Archives of Academic Emergency Medicine. 2023; 11(1): e39 REV I EW ART I C L E Needle Direction and Distance of Arteriovenous Fistula Cannulation in Hemodialysis Adequacy; a Systematic Re- view and Meta-Analysis Samad Karkhah1,2, Majid Pourshaikhian3, Pooyan Ghorbani Vajargah1,2, Morteza Zaboli Mahdiabadi4, Amirabbas Mollaei1,2, Saman Maroufizadeh5, Seyed Javad Hosseini6, Joseph Osuji7, Mohammad Taghi Moghadamnia3∗ 1. Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran. 2. Burn and Regenerative Medicine Research Center, Guilan University of Medical Sciences, Rasht, Iran. 3. Department of Prehospital Emergency Medicine, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran. 4. Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 5. Department of Biostatistics and Epidemiology, School of Health, Guilan University of Medical Sciences, Rasht, Iran. 6. Department of Nursing, Esfarayen Faculty of Medical Sciences, Esfarayen, Iran. 7. School of Nursing and Midwifery, Faculty of Health, Community, and Education, Mount Royal University, Calgary, Ab, Canada. Received: March 2023; Accepted: April 2023; Published online: 20 May 2023 Abstract: Introduction: This systematic review and meta-analysis aimed to summarize the evidence regarding the impact of nee- dle direction and distance of arteriovenous fistula (AVF) cannulation on KT/V (where k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea) and access recirculation (AR) as hemodialysis (HD) ad- equacy criteria. Methods: A comprehensive systematic search was performed on international and domestic electronic databases from the earliest to June 4, 2022 using keywords. Analysis was performed in STATA software v.14. Results: Three randomized control trials (RCTs) and four non-RCT articles were included in the final review. Six studies reported the effects of direction, while four mentioned the effects of distances of AVF cannulation on outcomes of HD adequacy based on KT/V or AR. Results of three non-RCT studies showed that retrograde direction decreased KT/V more than an- tegrade direction (ES: 0.44, 95% CI: -0.38 to 1.27). Two non-RCT studies showed that antegrade decreased AR compared to the retrograde direction (ES: -0.64, 95%CI: -1.94 to 0.67). However, the results of two RCTs indicated uncertainty about this issue. Two of the four studies suggested that a distance of 5 cm or more in arterial and venous needles had greater adequacy than a distance of less than 5 cm. However, other studies did not confirm this finding. Conclusion: Overall comparison of the results qualitatively and quantitatively indicated uncertainty about the effects of direction and dis- tance of AVF cannulation on HD adequacy outcomes. More studies with high-quality designs, such as RCTs, are required to better understand and adjudicate the effects of needle direction and distance of AVF cannulation on HD adequacy outcomes. Keywords: Vascular Access Devices; Arteriovenous Fistula; Catheterization; Renal Dialysis Cite this article as: Karkhah S, Pourshaikhian M, Ghorbani Vajargah P, Zaboli Mahdiabadi M, et al. Needle Direction and Distance of Arte- riovenous Fistula Cannulation in Hemodialysis Adequacy; a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2023; 11(1): e39. https://doi.org/10.22037/aaem.v11i1.1943. ∗Corresponding Author: Mohammad Taghi Moghadamnia; Department of Prehospital Emergency Medicine, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran. Email: moghadamnia@gums.ac.ir, Tel: +989113312939, ORCID: https://orcid.org/0000-0002-3380-5142. 1. Introduction As chronic renal failure progresses to end-stage renal dis- ease (ESRD), maintaining the quality of life and survival de- pend on the effectiveness of kidney replacement therapies (KRT), including hemodialysis (HD), peritoneal dialysis, and kidney transplantation (1). It was estimated that 4.9-9.7 mil- lion people required KRT in 2010 (2). The main objective of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 2 these treatments (HD or kidney transplantation) is to reduce life-threatening consequences and ultimately reduce deaths from uremia (3). Transplantation is superior to HD in im- proving quality of life, ensuring more prolonged survival, and lowering costs. However, HD is widely used in cases where transplantation is impossible and as a maintenance KRT (1, 4). HD accounts for 89% of treatments for ESRD patients world- wide (5). Adequate HD requires reliable vascular access (VA). If proper VA is not possible, the consequence will be pro- longed hospitalisation and increased costs (6). There are three types of VA for HD: arteriovenous fistulas (AVFs), ar- teriovenous grafts, and central venous catheters (7). AVF is the optimal method for VA due to its fewer complications, re- duced mortality rate, and increased