Red cell transfusion in outpatients with myelodysplastic syndromes: a feasibility and exploratory randomised trial.

Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.

Developing Guidance for Donor Intervention Randomized Controlled Trials: Initial Discussions From the Canada-United Kingdom 2022 Workshop.

BACKGROUND: Donor interventions, including medications, protocols, and medical devices administered to donors, can enhance transplantable organ quality and quantity and maximize transplantation success. However, there is paucity of high-quality evidence about their effectiveness, in part because of ethical, practical, and regulatory challenges, and lack of guidance about conduct of donor intervention randomized controlled trials (RCTs). METHODS: With the vision to develop authoritative guidance for conduct of donor intervention RCTs, we convened a workshop of Canadian-United Kingdom experts in organ donation and transplantation ethics, research, and policy to identify stakeholders, explore unique challenges, and develop research agenda to inform future work in this promising field. RESULTS: Donor intervention trials should consider perspectives of broad group of stakeholders including donors, transplant recipients, and their families; researchers in donation and transplantation; research ethics boards; and healthcare providers and administrators involved in donation and transplantation. Unique challenges include (1) research ethics (living versus deceased status of the donor at the time of intervention, intervention versus outcomes assessment in different individuals, harm-benefit analysis in donors versus recipients, consent, and impact on research bystanders); (2) outcome data standardization and linkage; and (3) regulatory and governance considerations. CONCLUSIONS: Donor intervention RCTs hold potential to benefit organ transplantation outcomes but face unique research ethics, outcome data, and regulatory challenges. By developing research agenda to address these challenges, our workshop was an important first step toward developing Canada-United Kingdom guidance for donor intervention RCTs that are poised to improve the quality and availability of transplantable organs.

Doppler ultrasound surveillance of recently formed haemodialysis arteriovenous fistula: the SONAR observational cohort study.

Background: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design: A prospective multicentre observational cohort study (the 'SONAR' study). Setting: Seventeen haemodialysis centres in the UK. Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial Registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

For people with advanced kidney disease, haemodialysis is best provided by an 'arteriovenous fistula', which is created surgically by joining a vein onto an artery at the wrist or elbow. However, these take about 2 months to develop fully ('mature'), and as many as 3 out of 10 fail to do so. We asked whether we could use early ultrasound scanning of the fistula to identify those that are unlikely to mature. This would allow us to decide whether it would be practical to run a large, randomised trial to find out if using early ultrasound allows us to 'rescue' fistulas that would otherwise fail. We invited adults to undergo serial ultrasound scanning of their fistula in the first few weeks after it was created. We then analysed whether we could use the data from the early scans to identify those fistulas that were not going to mature by week 10. Of the 333 fistulas that were created, about two-thirds reached maturity by week 10. We found that an ultrasound scan 4 weeks after fistula creation could reliably identify those fistulas that were going to mature. However, of those fistulas predicted to fail, about one-third did eventually mature without further intervention, and even without knowing what the early scans showed, another third were successfully rescued by surgery or X-ray-guided treatment at a later stage. Performing an early ultrasound scan on a fistula can provide reassurance that it will mature and deliver trouble-free dialysis. However, because scans are poor at identifying fistulas that are unlikely to mature, we would not recommend their use to justify early surgery or X-ray-guided treatment in the expectation that this will improve outcomes.

Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry.

BACKGROUND: The risk that a positive smoking history in lung donors could adversely affect survival of transplant recipients causes concern. Conversely, reduction of the donor pool by exclusion of donors with positive smoking histories could compromise survival of patients waiting to receive a transplant. We examined the consequences of donor smoking on post-transplantation survival, and the potential effect of not transplanting lungs from such donors. METHODS: We analysed the effect of donor smoking on 3 year survival after first adult lung transplantation from brain-dead donors done between July 1, 1999, and Dec 31, 2010, by Cox regression modelling of data from the UK Transplant Registry. We estimated the effect of acceptance of lungs from donors with positive smoking histories on survival and compared it with the effect of remaining on the waiting list for a potential transplant from a donor with a negative smoking history donor, by analysing all waiting-list registrations during the same period with a risk-adjusted sequentially stratified Cox regression model. FINDINGS: Of 1295 lung transplantations, 510 (39%) used lungs from donors with positive smoking histories. Recipients of such lungs had worse 3 year survival after transplantation than did those who received lungs from donors with negative smoking histories (unadjusted hazard ratio [HR] 1·46, 95% CI 1·20-1·78; adjusted HR 1·36, 1·11-1·67). Independent factors affecting survival were recipient's age, donor-recipient cytomegalovirus matching, donor-recipient height difference, donor's sex, and total ischaemic time. Of 2181 patients registered on the waiting list, 802 (37%) died or were removed from the list without receiving a transplant. Patients receiving lungs from donors with positive smoking histories had a lower unadjusted hazard of death after registration than did those who remained on the waiting list (0·79, 95% CI 0·70-0·91). Patients with septic or fibrotic lung disease registered in 1999-2003 had risk-adjusted hazards of 0·60 (95% CI 0·42-0·87) and 0·39 (0·28-0·55), respectively. INTERPRETATION: In the UK, an organ selection policy that uses lungs from donors with positive smoking histories improves overall survival of patients registered for lung transplantation, and should be continued. Although lungs from such donors are associated with worse outcomes, the individual probability of survival is greater if they are accepted than if they are declined and the patient chooses to wait for a potential transplant from a donor with a negative smoking history. This situation should be fully explained to and discussed with patients who are accepted for lung transplantation. FUNDING: National Health Service Blood and Transplant.

