Ann Truesdale

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

BACKGROUND Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. METHODS In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. FINDINGS 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%. INTERPRETATION We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. FUNDING UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

Active versus expectant management of third stage of labour: the Hinchingbrooke randomised controlled trial.

BACKGROUND This study tested the hypotheses that active management of the third stage of labour lowers the rates of primary postpartum haemorrhage (PPH) and longer-term consequences compared with expectant management, in a setting where both managements are commonly practised, and that this effect is not mediated by maternal posture. BACKGROUND 1512 women judged to be at low risk of PPH (blood loss >500 mL) were randomly assigned active management of the third stage (prophylactic oxytocic within 2 min of babys birth, immediate cutting and clamping of the cord, delivery of placenta by controlled cord traction or maternal effort) or expectant management (no prophylactic oxytocic, no cord clamping until pulsation ceased, delivery of placenta by maternal effort). Women were also randomly assigned upright or supine posture. Analyses were by intention to treat. FINDINGS The rate of PPH was significantly lower with active than with expectant management (51 [6.8%] of 748 vs 126 [16.5%] of 764; relative risk 2.42 [95% CI 1.78-3.30], p<0.0001). Posture had no effect on this risk (upright 92 [12%] of 755 vs supine 85 [11%] of 757). Objective measures of blood loss confirmed the results. There was more vomiting in the active group but no other important differences were detected. INTERPRETATION Active management of the third stage reduces the risk of PPH, whatever the womans posture, even when midwives are familiar with both approaches. We recommend that clinical guidelines in hospital settings advocate active management (with oxytocin alone). However, decisions about individual care should take into account the weights placed by pregnant women and their caregivers on blood loss compared with an intervention-free third stage.

Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial

BACKGROUND Calcineurin inhibitors are the most commonly used immunosuppressive drugs in liver transplantation, but the optimum initial immunosuppression regimen is not known. The aim of our study was to compare tacrolimus with microemulsified ciclosporin, in a regimen with standardised concomitant immunosuppressive therapy. METHODS In all liver transplant centres in the UK and Republic of Ireland, 606 patients undergoing a first orthotopic liver transplantation were randomly assigned open-label tacrolimus or microemulsified ciclosporin. Primary outcome was the combined frequency (whichever occurred first) of death, retransplantation, or treatment failure for immunological reasons, analysed by intention to treat. FINDINGS 96% of patients received the treatment allocated to them. The primary outcome was reached in 62 (21%) of 301 patients in the tacrolimus group versus 99 (32%) of 305 allocated microemulsified ciclosporin (relative risk 0.63 [95% CI 0.48-0.84], p=0.001; time-to-event analysis log-rank test p=0.002): deaths (50 [17%] vs 72 [24%]); retransplantations (11 [4%] vs 31 [10%]) treatment failure for immunological reasons (6 [2%] vs 12 [4%]). The relative risk for the composite outcome was in favour of tacrolimus. The main causes of death in both trial groups were sepsis and multiple organ failure (31 [10%] vs 30 [10%]), and the main cause for retransplantation was hepatic artery thrombosis (6 [2%] vs 17 [6%]). Renal dysfunction and the need for antihypertensive therapy were much the same in both groups. Tacrolimus was more diabetogenic. INTERPRETATION Clinical outcome at 1 year was better with tacrolimus-based immunosuppression than with microemulsified ciclosporin during the first year after liver transplantation. Tacrolimus should be the first choice of calcineurin inhibitor for patients receiving their first liver graft.

Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR).

OBJECTIVES To determine the comparative effectiveness and cost-effectiveness of conventional ventilatory support versus extracorporeal membrane oxygenation (ECMO) for severe adult respiratory failure. DESIGN A multicentre, randomised controlled trial with two arms. SETTING The ECMO centre at Glenfield Hospital, Leicester, and approved conventional treatment centres and referring hospitals throughout the UK. PARTICIPANTS Patients aged 18-65 years with severe, but potentially reversible, respiratory failure, defined as a Murray lung injury score > or = 3.0, or uncompensated hypercapnoea with a pH < 7.20 despite optimal conventional treatment. INTERVENTIONS Participants were randomised to conventional management (CM) or to consideration of ECMO. MAIN OUTCOME MEASURES The primary outcome measure was death or severe disability at 6 months. Secondary outcomes included a range of hospital indices: duration of ventilation, use of high frequency/oscillation/jet ventilation, use of nitric oxide, prone positioning, use of steroids, length of intensive care unit stay, and length of hospital stay - and (for ECMO patients only) mode (venovenous/veno-arterial), duration of ECMO, blood flow and sweep flow. RESULTS A total of 180 patients (90 in each arm) were randomised from 68 centres. Three patients in the conventional arm did not give permission to be followed up. Of the 90 patients randomised to the ECMO arm, 68 received that treatment. ECMO was not given to three patients who died prior to transfer, two who died in transit, 16 who improved with conventional treatment given by the ECMO team and one who required amputation and could not therefore be heparinised. Ninety patients entered the CM (control) arm, three patients later withdrew and refused follow-up (meaning that they were alive), leaving 87 patients for whom primary outcome measures were available. CM consisted of any treatment deemed appropriate by the patients intensivist with the exception of extracorporeal gas exchange. No CM patients received ECMO, although one received a form of experimental extracorporeal arteriovenous carbon dioxide removal support (a clear protocol violation). Fewer patients in the ECMO arm than in the CM arm had died or were severely disabled 6 months after randomisation, [33/90 (36.7%) versus 46/87 (52.9%) respectively]. This equated to one extra survivor for every six patients treated. Only one patient (in the CM arm) was known to be severely disabled at 6 months. Patients allocated to ECMO incurred average total costs of 73,979 pounds compared with 33,435 pounds for those undergoing CM (UK prices, 2005). A lifetime model predicted the cost per quality-adjusted life-year (QALY) of ECMO to be 19,252 pounds (95% confidence interval 7622 pounds to 59,200 pounds) at a discount rate of 3.5%. Lifetime QALYs gained were 10.75 for the ECMO group compared with 7.31 for the conventional group. Costs to patients and their relatives, including out of pocket and time costs, were higher for patients allocated to ECMO. CONCLUSIONS Compared with CM, transferring adult patients with severe but potentially reversible respiratory failure to a single centre specialising in the treatment of severe respiratory failure for consideration of ECMO significantly increased survival without severe disability. Use of ECMO in this way is likely to be cost-effective when compared with other technologies currently competing for health resources. TRIAL REGISTRATION Current Controlled Trials ISRCTN47279827.