durability compared to other VA types (8). For each HD, two needles are used to can- nulate the fistula (9). The arterial needle is responsible for drawing blood from the patient, while the venous needle is used to return the purified blood (10). In the usual approach, the arterial needle is placed at least 3 cm from the anastomo- sis site with the flow towards the end of the limb (retrograde) or heart (antegrade) and should be at least 5 cm away from the venous needle (11). Proper distance and direction of nee- dles inserted into the AVF can reduce recirculation and thus, increase HD quality (8, 11). Proper needle placement, prevents increased frequency or duration of HD, which puts patients at a lower risk of infec- tions and incurs increased costs (12). HD access recirculation (AR), in any case, reduces the quality of HD (13). Therefore, AR measurement can be considered an acceptable method for evaluating the quality of HD (14). AR is detected in HD when dialyzed blood returns to the dialysate through an ar- terial needle instead of entering the systemic circulation af- ter returning by the venous needle (15). Various factors can cause AR, including improper needle insertion, fistula steno- sis, and mechanical stenosis at the end of the vein (16). There are conflicting findings on the effect of the direction and distance of needles on the quality of HD. A study by Lim et al. showed no significant difference between the antegrade and retrograde cannulation methods and their needle dis- tance regarding the amount of AR (17). On the other hand, the results of another study by Vahedi et al. showed that AR in antegrade cannulation and a 3 cm needle distance was signif- icantly higher than in a retrograde manner with a 6 cm needle distance (13). Therefore, given the importance of the subject and the contradictory findings in this regard, this systematic review and meta-analysis aimed to summarize the evidence regarding the impact of needle direction and distance of AVF cannulation on HD adequacy. 2. Methods 2.1. Study registration and reporting The present systematic review and meta-analysis was con- ducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (18). How- ever, this review study has not been registered in the interna- tional prospective register of systematic reviews (PROSPERO) database. 2.2. Patient/population, intervention, compari- son, and outcomes (PICO) framework The PICO framework was used to clarify the purpose of the study. Accordingly, population (articles in which patients with AVF cannulation were examined), intervention (studies that compared needle direction and distance of AVF cannu- lation), and comparison (studies that had control or placebo groups to compare with the intervention groups), and finally, outcome (studies that measured the adequacy of HD based on KT/V and AR in relation to the insertion of the catheter in the AVF), were considered when including studies in the systematic review and meta-analysis. 2.3. Search strategy A comprehensive systematic search was performed on inter- national electronic databases such as Scopus, PubMed, Web of Science, and Iranian electronic databases such as Iran- medex, and Scientific Information Database (SID) with key- words extracted from Medical Subject Headings such as "Vas- cular access", "Arteriovenous fistula", "Graft", "Catheteriza- tions", "Puncture”, “Cannulation”, “Hemodialysis”, “Dialysis adequacy”, and “Recirculation” from the earliest to June 4, 2022. For example, the search strategy in PubMed/MEDLINE database included such search terms as ((“Vascular access”) OR (“Arteriovenous fistula”) OR (“Graft”) OR (“Catheteriza- tions”) OR (“Puncture”) OR (“Cannulation”) OR (“Needle dis- tance”) OR (“Needle direction”)) AND ((“Hemodialysis”) OR (“Renal dialysis”) OR (“HD”)) AND ((“Renal circulation”) OR (“dialysis adequacy”) OR (“recirculation”)). Keywords were combined with Boolean operators "AND" and "OR". Simi- lar to the method mentioned in the keyword search, Persian equivalents of the words were searched in Iranian electronic databases. The search was performed by two researchers, in- dependently. Items such as expert opinions, conference pre- sentations, dissertations, research and committee reports, and ongoing research, known as the gray literature, were not included in this systematic review. Gray literature includes articles produced in print and electronic formats but not peer-reviewed or evaluated by a commercial publisher (19). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e39 2.4. Inclusion and exclusion criteria RCTs and non-RCT studies in English and Persian, focusing on the effect of direction of AVF cannulation or needle dis- tance on HD adequacies such as kt/v, Urea Reduction Ratio (URR), and recirculation in the HD patients were included in this study. Letters to the editor, case reports, qualitative stud- ies, and reviews were excluded. 