Quality assurance in surgical trials of arteriovenous grafts for haemodialysis: A systematic review, a narrative exploration and expert recommendations.

BACKGROUND: Introducing new procedures and challenging established paradigms requires well-designed randomised controlled trials (RCT). However, RCT in surgery present unique challenges with much of treatment tailored to the individual patient circumstances, refined by experience and limited by organisational factors. There has been considerable debate over the outcomes of arteriovenous grafts (AVG) compared to AVF, but any differences may reflect differing practice and potential variability. It is essential, therefore, when considering an RCT of a novel surgical procedure or device that quality assurance (QA) is defined for both the new approach and the comparator. The aim of this systematic review was to evaluate the QA standards performed in RCT of AVG using a multi-national, multi-disciplinary approach and propose an approach for future RCT. METHOD: The methods of this have been previously registered (PROSPERO: CRD420234284280) and published. In summary, a four-stage review was performed: identification of RCT of AVG, initial review, multidisciplinary appraisal of QA methods and reconciliation. QA measures were sought in four areas - generic, credentialing, standardisation and monitoring, with data abstracted by a multi-national, multi-speciality review body. RESULTS: QA in RCT involving AVG in all four domains is highly variable, often sub-optimally described and has not improved over the past three decades. Few RCT established or defined a pre-RCT level of experience, none documented a pre-trial education programme, or had minimal standards of peri-operative management, no study had a defined pre-trial monitoring programme, and none assessed technical performance. CONCLUSION: QA in RCT is a relatively new area that is expanding to ensure evidence is reliable and reproducible. This review demonstrates that QA has not previously been detailed, but can be measured in surgical RCT of vascular access, and that a four-domain approach can easily be implemented into future RCT.

A practical review of barriers and challenges to a definitive randomised trial of grafts versus fistula.

A definitive randomised controlled trial of arteriovenous fistula (AVF) versus arteriovenous grafts (AVG) has been advocated for more than a decade, but as yet, none has been completed. The aim of this article is to summarise the theoretical barriers, review the difficulties in trial design and practicalities that have thus far prevented this from occurring.

What are the observed procedural costs of vascular access surgery? Protocol for a systematic review.

INTRODUCTION: A central component in the introduction of a novel surgical procedure or technique is an evaluation of its cost efficiency when compared with a benchmark standard of care. Accurate assessment of costs is thus essential in ensuring appropriate allocation of resources within a healthcare system. The treatment of kidney failure requires a significant volume of resources, and vascular access provision is the main modifiable cost. The costs of providing this service are obscured by generic NHS reference costs, which lack adequate granularity to allow meaningful comparisons between treatments. The aim of this systematic review will be to assess the reporting of procedural costs in all published economic analyses of vascular access surgery and perform a comparison of the reported procedural costs involved in arteriovenous fistula (AVF) and arteriovenous graft (AVG) creation. This will provide an estimate as to the accuracy of the NHS reference costs in this field. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A systematic search will be performed of the MEDLINE, Embase and Cochrane databases to identify full-text economic analyses of vascular access for haemodialysis in which the procedural cost of AVF or AVG creation is reported. Publications in English from 1 January 2000 to 30 August 2023, will be eligible for inclusion. Studies will be selected by title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Studies not reporting the procedural costs of surgery will be excluded. Data collected will pertain to procedural costs of AVF and AVG creation. Costs will be adjusted to a common currency using a gross domestic product (GDP) deflator index and conversion rates based on purchasing power parities for GDP. Comparison with NHS reference costs will indicate their reliability for use in future economic analyses in this field. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023458779.

Early-cannulation arteriovenous grafts: Multidisciplinary learning is essential to optimize outcomes.

BACKGROUND: It is likely that there will be an increasing role for early-cannulation arteriovenous grafts (ecAVG) with a wider recognition of the need to tailor vascular access to avoid futile procedures and unnecessary TCVC. However, experience of these products is not common and limited to early surgical adopters, with little information on the systemic changes and multi-disciplinary care needed to optimize outcomes. The aim of this study was to report the impact of a multi-disciplinary approach on quantifiable outcomes. METHODS: A retrospective analysis of a prospectively maintained database of 295 ecAVG implanted over an 8-year time-period was performed. Indicative outcomes were chosen to reflect nephrology (patient selection), nursing care (cannulation complications of infection and pseudoaneurysm) and radiology (thrombosis) on cumulative impact (functional patency) over three distinct time periods. RESULTS: The incidence of ecAVG increased 10-fold over the three time periods. The use of ecAVG changed significantly from salvage tertiary access to TCVC avoidance and salvage of existing AVF. Nursing complications reduced markedly with significantly fewer over-cannulation episodes and pseudo-aneurysms. With an improved pro-active surveillance programme, the time to first thrombosis doubled and the risk of thrombosis halved. Ultimately this resulted in significantly improved functional patency with a risk of ecAVG loss less than one-third by the last time-period. CONCLUSIONS: All aspects of ecAVG use require scrutiny and critical appraisal. Failure or success is not simply achieved by performing good technical surgery with an efficacious product, but by the care taken across a wide range of elements spanning case selection, implantation, use and maintenance.

