Abstract

Chronic hemodialysis therapy required regular entry into the patient’s blood stream with adequate flow. The use of arteriovenous fistulas and grafts is linked with lower morbidity and mortality than the use of catheters. However, these types of accesses are frequently affected by stenoses, which decrease the flow and lead to both inadequate dialysis and access thrombosis. The idea of duplex Doppler ultrasound surveillance is based on the presumption that in-time diagnosis of an asymptomatic significant stenosis and its treatment prolongs access patency. Details of performed trials are con- flicting, and current guidelines do not support ultrasound surveillance. This review article summarizes the trials performed and focuses on the reasons of conflicting results. We stress the need of precise standardized criteria of significant access stenosis and the weakness of the metaanalyses performed.

Keywords

Hemodialysis, hemodialysis vascular access, ultrasonography, arteriovenous fistula, arteriovenous graft

Date received: 19 December 2019; accepted: 17 April 2020

Introduction

Only few other hemodialysis access topics are more pas- sionately debated as ultrasound surveillance. The invention of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) as vascular access for hemodialysis considerably decreased patients’ morbidity and mortality. The patency of AVFs and AVGs is being threatened mostly by the development of a stenosis, which can lead to access dys- function, inadequate dialysis, and/or access thrombosis. The latter represents an acute risk of access abandonment, and its therapy is more complicated and painful and cost- lier than the treatment of a (significant) stenosis. It seems, therefore, logical that treating significant stenoses before thrombosis occurs should be beneficial. However, it remains unclear when the risk of acute thrombosis due to stenosis is high enough to justify the preemptive interven- tion. Moreover, the definition of a hemodynamically sig- nificant stenosis varies between centers.

Stenosis is a vessel narrowing that could cause signifi- cant pressure drop and flow volume decrease, but also

1 Center for Vascular Access, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic

2 3rd Department of Internal Medicine, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
3 Division of Nephrology, Miulli General Hospital, Acquaviva delle Fonti,

Italy
4 Institute of Life Sciences, Sant’Anna of Advanced Studies and

Department of Internal Medicine, Pisa University, Pisa, Italy
5 Vascular Laboratory, Bravis Hospital, Bergen op Zoom, The

Netherlands
6 Vascular Access Clinic, Asklepios Clinic Barmbek, Hamburg, Germany 7 Department of Internal Medicine, Leiden University Medical Center, The

Netherlands
8 Service of Vascular Surgery, Department of Heart and Vessels,

University Hospital, Lausanne, Switzerland
9 Department of Nephrology, Clinical Hospital Centre Zemun, Belgrade,

Serbia
10 School of Medicine, University of Belgrade, Belgrade, Serbia
11 Nephrology Department, Parc Taul ́ı University Hospital, Parc Taul ́ı

Research and Innovation Institute (I3PT), Autonomous University of Barcelona, Barcelona, Spain

Corresponding author:

Jan Malik, 3rd Department of Internal Medicine, General University Hospital and First Faculty of Medicine, Charles University, U nemocnice 1, 128 08 Prague, Czech Republic.
Email: jan.malik@vfn.cz

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The Journal of Vascular Access

trigger mechanisms of thrombosis due to endothelial cell denudation and both platelet and von Willebrand factor activation in the case of very high shear stress (*flow velocity).1,2 The presence of a stenosis can be detected by routine physical examination and/or by signs of dys- function that manifest themselves during the dialysis ses- sion (monitoring). Such stenoses are clinically significant and include edema anatomically distal to the venous ste- nosis, prolonged bleeding, needling problems, fall of flow volume, decrease of dialysis dose due to higher recircula- tion, and so forth. However, the accuracy of clinical diag- nosis of a stenosis depends on the stenosis location, on vascular access and patient’s characteristics (depth, flow volume, vein branching, and compliance), and highly on the experience of the hemodialysis unit team, which is not always optimal.3,4 In a recent study by Castro et al.,5 the clinical suspicion on AVF stenosis was not confirmed in 27% of cases. Some stenoses remain clinically asympto- matic, which explains at least part of the “sudden” throm- bosis that develops without any warning signs. All these reasons led to the development of surveillance techniques.