2.5. Study selection Data management was performed using EndNote 8X soft- ware. Two researchers independently evaluated the eligibil- ity of studies for inclusion based on pre-determined inclu- sion and exclusion criteria. Studies included in this review were selected after eliminating duplicates, evaluating titles and abstracts, and reviewing the full texts of the selected ar- ticles. A third researcher resolved any differences and con- tradictions between the other two researchers. Finally, the resource list was evaluated manually to prevent data loss. 2.6. Data extraction and quality assessment The Joanna Briggs Institute ( JBI) critical appraisal checklist was used to assess the quality of randomized control trials (RCTs) and non-RCTs studies (20). This tool assesses the internal validity, the similarity of participants of compared groups, the reliability of outcomes measured, and the appro- priateness of statistical analysis of RCT and non-RCT studies in 13 and 9 items, respectively. In this systematic review and meta-analysis, researchers extracted information including first author name, year of publication, location, design, sam- ple size, type of intervention, duration of the study, dura- tion of intervention and follow-up, male/female ratio, age, type of control group, tool characteristics, specific statistical tests, and key results of studies. The quality of the studies in this systematic review and meta-analysis was evaluated by two researchers, separately, using a three-point reading range that included "yes" (score 1), "no" (score 2), and "not applicable / not clear" (score 0) (20). The quality assessment levels of the studies in the JBI checklists were good (≥8), fair (6-7), and poor (≤5) (21). 2.7. HD adequacy assessment techniques 2.7.1. KT/V KT/V, where K is the dialyzer urea clearance (expressed in liters per hour), T is the duration of dialysis (expressed in hours), and V is the volume of distribution of urea, is a di- mensionless ratio that represents fractional urea clearance (expressed in liters) (22). A level less than 0.8 indicates in- sufficient HD (23). 2.7.2. AR Blood is typically pumped from the dialysis access at 300 to 500 cc/min during HD. A failing AV access can significantly reduce flow to less than the HD machine’s blood pump rate. This situation can result in some dialyzed blood exiting the dialyzer through the venous needle and then reentering the dialyzer through the arterial side to support the extracorpo- real blood flow rate set by the blood pump. This condition is known as AR (24, 25). 2.7.3. URR Another method of measuring HD adequacy is URR. This method is calculated using the formula (pre-urea – post- urea/pre-urea) in HD (26). The acceptable level of URR is 65% and above (23). A URR of less than 65% is linked to higher patient morbidity and mortality. The mortality rate was observed to drop by up to 11% for every 5% rise in URR (27). 2.7.4. Ultrasound-based technique The ultrasound dilution (USD) method measures access flow (Qa) during HD. The advantages of the USD technique in- clude being easy to use and providing an immediate re- sponse. Qa is measured through USD using the formula (Qa=Qb(1-r/r)), where Qb is the dialyzer blood flow rate and r is the fraction of recirculated blood entering the dialyzer (28). 2.8. Statistical analysis Analysis was performed using STATA software v.14. Hetero- geneity was measured using I2 statistic. 0% to 40% was con- sidered unimportant; 30% to 60%: may represent moderate heterogeneity; 50% to 90% may represent substantial hetero- geneity; and 75% to 100% considerable heterogeneity. Due to the considerable heterogeneity between studies, the ran- dom effect model and inverse-variance method were used to estimate the mean difference. Since RCTs and non-RCT stud- ies have different weights in the evidence hierarchy pyramid, each should be analysed separately. A confidence interval of 95% was considered a significant level. Pooled effect size re- lated to the effects of needle direction on the KT/V and AR was reported on a forest plot. 2.9. Publication bias Although the number of effect sizes related to the effect of needle direction on the KT/V and AR was less than 10, a pub- lication bias test was performed. The funnel plot and result of the Egger’s test were used to assess publication bias. 2.10. Sensitivity analysis Sensitivity analysis was performed to determine the pooled effect sizes related to the effect of needle direction on the KT/V and AR. 2.11. Certainty of evidence The certainty of the evidence was assessed through the Grade of Recommendation, Assessment, Development, and Evalu- ation (GRADE) approach. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 4 Table 1: Basic characteristics of the studies included in this systematic review First Au- thor/year Location Study characteris- tics* Male/ Female ratio (%) Age (year) mean(SD) Control group Tool charac- teristics Specific statistical tests Key results JBI Score Dias et al., 2008 (29) Brazil 1. Quasi- experimental 2. 174 3. Antegrade vs. ret- rograde cannulation with distance be- tween needles more than 5 cm vs. less than 5 cm 4. N/A 5. 4 hours 6. 0 59.77/ 40.23 51.90 (15.57) N/A • Kt/V • AR • ANOVA • Pearson linear cor- relation • Kt/V in the group of ret- rograde cannulations with 5 cm or more distance be- tween needles was higher than in other groups (except temporary double lumen catheter group) (P<0.05). • AR in the group of ret- rograde cannulations with 5 cm or more dis- tance between needles was lower than in other groups (P<0.05). Fair Ozmen et al., 2008 (30) Turkey 1. Quasi- experimental 2. 22 3. Antegrade vs. ret- rograde cannulation 4. 8 weeks 5. N/A 6. 0 N/A N/A N/A Kt/V T-test There was no significant dif- ference between antegrade and retrograde cannulation in the amount of Kt / V (P=0.123). Fair Rothera et al., 2011 (10) UK 1. RCT (Crossover) 2. 12 3. Cannulation with distance between needles 5 cm vs. 2.5 cm 4. N/A 5. N/A 6. 0 N/A N/A The distance between the two needles in five consecutive HD sessions was 5 cm in half of the participants and 2.5 cm in the same number of HD patients. • AR • Blood access flow rate • EID • Kol- mogorov– Smirnov normality test • Shapiro– Wilk nor- mality test • Paired t- test • The blood access flow rate was significantly higher when the distance between the two needles was 2.5 cm than when the distance be- tween the two needles was 5 cm (P=0.014). • There were no significant differ- ences between 2.5 and 5 cm needle distances in the amount of EID (P=0.139). Good Reyes, 2016 (31) Philippines1. RCT 2. 20 (10/10) 3. Antegrade vs. ret- rograde cannulation 4. N/A 5. N/A 6. 0 N/A N/A Arterial needles in AVFs were implanted in this group as antegrade. • URR • Kt/V • AR N/A • The URR in antegrade can- nulation was significantly higher than in retrograde cannulation (P<0.05). • The Kt/V in antegrade can- nulation was significantly higher than in retrograde cannulation (P<0.05). • There was no signifi- cant difference between antegrade and retrograde cannulation in the amount of AR (P>0.05). Good Elias et al., 2018 (11) France 1. Quasi- experimental 2. 14 3. Antegrade vs. ret- rograde cannulation in distance between needles 2.5 cm 4. N/A 5. N/A 6. 0 57.14/42.86 62.30 (15.57) Participants underwent HD three times with arterial needles in antegrade cannulation and then with arterial needles in retrograde cannulation. • Kt/V • AR • Non- paramet- ric paired test • Signed rank test • There was no significant difference between the an- tegrade and retrograde can- nulation with a 2.5 cm dis- tance between needles in the amount of Kt/V (P=0.20). • There was no significant difference between the an- tegrade and retrograde can- nulation with a 2.5 cm dis- tance between needles in the amount of AR (P>0.05). Fair This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e39 Table 1: Basic characteristics of the studies included in this systematic review First Au- thor/year Location Study characteris- tics* Male/ Female ratio (%) Age (year) mean(SD) Control group Tool charac- teristics Specific statistical tests Key results JBI Score Lim et al., 2018 (17) South Korea 1. Quasi- experimental 2. 30 7. Antegrade vs. retrograde cannu- lation with distance between needles 7 cm vs. 5 cm 4. 3 weeks 5. N/A 6. 0 43.33/56.67 55.50 (13.21) N/A AR ANOVA There was no significant dif- ference between the ante- grade and retrograde can- nulation and their needle distance in the amount of AR (P=1.00). Fair Vahedi et al., 2018 (13) Iran 1. RCT 2. 22 8. Antegrade vs. retrograde cannu- lation with distance between needles 3 cm vs. 6 cm 4. N/A 5. 4 hours 6. 0 54.55/45.45 53.00 (16.75) N/A AR • Gen- eralized esti- mating equations • Odds ra- tio The AR in antegrade can- nulation and 3 cm nee- dles distance was signifi- cantly higher than in retro- grade manner and 6 cm nee- dles distance (P<0.05). Good RCT: Randomized clinical trial; HD: Hemodialysis; AR: Access recirculation; EID: Effective ionic dialysance; URR: Urea reduction rate; ANOVA: Analysis of variance; JBI: Joanna Briggs Institute; Kt/V: k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea; AVF: arteriovenous fistula; N/A: not available. *:1. Design; 2. Sample Size (I/C); 3. Intervention; 4. Duration of study; 5. Duration of intervention; 6. Duration of follow-up. 3. Results 3.1. Study selection As shown in figure 1, after a thorough search of electronic databases, 2,228 articles were obtained. After deleting 402 duplicate articles, 1,826 articles remained. After reviewing the titles and abstracts of the articles, 1,634 articles were ex- cluded from the study due to discrepancies with the research purpose. Then another 126 articles were excluded due to their non-experimental design. Full-text evaluation of the re- maining 56 articles led to the elimination of another thirty- four due to poor design and results. Another fifteen articles were excluded due to a lack of appro- priate information. Finally, this systematic review and meta- analysis utilized seven studies (10, 11, 13, 17, 29-31). 