Is a randomised controlled trial of take home naloxone distributed in emergency settings likely to be feasible and acceptable? Findings from a UK qualitative study exploring perspectives of people who use opioids and emergency services staff.

OBJECTIVE: Distribution of take-home naloxone (THN) by emergency services may increase access to THN and reduce deaths and morbidity from opioid overdose. As part of a feasibility study for a randomised controlled trial (RCT) of distribution of THN kits and education within ambulance services and Emergency Departments (EDs), we used qualitative methods to explore key stakeholders' perceptions of feasibility and acceptability of delivering the trial. METHODS: We undertook semi-structured interviews and focus groups with 26 people who use opioids and with 20 paramedics and ED staff from two intervention sites between 2019 and 2021. Interviews and focus groups were recorded, transcribed verbatim and analysed using Framework Analysis. RESULTS: People using opioids reported high awareness of overdose management, including personal experience of THN use. Staff perceived emergency service provision of THN as a low-cost, low-risk intervention with potential to reduce mortality, morbidity and health service use. Staff understood the trial aims and considered it compatible with their work. All participants supported widening access to THN but reported limited trial recruitment opportunities partly due to difficulties in consenting patients during overdose. Procedural problems, restrictive recruitment protocols, limited staff buy-in and patients already owning THN limited trial recruitment. Determining trial effectiveness was challenging due to high levels of alternative community provision of THN. CONCLUSIONS: Distribution of THN in emergency settings was considered feasible and acceptable for stakeholders but an RCT to establish the effectiveness of THN delivery is unlikely to generate further useful evidence due to difficulties in recruiting patients and assessing benefits.

Interventions to improve the management of pain in emergency departments: systematic review and narrative synthesis.

INTRODUCTION: Pain management in emergency departments (ED) is often inadequate despite the availability of effective analgesia, with many patients receiving insufficient and untimely analgesia. We conducted a systematic literature review to identify interventions that could improve pain management in the ED. METHODS: We systematically searched seven databases for studies reporting pain management outcomes after intervention to change professional practice to improve pain management in the ED, compared with pain management before or without intervention. Data was synthesised using principles of narrative synthesis. RESULTS: We identified 43 relevant studies, including 40 uncontrolled before-and-after studies. Interventions included implementation of guidelines and protocols, educational interventions, pain scoring tools and changes in nursing roles, with many multifaceted interventions incorporating two or more of these elements. Interventions aimed to improve assessment and documentation of pain, knowledge and awareness of pain management and reduce time to analgesia. Due to the high probability of bias in study design and significant variation between studies, it was not possible to estimate the overall effectiveness of interventions, or identify which had the greatest impact. Intervention to improve pain management was reported to have some positive impact in most studies, but these findings may be explained by limitations in study design. CONCLUSIONS: Many interventions reported improvements in pain management, but current evidence is insufficient to recommend any for widespread adoption. In order to improve pain management we need to understand more about the theory underlying interventions, the context in which interventions work, and develop interventions based on this stronger theoretical understanding.