Use of computed tomography angiography to evaluate the vascular anatomy of the distal portion of the forelimb of horses.

OBJECTIVE: To provide a detailed description of the vascular anatomy of the distal portion of the forelimbs of horses by use of computed tomography angiography (CTA). SAMPLE POPULATION: 6 forelimbs of 5 horses and 1 forelimb from an equine cadaver; none of the horses had orthopedic or vascular disease. PROCEDURE: Horses were anesthetized and CTA was conducted on the dependent forelimb. A catheter was inserted in the median artery, and contrast medium was infused at a rate of 3 mL/s. A computed tomography (CT) scanner was used to obtain contiguous slices from the region of the proximal sesamoid bones to the toe. All horses were allowed to recover from anesthesia. To help identify vessel patterns in the distal portion of the forelimb, the median artery and lateral palmar digital vein of a heparinized forelimb obtained from an equine cadaver were infused with red and blue polymethylmethacrylate and the distal portion of that forelimb was then sectioned to correspond to CTA images. RESULTS: Vessel patterns in CTA images matched vascular anatomic structures of the cadaver forelimb and were consistent with published anatomic structures. Major and minor vessels were consistently visible in CTA images of all horses. There were no complications reported in any horses. CONCLUSIONS AND CLINICAL RELEVANCE: Use of CTA provided a highly detailed depiction of the vasculature of the distal portion of the equine forelimb. This was a safe technique and should be useful in the evaluation of the blood supply to the distal portion of the forelimb.

Incidence, determinants, and outcome of chronic kidney disease after adult heart transplantation in the United Kingdom.

BACKGROUND: We investigated the incidence of chronic kidney disease (CKD) in the United Kingdom heart transplant population, identified risk factors for the development of CKD, and assessed the impact of CKD on subsequent survival. METHODS: Data from the UK Cardiothoracic Transplant Audit and UK Renal Registry were linked for 1732 adult heart transplantations, 1996 to 2007. Factors influencing time to CKD, defined as National Kidney Foundation CKD stage 4 or 5 or preemptive kidney transplantation, were identified using a Cox proportional hazards model. The effects of distinct CKD stages on survival were evaluated using time-dependent covariates. RESULTS: A total of 3% of patients had CKD at transplantation, 11% at 1-year and more than 15% at 6 years posttransplantation and beyond. Earlier transplantations, shorter ischemia times, female, older, hepatitis C virus positive, and diabetic recipients were at increased risk of developing CKD, along with those with impaired renal function pretransplantation or early posttransplantation. Significant differences between transplantation centers were also observed. The risk of death was significantly higher for patients at CKD stage 4, stage 5 (excluding dialysis), or on dialysis, compared with equivalent patients surviving to the same time point with CKD stage 3 or lower (hazard ratios of 1.66, 8.54, and 4.07, respectively). CONCLUSIONS: CKD is a common complication of heart transplantation in the UK, and several risk factors identified in other studies are also relevant in this population. By linking national heart transplantation and renal data, we have determined the impact of CKD stage and dialysis treatment on subsequent survival in heart transplant recipients.

Incidence and outcome of Levitronix CentriMag support as rescue therapy for early cardiac allograft failure: a United Kingdom national study.

OBJECTIVE: Primary graft failure is the most common cause of mortality early after heart transplantation. The availability of relatively low-cost short-term mechanical support devices has altered the management of primary graft failure but there are few data on clinical outcome. Here, we describe the UK experience with Levitronix CentriMag support following heart transplantation across multiple centres. METHODS: Data for all adult heart transplants and all CentriMag devices used within 30 days of heart transplantation in the UK between November 2003 and July 2008 were collected. Transplant characteristics were compared for those who did and did not receive CentriMag support, and device outcomes and survival rates were summarised. RESULTS: A total of 572 heart transplants were performed in this period. As many as 38 patients (6.6%) were implanted with CentriMag devices for primary graft failure. Four patients received extracorporeal membrane oxygenation concurrently and were excluded from further analysis. There were no significant differences in transplant characteristics between the patients who received CentriMag support and those who did not. Twelve patients were explanted; nine survived but three died shortly afterwards. Five underwent acute retransplantation; two survived and three died. Seventeen patients died on support. The 30-day and 1-year survival rates were 50% (95% confidence interval (CI) 32-65%) and 32% (95% CI 18-48%), respectively. Patients who previously had a bridge-to-transplant ventricular assist device (VAD) had significantly better survival than those who did not (1-year survival 71% vs 22%, p = 0.029). CONCLUSIONS: Primary graft failure remains an important early complication of heart transplantation. Levitronix CentriMag support led to the salvage of 32% of patients with severe allograft failure.

UK guidelines for referral and assessment of adults for heart transplantation.

Patients with advanced heart failure have a dismal prognosis and poor quality of life. Heart transplantation provides an effective treatment for a subset of these patients. This article provides cardiologists with up-to-date information about referral for transplantation, the role of left ventricular assist devices prior to transplant, patient selection, waiting-list management and donor heart availability. Timing is of central importance; patients should be referred before complications (eg, cardiorenal syndrome or secondary pulmonary hypertension) have developed that will increase the risk of, or potentially contraindicate, transplantation. Issues related to heart failure aetiology, comorbidity and adherence to medical treatment are reviewed. Finally, the positive role that cardiologists can play in promoting and facilitating organ donation is discussed.

Trends in adult heart transplantation: a national survey from the United Kingdom Cardiothoracic Transplant Audit 1995-2007.

OBJECTIVE: The management of heart failure (HF), peri-transplant care and immunosuppression has changed in the last decade. Here we describe the changes that have occurred in the UK national programme of adult heart transplantation (HTx). METHODS: Using the data accrued with the UK Cardiothoracic Transplant Audit we undertook a prospective cohort study of 2958 consecutive adult patients listed for HTx and 2005 adult orthotopic HTx performed in three time periods - Era-1 (July 1995-March 1999, 1321 listed, 907 transplanted), Era-2 (April 1999-March 2003, 842 listed, 600 transplanted) and Era-3 (April 2003-March 2007, 795 listed, 498 transplanted). RESULTS: The median time on the waiting list reduced from 109 days in Era-1 to 40 days in Era-3. The proportion of HTx in non-ambulatory HF patients requiring inotropic or circulatory support increased from 12% in Era-1 to 35% in Era-3. The proportion undergoing HTx for non-ischaemic dilated cardiomyopathy increased from 40% in Era-1 to 58% in Era-3 while ischaemic cardiomyopathy decreased. Survival after HTx remained constant (81% (95% CI: 78-83%) at 1 year in Era-1 and 80% (95% CI: 77-84%) in Era-3). There was an increase in the use of mycophenolate and induction therapy and a reduction in rejection episodes over the eras. CONCLUSIONS: Although waiting list and HTx activity have declined, HTx continues to have an important role in the management of advanced HF, especially for patients on inotropic or circulatory support. Despite a deterioration of donor organ quality, survival after HTx has remained unchanged.

Factors that influence access to the national renal transplant waiting list.

BACKGROUND: Registry data can be used to examine whether there are differences between individual renal units in the proportion of dialysis patients listed for renal transplantation, to investigate possible reasons for any differences observed, and to discover whether highlighting these anomalies can influence practice. METHODS: A cross-sectional study of 12, 401 prevalent adult dialysis patients from 41 renal units across England and Wales was performed. The proportion of patients registered on the deceased donor transplant waiting list was determined for each renal unit. Patient- and center-specific factors that influence the probability of being listed for transplantation were identified and used to adjust for differences observed between units. The annual change in the size of the transplant waiting list was examined before and after presentation of these data. RESULTS: A total of 23.3% of patients were active on the transplant waiting list. PATIENT: Specific variables significantly associated with listing were age, primary renal disease, graft number, social deprivation, and ethnicity but not gender. Centre-specific variables included size of renal unit, size of living donor program, and listing practice for living donor transplantation. Whether the renal unit was also a transplant unit was not significant. After adjusting for these variables, there remained unexplained variation between renal units in the proportion of dialysis patients on the waiting list. An increase in the number of patients listed for transplantation has been observed since presenting these data. CONCLUSIONS: Differences in listing practice exist between centers that cannot be explained by the patient case mix or center characteristics examined.

The importance of cold and warm cardiac ischemia for survival after heart transplantation.

BACKGROUND: Ischemia time is a risk factor for mortality after heart transplantation that can be influenced by organizational factors such as transport arrangements and organ allocation. METHODS: We used the United Kingdom Cardiothoracic Transplant Audit database to analyze the outcome of 1491 first isolated orthotopic adult heart transplants performed between April 1995 and March 2004. Ischemia time and its components (transport time and surgical implant time) were related to 30-day mortality using a multivariable logistic regression model. RESULTS: The median total ischemia time increased from 171 min (interquartile range: 149-198) to 213 min (interquartile range: 181-256) during the study period (P<0.0001). This was due to an increase in transport times that was partly explained by increased organ exchange between centers and also because of an increase in surgical implant times. Thirty-day survival decreased over the study period (91%-84%) with some evidence of a linear trend towards decreasing survival over time (P=0.089). After correcting for other known risk factors, the odds ratio of death within 30 days associated with each 15 min increment in transport time was 1.06 (95% confidence interval: 1.01-1.12) and with each 15 min increment in surgical implant time was 1.11 (95% confidence interval: 1.04-1.18). CONCLUSION: Both transport and implant times were directly related to 30-day mortality after heart transplantation. Ischemia time should be considered in organ allocation and controlled during the heart transplant procedure.