Vanguard Multi-Centre Feasibility Trial to Determine if Buttonhole Versus Step Ladder Cannulation for High Dose Hemodialysis is Associated With Reduced Overall Cost
Phase: NA
Conditions: Renal Failure
Sponsor: Ottawa Hospital Research Institute

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Vanguard Multi-Centre Feasibility Trial to Determine if Buttonhole Versus Step-
Ladder Cannulation for Home Hemodialysis is Associated with Reduced  
Overall Cost 
 
Primary Objectives: To determine the feasibility of 1) randomizing patients to step-
ladder versus buttonhole cannulation techniques, and 2) coordinating the multiple 
Canadian sites that are required for the definitive study. 
Secondary Objectives: To determine 1) if buttonhole cannulation, compared to step-
ladder cannulation is associated with reduced training time for home hemodialysis 
patients, 2) if buttonhole cannulation, compared to step-ladder cannulation is associated 
with reduced overall cost, 3) if buttonhole cannulation, compared to step-ladder 
cannulation is associated with reduced complications (infection – local and systemic, 
radiologic/surgical interventions, re-trains for needle insertion difficulties, hematoma 
formation, aneurysm formation, missed insertions), 4) if buttonhole cannulation, 
compared to step-ladder cannulation is associated with reduced patient discomfort with 
needling for intensive home hemodialysis patients, and 5) to describe the overall patient 
population to help explain recruitment challenges 
 
Background 
 
High Dose Hemodialysis 
 
Patients treated for end stage renal disease (ESRD) with conventional hemodialysis have 
a shorter life expectancy and a poorer quality of life than the general population1. The 
intermittent nature of CHD has been hypothesized to contribute to the poor outcomes.  In 
an attempt to reduce morbidity and mortality for this patient population, a few novel 
therapeutic approaches have been undertaken. As an alternative to CHD, there are an 
increasing number of patients being treated with daily, or high dose hemodialysis.  With 
short daily hemodialysis, the frequency of dialysis is increased but the overall weekly 
dialysis time is usually equivalent to conventional hemodialysis (~12 hours). With 
nocturnal or extended hours hemodialysis, both the frequency and time with which 
patients undergo dialysis is usually increased.  Compared to conventional hemodialysis, 
high dose hemodialysis has been shown to enhance clearance of urea, β2-microglobulin,2 
and phosphate.3-6 Some patients are able to discontinue fluid, sodium, and phosphate 
restrictions (including phosphate binders).  The cardiovascular benefits of high dose 
include better control of blood pressure,7,8 with most patients no longer requiring anti-
hypertensive medication, regression of left-ventricular hypertrophy,4,6,9-11 increased 
ejection fraction,12 and an improved lipid profile.13 In many patients, anemia improves 
and erythropoietin requirements decrease.14 Many patients feel better, have a significantly 
improved quality of life, and some return to work.1 In addition, high dose hemodialysis 
has been shown to reduce overall cost in North American economic systems.15,16 
 
Vascular Access in Intensive Dialysis 
In spite of all of the potential benefits associated with home hemodialysis, there are 
significant concerns about vascular access complications. The increased frequency of 
dialysis access use may have differential effects depending on access type. For patients 

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who use a central venous catheter (CVC), the increased frequency of opening the CVC in 
order to connect the access to the bloodlines of the hemodialysis circuit may result in an 
increased risk of infection, air embolism or hemorrhage. In spite of this theoretical risk, a 
study of 33 patients pre/post conversion from conventional hemodialysis to nocturnal 
hemodialysis did not demonstrate an increased risk of infection. 17For patients with an 
arteriovenous fistula (AVF) or arteriovenous graft (AVG), the increased frequency of 
placing needles in the access may be associated with an increased risk of hematoma 
formation from missed needle sticks, aneurysms, infections and patient discomfort. This 
is supported by one systematic review of the literature in which the use of an AVF for 
more frequent dialysis appears to be associated with an increased risk of complications.18  
 
Buttonhole versus Stepladder Cannulation of an AVF 
In conventional hemodialysis, the AVF is recommended as the access of choice for 
hemodialysis secondary to a lower complication rate than CVCs and AVGs. However, 
the AVF may be associated with greater challenges for needling because of short 
segments of useable access or deeper location in the subcutaneous tissue of the arm than 
an AVG. There is also pain associated with placing the needles (compared to CVC use) 
that may have a negative impact on quality of life.  
The insertion of needles into an AVF has traditionally been via the step ladder or 
continuous site rotation technique. However, the buttonhole method was introduced in 
the 1970’s in an attempt to address some of the challenging issues associated with AVF 
accesses. 19In the buttonhole technique, a constant site is used for needle placement that 
ultimately results in a fibrous tract. Once the tract has formed blunt needles can be used 
instead of sharp needles for each treatment. The presence of a tract may simplify the 
needle insertion technique and lead to enhanced patient confidence with needle 
placement. Although no studies have reported training times in association with needle 
insertion technique, Pipkin et al have demonstrated a mean reduction in training time for 
home hemodialysis patients of 5 days when a central venous catheter was used for an 
access compared to an AVF.20 It is reasonable to assume that well established buttonholes 
may also lead to a similar reduction in training times. Other reported benefits of 
buttonhole cannulation include less painful needling,21-24 fewer needle infiltrations,19,24,25 
fewer interventions26 and a reduction in aneurysm size.23  While earlier studies 
demonstrated a reduction in pain with buttonhole needling, more recent studies show 
either no reduction in pain,27 ,28 or even an increase in pain.26 However, the effect of 
frequency of use on the maintenance of the buttonhole and the perception of pain has not 
been explored. Importantly however, there has also been increasing concern about the 
potential for an increased risk of infection using the buttonhole cannulation technique 
with estimates of Staphylococcus aureus (S. aureus) bacteremia for patients receiving 
high dose dialysis between 0.15 to 0.60 episodes per 1000 patient-days across 4 
studies.29-32 In an indirect comparison between high dose home hemodialysis with 
buttonhole cannulation versus in-centre conventional hemodialysis with rope-ladder 
cannulation, the relative risk for bacteremia ranged between 30 to 120.  Importantly, 
S.aureus bacteremia was associated with devastating consequences, including septic 
arthritis, septic pulmonary emboli, vertebral osteomyelitis, and death in a single centre’s 
experience.33 In one small study, the risk of infection associated with buttonhole 

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cannulation was prevented by the application of topical mupirocin at the buttonhole sites 
post hemodialysis.  
 
Differences between Conventional In-Centre and Home Hemodialysis 
Although ease of cannulation is important in-centre, it is even more important for patients 
at home. It is unclear if the potential ease of use of buttonhole cannulation might lead to 
enhanced home hemodialysis recruitment rates and reduced training time. The ease of use 
of CVCs likely contributed to the decreased training time that was required for patients 
with this type of access in the Frequent Hemodialysis Network Trial. There is emerging 
controversy about reduced pain on needle insertion with buttonhole cannulation in centre. 
However, it is unclear is using the buttonholes more frequently might result in reduced 
cannulation pain secondary to ‘enhanced’ maintenance of the fibrous tract.  Lastly, for 
patients who are treated in-centre, needles are typically inserted by skilled allied health 
team members. At home, needles are inserted by the patient or a family member helper 
who must be trained to perform home hemodialysis. It is unclear if allied health team 
members are more likely to follow strict rules for cleanliness compared to patients at 
home such that infection risks might be less in-centre. Also, the enhanced frequency of 
use of the buttonholes for high dose hemodialysis might be associated with an increased 
risk of infection.  
 
Summary and Conclusions 
There is increasing interest in high dose home hemodialysis therapies. Although both 
needle cannulation techniques have been used for home hemodialysis, the relative 
benefits and risks of the two techniques have never been explored in a randomized 
controlled trial. The potential advantages of buttonhole cannulation for this patient 
population may be enhanced recruitment, reduced training time, reduced aneurysm 
formation and a reduced number of interventions. The reduction in training time may 
result in significant savings to the hospitals in which reimbursed training days are fixed. 
The benefits may be offset by the potential for an increased risk of infection. However, 
the potential benefits and risks of buttonhole cannulation versus step-ladder cannulation 
remain speculative as they have not been studied in a rigorous prospective trial of home 
hemodialysis patients treated with high dose hemodialysis.  
 
Study Design: The proposed 12 month vanguard study will be a randomized controlled 
trial of patients training for home hemodialysis. The primary outcome for the proposed 
study is feasibility to recruit to the two different needle cannulation arms and 
coordination of the study centres. Additionally, demographic data will be retrospectively 
collected on patients who trained to do home hemodialysis, but were not eligible for the 
study to help explain recruitment challenges.   
 
Patient Population: 
Inclusion Criteria 
The following inclusion criteria will be used: 1. Adult patients > 18 years old, 2. Training 
for home hemodialysis using self cannulation, 3. Returning to train to use an AVF (i.e. 
went home using a CVC or another access that has failed), 4. Able to give informed 

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consent, 5. Arteriovenous fistula (patients with segments of grafts that are not at the sites 
of needle insertion may be included), and 6. Life expectancy of greater than 12 months 
Exclusion Criteria 
The following exclusion criteria will be used: 1. Potential to be lost from the program 
within 12 months of training (planned living donor transplant, transfer to PD or move 
from training centre catchment area), 2. Short segments or aneurysms within the AVF 
that the attending nephrologist believes require buttonhole cannulation, 3. Mechanical 
heart valves, 4. Patients who require intradermal lidocaine for needle insertion 
 
Study Overview 
After obtaining informed consent, basic demographic data will be collected including age, 
sex, cause of end stage renal disease, arteriovenous access history [date of creation, 
previous interventions (angioplasties, surgical revisions), previous infections] and 
comorbidity information to calculate the Charlson comorbidity index. Demographic data 
will also be retrospectively collected on patients who were training for home 
hemodialysis but were not eligible to participate in the study.  
 
All eligible patients will be randomized to either step ladder or buttonhole cannulation 
technique for needle insertion. Randomization will be determined via a computer 
generated randomization code with stratification by site and AVF type (incident vs. 
prevalent). The group assignment will be kept in sealed opaque envelopes and provided 
to sites via the coordinating centre at the time of study consent. Only the investigators 
will be aware of the training time as an objective of the study as the intervention cannot 
be blinded and the outcome is potentially influenced by factors other than needle 
insertion technique. For consent and the remainder of the health team; the purpose of the 
study will be to determine feasibility, infection rates and other complications associated 
with the two different needle insertion techniques. Each Research Ethics Board will need 
to approve that one of the study objectives will be concealed.  
 
Data collection forms will be developed with the assistance of the Ottawa Hospital 
Methods Centre and pilot tested at 2 sites (Ottawa and University Health Network) prior 
to the creation of an electronic data capture form to be used by all participating sites. The 
amount of time required to consent patients, complete the case report forms and follow 
each patient for the complication outcomes will be documented at these two sites so that 
this data can be used to inform the definitive trial budget.  
 
After ensuring that the case report forms and access documentation tool are useable and 
all necessary information is being collected, the remaining programs will begin to recruit 
patients. Each program will be responsible for keeping a log of all patients who are 
training for home hemodialysis and the proportion of patients who are candidates for the 
study. Of the patients that are candidates for the study, the number of patients who are 
randomized to the study will be tracked. Reasons for not participating in the study for all 
potential candidates will be documented and reviewed at quarterly meetings. If themes 
are identified that are limiting enrollment, solutions will be proposed by the investigators 
and implemented if possible. 
 

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Needle Insertion Techniques  
Step ladder insertion technique: The AVF site will be cleaned with 2% 
chlorhexidine/alcohol 70% prior to needle insertion. If the patient develops contact 
dermatitis, the AVF site will be cleansed with 2% cholorhexidine, 70% alcohol, povidone 
iodine or antibacterial soap alone. Sites will be rotated with needles placed at least 2-
3cms between needle tips.  
Buttonhole insertion technique: The AVF site will be cleaned as above except cleansing 
will occur before and after buttonhole scab removal. A minimum of 2 buttonholes will be 
developed for patients undergoing double needle hemodialysis (1 for single needle) by a 
nurse or patient (at the discretion of the health care team) trained in the technique. 
Buttonhole sites will be created at a 20-30 degree angle at least 3 cm from the arterial or 
venous anastomosis. Once the buttonhole is established with sharp needles, blunt needles 
will be used. At this time, the patient will be instructed on needle insertion technique if 
they were not taught to develop the buttonholes initially. Scabs will be removed from the 
buttonholes either with an alcohol or saline soaked gauze; the use of  needles or tweezers 
to remove scabs will be discouraged.. Post hemodialysis, mupirocin (or other suitable 
antimicrobial cream if patient develops contact dermatitis/allergy, for example: 
polysporin, betadine ointment or PHMB antimicrobial dressings) will be applied to the 
buttonhole sites to reduce the risk of infection.  
 
Time to Train 
Patients will be trained according to usual home dialysis unit policies with the exception 
of the needle insertion protocol. Any difficulties with training needle insertion will be 
documented by the nurse educator. The time required to teach proficiency in self 
cannulation will be documented (the number of days required for the patient to 
competently place their own needles without the assistance of the dialysis nurse). Total 
training time will be the numbers of days required from start of training to discharge to 
home. Any missed days secondary to statutory holidays, appointments or other illness 
unrelated to access needle insertion technique will not be included in the training days 
calculation. If a patient has to return to the home dialysis unit to develop a new 
buttonhole site, the training time will also be documented and added to the total training 
time.  
 
AVF Access Complications 
The home hemodialysis run sheet will be modified so that the patient can record any 
instances of hematoma formation (obvious bruising at the arteriovenous site that occurs at 
the time of needle insertion or withdrawal) or missed needle sticks (unable to use the 
needle for dialysis). For buttonhole cannulation, the need to use a sharp needle instead of 
the usual blunt needle will be considered a missed needle stick even if a separate needle 
insertion site is not required. Patients will be instructed to come to the home dialysis unit 
if they notice any localized signs of infection over the AVF including heat, erythema, 
purulent drainage or induration. A swab will be sent for gram stain, culture and 
sensitivity; infection will be diagnosed if neutrophils are present with cultured bacteria. 
Additionally patients will be asked to contact the unit and present themselves to the 
nearest emergency department if they develop fever, chills and/or hypotension with the 
hemodialysis treatment. An access related bacteremia will be defined using CDC criteria 

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(at least one of the following:  1) Patient has a recognized pathogen cultured from one or 
more blood cultures and the pathogen is not related to an infection at another site or 2) 
patient has fever, chills, and/or hypotension as well as positive laboratory cultures from 
two or more blood samples drawn on separate occasions which are not related to 
infection at another site and do not reflect contamination). As the most common pathogen 
is S. aureus, all patients with S. aureus related bacteremia will be monitored for 
metastatic complications including an echocardiogram at the discretion of the treatment 
center. Access interventions including angioplasties and surgical revisions will be 
documented. The vascular access coordinator, or similarly trained individual, will 
document the presence of aneurysms at the start and completion of the study. A 
standardized tool for assessment of the number of aneurysms, size and potential risk of 
rupture (thinness of skin) will be developed with the assistance of skilled vascular access 
coordinators (access documentation tool).  
 
Costs of Vascular Access 
Any additional days of training and any days required for re-training will be included in 
the overall cost. Any differences in the cost of the blunt versus sharp needles and the 
mupirocin for buttonhole cannulation will be included in the overall cost. Treatment for 
infection including antibiotics and hospitalizations will be included and costed according 
to established principles. Similarly, the cost associated with any required angiogram 
(leading to an angioplasty), angioplasty or surgical revision will be included.  
 
Visual Analogue Scale – Pain with Needling (Appendix 1) 
All patients will continue (or start) with the step ladder insertion technique for the first 2 
to 3 days at which time they will use the validated 10 cm visual analogue scale to rate the 
pain they experience with needle insertion. The visual analogue scale will be repeated at 
2 additional time points – at the end of training and approximately 2 months after 
graduating home hemodialysis training. As many of the programs train 3 days per week, 
the additional time point is to capture the potential differences in perceived needling pain 
with increased frequency of needle insertion. It is unclear if buttonholes are easier to 
maintain when used more than 3 days per week as this may be associated with less pain 
on needle insertion. Topical anesthetics will not be withheld during assessments of pain 
with the visual analogue scale but the requirement for use will be documented.  
 
Sample Size Calculation 
There are a limited number of patients who start home HD each year in Canada. If we are 
unable to get at achieve at least 70% enrollment in the pilot study – it is very unlikely that 
we will be able to successfully undertake a study with a larger sample size. For the 
purposes of the feasibility pilot, the first 2 centres (Ottawa and University Health 
Network) will recruit participants for 18 months with the remaining centre’s participating 
for 12 months. All patients who are eligible for the study will be approached for 
recruitment. Our goal is to demonstrate that we can successfully recruit. For the definitive 
study to explore the differences in training time between the two needle cannulation 
techniques: The mean number of training days for patients with an AVF in the FHN 
studies was 27.7 with a standard deviation of 10.4 (20). This was reduced by 5 days for 
patients using a central venous catheter. Assuming that a buttonhole cannulation would 

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have a similar impact on training time, 69 patients per groups would give us 80% power 
to detect this difference. The number required in the trial increases to 107 if the 
difference is 4 days.  
 