A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

OBJECTIVES: To determine whether non-invasive ventilation reduces mortality and whether there are important differences in outcome by treatment modality. DESIGN: Multicentre open prospective randomised controlled trial. SETTING: Patients presenting with severe acute cardiogenic pulmonary oedema in 26 emergency departments in the UK. PARTICIPANTS: Inclusion criteria were age > 16 years, clinical diagnosis of acute cardiogenic pulmonary oedema, pulmonary oedema on chest radiograph, respiratory rate > 20 breaths per minute, and arterial hydrogen ion concentration > 45 nmol/l (pH < 7.35). INTERVENTIONS: Patients were randomised to standard oxygen therapy, continuous positive airway pressure (CPAP) (5-15 cmH2O) or non-invasive positive pressure ventilation (NIPPV) (inspiratory pressure 8-20 cmH2O, expiratory pressure 4-10 cmH2O) on a 1:1:1 basis for a minimum of 2 hours. MAIN OUTCOME MEASURES: The primary end point for the comparison between NIPPV or CPAP and standard therapy was 7-day mortality. The composite primary end point for the comparison of NIPPV and CPAP was 7-day mortality and tracheal intubation rate. Secondary end points were breathlessness, physiological variables, intubation rate, length of hospital stay and critical care admission rate. Economic evaluation took the form of a cost-utility analysis, taken from an NHS (and personal social services) perspective. RESULTS: In total, 1069 patients [mean age 78 (SD 10) years; 43% male] were recruited to standard therapy (n = 367), CPAP [n = 346; mean 10 (SD 4) cmH2O] or NIPPV [n = 356; mean 14 (SD 5)/7 (SD 2) cmH2O]. There was no difference in 7-day mortality for standard oxygen therapy (9.8%) and non-invasive ventilation (9.5%; p = 0.87). The combined end point of 7-day death and intubation rate was similar, irrespective of non-invasive ventilation modality (CPAP 11.7% versus NIPPV 11.1%; p = 0.81). Compared with standard therapy, non-invasive ventilation was associated with greater reductions (treatment difference, 95% confidence intervals) in breathlessness (visual analogue scale score 0.7, 0.2-1.3; p = 0.008) and heart rate (4/min, 1-6; p = 0.004) and improvement in acidosis (pH 0.03, 0.02-0.04; p < 0.001) and hypercapnia (0.7 kPa, 0.4-0.9; p < 0.001) at 1 hour. There were no treatment-related adverse events or differences in other secondary outcomes such as myocardial infarction rate, length of hospital stay, critical care admission rate and requirement for endotracheal intubation. Economic evaluation showed that mean costs and QALYs up to 6 months were 3023 pounds and 0.202 for standard therapy, 3224 pounds and 0.213 for CPAP, and 3208 pounds and 0.210 for NIPPV. Modelling of lifetime costs and QALYs produced values of 15,764 pounds and 1.597 for standard therapy, 17,525 pounds and 1.841 for CPAP, and 17,021 pounds and 1.707 for NIPPV. These results suggest that both CPAP and NIPPV accrue more QALYs but at higher cost than standard therapy. However, these estimates are subject to substantial uncertainty. CONCLUSIONS: Non-invasive ventilatory support delivered by either CPAP or NIPPV safely provides earlier improvement and resolution of breathlessness, respiratory distress and metabolic abnormality. However, this does not translate into improved short- or longer-term survival. We recommend that CPAP or NIPPV should be considered as adjunctive therapy in patients with severe acute cardiogenic pulmonary oedema in the presence of severe respiratory distress or when there is a failure to improve with pharmacological therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07448447.

Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis.

AIM: To estimate the sensitivity and specificity of computed tomography (CT) for the diagnosis of deep vein thrombosis (DVT) in patients with suspected DVT and pulmonary embolus (PE). MATERIALS AND METHODS: A search of the medical literature and citation lists was undertaken, and selected studies comparing CT to a reference standard in patients with suspected DVT or PE were retrieved. Data were analysed by random effects meta-analysis. RESULTS: Thirteen articles were included in the meta-analysis. Most compared CT to ultrasound in patients with clinically suspected PE. The sensitivity ranged from 71-100%, while specificity ranged from 93-100%. The pooled estimate of sensitivity was 95.9% (95% CI 93 to 97.8%) and the pooled estimate of specificity was 95.2% (93.6 to 96.5%). However, pooled estimates should be interpreted with caution as these were subject to significant heterogeneity (p=0.025 and p<0.001, respectively). Most studies only appeared to report proximal DVT. Too few data were available to estimate sensitivity for distal DVT. CONCLUSIONS: CT has a similar sensitivity and specificity to ultrasound in patients with suspected PE where investigation of suspected DVT is required. There is insufficient research to determine the diagnostic accuracy of CT in patients with suspected DVT alone.

The value of clinical features in the diagnosis of acute pulmonary embolism: systematic review and meta-analysis.

BACKGROUND: Clinical assessment of patients with suspected pulmonary embolus (PE) is used to estimate the probability of PE and determine what (if any) diagnostic testing is required. AIM: We aimed to estimate the diagnostic value of individual clinical features used to determine the pre-test probability of acute PE. DESIGN: Systematic review and meta-analysis. METHODS: We searched electronic databases (1966 to May 2007) and the bibliographies of retrieved articles for any article that reported the diagnostic performance of clinical features compared to a reference standard diagnostic test in patients with suspected acute pulmonary embolism. Likelihood ratios were calculated for each feature and pooled using a random effects model, as implemented by MetaDiSc statistical software. RESULTS: We identified 18 studies for inclusion with a total of 5997 patients. The most useful features (pooled likelihood ratio) for ruling in PE were syncope (2.38), shock (4.07), thrombophlebitis (2.20), current DVT (2.05), leg swelling (2.11), sudden dyspnoea (1.83), active cancer (1.74), recent surgery (1.63), haemoptysis (1.62) and leg pain (1.60); while the most useful features for ruling out PE were the absence of sudden dyspnoea (0.430), any dyspnoea (0.521) and tachypnea (0.561). All other clinical features had likelihood ratios near to one. Many of the analyses involved pooling results that had significant heterogeneity, so these estimates should be used with caution. CONCLUSION: Individual clinical features only slightly raise or lower the probability of PE. In isolation, they have limited diagnostic value and none can be used to rule in or rule out PE without further testing.

Meta-analysis of plethysmography and rheography in the diagnosis of deep vein thrombosis.

BACKGROUND: Plethysmography and rheography techniques have been widely studied as diagnostic tests for deep vein thrombosis (DVT). This study aimed to systematically review the accuracy of these tests for diagnosing clinically suspected DVT. METHODS: The following databases were searched: Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club (1966 to 2004), and citation lists of retrieved articles. Studies that compared plethysmography or rheography to a reference standard of ultrasound or contrast venography were selected. Standardised data were extracted and study quality determined against validated criteria. Data were analysed by random effects meta-analysis and meta-regression. RESULTS: The meta-analysis included 78 studies, reporting 82 patient cohorts. Sensitivity and specificity (95% CI) were: 75% (73% to 77%) and 90% (89% to 91%) for impedance plethysmography, 83% (81% to 85%) and 81% (79% to 82%) for strain-gauge plethysmography, 85% (79% to 90%) and 91% (81% to 95%) for air plethysmography, 91% (87% to 94%) and 71% (66% to 75%) for light-reflex rheography, and 86% (83% to 89%) and 93% (91% to 95%) for phleborheography. Meta-regression was limited by poor reporting of studies. There was some evidence that diagnostic performance depended on the proportion of males in the cohort and reporting of study setting. CONCLUSIONS: Although plethysmography and rheography techniques add diagnostic value, they have inadequate diagnostic performance to act as a stand-alone test in DVT diagnosis. Evaluation of their role in combination with other tests, or standardised clinical assessment, is required.

Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

OBJECTIVES: To estimate the diagnostic accuracy of non-invasive tests for proximal deep vein thrombosis (DVT) and isolated calf DVT, in patients with clinically suspected DVT or high-risk asymptomatic patients, and identify factors associated with variation in diagnostic performance. Also to identify practical diagnostic algorithms for DVT, and estimate the diagnostic accuracy, clinical effectiveness and cost-effectiveness of each. DATA SOURCES: Electronic databases (to April 2004). A postal survey of hospitals in the UK. REVIEW METHODS: Selected studies were assessed against validated criteria. A postal survey of hospitals in the UK was undertaken to describe current practice and availability of tests, and identify additional diagnostic algorithms. Pooled estimates of sensitivity, specificity and likelihood ratios were obtained for each test using random effects meta-analysis. The effect of study-level covariates was explored using random effects metaregression. A decision-analytic model was used to combine estimates from the meta-analysis and estimate the diagnostic performance of each algorithm in a theoretical population of outpatients with suspected DVT. The net benefit of using each algorithm was estimated from a health service perspective, using cost--utility analysis, assuming thresholds of willingness to pay of pound 20,000 and pound 30,000 per quality-adjusted life-year (QALY). The model was analysed probabilistically and cost-effectiveness acceptability curves were generated to reflect uncertainty in estimated cost-effectiveness. RESULTS: Individual clinical features are of limited diagnostic value, with most likelihood ratios being close to 1. Wells clinical probability score stratifies proximal, but not distal, DVT into high-, intermediate- and low-risk categories. Unstructured clinical assessment by experienced clinicians may have similar performance to Wells score. In patients with clinically suspected DVT, D-dimer has 91% sensitivity and 55% specificity for DVT, although performance varies substantially between assays and populations. D-dimer specificity is dependent on pretest clinical probability, being higher in patients with a low clinical probability of DVT. Plethysmography and rheography techniques have modest sensitivity for proximal DVT, poor sensitivity for distal DVT, and modest specificity. Ultrasound has 94% sensitivity for proximal DVT, 64% sensitivity for distal DVT and 94% specificity. Computed tomography scanning has 95% sensitivity for all DVT (proximal and distal combined) and 97% specificity. Magnetic resonance imaging has 92% sensitivity for all DVT and 95% specificity. The diagnostic performance of all tests is worse in asymptomatic patients. The most cost-effective algorithm discharged patients with a low Wells score and negative D-dimer without further testing, and then used plethysmography alongside ultrasound, with venography in selected cases, to diagnose the remaining patients. However, the cost-effectiveness of this algorithm was dependent on assumptions of test independence being met and the ability to provide plethysmography at relatively low cost. Availability of plethysmography and venography is currently limited at most UK hospitals, so implementation would involve considerable reorganisation of services. Two algorithms were identified that offered high net benefit and would be feasible in most hospitals without substantial reorganisation of services. Both involved using a combination of Wells score, D-dimer and above-knee ultrasound. For thresholds of willingness to pay of pound 10,000 or pound 20,000 per QALY the optimal strategy involved discharging patients with a low or intermediate Wells score and negative D-dimer, ultrasound for those with a high score or positive D-dimer, and repeat scanning for those with positive D-dimer and a high Wells score, but negative initial scan. For thresholds of pound 30,000 or more a similar strategy, but involving repeat ultrasound for all those with a negative initial scan, was optimal. CONCLUSIONS: Diagnostic algorithms based on a combination of Wells score, D-dimer and ultrasound (with repeat if negative) are feasible at most UK hospitals and are among the most cost-effective. Use of repeat scanning depends on the threshold for willingness to pay for health gain. Further diagnostic testing for patients with a low Wells score and negative D-dimer is unlikely to represent a cost-effective use of resources. Recommendations for research include the evaluation of the costs and outcomes of using the optimal diagnostic algorithms in routine practice, the development and evaluation of algorithms appropriate for specific groups of patients with suspected DVT, such as intravenous drug abusers, pregnant patients and those with previous DVT, the evaluation of the role of plethysmography: interaction with other diagnostic tests, outcome of low-risk patients with negative plethysmography and measurement of the costs of providing plethysmography, and methodological research into the incorporation of meta-analytic data into decision-analytic modelling.

How should we diagnose suspected deep-vein thrombosis?