Use of recombinant activated factor VII in primary postpartum hemorrhage - The northern European registry 2000-2004

OBJECTIVE: To collect data from nine European countries for cases of obstetric hemorrhage between 2000 and 2004 in which recombinant activated factor VII (rFVIIa) was used. METHODS: The cases were identified through national surveys. Standardized case report forms included sociodemographic details, past medical and obstetric history, and details of the progress and management of labor in which the postpartum hemorrhage occurred. Clinicians were asked to describe subjectively the effect of rFVIIa administration using two mutually exclusive categories: 1) bleeding reduced or 2) bleeding unchanged or worse. RESULTS: A total of 113 forms were returned (88%) with 97 (86%) classified as treatment, and 16 (14%) as “secondary prophylaxis.” Clinicians noted improvements after a single dose for 80% of women in the treatment group, and for 75% in the secondary “prophylaxis” group. However, rFVIIa failed in 15 cases (13.8%). Few serious adverse events were noted related to rFVIIa administration; there were four cases of thromboembolism, one myocardial infarction, and one skin rash. CONCLUSION: Clinical reports and hematologic data suggest improvement for more than 80% of women after rFVIIa administration and few adverse effects. LEVEL OF EVIDENCE: II

The Ipswich Childbirth Study: 1. A randomised evaluation of two stage postpartum perineal repair leaving the skin unsutured

Objective To evaluate a policy of two stage postpartum perineal repair leaving the skin unsutured.

The Ipswich Childbirth Study: 2. A randomised comparison of polyglactin 910 with chromic catgut for postpartum perineal repair

Objective To compare polyglactin 910 sutures with chromic catgut sutures for postpartum perineal repair.

A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636].

The number of individuals with age-related cognitive impairment is rising dramatically in the UK and globally. There is considerable interest in the general hypothesis that improving the diet of older people may slow the progression of cognitive decline. To date, there has been little attention given to the possible protective role of n-3 long-chain polyunsaturated fatty acids (n-3 LCPs) most commonly found in oily fish, in age-related loss of cognitive function. The main research hypothesis of this study is that an increased dietary intake of n-3 LCPs will have a positive effect on cognitive performance in older people in the UK.To test this hypothesis, a double-blind randomised placebo-controlled trial will be carried out among adults aged 70–79 years in which the intervention arm will receive daily capsules containing n-3 LCP (0.5 g/day docosahexaenoic acid and 0.2 g/day eicosapentaenoic acid) while the placebo arm will receive daily capsules containing olive oil. The main outcome variable assessed at 24 months will be cognitive performance and a second major outcome variable will be retinal function. Retinal function tests are included as the retina is a specifically differentiated neural tissue and therefore represents an accessible window into the functioning of the brain.The overall purpose of this public-health research is to help define a simple and effective dietary intervention aimed at maintaining cognitive and retinal function in later life. This will be the first trial of its kind aiming to slow the decline of cognitive and retinal function in older people by increasing daily dietary intake of n-3 LCPs. The link between cognitive ability, visual function and quality of life among older people suggests that this novel line of research may have considerable public health importance.

The Ipswich childbirth study: one year follow up of alternative methods used in perineal repair

Objective To assess the long term implications of four alternative approaches to postpartum perineal repair.

Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol

BackgroundThere is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum.Methods/DesignThe study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged ≤ 16 years who are ventilated, have an arterial line in-situ and are receiving vasoactive support following injury, major surgery or in association with critical illness in whom it is anticipated such treatment will be required to continue for at least 12 hours, tight control will increase the numbers of days alive and free of mechanical ventilation at 30 days, and lead to improvement in a range of complications associated with intensive care treatment and be cost effective.Children in the tight control group will receive insulin by intravenous infusion titrated to maintain BG between 4 and 7.0 mmol/l. Children in the control group will be treated according to a standard current approach to BG management.Children will be followed up to determine vital status and healthcare resources usage between discharge and 12 months post-randomisation. Information regarding overall health status, global neurological outcome, attention and behavioural status will be sought from a subgroup with traumatic brain injury (TBI).A difference of 2 days in the number of ventilator-free days within the first 30 days post-randomisation is considered clinically important. Conservatively assuming a standard deviation of a week across both trial arms, a type I error of 1% (2-sided test), and allowing for non-compliance, a total sample size of 1000 patients would have 90% power to detect this difference. To detect effect differences between cardiac and non-cardiac patients, a target sample size of 1500 is required. An economic evaluation will assess whether the costs of achieving tight BG control are justified by subsequent reductions in hospitalisation costs.DiscussionThe relevance of tight glycaemic control in this population needs to be assessed formally before being accepted into standard practice.Trial RegistrationCurrent Controlled Trials ISRCTN61735247