Analysis 
For the purposes of the pilot study, basic demographic characteristics of the included and 
excluded patients will be described using appropriate descriptive statistics. This data will 
be retrospectively collected on patients who were not enrolled in the study.  The percent 
of qualified patients enrolled in the study for the pilot study to be successful will be 
≥70%. The secondary outcomes will be analyzed on an intent to treat basis upon 
completion of the main study assuming that this trial is feasible. The comparison of mean 
training times will be done with an un-paired t-test. A linear regression analysis will also 
be undertaken to examine predictors of training time including age, sex and Charlson 
comorbidity score in addition to needle insertion technique. Any differences in pain 
scores depending of frequency of cannulation will be explored within cannulation 
techniques. If no differences exist by frequency of cannulation, the data will be combined 
and the median pain scores will be assessed with a Wilcoxin rank sum test. The different 
types of complications and costs will be categorized and the overall mean differences will 
be assessed with an unpaired t-test. Any differences in outcomes by frequency of 
cannulation will also be explored within each of the secondary outcomes.  
 
For patients who return to train on cannulation technique (started home HD with a CVC 
or other access that failed); their data will not be included in overall training time but all 
other study outcomes will be tracked and included in the analysis infections and 
complications.  
 
The retrospectively collected demographic data will be analyzed in order to describe the 
patient population.  
 
Data Safety Monitoring Board 
 
Drs. Hiremath and Ramsay in addition to Paula Fraser (vascular access coordinator) have 
agreed to monitor the outcomes of this study. If we detect infection rates that are 
comparable to or greater to the benchmark for central venous catheters as adopted by the 
Ottawa Hospital - the study will be stopped (external benchmark bacteremia rate of 4.6 
per 100 patient months, Nephrology News and Issues 2005, 37-43) 
 
Study Investigators 
The definitive study will be part of the Canadian Intensive Hemodialysis Physician 
Group with representation from across Canada. The vanguard study will be collecting 
information from sites in Ottawa (Dr. Deborah Zimmerman), Toronto (Drs. Gihad 
Nesrallah, Philip McFarlane and Christopher Chan), Calgary (Dr. Jennifer MacRae) and 
Vancouver (Dr. Michael Copland). All investigators have experience in high dose 
hemodialysis and clinical investigation. Dr. McFarlane has additional experience in 
economic analysis and Dr. MacRae has just published a study of buttonhole versus 
stepladder cannulation in the in-centre conventional hemodialysis population. All 

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together, these sites train approximately 70 patients for high dose hemodialysis per year 
which will provide an adequate number of participants to ensure the success of this pilot 
study within the 2 years allotted for this grant. If no changes to the protocol are required, 
feasibility clearly established and sample size achievable, the pilot study data will be 
retained for the definitive trial.  
 

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Appendix 2 
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Mucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur R, Pierratos A. Control of 
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Mohr PE, Neumann PJ, Franco SJ, Marainen J, Lockridge R, Ting G. The case for 
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16. 
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van Loon MM, Goovaerts T, Kessels AGH, van der Sande FM, Tordoir JHM. 
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Figueiredo AE, Viegas A, Monteiro M, Poli-de-Figueiredo CE. Research into 
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28. 
Struthers J, Allan A, Peel RK, Lambie SH. Buttonhole needling of ateriovenous 
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Muir CA KS, Hawley CM, Gallagher MP, Snelling P, Jardine MJ. . Buttonhole 
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Nov. 8-13, 2011; Philadelphia, PA. 

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31. 
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Fistulae: Long-Term Safety and the Efficacy of Prophylactic Antimicrobial 
Cream. Abstract SA-PO2501 at: American Society of Nephrology 2009 Meeting; 
Oct. 27-Nov. 1, 2009; San Diego, CA.  . 
32. 
Van Eps CL, Jones M, Ng T, et al. The impact of extended-hours home 
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septic events related to dialysis access. Hemodial Int. Oct 2010;14(4):451-463. 
33. 
Nesrallah GE, Cuerden M, Wong JH, Pierratos A. Staphylococcus aureus 
bacteremia and buttonhole cannulation: long-term safety and efficacy of 
mupirocin prophylaxis. Clinical journal of the American Society of Nephrology : 
CJASN. Jun 2010;5(6):1047-1053.