BACKGROUND: Many different approaches are used to diagnose suspected deep-vein thrombosis (DVT), but there has been little formal comparison of strategies. AIM: To identify the most cost-effective strategy for the UK National Health Service (NHS). DESIGN: Systematic review, meta-analysis and cost-effectiveness analysis. METHODS: We identified 18 strategies and estimated the diagnostic performance of constituent tests by systematic review and meta-analysis. Outcomes of testing and treatment were estimated from published data or by an expert panel. Costs were estimated from NHS reference costs and published data. We built a decision-analysis model to estimate, for each strategy, the overall accuracy, costs, and outcomes (valued as quality-adjusted life-years, QALYs), compared to a 'no testing, no treatment' alternative. Probabilistic analysis estimated the net benefit of each strategy at varying thresholds for willingness to pay for health gain. RESULTS: At the thresholds for willingness to pay recommended by the National Institute for Clinical Excellence (20,000 pounds sterling-30,000 pounds sterling per QALY), the optimal strategy was to discharge patients with a low or intermediate Wells score and negative D-dimer, limiting ultrasound to those with a high score or positive D-dimer. Strategies using radiological testing for all patients were only cost-effective at 40,000 pound sterling per QALY or more. DISCUSSION: The optimal strategy for DVT diagnosis is to use ultrasound selectively in patients with a high clinical risk or positive D-dimer. Radiological testing for all patients does not appear to be a cost-effective use of health service resources.

Can we use routine data to evaluate organizational change? Lessons from the evaluation of business process re-engineering in a UK teaching hospital.

OBJECTIVE: To review and critically evaluate a multidisciplinary independent evaluation of business process re-engineering within a UK hospital using routine data. METHODS: Routine data measures of hospital cost efficiency are used to compare rates of changes at Leicester Royal Infirmary (LRI) with a 'peer group' of 22 teaching hospitals and to ascertain changes attributable to re-engineering. Different adjustment factors are quantified and the robustness of individual measures discussed. In addition to providing context to the quantitative primary research and the qualitative research on change management, service performance and quality indicators not captured in overall efficiency measures are assessed using detailed routine data measures. RESULTS: LRI is one of the most efficient teaching hospitals in England and continued improvement during re-engineering is shown to be at a faster rate than the peer group average, although attribution of changes is difficult. Lack of availability and inconsistency of data for support services meant that many re-engineering initiatives are not quantifiable using routine data measures. CONCLUSIONS: When combining different measures, routine data is a valuable tool in evaluating organizational change initiatives. However, use in future evaluations would require consistent benchmarking of routine data.

How is deep vein thrombosis diagnosed and managed in UK and Australian emergency departments?

BACKGROUND: Recent research has identified technologies that may be of value in the diagnosis and management of deep vein thrombosis (DVT). We aimed to survey current practice in the United Kingdom (UK) and Australia to determine the extent to which these technologies have been implemented in these two healthcare systems. METHODS: We undertook a postal survey of 255 hospitals in the UK and 89 hospitals in Australia, requesting details of individual diagnostic tests, use of diagnostic algorithms, and management of DVT. RESULTS: We received replies from 186/255 UK hospitals (73%) and 84/89 of Australian hospitals (94%). Ultrasonography and laboratory based D-dimer were the most commonly available tests. We received 43 different algorithms from 51 hospitals. With only a very few exceptions, DVT diagnosis was ruled in by positive venography or positive ultrasound without venographic confirmation. By contrast a variety of different criteria were used to rule out DVT. Most algorithms used a combination of low clinical risk and negative D-dimer to rule out DVT, but some required all patients to receive ultrasound or venography. Few ruled out on the basis of low clinical risk or negative D-dimer alone. Low molecular weight heparins were overwhelmingly the treatment of choice for established DVT. Most departments (214/264; 81%) offered outpatient treatment. CONCLUSION: Recently developed technologies for the diagnosis and treatment of DVT have been widely implemented in the UK and Australia. Variation in practice, and thus presumably uncertainty, seems to be greatest in relation with the criteria used to rule out DVT.

Variation in the diagnostic performance of D-dimer for suspected deep vein thrombosis.