Quality assurance in surgical trials of arteriovenous grafts for haemodialysis: protocol for a systematic review.

INTRODUCTION: Decisions regarding the optimal vascular access for haemodialysis patients are becoming increasingly complex, and the provision of vascular access is open to variations in systems of care as well as surgical experience and practice. Two main surgical options are recognised: arteriovenous fistula and arteriovenous graft (AVG). All recommendations regarding AVG are based on a limited number of randomised controlled trials (RCTs). It is essential that when considering an RCT of a surgical procedure, an appropriate definition of quality assurance (QA) is made for both the new approach and the comparator, otherwise replication of results or implementation into clinical practice may differ from published results. The aim of this systematic review will be to assess the methodological quality of RCT involving AVG, and the QA measures implemented in delivering interventions in these trials. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A systematic search will be performed of the MEDLINE, Embase and Cochrane databases to identify relevant literature. Studies will be selected by title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Data collected will pertain to generic measures of QA, credentialing of investigators, procedural standardisation and performance monitoring. Trial methodology will be compared against a standardised template developed by a multinational, multispecialty review body with experience in vascular access. A narrative approach will be taken to synthesise and report data. ETHICS AND DISSEMINATION: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations, with the ultimate aim of providing recommendations for future RCT of AVG design.

Recruitment into randomised trials of arteriovenous grafts: A systematic review.

Although randomised controlled trials (RCT) are considered the optimal form of evidence, there are relatively few in surgery. Surgical RCT are particularly likely to be discontinued with poor recruitment cited as a leading reason. Surgical RCT present challenges over and above those seen in drug trials as the treatment under study may vary between procedures, between surgeons in one unit, and between units in multi-centred RCT. The most contentious and debated area of vascular access remains the role of arteriovenous grafts, and thus the quality of the data that is used to support opinions, guidelines and recommendations is critical. The aim of this review was to determine the extent of variation in the planning and recruitment in all RCT involving AVG. The findings of this are stark: there have been only 31 RCT performed in 31 years, the vast majority of which exhibited major limitations severe enough to undermine the results. This underlines the need for better quality RCT and data, and further inform the design of future studies. Perhaps most fundamental is the planning for a RCT that accounts for the intended population, the uptake of a RCT and the attrition for the significant co-morbidity in this population.

Cardiorespiratory Optimisation By Arteriovenous fistula Ligation after renal Transplantation (COBALT): study protocol for a multicentre randomised interventional feasibility trial.

INTRODUCTION: Cardiovascular events are a major cause of mortality following successful kidney transplantation.Arteriovenous fistulas (AVFs) are considered the best option for haemodialysis, but may contribute to this excess mortality because they promote adverse cardiac remodelling and ventricular hypertrophy. This raises the question whether recipients with a well-functioning kidney transplant should undergo elective AVF ligation. METHODS AND ANALYSIS: The COBALT feasibility study is a multicentre interventional randomised controlled trial (RCT) that will randomise renal transplant patients with stable graft function and a working AVF on a 1:1 basis to standard care (continued conservative management) or to AVF ligation. All patients will perform cardiopulmonary exercise testing (CPET) on recruitment and 6 months later. Daily functioning and quality of life will be additionally assessed by questionnaire completion and objective measure of physical activity. The primary outcome-the proportion of approached patients who complete the study (incorporating rates of consent, receipt of allocated intervention and completion of both CPETs without withdrawal)-will determine progression to a full-scale RCT. Design of the proposed RCT will be informed by an embedded qualitative assessment of participant and healthcare professional involvement. ETHICS AND DISSEMINATION: This study has been approved by the East Midlands-Derby Research Ethics Committee (22/EM/0002) and the Health Research Authority. The results of this work will be disseminated academically through presentation at national and international renal meetings and via open access, peer-reviewed outputs. Existing networks of renal patient groups will also be used to disseminate the study findings to other key stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN49033491.

Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study protocol : a randomised controlled trial comparing primary unassisted patency at 1 year of primary arteriovenous fistulae created under regional compared to local anaesthesia.

INTRODUCTION: Arteriovenous fistulae (AVF) are the 'gold standard' vascular access for haemodialysis. Universal usage is limited, however, by a high early failure rate. Several small, single-centre studies have demonstrated better early patency rates for AVF created under regional anaesthesia (RA) compared with local anaesthesia (LA). The mechanistic hypothesis is that the sympathetic blockade associated with RA causes vasodilatation and increased blood flow through the new AVF. Despite this, considerable variation in practice exists in the UK. A high-quality, adequately powered, multicentre randomised controlled trial (RCT) is required to definitively inform practice. METHODS AND ANALYSIS: The Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study is a multicentre, observer-blinded RCT comparing primary radiocephalic/brachiocephalic AVF created under regional versus LA. The primary outcome is primary unassisted AVF patency at 1 year. Access-specific (eg, stenosis/thrombosis), patient-specific (including health-related quality of life) and safety secondary outcomes will be evaluated. Health economic analysis will also be undertaken. ETHICS AND DISSEMINATION: The ACCess study has been approved by the West of Scotland Research and ethics committee number 3 (20/WS/0178). Results will be published in open-access peer-reviewed journals within 12 months of completion of the trial. We will also present our findings at key national and international renal and anaesthetic meetings, and support dissemination of trial outcomes via renal patient groups. TRIAL REGISTRATION NUMBER: ISRCTN14153938. SPONSOR: NHS Greater Glasgow and Clyde GN19RE456, Protocol V.1.3 (8 May 2021), REC/IRAS ID: 290482.

Long-Term Functional Patency and Cost-Effectiveness of Arteriovenous Fistula Creation under Regional Anesthesia: a Randomized Controlled Trial.

BACKGROUND: Regional anesthesia improves short-term blood flow through arteriovenous fistulas (AVFs). We previously demonstrated that, compared with local anesthesia, regional anesthesia improves primary AVF patency at 3 months. METHODS: To study the effects of regional versus local anesthesia on longer-term AVF patency, we performed an observer-blinded randomized controlled trial at three university hospitals in Glasgow, United Kingdom. We randomly assigned 126 patients undergoing primary radiocephalic or brachiocephalic AVF creation to receive regional anesthesia (brachial plexus block; 0.5% L-bupivacaine and 1.5% lidocaine with epinephrine) or local anesthesia (0.5% L-bupivacaine and 1% lidocaine). This report includes findings on primary, functional, and secondary patency at 12 months; reinterventions; and additional access procedures (primary outcome measures were previously reported). We analyzed data by intention to treat, and also performed cost-effectiveness analyses. RESULTS: At 12 months, we found higher primary patency among patients receiving regional versus local anesthesia (50 of 63 [79%] versus 37 of 63 [59%] patients; odds ratio [OR], 2.7; 95% confidence interval [95% CI], 1.6 to 3.8; P=0.02) as well as higher functional patency (43 of 63 [68%] versus 31 of 63 [49%] patients; OR, 2.1; 95% CI, 1.5 to 2.7; P=0.008). In 12 months, 21 revisional procedures, 53 new AVFs, and 50 temporary dialysis catheters were required. Regional anesthesia resulted in net savings of £195.10 (US$237.36) per patient at 1 year, and an incremental cost-effectiveness ratio of approximately £12,900 (US$15,694.20) per quality-adjusted life years over a 5-year time horizon. Results were robust after extensive sensitivity and scenario analyses. CONCLUSIONS: Compared with local anesthesia, regional anesthesia significantly improved both primary and functional AVF patency at 1 year and is cost-effective. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Local Anaesthesia versus Regional Block for Arteriovenous Fistulae, NCT01706354.

How to set up a clinical trial.

Clinical trials are considered the gold-standard method for the evaluation of healthcare interventions. However, randomised control trials are complex to perform and many researchers, especially those in the early stages of their career, can find it challenging to know where to start set up, contribute to or lead a trial. This guide provides an introduction to trials and also practical advice to help potential investigators complete their clinical trial to time and to budget by signposting the pathway through the complex regulatory landscape. The authors draw on their own recent experiences of running clinical trials and provide tips and tricks for troubleshooting common problems encountered including trial design and documentation.