Surveillance is defined as the periodic evaluation of the vascular access by using diagnostic tests that may involve special instrumentation and staff and for which an abnor- mal test result suggests the presence of dysfunction.6 The rationale of surveillance is based on the hypothesis that corrective intervention of an identified progressive stenosis (such as percutaneous transluminal angioplasty (PTA)) can prevent complete occlusion of AVF/AVG and prolong access lifespan.7 Besides regular access flow volume mea- surement using dilutional techniques, Doppler ultrasono- graphy (DUS), is the most investigated and used method. The main advantage of DUS is its ability to provide non- invasive, precise, and reproducible data on the morphology and flow dynamics of the arteriovenous access.8 However, a number of trials have been published, and the data about DUS surveillance benefits were conflicting.9–13 In the absence of precise standardized definition of a significant stenosis or adequate level of experience, DUS (but also angiography) could be an operator-dependent method and, indeed, the indication to preemptive therapy (1⁄4 significant stenosis) differed from study to study. The absence of strict ultrasound diagnostic criteria of an asymptomatic stenosis could explain the lack of surveillance benefit in some trials, and we describe them in detail below and in Table 1. Moreover, the technology of DUS has improved consider- ably since the first reports of AVF/AVG ultrasound exam- ination and (negative) trials of surveillance, and its improvement is an ongoing process. The higher working frequency of the ultrasound probes provide better axial spatial resolution, and the higher frame rate corresponds to the higher temporal resolution. Moreover, the size of the ultrasound devices has decreased considerably, which led to their easier transportation even to the patients’ beds and hemodialysis chairs.

Table 1. Complex criteria of a significant vs borderline stenosis—according to Malik et al.13 and Ishii et al.14

Significant

Main criteria
Diameter reduction by >50%
Peak systolic velocity increase >2–3" Additional criteria (#1):
Residual diameter <1.9–2.0 mm
Flow volume decrease by >25%a)
Flow volume <600 mL/min for AVGs, <500

mL/min for AVFs

Borderline

No additional criterion

If only the main criteria are present, the stenosis is borderline and ree- valuation is indicated within 6–8 weeks. Significant stenoses are indicated to correction.
aFlow volume decrease by >25% if the previous value was <1000 mL/min.

There is a general agreement that clinically significant stenoses should be treated. In these cases, DUS can help to identify the location of the stenosis, which is important for the appropriate puncture site during the percutaneous pro- cedure. A debate continues about the indication of asymp- tomatic stenoses diagnosed by any imaging method. We believe that only the usage of strict diagnosis criteria could justify the ultrasound surveillance.

Stenosis definition by DUS

Several criteria have been used for the description of a significant stenosis by DUS.

Percentage of diameter reduction

Percentage of diameter reduction is the oldest morpholo- gical assessment of a stenosis, used not only in DUS, but also in angiography. The main problem of this criterion is that the outflow veins have typically irregular lumen, so there is frequently no reference segment for the estimation of stenosis percentage in AVFs. Moreover, many stenoses are asymmetric, and then the estimated severity of the stenosis depends on the direction from which it is viewed. Stenosis visualization in two perpendicular directions could lessen this limitation. Nevertheless, it is diameter narrowing in B-mode (and in color Doppler), which turns the attention of the examiner to the particular vessel seg- ment. Percentage of stenosis (>50%) was used as the single criterion of significance in some trials.9–11 Using only this criterion is unreliable because B-mode does not always delineate low-echogenic structures, such as intimal hyper- plasia, degenerative venous valves, or recent thrombosis.

Peak systolic velocity

Peak systolic velocity (PSV) increase in comparison to a non-stenosed segment is another widely used criterion.8–13 The velocity increase is caused by the stenosis itself and by

Malik et al.

3

Figure 1. Correct orientation of the Doppler angle in the vas- cular lumen.
The cosinus of the Doppler angle is a part of the equation transforming the Doppler frequency shift into the velocity. Therefore, it should be always the same for the follow-up. Man- ufacturers set it usually to 60$.

the recirculation zone due to flow turbulence just behind the stenosis. Sometimes it is expressed as a PSV ratio (PSR). AVG stenosis with PSR 2.0–2.9 had 50%–74% stenosis on angiography, and AVG stenosis with PSR # 3.0 had #75% stenosis.12 The velocities should be always recorded by the same Doppler angle, which is usually set to 60$ by the ultrasound manufacturers (Figure 1), but could be changed appropriately by the examiner. It should not exceed 60$. This is related to the formula that calculates the velocity, which includes the cosine of the angle in the numerator. Irregular (asymmetrical) stenoses cause higher pressure drop and velocity increase than symmetrical stenoses of the same area reduction.15 The velocity increase mirrors the pressure gradient caused by the stenosis according to the Bernoulli equation. This is because the outflow vein is softer or easily collapsible and anatomically proximal to a significant steno- sis during palpation or ultrasound evaluation. The use of absolute PSV values as the only criterion is confounding because the increase of PSV does not have the same signifi- cance when it is or it is not associated to a drop of the flow rate

Flow volume (Qa)

Flow volume (Qa) is frequently considered as the function of the access and is obtainable during DUS examination. For precise values, it has to be measured in a straight vascular segment free of stenoses. In AVFs, Qa is usually measured in the brachial artery, supposing that the vast majority of the flow volume (>90%) enters the AVF. In AVGs, Qa is mea- sured directly in the graft close to its venous anastomosis (Figure 2). Low values are linked to higher thrombosis risk16 and to increased blood recirculation, with subsequent decrease of the dialysis dose—Kt/V (especially in the pop- ular high-flow regimes). On the contrary, high Qa could be detrimental for the heart or could be responsible for hand

Figure 2. Flow volume measurement in the graft.
The flow volume calculation is based on the following formula: Qa 1⁄4 pr2 " TAMEAN, where r is the radius of the examined graft and TAMEAN is the time-averaged mean velocity inside. The latter is an integral value during the heart cycle of the average velocity layer (flow velocity is the fastest in the middle and the slowest along the vascular wall). TAMEAN must not be replaced by TAMAX, which is the time velocity integral of the fastest velocity only—using TAMAX would lead to significant overesti- mation of Qa. Pulse wave Doppler sample size should be wide enough to cover most of the vessel lumen because of the different speeds of blood inside the vessel from the center to the wall.

Figure 3. RD measurement.
There is excessive intimal hyperplasia in the outflow vein causing the stenosis. By diameter reduction, this stenosis would be significant if compared with the left or right part of the vein. Nevertheless, the RD is 2.35 mm, so this stenosis was considered borderline, and soon, reevaluation (within 6–8 weeks) was indicated.

ischemia.17 In considering preemptive correction, studies regarded stenoses as significant either at a flow volume decrease by 20%–25% and/or at a cut-off value of <500– 600 mL/min.13–14,18–20 However, the problem is that the actual Qa does not depend only on stenosis severity, but also on the actual hydration status and blood pressure similar to and in relation with the cardiac output. Natural/physiolo- gic variation of repeated Qa exceeds 20%.21 It is advisable to validate Qa values obtained by DUS with dilutional tech- niques performed during hemodialysis.

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The Journal of Vascular Access

Residual diameter (RD) of the stenosis could be pre- cisely analyzed by the modern high quality ultrasound devices (Figure 3).8 The cut-off value <2.0 mm was arbi- trarily set and confirmed clinically when used as a part of the “complex stenosis criteria” in AVGs13,22,23 and vali- dated against angiography.8 In AVFs, an Australian study showed that the RD < 2.7 mm was associated with 90% sensitivity and 80% specificity of AVF dysfunction.18 According to a recent study, RD < 2.5 mm is associated with lower Qa.24 Another current Japanese study with AVFs determined the RD cut-off value to be <1.86 mm.14 As long as the stenosis is asymmetrical, it should be again visualized by two perpendicular views, and for the diagnosis of a significant stenosis, the RD should be below the cut-off value in both..

The resistive index (RI) of the flow pattern in the feed- ing artery has been tested in several studies, and although it is used in the assessment of the transplanted kidney,25 the results in AVFs and AVGs are not conclusive. Values above 0.6–0.7 indicated stenosis.26,27 The RI is defined by the following equation: RI 1⁄4 (PSV % end diastolic velocity)/PSV. RI increases especially in juxtaanastomotic stenoses.

Some centers and trials have used the complex criteria of a significant stenosis, comprising the combination of two main criteria (>50% diameter reduction þ PSR >3) and at least one additional criterion (RD, flow volume decrease, or low Qa—see Table 1).28 AVG stenoses with a lack of any additional criterion (1⁄4 borderline stenoses) possess low risk of thrombosis (ca. 1% during 6–8 weeks since the primary diagnosis).22 Only 54% of borderline AVF stenoses progressed into significant stenosis in the study by Castro et al.5 The complex stenosis criteria (Table 1) have been developed for the “Watch and wait strategy.” These criteria were used in the largest randomized trial testing ultrasound surveillance and proving its benefit,13 but also in other trials.19,28 Unfortunately, the majority of trials used only >50% diameter reduction as the only cri- terion of stenosis.9–11 The second largest randomized con- trolled trial (RCT) of ultrasound surveillance that did not prove its benefit used complex criteria, but included RD < 4.0 mm.29 The latter cut-off value is quite high and could be found in many normally functioning AVFs/AVGs.

The key question is this: can ultrasound surveillance provide reliable guidance for the clinician as to which ste- nosis should be treated and when? The identification of such high-risk stenosis is based on the understanding of stenosis pathophysiology and on their detailed morpholo- gical and functional (Qa) evaluation.22 DUS enables com- plex evaluation of the stenosis significance, which was, however, used only in a few published trials as mentioned above. Moreover, DUS performed early after AVG cre- ation can also predict future risk of AVG abandonment and thus select high-risk AVGs that could profit from the sur- veillance most.30 DUS is even more frequently performed

in AVFs after their creation, although the optimal criteria are discussed.31

AVF/AVG thrombosis, however, can also develop not only because of stenosis progression, but also due to other mechanisms, such as hypotension, dehydration, unwished outer compression during sleep, thrombophilia, and so forth. Moreover, the aforementioned complex stenosis cri- teria cannot be used mechanically. One such example is a branched AVF—if an outflow vein stenosis is diagnosed, but Qa (measured in the brachial artery) is adequate and the alternative outflow vein (branch) is suitable for hemodia- lysis needling, the stenosis could be left without interven- tion. Alternatively, when a decreased Qa is calculated, but there is no clear high-grade stenosis, it is worth to estimate patient’s hydration, for example, by the visualization of the inferior vena cava diameter and collapsibility when the ultrasound device is equipped with abdominal or echocar- diography probes.32 Whole-body bioimpedance spectro- scopy is frequently used in hemodialysis units for the assessment of hydration.

Stenoses in AVFs

Anatomically distal AVF is the first access of choice. The more frequent upper extremity fistulas include radio- cephalic, ulno-basilic and brachiocephalic fistulas, Gracz fistula (median cubital vein attached to the brachial or radial artery), and transposed basilic vein. They have a long life- span, low risk of complications, and their use is associated with the longest life expectancy.33 The main limitation of AVFs is non-maturation, as up to 40%–60% of AVFs are never suitable for hemodialysis without additional AVF pro- cedures to34 facilitate maturation and the maturation rate of AVFs is suggested as a surgical quality indicator.35 Many factors responsible for these unsatisfactory early results have been identified, and they lead to outflow vein or inflow artery stenoses. Early DUS can identify such stenosis and provide an indication to percutaneous or surgical therapy— so-called assisted maturation.36,37 Later on, stenoses develop mostly in the outflow vein close to the anastomosis in distal forearm AVFs and more proximally in the outflow vein (cephalic arch) in brachiocephalic AVFs.38

Stenoses in AVGs

The most frequent AVGs are forearm—they begin at the radial or brachial artery and are straight or curved and are attached to the basilic vein. More proximal grafts originate at the brachial or even subclavian artery and are attached to the cephalic or subclavian vein. Lower extremity grafts are created in the case of occluded central veins and are straight (between popliteal artery and some groin vein) or looped (femoral artery to femoral or great saphenous vein). AVGs have a higher rate of complications and a shorter lifespan than AVFs. Therefore, AVG is the vascular access

Malik et al.

5

that is created and recommended especially in patients with abandoned subcutaneous veins, with AVF non-maturation, but also in elderly patients, thanks to AVG’s higher maturation rate.39

Unfortunately, no currently available graft is as good as an AVF that matured without intervention. DUS performed early after AVG creation can predict future complications and thus select patients who would profit more from ultra- sound surveillance.30 AVGs are generally more prone to later stenosis development than AVFs. The typical site of stenosis development is at the venous anastomosis and at the adjacent part of the outflow vein. This is caused by the formation of intimal hyperplasia after creation. Cannulation-related stenoses could also develop in the graft itself, especially when the areal puncture technique is applied instead of the recommended rope-ladder tech- nique.40 In this case, the graft wall disruption and subse- quent healing are responsible. Both development of intimal hyperplasia and puncture healing are slow-acting mechan- isms, which give time for surveillance.22

Ultrasound surveillance in the guidelines

Some published vascular access guidelines support DUS as a screening tool for detecting stenosis and to perform pre- emptive interventions to prevent the loss of the AV access. The Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for vascular access, published in 2006, recommended direct flow measurement and DUS as preferred techniques that may be used in AVF surveillance and preemptive correction of luminal stenosis of >50% when the access flow rate is less than 600 mL/min in AVGs, and '400–500 mL/min in AVFs, even if the access is still able to provide adequate hemodialysis.41

Recent Spanish guidelines have recommended DUS as the first visualization method in the case of clinical suspi- cion on access dysfunction or stenosis, and regarding sur- veillance, both DUS and dilution methods for AVFs but not for AVGs.42 The European Society for Vascular Surgery guidelines also recommended DUS as a non-invasive tool to be the first line imaging method only in patients with suspected vascular access dysfunction.43 The new Eur- opean Renal Best Practice (ERBP) guideline on AV access specifies that the evidence for surveillance of AVFs is inconclusive and needs more research. In addition, they recommend not to perform routine surveillance of AVGs with access flow measurements or DUS.44

Clinical trials on vascular access surveillance

Current statements of the societies are based especially on the results of the metaanalyses.44,45 Their authors included all RCTs testing the benefit of DUS surveillance and pre- emptive treatment of stenoses. The conclusions of both

Table 2. The use of DUS as answered by the VAS council and board members.

Do you routinely perform/support ultrasound examination after access creation?

Do you perform/support duplex Doppler ultrasound in the case of access problems (puncture difficulties, limb edema, decrease of dialysis dose . . . ?)

Do you check the access by ultrasound regularly? Do you indicate PTA if a severe stenosis is found?

AVF AVG 75% 75%

100% 91%

55% 55% 73%a 73%a

PTA: percutaneous transluminal angioplasty; AVF: arteriovenous fistula; AVG: arteriovenous graft. Percentage of “YES” is depicted.

a Half responded “only if symptomatic.”

metaanalyses are similar: Preemptive stenosis correction of a functional arteriovenous access does not improve access longevity; although results for native AVF are pro- mising, existing evidence is insufficient to guide clinical practice and health policy.

The board and council members of the Vascular Access Society were asked about their practice in DUS surveil- lance. The results are given in Table 2, and they illustrate the current uncertainty about the clinical value of vascular access surveillance. The results of the largest RCT evi- denced the benefit of DUS surveillance and preemptive therapy of carefully assessed stenoses.13 On the contrary, the metaanalyses had negative results.45,46 Nevertheless, the number of patients included in the metaanalyses is scarce: six RCTs enrolled 612 patients with the primary endpoint of thrombosis, and four RCTs enrolled 443 patients for access loss.47 Some of the studies included prevalent patients, while others included solely incident patients at the time of access creation. The most important differences were, however, in the definition of significant stenosis that was indicated to percutaneous or surgical correction (Table 3). Performing a metaanalysis from so different studies leads therefore to significant oversimpli- fication. The final answer to whether to do or not to do DUS surveillance is therefore in including more patients with the use of the complex stenosis criteria and clear indication criteria of percutaneous treatment, ideally in a multicenter study with defined inclusion criteria and end- points (thrombosis and cumulative patency).