BACKGROUND: Numerous studies have evaluated the accuracy of D-dimer in diagnosing suspected deep vein thrombosis (DVT), but results are conflicting. AIM: To overview estimates of the diagnostic accuracy of D-dimer and identify causes of variation. DESIGN: Systematic review, meta-analysis and meta-regression. METHODS: We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, citation lists, and contacted manufacturers. We selected studies that compared D-dimer to a reference standard in patients with suspected DVT. Data were analysed by random effects meta-analysis and meta-regression. RESULTS: We included 97 studies reporting 198 assays in 99 different patient groups. Overall estimated sensitivity and specificity of D-dimer were 90.5% and 54.7%, but both estimates were subject to significant heterogeneity (p < 0.001). Meta-regression identified that some heterogeneity was explained by study setting, exclusion criteria, whether recruitment was consecutive or the study prospective, whether D-dimer and the reference standard were measured blind, and whether the D-dimer threshold was determined a priori. Sensitivity and specificity also varied between ELISA (94% and 45% respectively), latex (89% and 55%) and whole blood agglutination assays (87% and 68%). Sensitivity was higher for proximal than distal DVT. Specificity was dependent upon whether clinical probability of DVT was high (specificity 51%), intermediate (67%) or low (78%). DISCUSSION: D-dimer has good sensitivity, but poor specificity, for DVT. Estimates are subject to substantial heterogeneity from various sources. D-dimer specificity appears to be strongly dependent upon the pre-test clinical probability of DVT.

Evidence for ovarian self-incompatibility as a cause of self-sterility in the relictual woody angiosperm, Pseudowintera axillaris (Winteraceae).

Species within the genus Pseudowintera exhibit high rates of self-sterility. Self-sterility in the genus has been previously posited-but not confirmed-to be the result of late-acting ovarian self-incompatibility (OSI) functioning within nucellar tissue of the ovule to prevent self pollen tubes from entering the embryo sac. Structural and functional aspects of pollen-carpel interactions and early seed development following cross- and self-pollination were investigated in P. axillaris to determine the site, timing and possible mechanisms of self-sterility. No significant differences were observed between pollen tube growth, ovule penetration and double fertilization following cross- and self-pollination. Pollen tubes exhibited phasic growth in an extracellular matrix composed of proteins and carbohydrates, as well as arabinogalactans/arabinogalactan proteins. A uniform failure in embryo sac development prior to division of the zygote was apparent within 15 d following double fertilization by self gametes. Results indicate that SI mechanisms in P. axillaris do not prevent double fertilization from occurring. Instead, mechanisms of self-sterility affect post-zygotic development of the embryo sac. Although self-sterility may be attributed to inbreeding depression, given the post-zygotic nature of failure in embryo sac development, the possibility of late-acting OSI is discussed.

Cost-effectiveness of high-dose chemotherapy in first-line treatment of advanced multiple myeloma.

The cost-effectiveness of high-dose chemotherapy in multiple myeloma was considered as part of a UK National Health Service Executive regional evidence-based appraisal process. The use of high-dose chemotherapy supported by autologous stem cell transplantation in patients under 65 years of age was shown to provide a marginal benefit of 0.7 life-years over conventional chemotherapy. This corresponded to an incremental cost 'per life-year gained' figure of approximately pound15 000, based upon initial treatment costs and trial-period data only. The use of high-dose chemotherapy in the first-line treatment of advanced multiple myeloma improves event-free and overall survival and appears to be a cost-effective treatment option.

The cost-effectiveness of high dose chemotherapy in the treatment of relapsed Hodgkin's disease and non-Hodgkin's lymphoma.

As part of an NHS Executive Trent regional initiative we considered the role and cost-effectiveness of high dose chemotherapy in the treatment of relapsed Hodgkin's disease and non-Hodgkin's lymphoma. The key trials and case series show an additional patient benefit of 0.8-1.1 life years over standard chemotherapy. We estimate incremental cost per life year gained of 12 800 pound silver-17 600 pound silver, which reduces further if long-term benefits are considered. High dose chemotherapy in these conditions is both life-saving and cost-effective.