Phylogenetic analysis of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients.

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/ß-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.

Genome mining, isolation, chemical synthesis and biological evaluation of a novel lanthipeptide, tikitericin, from the extremophilic microorganism Thermogemmatispora strain T81.

Genome mining of the New Zealand extremophilic microorganism Thermogemmatispora strain T81 indicated the presence of biosynthetic machinery to produce several different peptidic natural products. Solid-phase culture of T81 led to the isolation of tikitericin 1, a new lanthipeptide characterised by four (methyl)lanthionine bridges. The mass-guided isolation and structural elucidation of tikitericin 1 is described together with its total synthesis via Fmoc-solid-phase peptide synthesis (SPPS). The key non-canonical (methyl)lanthionine residues were synthesised in solution phase via an improved synthetic route and subsequently assembled to construct the peptide backbone using Fmoc-SPPS. N-Terminal truncated analogues of tikitericin (2-5) were also prepared in order to evaluate the contribution of each sequential ring of the polycyclic lanthipeptide to the antibacterial activity.

The Role of Qutenza® (Topical Capsaicin 8%) in Treating Neuropathic Pain from Critical Ischemia in Patients with End-Stage Renal Disease: An Observational Cohort Study.

Objective: Current treatment strategies for painful critical ischemia in patients with end-stage renal disease (ESRD) are suboptimal. A drug that is non-renally excreted has minimal systemic absorption and does not require dose adjustment in renal failure is attractive. The aim of this study was to evaluate the safety and efficacy of Qutenza® (topical capsaicin 8%) for chronic neuropathic pain from critical ischemia in patients with ESRD. Design and Setting: A prospective cohort study was conducted in a single-center, university teaching hospital. Patients: Twenty patients with ESRD were treated with Qutenza® for neuropathic pain from critical limb ischemia. Methods: Patients were followed-up at 1, 6 and 12 weeks post-treatment. The primary end point was the difference in visual analog scale (VAS) between baseline and week 12. Secondary end points were Brief Pain Inventory questionnaire (BPI) scores, quality of life assessment (EQ-5D) and patient global impression of change (PGIC). Safety and tolerability data were also collected. The trial was prospectively registered with clinical trials databases (EudraCT: 2012-001586-32; NCT01704313). Results: There was significant reduction in VAS from baseline to week 12 (-20+/-7%; P = 0.02). There was a significant reduction in all seven domains of the BPI. Quality of life also improved at 12 weeks following treatment in two of the EQ-5D domains (mobility and pain). Qutenza® was well tolerated with no significant side effects in this patient cohort, which included 20% diabetics. Conclusions: In this small, observational study Qutenza® treatment has been shown to be effective and well-tolerated to treat neuropathic pain from critical ischemia in patients with ESRD.

A randomized controlled trial and cost-effectiveness analysis of early cannulation arteriovenous grafts versus tunneled central venous catheters in patients requiring urgent vascular access for hemodialysis.

OBJECTIVE: Early cannulation arteriovenous grafts (ecAVGs) are proposed as an alternative to tunneled central venous catheters (TCVCs) in patients requiring immediate vascular access for hemodialysis (HD). We compared bacteremia rates in patients treated with ecAVG and TCVC. METHODS: The study randomized 121 adult patients requiring urgent vascular access for HD in a 1:1 fashion to receive an ecAVG with or without (+/-) an arteriovenous fistula (AVF; n = 60) or TCVC+/-AVF (n = 61). Patients were excluded if they had active systemic sepsis, no anatomically suitable vessels, or an anticipated life expectancy <3 months. The primary end point was the culture-proven bacteremia rate at 6 months, with the trial powered to detect a reduction in bacteremia from 24% to 5% (α = .05, ß = .8). Secondary end points included thrombosis, reintervention, and mortality. A cost-effectiveness analysis was also performed. RESULTS: Culture-proven bacteremia developed in 10 patients (16.4%) in the TCVC arm ≤6 months compared with two (3.3%) in the ecAVG+/-AVF arm (risk ratio, 0.2; 95% confidence interval, 0.12-0.56; P = .02). Mortality was also higher in the TCVC+/-AVF cohort (16% [n = 10] vs 5% [n = 3]; risk ratio, 0.3; 95% CI, 0.08-0.45; P = .04). The difference in treatment cost between the two arms was not significant (£11,393 vs £9692; P = .24). CONCLUSIONS: Compared with TCVC+/-AVF, a strategy of ecAVG+/-AVF reduced the rate of culture-proven bacteremia and mortality in patients requiring urgent vascular access for HD. The strategy also proved to be cost-neutral.

A comparison of the effects of oral vs. intravenous hydration on subclinical acute kidney injury in living kidney donors: a protocol of a randomised controlled trial.

BACKGROUND: Optimal treatment for established renal failure is living donor kidney transplantation. However this pathway exposes healthy individuals to significant reduction in nephron mass via major surgical procedure. Laparoscopic donor nephrectomy is now the most common method for live donor transplantation, reducing both donor post-operative pain and recovery time. However this procedure exposes kidneys to additional haemodynamic stresses. It has been suggested that donor hydration-particularly the use of preoperative intravenous fluids-may counteract these stresses, reducing subclinical acute kidney injury and ultimately improving long-term renal function. This may be important in both preservation of donor renal function and recipient graft longevity. METHODS/DESIGN: A prospective single-centre single-blinded randomized controlled trial will be carried out to determine the effects of donor preoperative intravenous fluids. The primary outcome is donor subclinical acute kidney injury (defined as plasma NGAL, >153 ng/ml) on day 1 postoperatively. Secondary outcomes include intraoperative haemodynamics, recipient subclinical acute kidney injury, perioperative complications and donor sleep quality. Donors will be randomised into two groups: the intervention group will receive active pre-hydration consisting of three litres of intravenous Hartmann's solution between midnight and 8 am before morning kidney donation, while the control group will not receive this. Both groups will receive unlimited oral fluids until midnight, as is routine. Plasma NGAL will be measured at pre-specified perioperative time points, intraoperative haemodynamic data will be collected using non-invasive cardiac output monitoring and clinical notes will be used to obtain demographic and clinical data. The researcher will be blinded to the donor fluid hydration status. Blinded statistical analysis will be performed on an intention-to-treat basis. A prospective power calculation estimates a required sample size of 86 patients. DISCUSSION: This study will provide important data, as there is currently little evidence about the use of donor preoperative fluids in laparoscopic nephrectomy. It is hoped that the results obtained will guide future clinical practice. TRIAL REGISTRATION: This study has been approved by the West of Scotland Research Ethics Committee 3 (reference no. 14/WS/1160, 27 January 2015) and is registered with the International Standard Randomised Controlled Trial Number Register (reference no. ISRCTN10199225 , 20 April 2015).

Effect of regional versus local anaesthesia on outcome after arteriovenous fistula creation: a randomised controlled trial.

BACKGROUND: Arteriovenous fistulae are the optimum form of vascular access in end-stage renal failure. However, they have a high early failure rate. Regional compared with local anaesthesia results in greater vasodilatation and increases short-term blood flow. This study investigated whether regional compared with local anaesthesia improved medium-term arteriovenous fistula patency. METHODS: This observer-blinded, randomised controlled trial was done at three university hospitals in Glasgow, UK. Adults undergoing primary radiocephalic or brachiocephalic arteriovenous fistula creation were randomly assigned (1:1; in blocks of eight) using a computer-generated allocation system to receive either local anaesthesia (0·5% L-bupivacaine and 1% lidocaine injected subcutaneously) or regional (brachial plexus block [BPB]) anaesthesia (0·5% L-bupivacaine and 1·5% lidocaine with epinephrine). Patients were excluded if they were coagulopathic, had no suitable vessels, or had a previous failed ipsilateral fistula. The primary endpoint was arteriovenous fistula patency at 3 months. We analysed the data on an intention-to-treat basis. This study was registered with ClinicalTrials.gov (NCT01706354) and is complete. FINDINGS: Between Feb 6, 2013, and Dec 4, 2015, 163 patients were assessed for eligibility and 126 patients were randomly assigned to local anaesthesia (n=63) or BPB (n=63). All patients completed follow-up on an intention-to-treat basis. Primary patency at 3 months was higher in the BPB group than the local anaesthesia group (53 [84%] of 63 patients vs 39 [62%] of 63; odds ratio [OR] 3·3 [95% CI 1·4-7·6], p=0·005) and was greater in radiocephalic fistulae (20 [77%] of 26 patients vs 12 [48%] of 25; OR 3·6 [1·4-3·6], p=0·03). There were no significant adverse events related to the procedure. INTERPRETATION: Compared with local anaesthesia, BPB significantly improved 3 month primary patency rates for arteriovenous fistulae. FUNDING: Regional Anaesthesia UK, Darlinda's Charity for Renal Research.