Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants.

BACKGROUND: Neonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high. OBJECTIVES: To determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support. SEARCH STRATEGY: The Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007. SELECTION CRITERIA: All randomised trials comparing neonatal ECMO to conventional ventilatory support. DATA COLLECTION AND ANALYSIS: The authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data. MAIN RESULTS: The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. AUTHORS' CONCLUSIONS: A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life

Efficient Research Design: Using Value-of-Information Analysis to Estimate the Optimal Mix of Top-down and Bottom-up Costing Approaches in an Economic Evaluation alongside a Clinical Trial.

In designing economic evaluations alongside clinical trials, analysts are frequently faced with alternative methods of collecting the same data, the extremes being top-down ("gross costing") and bottom-up ("micro-costing") approaches. A priori, bottom-up approaches may be considered superior to top-down approaches but are also more expensive to collect and analyze. In this article, we use value-of-information analysis to estimate the efficient mix of observations on each method in a proposed clinical trial. By assigning a prior bivariate distribution to the 2 data collection processes, the predicted posterior (i.e., preposterior) mean and variance of the superior process can be calculated from proposed samples using either process. This is then used to calculate the preposterior mean and variance of incremental net benefit and hence the expected net gain of sampling. We apply this method to a previously collected data set to estimate the value of conducting a further trial and identifying the optimal mix of observations on drug costs at 2 levels: by individual item (process A) and by drug class (process B). We find that substituting a number of observations on process A for process B leads to a modest £ 35,000 increase in expected net gain of sampling. Drivers of the results are the correlation between the 2 processes and their relative cost. This method has potential use following a pilot study to inform efficient data collection approaches for a subsequent full-scale trial. It provides a formal quantitative approach to inform trialists whether it is efficient to collect resource use data on all patients in a trial or on a subset of patients only or to collect limited data on most and detailed data on a subset.This is the author accepted manuscript. The final version is available from SAGE via http://dx.doi.org/10.1177/0272989X1562218

CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure.

BACKGROUND: An estimated 350 adults develop severe, but potentially reversible respiratory failure in the UK annually. Current management uses intermittent positive pressure ventilation, but barotrauma, volutrauma and oxygen toxicity can prevent lung recovery. An alternative treatment, extracorporeal membrane oxygenation, uses cardio-pulmonary bypass technology to temporarily provide gas exchange, allowing ventilator settings to be reduced. While extracorporeal membrane oxygenation is proven to result in improved outcome when compared to conventional ventilation in neonates with severe respiratory failure, there is currently no good evidence from randomised controlled trials to compare these managements for important clinical outcomes in adults, although evidence from case series is promising. METHODS/DESIGN: The aim of the randomised controlled trial of Conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) is to assess whether, for patients with severe, but potentially reversible, respiratory failure, extracorporeal membrane oxygenation will increase the rate of survival without severe disability ('confined to bed' and 'unable to wash or dress') by six months post-randomisation, and be cost effective from the viewpoints of the NHS and society, compared to conventional ventilatory support. Following assent from a relative, adults (18-65 years) with severe, but potentially reversible, respiratory failure (Murray score >/= 3.0 or hypercapnea with pH < 7.2) will be randomised for consideration of extracorporeal membrane oxygenation at Glenfield Hospital, Leicester or continuing conventional care in a centre providing a high standard of conventional treatment. The central randomisation service will minimise by type of conventional treatment centre, age, duration of high pressure ventilation, hypoxia/hypercapnea, diagnosis and number of organs failed, to ensure balance in key prognostic variables. Extracorporeal membrane oxygenation will not be available for patients meeting entry criteria outside the trial. 180 patients will be recruited to have 80% power to be able to detect a one third reduction in the primary outcome from 65% at 5% level of statistical significance (2-sided test). Secondary outcomes include patient morbidity and health status at 6 months. DISCUSSION: Analysis will be based on intention to treat. A concurrent economic evaluation will also be performed to compare the costs and outcomes of both treatments

Direct health costs of inflammatory polyarthritis 10 years after disease onset:Results from the Norfolk Arthritis Register

Objectives: To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset. Methods: Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data. Results: A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6–15.4). The mean direct medical cost per patient over the 6-month period was £1496 for IP (inflated for 2013 prices). This compared with £582 (95% CI £355–£964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%). Conclusion: The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use

Social and economic costs of food allergies in Europe: translation and trans-cultural adaptation into different languages of a questionnaire to measure costs and health utility

Background: With the growth in international comparative research in the field of health economics, new tools to collect comparative data from disparate countries are required to measure and compare the costs of illnesses. Methods: A multistep approach was used to translate an English questionnaire to measure the costs of food allergies across 12 European countries, using WHO guidelines as a minimum standard. Greek, Polish and Spanish translations are presented as case studies. Survey response rates and item non-response rates were analysed to evaluate the process. Results: Questionnaires were adapted to reflect different health professions and health settings in each country. Spain achieved the highest response rate (85%) and lowest item non-response rate (85%; 1.52%) compared to Poland (68%; 4.97%) and Greece (38%; 10.64%). Spain implemented a more complex translation protocol than Poland and Greece. Conclusion: More complex translation protocols yield better results, but this paper concludes that good channels of communication between originators of questionnaires and translators is most effective way of ensuring good quality outcomes

What is known about the long-term economic impact of centre-based early childhood interventions?

There is a substantial literature about cost-benefi t studies of social welfare interventions. It is widely assumed, and widely quoted by politicians and policymakers, that early childhood interventions in particular are effective and bring returns in the order of seven dollars saved for every one dollar spent. These savings do not appear to be apparent until the children who received the intervention reach adulthood. We wished to scrutinise this evidence in detail

Leukotriene antagonists as first-line or add-on asthma controller therapy

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score =6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score =1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group

Economics methods in Cochrane systematic reviews of health promotion and public health related interventions.

Peer reviewedPublisher PD

Psycho-educational interventions for adults with severe or difficult asthma: a systematic review.

types: Journal Article; Research Support, Non-U.S. Gov't; ReviewThis is the author's version of the work that was accepted for publication in the Journal of Asthma. The final version can be accessed via the DOI in this record.Research highlights psychosocial factors associated with adverse asthma events. This systematic review therefore examined whether psycho-educational interventions improve health and self-management outcomes in adults with severe or difficult asthma. Seventeen controlled studies were included. Characteristics and content of interventions varied even within broad types. Study quality was generally poor and several studies were small. Any positive effects observed from qualitative and quantitative syntheses were mainly short term and, in planned subgroup analyses (involving < 5 trials), effects on hospitalizations, quality of life, and psychological morbidity in patients with severe asthma did not extend to those in whom multiple factors complicate management.UK NHS Health Technology Assessment Programm

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes