Catriona McDaid

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review

Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.

Impact of presumed consent for organ donation on donation rates: a systematic review

Objectives To examine the impact of a system of presumed consent for organ donation on donation rates and to review data on attitudes towards presumed consent. Design Systematic review. Data sources Studies retrieved by online searches to January 2008 of Medline, Medline In-Process, Embase, CINAHL, PsycINFO, HMIC, PAIS International, and OpenSIGLE. Studies reviewed Five studies comparing donation rates before and after the introduction of legislation for presumed consent (before and after studies); eight studies comparing donation rates in countries with and without presumed consent systems (between country comparisons); 13 surveys of public and professional attitudes to presumed consent. Results The five before and after studies represented three countries: all reported an increase in donation rates after the introduction of presumed consent, but there was little investigation of any other changes taking place concurrently with the change in legislation. In the four best quality between country comparisons, presumed consent law or practice was associated with increased organ donation—increases of 25-30%, 21-26%, 2.7 more donors per million population, and 6.14 more donors per million population in the four studies. Other factors found to be important in at least one study were mortality from road traffic accidents and cerebrovascular causes, transplant capacity, gross domestic product per capita, health expenditure per capita, religion (Catholicism), education, public access to information, and a common law legal system. Eight surveys of attitudes to presumed consent were of the UK public. These surveys varied in the level of support for presumed consent, with surveys conducted before 2000 reporting the lowest levels of support (28-57%). The most recent survey, in 2007, reported that 64% of respondents supported a change to presumed consent. Conclusion Presumed consent alone is unlikely to explain the variation in organ donation rates between countries. Legislation, availability of donors, organisation and infrastructure of the transplantation service, wealth and investment in health care, and public attitudes to and awareness of organ donation may all play a part, but their relative importance is unclear. Recent UK surveys show support for presumed consent, though with variation in results that may reflect differences in survey methods.

A systematic review of continuous positive airway pressure for obstructive sleep apnoea–hypopnoea syndrome

We conducted a systematic review of current evidence on the effectiveness of continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnoea-hypopnoea syndrome (OSAHS). The primary outcomes were subjective sleepiness, using Epworth Sleepiness Scale (ESS) and objective sleepiness using Maintenance of Wakefulness Test (MWT) and Multiple Sleep Latency Test (MSLT). Mean difference (MD) in endpoints was used to compare CPAP to usual care, placebo and dental devices. The analysis was stratified by symptom and disease severity at baseline. CPAP significantly reduced ESS score compared to control (MD -2.7, 95% CI -3.45, -1.96). The benefit was greatest in patients whose symptoms were severe at baseline: severely symptomatic population (MD -5.0, -6.5, -3.5); moderate (MD -2.3, -3.0, -1.6); mild (MD -1.1, -1.8, -0.3). CPAP significantly improved MWT score compared to control (MD 3.3, 1.3, 5.3) but not on the MSLT. There was no statistically significant difference between CPAP and dental devices on the ESS, MWT or MSLT, in a population with moderate symptoms. There was some evidence of benefit for blood pressure with CPAP compared to control. CPAP is an effective treatment for OSAHS in moderate to severe symptomatic patients and there may be benefits for mild symptoms. Dental devices may be a treatment option for moderate symptoms.

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review.