3.2. Study characteristics As mentioned in tables 1 & 2, a total of 294 HD patients en- tered this systematic review and meta-analysis in seven stud- ies (10, 11, 13, 17, 29-31). Their mean age was 55.67 (SD = 15.27) years. 53.69% of the patients were male, and 96.60% were in the intervention group. Four studies (11, 17, 29, 30) had non-RCT, and three (10, 13, 31) had RCT designs. Of the studies in this systematic review, two (17, 30) reported an av- erage study duration of 5.5 weeks. Two studies (13, 29) also reported a duration of intervention that averaged 4 hours. To assess HD adequacy, six studies (10, 11, 13, 17, 29, 31) used AR, 4 articles (11, 29-31) used KT/V, one study (10) used blood access flow rate, while one other study (10) used effective ionic dialysance (EID). Also, one study (31) used urea reduc- tion rate (URR). The studies included in this review were con- ducted in Brazil (29), France (11), Iran (13), the Philippines (31), South Korea (17), Turkey (30), and the UK (10). Three studies (10, 11, 31) had control groups. 3.3. Methodological Quality assessment of eligi- ble studies As shown in figures 2 and 3, of the seven studies (10, 11, 13, 17, 29-31), two (10, 11) had a good quality level, while five (13, 17, 29-31) had an acceptable quality level. 3.4. Effect of needle direction in AVF cannulation on HD adequacy based on KT/V Four studies (11, 29-31) (one RCT (31) and three non-RCTs (11, 29, 30)) reported the effects of direction on HD adequacy based on KT/V. The RCT study (31) indicated that antegrade direction improved HD adequacy. This study did not report a standard deviation (31). Therefore there was insufficient data to report the effects of direction on KT/V and AR based This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 6 Table 2: Interventions of the studies included in the systematic review First Au- thor/ year Intervention Pro- gram Description Dias et al., 2008 (29) Antegrade and retro- grade cannulation Patients undergoing HD were divided into the following five groups: • Group 1: The placement of the needles in this group was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other in this group was 5 cm or more. • Group 2: The placement of the needles in this group was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other in this group was less than 5 cm. • Group 3: The placement of the needles in this group was antegrade, with both arterial and venous sets pointing toward the heart. The distance of the needles from each other in this group was 5 cm or more. • Group 4: The placement of the needles in this group was antegrade, with both arterial and venous sets pointing toward the heart. The distance of the needles from each other in this group was less than 5 cm. • Group 5: In this group, patients had a temporary double lumen catheter. To evaluate Kt / V, five blood samples of 3 to 5 ml were taken before and after HD. Also, to evaluate AR, three blood samples were taken from arterial and venous sets and limb contralateral to VA. Ozmen et al., 2008 (30) Antegrade and retro- grade cannulation Participants underwent two different interventions for HD, as follows: • Month 1: The placement of the needles was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. • Month 2: The placement of the needles was antegrade, with both arterial and venous sets pointing to- ward the heart. Blood samples were taken before and after HD in the middle of the treatment week and four times a month in each direction. Rothera et al., 2011 (10) Antegrade cannula- tion The distance between the two needles in five consecutive HD sessions was 5 cm in half of the participants and 2.5 cm in the same number of HD patients. In the other Overall, a maximum of 60 HD sessions were performed for each group. During each HD, AR was measured as a percentage, EID as an ml/min, and blood flow rate as an ml/min. EID was measured in the first half hour, one and a half hours, and the last half hour of HD. AR and blood flow rate were measured in the first half hour of HD. Reyes, 2016 (31) Antegrade and retro- grade cannulation Patients participating in this study were divided into two groups, as follows: • Intervention group: The