants) which fulfilled our inclusion criteria, and identified a further six ongoing studies. Quality was assessed across six risk of bias domains: randomization sequence generation, allocation concealment, blinding, missing outcome data, selective reporting and other biases. Data were meta-analyzed where possible and presented as mean differences with 95% confidence intervals. Study quality was moderate. Compared with no block or saline placebo, transversus abdominis plane block provided significantly less postoperative pain at rest on a 10 cm visual analog scale at 2h (mean difference -2.14 cm, 95% confidence interval (CI) -3.57 to -0.71) but not at 24h postoperatively (-0.52 cm, 95% CI -1.49 to 0.45). Pain on movement showed similar results. Transversus abdominis plane block resulted in significantly less postoperative requirement for morphine use at 24h (-11.76 mg, 95% CI -18.77 to -4.75) but not at 48 h (-16.01 mg, 95% CI -39.40 to 7.39). Evidence exists for the short-term efficacy (within 24 h) of transversus abdominis plane blocks during hysterectomy in terms of reported pain and morphine consumption, which may not be sustained at 48 h. Updates to this review should be undertaken periodically, and until further robust evidence is available, anesthetists should not rush to adopt this procedure into routine practice.

Psychological therapies for chronic pelvic pain: systematic review of randomized controlled trials.

Chronic pelvic pain (CPP), a common cause of disability in women, is a condition best viewed in the biopsychosocial framework. Psychological interventions are frequently considered alongside medical and surgical treatments. Our objective was to evaluate the effectiveness of psychological therapies for the treatment of CPP. Electronic literature searches were conducted in Medline, Embase, PsycInfo and DARE databases from database inception to April 2010. Reference lists of selected articles were searched for further articles. The studies selected were randomized controlled trials of psychological therapies in patients with CPP compared with no treatment, standard gynecological treatment or another form of psychological therapy. Two reviewers independently selected articles without language restrictions and extracted data covering study characteristics, study quality and results. Reduction in pain, measured using visual analog scales or other measurements, was the main outcome measure. Of the 107 citations identified, four studies satisfied the inclusion criteria. Compared with no psychological intervention, therapy produced a standardized mean pain score of -3.27 [95% confidence interval (CI) -4.52 to -2.02] and 1.11 (95% CI -0.05 to 2.27) at 3 months and -3.95 (95% CI -5.35 to -2.55) and 0.54 (95% CI -0.78 to 1.86) at 6 months and greater, based on a visual analog scale score of 0-10. The current evidence does not allow us to conclude whether psychological interventions have an effect on self-reported pain scores in women with CPP.

Dysmenorrhoea.

INTRODUCTION: Dysmenorrhoea may begin soon after the menarche, after which it often improves with age, or it may originate later in life after the onset of an underlying causative condition. Dysmenorrhoea is common, and in up to 20% of women it may be severe enough to interfere with daily activities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for primary dysmenorrhoea? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupressure, acupuncture, aspirin, behavioural interventions, contraceptives (combined oral), fish oil, herbal remedies, magnets, non-steroidal anti-inflammatory drugs, paracetamol, progestogens (intrauterine), spinal manipulation, surgical interruption of pelvic nerve pathways, thiamine, toki-shakuyaku-san, topical heat, transcutaneous electrical nerve stimulation (TENS), vitamin B12, and vitamin E.

Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy.

BACKGROUND: Adenomyosis is a common condition that causes substantial morbidity. Until recently, the reference standard for a definitive diagnosis was histology of hysterectomy specimens. Ultrasound and magnetic resonance imaging (MRI) may allow accurate non-invasive diagnosis. OBJECTIVE: To compare the diagnostic accuracy of these techniques. DESIGN: Systematic review with meta-analysis. POPULATION: Women who had ultrasound and/or MRI, and whose results were compared with a reference standard. METHODS: Electronic searches were conducted in literature databases from database inception to 2010. The reference lists of known relevant articles were searched for further articles. Selected studies reported data on ultrasound and/or MRI with histological confirmation of diagnosis. Two reviewers independently selected articles without language restrictions, and extracted data in the form of 2 × 2 tables. We computed sensitivity and specificity for individual studies and pooled these results in a meta-analysis. We also performed meta-regression to examine how the index tests compared on diagnostic accuracy. RESULTS: Twenty-three articles (involving 2,312 women) satisfied the inclusion criteria. Transvaginal ultrasound had a pooled sensitivity of 72% (95% CI 65-79%), specificity of 81% (95% CI 77-85%), positive likelihood ratio of 3.7 (95% CI 2.1-6.4) and negative likelihood ratio of 0.3 (95% CI 0.1-0.5). MRI had a pooled sensitivity of 77% (95% CI 67-85%), specificity of 89% (95% CI 84-92%), positive likelihood ratio of 6.5 (95% CI 4.5-9.3), and negative likelihood ratio of 0.2 (95% CI 0.1-0.4). The results show that a correct diagnosis was obtained more often with MRI. CONCLUSION: Transvaginal ultrasound and MRI show high levels of accuracy for the non-invasive diagnosis of adenomyosis.

Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial.

CONTEXT: Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE: To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION: Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES: The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS: After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION: Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION: controlled-trials.com Identifier: ISRCTN41196151.