OBJECTIVES To determine which class of non-opioid analgesics - paracetamol (acetaminophen), NSAIDs or COX-2 inhibitors - is the most effective at reducing morphine consumption and associated adverse effects when used as part of multimodal analgesia following major surgery. DATA SOURCES A systematic literature review was conducted using MEDLINE, EMBASE and CENTRAL databases, searched from January 2003 to February 2009 and updating an earlier review. REVIEW METHODS Randomised controlled trials comparing paracetamol, NSAIDs or COX-2 inhibitors to each other or placebo, in adults receiving patient-controlled analgesia (PCA) with morphine following major surgery, were included. The COX-2 inhibitors rofecoxib and valdecoxib were excluded. Only trials that reported 24-hour morphine consumption were included. Other outcomes of interest were morphine-related adverse effects and adverse effects related to the non-opioids. Adequacy of randomisation, concealment of allocation, double blinding, and the flow of patients within the trial was assessed. The main analysis was a mixed treatment comparison (MTC) evaluating the relative effects of the four treatment classes. Four main outcomes were prioritised: 24-hour morphine consumption, sedation, nausea and vomiting, and surgical bleeding. Studies reporting nausea alone were pooled with studies reporting postoperative nausea and vomiting (PONV). Comparisons were described as statistically significant (at 5% level) when the credibility interval (CrI) did not cross 1 for odds ratio (OR) and zero for mean difference (MD). Trials making direct comparisons between the active interventions were also pooled in a meta-analysis using a random effects model. Sensitivity analyses were performed to assess the effects of study quality, individual drugs, and baseline morphine consumption. RESULTS Sixty relevant studies were identified. When paracetamol, NSAIDs or COX-2 inhibitors were added to PCA morphine, there was a statistically significant reduction in morphine consumption: paracetamol (MD -6.34 mg; 95% CrI -9.02 to -3.65); NSAIDs (MD -10.18; 95% CrI -11.65 to -8.72); and COX-2 inhibitors (MD -10.92; 95% CrI -12.77 to -9.08). NSAIDs and COX-2 inhibitors were both significantly better than paracetamol, and there was no significant difference between NSAIDs and COX-2 inhibitors (MD -0.74; 95% CrI -3.03 to 1.56). There was a significant reduction in nausea and PONV with NSAIDs compared to placebo (OR 0.70; 95% CrI 0.53 to 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared to paracetamol or COX-2 inhibitors. CONCLUSIONS 24-hour morphine consumption decreased by 6.3 mg to 10.9 mg, compared to placebo, when paracetamol, NSAID or COX-2 inhibitors were added to PCA morphine following surgery. Differences in effect between the three drug classes were small and unlikely to be of clinical significance. There does not appear to be a strong case for recommending routine addition of any of the three non-opioids to PCA morphine in the 24 hours immediately after surgery, or for favouring one drug class above the others.

A systematic review of presumed consent systems for deceased organ donation

OBJECTIVES To examine the impact of presumed consent legislation on organ donation and to review data on attitudes to presumed consent among the public, professionals and any other stakeholders. DATA SOURCES Eight electronic databases (MEDLINE, MEDLINE In-Process, EMBASE, CINAHL, PsycINFO, HMIC, PAIS International and OpenSIGLE) were searched from inception to January 2008. Supplementary internet searches were also performed. REVIEW METHODS A systematic review of studies comparing donation rates in a single country before and after the introduction of a presumed consent law or in countries with and without presumed consent systems. The methodological quality of these studies was assessed and a narrative synthesis of results undertaken. Surveys of attitudes towards presumed consent legislation were also included. RESULTS Over 2000 potentially relevant citations were identified, of which 13 studies met the inclusion criteria for the primary objective and 13 for the secondary objective. For the primary objective, eight studies were between-country comparisons and five were before-and-after studies. Four of the between-country comparisons were of sufficient methodological quality to provide reliable results. In all four studies presumed consent law or practice was associated with increased rates of organ donation, ranging from an increase of 2.7 donors per million population (pmp) in one study to 6.14 donors per million in another, and an increase of between 20% and 30% in two other studies. Factors other than presumed consent that had an impact on organ donation rates were mortality from road traffic accidents and cerebrovascular accident, the transplant capacity of a country, gross domestic product per capita and health expenditure per capita, religion, education, public access to information and a common law legal system. The five before-and-after studies represented three countries, all of which reported an increase in donation rates following the introduction of a presumed consent system (Austria, from 4.6 to 27.2 donors pmp over a 5-year period; Belgium, increase in kidney donation from 10.9 to 41.3 pmp during a 3-year period; Singapore, increase in kidney procurement from 4.7 to 31.3 per year in the 3 years after the change in legislation). There was very limited investigation of any other changes taking place concurrently with the changes in legislation across this set of studies. Of the 13 studies addressing the secondary objective, eight were surveys of the UK public, four were from other countries and one was an international survey of health professionals. There was variation among the UK surveys in the level of support for presumed consent, with surveys conducted before 2000 reporting the lowest levels of support (28-57%). The most recent survey by YouGov in 2007 reported that 64% of respondents supported a change to presumed consent. CONCLUSIONS Presumed consent alone is unlikely to explain the variation in organ donation rates between different countries. A combination of legislation, availability of donors, transplantation system organisation and infrastructure, wealth and investment in health care, as well as underlying public attitudes to and awareness of organ donation and transplantation, may all play a role, although the relative importance of each is not clear. Further reviews could investigate the factors likely to modify donor rates, such as procedures for family involvement. The way in which families of any potential donor are approached is likely to be an important factor and a review of qualitative research examining the experience of relatives in this context would be useful.

Interventions for adult Eustachian tube dysfunction: a systematic review.