placement of the needles was retrograde, with the arterial set toward the ex- tremity of the arm and the venous set toward the heart. • Control group: The placement of the needles was antegrade, with both arterial and venous sets pointing toward the heart. Blood samples were taken before HD, the first 30 minutes of HD, and after HD. URR, Kt / v, and AR were used to evaluate the adequacy of HD. Elias et al., 2018 (11) Antegrade and retro- grade cannulation Participants underwent HD three times with arterial needles in antegrade cannulation and then with ar- terial needles in retrograde cannulation. The distance between HD needles was 2.5 cm. In general, a maximum of 84 HD sessions were performed on these patients. AR was measured in the first 30 minutes of HD and Kt / V in the last 30 minutes of HD. Lim et al., 2018 (17) Antegrade and retro- grade cannulation Participants underwent three different interventions for HD, as follows: • Week 1: The placement of the needles was antegrade, with both arterial and venous sets pointing toward the heart. The distance of the needles from each other was 7 cm. • Week 2: The placement of the needles was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other was 5 cm. • Week 3: The placement of the needles was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other was 7 cm. Vahedi et al., 2018 (13) Antegrade and retro- grade cannulation Participants underwent four different interventions for HD, as follows: • Session 1: The placement of the needles was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other was 3 cm. • Session 2: The placement of the needles was antegrade, with both arterial and venous sets pointing toward the heart. The distance of the needles from each other was 3 cm. • Session 3: The placement of the needles was retrograde, with the arterial set toward the extremity of the arm and the venous set toward the heart. The distance of the needles from each other was 6 cm. • Session 4: The placement of the needles was antegrade, with both arterial and venous sets pointing toward the heart. The distance of the needles from each other was 6 cm. To assess AR, a blood sample was taken 30 minutes after the start of HD, after the device was turned off, a blood sample was taken from the arterial line and a blood sample was taken from the venous line of the filter. HD: Hemodialysis; EID: Effective ionic dialysance; Kt/V: k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea; AR: Access recirculation; VA: vascular access; URR: Urea reduction rate. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 7 Archives of Academic Emergency Medicine. 2023; 11(1): e39 Table 3: Grade of Recommendation, Assessment, Development, and Evaluation (GRADE) approach summary for this study -Outcome -Number of included effect sizes - Number of participants Risk of bias Consistency Directness Precision Publication bias Summary of findings (effect size) Quality -AR -3 -182 Non-RCT studies were included analysis Considerable heterogeneity + - Was not detected* -0.64 (-1.94, 2.65) Low -KT/V -4 -226 Non-RCT studies were included analysis Considerable heterogeneity + - Was not detected * 0.44 (-0.38,1.27) Low *: Number of studies was less than 10. RCT: randomized clinical trial; AR: Access recirculation; Kt/V: k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea. on RCT studies. The Results of three non-RCT studies (11, 29, 30) showed that retrograde direction decreased KT/V more than antegrade direction. However, this difference was statistically insignificant (ES: 0.44, 95%CI: -0.38 to 1.27, Z=1.05, I2:87.0%, P=0.29, Figure 4). 3.5. Effect of needle direction in AVF cannulation on HD adequacy based on AR Five studies (11, 13, 17, 29, 31) (two RCTs (13, 31) and three non-RCTs (11, 17, 29)) reported the effects of direction on HD adequacy based on the AR. The results of two studies (one RCT and one non-RCT) (13, 29) showed that AR in the retro- grade cannulation method is less than in the antegrade can- nulation method. Also, three studies (one RCT and two non- RCT) (11, 17, 31) did not show a significant difference in AR in the two antegrade and retrograde cannulation methods. One RCT study (13) did not report sufficient data. Therefore meta-analysis was not performed based on RCTs. Also, the results of three non-RCT studies (11, 17, 29) showed that the antegrade direction decreased AR when compared to the ret- rograde direction, but it was not statistically significant (ES: -0.64, 95%CI: -1.94 to 0.67, Z=0.96, I2:92.5%, P=0.34, Figure 5). 3.6. Effect of needles’ distance in AVF cannula- tion on HD adequacy based on KT/V Of the studies included in this review, one non-RCT study (29) reported the effect of needle distance in AVF cannulation on HD adequacy based on KT/V. This study (29) suggested that a distance of 5 cm or more between arterial and venous needles had greater adequacy than a distance of less than 5 cm. 3.7. Effect of needles’ distance in AVF cannula- tion on HD adequacy based on AR Of the studies included in this review, four studies (10, 13, 17, 29) reported the effect of needle distance in AVF cannulation on HD adequacy based on AR. Two studies (one RCT and one non-RCT) (13, 29) demonstrated that a distance of 5 cm or more between arterial and venous needles had greater ade- quacy and lower AR than a distance of less than 5 cm. How- ever, one RCT study (10) showed that a distance of 2.5 cm be- tween arterial and venous needles had greater adequacy and lower AR than a distance of 5 cm. One non-RCT study (17) did not show a significant difference between 5 cm and 7 cm needle distances in HD adequacy based on AR. 3.8. Publication bias Funnel plots indicated asymmetric views (Figure 6); however, the results of the Egger’s test did not confirm the presence of publication bias for effect sizes of AR (P=0.99) and KT/V (P=0.74). 3.9. Sensitivity analysis Sensitivity analysis showed that pooled effect size regarding the effect of directions on the KT/V was not dependent on a single study (95% CI: -0.62 to 1.77). In addition, pooled ef- fect size regarding the effect of directions on the AR was not dependent on a single study, either (95% CI: -3.32 to 2.37). 3.10. Certainty of the evidence The body of evidence assessed using the GRADE approach received an overall certainty rate of low for both outcomes (Table 3). 4. Discussion Meta-analysis showed that retrograde direction decreased KT/V more than antegrade, but it was not statistically signif- icant. Also, the antegrade direction decreased AR compared to the retrograde; however, this was not statistically signifi- cant. One cross-sectional study showed that antegrade cannula- tion increases KT/V in HD patients (32). Another cross- sectional research found that the frequency of AR in the ret- rograde cannulation method was higher than in the ante- grade method (33). In a study with 7,058 patients, Parisotto et This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 8 Figure 1: Flow diagram of the study selection process. Figure 2: Methodological quality assessment of randomized clinial trial (RCT) studies using Joanna Briggs Institute ( JBI) checklist. al. (2014) indicated that the retrograde cannulation method would increase the risk of failure in HD (34). These findings were in line with the results of the current meta-analysis. Another study found that most HD staff used the antegrade direction to access AVF (35). The two RCT stud- ies included in the study showed controversial results. How- ever, the results of other studies showed that direction has some impact on HD adequacy. Therefore, the recommenda- tion to use one particular direction is unsettled due to a lack of definitive evidence and guidelines on VA give little impor- tance to cannulation techniques . More studies with good- quality designs such as RCTs are suggested. RCT study de- sign, after meta-analysis and systematic review studies, pro- duce valid and reliable findings and researchers should con- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 9 Archives of Academic Emergency Medicine. 2023; 11(1): e39 Figure 3: Methodological quality assessment of quasi-experimental studies using Joanna Briggs Institute ( JBI) checklist. Figure 4: Effect size (ES) comparison for the effect of antegrade and retrograde directions on KT/V. Kt/V: k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea; CI:confidence interval. sider this characteristic. However, when there is limited ev- idence in studies with RCT design, assessment of other de- signs, such as non-RCT, becomes inevitable. We did not perform quantitative analysis to evaluate the ef- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 10 Figure 5: Effect size (ES) comparison for the effect of antegrade and retrograde directions on AR. AR: Access recirculation; CI:confidence interval. Figure 6: Funnel plots of effect sizes (ES) for AR (left) and KT/V (right). AR: Access recirculation; Kt/V: k is the dialyzer urea clearance, t, the duration of dialysis, and V, the volume of distribution of urea. fect of distance on dialysis adequacy criteria due to insuffi- cient data in the articles. However, qualitative comparison of the results of the two RCT and two Non-RCT studies indi- cated contradictory findings. One cause of AR is the lack of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 11 Archives of Academic Emergency Medicine. 2023; 11(1): e39 correct placement of AVF, so reducing the distance between two needles can increase returning of dialyzed blood to the arterial line and thereby decrease HD adequacy (33). One cross-sectional study in Iran showed that cannulation with a needle distance less than 5 cm had more AR and lower HD adequacy than other methods (33). Heterogeneity between studies was considered significant based on I2 value. The source of heterogeneity can be related to the distance of needles, the number of sessions, and pa- tients’ demographic characteristics in each study. Certainty of evidence was evaluated and found to be at a low level based on the GRADE approach. Results related to AR and KT/V based on the non-RCTs studies showed that there are heterogeneity and wide confidence interval between studies. This finding again confirms the need for vigorous studies to better adjudicate the effects of distance and direction of the needle on HD adequacy. One of the most common ways of accessing blood vessels in patients with HD is an AVF (36). Patients under HD require VA with proper functioning to survive (37). Incorrect pro- cedures in AVF cannulation can reduce HD adequacy and increase AR (38). The current study showed that there are ambiguous issues about the effects of direction and distance of AVF cannulation in HD patients. As a result, it is recom- mended that researchers pay more attention to this vital is- sue. 4.1. Limitations This study had some limitations. Meta-analysis was per- formed on the effects of direction on KT/V and AR based on non-RCT studies since some of the included RCT studies had insufficient data. We described the result of RCTs qualita- tively. Although only seven articles were included in the re- view and analysis, this study can attract the attention of re- searchers and motivate them to conduct more studies with higher-quality designs on this topic. Despite a comprehen- sive search of databases, not all studies on this subject may have been found, so it may have reporting bias. Finally, only studies in English and Persian were included in the present study, so it may have language bias. 4.2. Implications for health managers and poli- cymakers Although the results of the meta-analysis suggested ante- grade was more effective than retrograde, making any defini- tive recommendation based on this finding is problematic because of the low strength of the evidence. Also, findings showed controversy and uncertainty about the effect of nee- dle distance on HD adequacy outcomes. More RCT studies and more data are required to make better evidence-based decisions regarding the effect of needle direction on HD effi- cacy. 4.3. Implications for future research Due to the heterogeneous nature of the results in this sys- tematic review, it is suggested that researchers conduct more interventional studies to investigate the effect of antegrade and retrograde cannulation methods and needle distance on HD adequacy and AR. 5. Conclusion Overall, the findings from this study are inconclusive and support the uncertainty regarding the effects of directions and distances of AVF cannulation. However, a meta-analysis based on non-RCTs showed that antegrade direction had in- significant positive effects on HD adequacy, decreasing AR and improving KT/V. Future RCT studies are suggested to in- crease knowledge about the issue of needle direction and dis- tances and their impacts on AVF cannulation. 6. Declarations 6.1. Acknowledgments None. 6.2. Conflict of interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 6.3. Fundings and supports This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 6.4. Authors’ contribution All authors have agreed on the final version of this manuscript. Those listed as authors are qualified for author- ship according to the following criteria: They have made sub- stantial contributions to conception and design, or acquisi- tion of data, or analysis and interpretation of data; been in- volved in drafting the manuscript or revising it critically for important intellectual content; and have given final approval of the version to be published. Each author participated suf- ficiently in the work, has taken public responsibility for ap- propriate portions of the content, and has agreed to be ac- countable for all aspects of the work in ensuring that ques- tions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 6.5. Ethics approval This review study has not been registered in the interna- tional prospective register of systematic reviews (PROSPERO) database. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index S. Karkhah et al. 12 6.6. Data availability The datasets generated and analyzed during the current study are available from the corresponding author upon rea- sonable request. References 1. van der Tol A, Lameire N, Morton RL, Van Biesen W, Van- holder R. An international analysis of dialysis services re- imbursement. 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