BACKGROUND Eustachian tube dysfunction (ETD) is the inability of the Eustachian tube (ET) to adequately perform at least one of its functions: to protect the middle ear from sources of disease, to ventilate the middle ear, and to help drain secretions away from the middle ear. There are a number of treatment options for ETD, but there is little consensus about management. OBJECTIVES To determine the clinical effectiveness of interventions for adult ETD and to identify gaps in the evidence to inform future research. DATA SOURCES Twelve databases were searched up to October 2012 for published and unpublished studies in English (e.g. MEDLINE from 1946, EMBASE from 1974, Biosis Previews from 1969 and Cumulative Index to Nursing and Allied Health Literature from inception). References of included studies, relevant systematic reviews and regulatory agency websites were checked. REVIEW METHODS A systematic review was undertaken. Controlled studies evaluating prespecified treatments for adult patients diagnosed with ETD were eligible. Uncontrolled studies with at least 10 participants were included for interventions where no controlled studies were found. Outcomes included change in symptoms severity/frequency (primary outcome), quality of life, middle ear function, hearing, clearance of middle ear effusion, early ventilation tube extrusion, additional treatment, adverse events and complications. All aspects of the review process were performed using methods to reduce reviewer error and bias. Owing to heterogeneous data, a quantitative synthesis could not be performed, and results were reported in a narrative synthesis. RESULTS Nineteen studies were included: three randomised controlled trials (RCTs) and two non-RCTs evaluating pharmacological interventions or mechanical devices for middle ear pressure equalisation; and 13 case series and one retrospective controlled before-and-after study evaluating surgical interventions. None was conducted in the UK. All studies were small (11 to 108 participants). Most non-surgical studies reported including mixed populations of adults and children. All except two studies were at high risk of bias, and subject to multiple limitations. Based on a single RCT, nasal steroids showed no improvement in symptoms or middle ear function for patients with otitis media with effusion and/or negative middle ear pressure. Very short-term improvements in middle ear function were observed in patients receiving directly applied topical decongestants or a combination of antihistamine and ephedrine. Single trials found two pressure equalisation devices were each associated with significant short-term improvements in symptoms, middle ear function and/or hearing. Eustachian tuboplasty (seven case series) and balloon dilatation (three case series) were associated with improved outcomes. Positive results were also reported for myringotomy (two case series), directly applied topical steroids (one case series) and laser point coagulation (one controlled before-and-after study). High rates of co-interventions were documented. Minor complications of surgery and pharmacological treatments but no serious adverse effects were reported. LIMITATIONS The evidence was limited in quantity and overall was of poor quality. No data were identified on several interventions despite extensive searches. CONCLUSIONS It is not possible to draw conclusions regarding the effectiveness of any of the interventions for the treatment of adults with an ETD diagnosis, and there is insufficient evidence to recommend a trial of any particular intervention. Further research is needed to address lack of consensus on several issues, including the definition of ETD in adults, its relation to broader middle ear ventilation problems and clear diagnostic criteria. STUDY REGISTRATION This study is registered as PROSPERO CRD42012003035. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Systematic review of the limited evidence base for treatments of Eustachian tube dysfunction: a health technology assessment

The Health Technology Assessment programme commissioned a wide‐ranging review of treatments for adult Eustachian tube dysfunction. Treatments range from advice and observation and pharmacological treatments to surgical options.

Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of enhanced external counterpulsation (EECP) compared with usual care and placebo for refractory stable angina and heart failure, and to undertake analyses of the expected value of information to assess the potential value of future research on EECP. DATA SOURCES Major electronic databases were searched between November 2007 and March 2008. REVIEW METHODS A systematic review of the literature was undertaken and a decision model developed to compare EECP treatment with no treatment in adults with chronic stable angina. RESULTS Five studies were included in the review. In the Multicenter Study of Enhanced External Counterpulsation (MUST-EECP), time to greater than or equal to 1-mm ST segment depression (exercise-induced ischaemia) was statistically significantly improved in the EECP group compared with the control group (sham EECP), mean difference (MD) 41 seconds [95% confidence interval (CI) 9.10-73.90]. However, there was no statistically significant difference between the EECP and control groups in the change in exercise duration from baseline to end of treatment, self-reported angina episodes or daily nitroglycerin use, and the clinical significance of the limited benefits was unclear. There was also a lack of data on long-term outcomes. There were more withdrawals due to adverse events in the EECP group than in the control group, as well as a greater proportion of patients with adverse events [relative risk (RR) 2.13, 95% CI 1.35-3.38]. The three non-randomised studies compared EECP with elective percutaneous coronary intervention (PCI) and usual care. There was a high risk of selection bias in all three studies and the results should be treated with considerable caution. The study comparing an EECP registry with a PCI registry reported similar 1-year all-cause mortality in both groups. In the Prospective Evaluation of EECP in Congestive Heart Failure (PEECH) trial, patients with heart failure were randomised to EECP or to usual care (pharmacotherapy only). At 6 months post treatment, the proportion of patients achieving at least a 60-second increase in exercise duration was higher in the EECP group (RR 1.39, 95% CI 0.89-2.16), but the proportion with an improvement in peak VO2 was similar in both groups. The clinical significance of this is unclear. The proportion of patients in the EECP group with an improvement in New York Heart Association classification was higher (RR 2.25, 95% CI 1.25-4.06) at 6 months, as was mean exercise duration, MD 34.6 (95% CI -4.86 to 74.06). There were more withdrawals in the EECP group than in the control group as a result of adverse events (RR 1.05, 95% CI 0.67-1.66). There were limitations in the generalisability of results of the trial and, again, a lack of data on long-term outcomes. The review of cost-effectiveness evidence found only one unpublished study but demonstrated that the long-term maintenance of quality of life benefits of EECP is central to the estimate of its cost-effectiveness. The incremental cost-effectiveness ratio of EECP was 18,643 pounds for each additional quality-adjusted life-year (QALY), with a probability of being cost-effective of 0.44 and 0.70 at cost-effectiveness thresholds of 20,000 pounds and 30,000 pounds per QALY gained respectively. Results were sensitive to the duration of health-related quality of life (HRQoL) benefits from treatment. CONCLUSIONS The results from a single randomised controlled trial (MUST-EECP) do not provide firm evidence of the clinical effectiveness of EECP in refractory stable angina or in heart failure. High-quality studies are required to investigate the benefits of EECP, whether these outweigh the common adverse effects and its long-term cost-effectiveness in terms of quality of life benefits.

The effectiveness of interventions in the management of patients with primary frozen shoulder

There are many types of treatment used to manage the frozen shoulder, but there is no consensus on how best to manage patients with this painful and debilitating condition. We conducted a review of the evidence of the effectiveness of interventions used to manage primary frozen shoulder using the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Physiotherapy Evidence Database, MEDLINE and EMBASE without language or date restrictions up to April 2009. Two authors independently applied selection criteria and assessed the quality of systematic reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Data were synthesised narratively, with emphasis placed on assessing the quality of evidence. In total, 758 titles and abstracts were identified and screened, which resulted in the inclusion of 11 systematic reviews. Although these met most of the AMSTAR quality criteria, there was insufficient evidence to draw firm conclusions about the effectiveness of treatments commonly used to manage a frozen shoulder. This was mostly due to poor methodological quality and small sample size in primary studies included in the reviews. We found no reviews evaluating surgical interventions. More rigorous randomised trials are needed to evaluate the treatments used for frozen shoulder.

Reporting of article retractions in bibliographic databases and online journals

Retraction of journal papers containing falsified data plays a central role in “correcting” the scientific record. Of 395 articles retracted between 1982 and 2002, Nath et al. classified 62% as retracted as a result of mistake, 27% because of deliberate falsification or fabrication of data, and 11% without a clear reason for retraction [1]. There is evidence that retracted papers continue to be cited without reference to the retraction: Budd et al. found that 235 retracted articles were cited 2,034 times after retraction notices. Examination of 299 of these citations showed that only 19 referred to the retraction [2]. Similarly, Neale et al.s analysis of 102 articles from PubMed showed that many of these papers were subsequently cited by other researchers who were unaware that the papers had been affected by scientific misconduct [3]. Limitations in the processes for recording retractions have been noted elsewhere, and the responsibilities of authors, journal editors, and research institutions have been highlighted [4, 5]. Following the Poehlman case in 2005, where ten articles based on fabricated data by that author were retracted, Sox and Rennie identified several opportunities for publishers to prevent citation of retracted papers [5]. These included journal editors checking the reference lists of submitted manuscripts on the National Library of Medicine website, retraction notices being linked to retracted articles on journal websites, retraction notices being prominently displayed in electronic journals, and free access to the full text of retraction notices being facilitated. While undertaking a systematic review on post-surgery analgesia [6], the authors realized that several of the papers identified for possible inclusion were by Scott S. Reuben, who was at that point being investigated for producing papers based on falsified data [7]. Twenty-one papers or abstracts authored by Reuben were under question at that time, and there was considerable publicity, while official retractions began to be made by journals. Although the presence of this publicity made it easy to weed out those articles from the systematic review, the situation offered an opportunity to conduct a case study to investigate whether databases and journals record notices of article retractions in a way that ensures they can be easily identified, even in the absence of such public discussion.