Perspective: is it the time to change the surveillance paradigm?

Although the guidelines are not favorable, the authors of this article are convinced that ultrasound should play a pivotal role in the AVF/AVG management, as it is a precise and highly reproducible method in experienced hands. For the greater distribution of AVF/AVG ultrasound imaging, it is necessary to (1) standardize the examination

6 The Journal of Vascular Access

Table 3. Duplex Doppler cut-off criteria of a significant AVG stenosis (used as the indication to angiography and intervention)—from the work by Malik et al.28

Trial first author

Mayer et al.9 Lumsden et al.10 Ram et al.11 Robbin et al.29 Malik et al.13

No of subjects US/control

35/35 32/32 32/34 65/61 97/92

Diameter reduction in B-mode

>50% >50% >50% >50% >50%

Peak velocity increase

Qa decrease

Qa cut-off value (mL/min)

Residual diameter (mm)

Prolonged1⁄4survival in ultrasound surveillance arm?

technique, (2) define the technical demands of the ultra- sound devices, and (3) standardize the criteria of signifi- cant stenosis in a well-controlled multicenter trial.

Ultrasound should be the first technique of choice in the evaluation of maturation, regardless of physical examina- tion. The goal in the maturation phase should be the search for potentially correcting inflow or outflow defects, often the basis of late stenoses. Hemodynamics and anatomy of AVF and graft vary from case to case, so the examination should be tailored for each patient in order to identify early the sites and causes of stenosis during the maturation phase. Although it has not been proven, it is logical that surveillance is most important in accesses at greater risk. To put things in perspective, top-end ultrasound devices and profound operator training should be a must in dedi- cated vascular access centers. Nevertheless, as in any field of medicine, clinical judgment is more important than only the results of ultrasonography. It includes also the history of previous thrombosis, thrombophilia, lack of other suit- able veins for another arteriovenous access, and so forth.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: JM is supported by the by the grant of the Agency of Health Research of the Czech Republic 17-31796A.

ORCID iDs

Jan Malik
Mario Meola
Cora de Bont
Joris I Rotmans
Jose Ibeas https://orcid.org/0000-0002-1292-7271

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42. Roca-Tey R, Ibeas J, Moreno T, et al. Dialysis arteriove- nous access monitoring and surveillance according to the 2017 Spanish guidelines. J Vasc Access 2018; 19(5): 422–429.

43. Schmidli J, Widmer MK, Basile C, et al. Editor’s choice— vascular access: 2018 clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2018; 55(6): 757–818.

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44.

45.

Gallieni M, Hollenbeck M, Inston N, et al. Clinical practice guideline on peri- and postoperative care of arteriovenous fistulas and grafts for haemodialysis in adults. Nephrol Dial Transpl 2019; 34: 1–42.

Tonelli M, James M, Wiebe N, et al. Ultrasound monitoring to detect access stenosis in hemodialysis patients: a sys- tematic review. Am J Kidney Dis 2008; 51: 630–640.

46. Ravani P, Quinn RR, Oliver MJ, et al. Preemptive correc- tion of arteriovenous access stenosis: a systematic review and meta-analysis of randomized controlled trials. Am J Kidney Dis 2016; 67: 446–460.

47. Tessitore N and Poli A. Pro: vascular access surveillance in mature fistulas: is it worthwhile? Nephrol Dial Transpl 2019; 34: 1102–1106.

Advances in vascular anatomy and pathophysiology using high resolution and multiparametric sonography

11297298211020150.pdf

Abstract

JVA The Journal of Vascular Access

B-mode and Color Doppler are the first-line imaging modalities in cardiovascular diseases. However, conventional ultrasound (US) provides a lower spatial and temporal resolution (70–100 frames per second) compared to ultrafast technology which acquires several thousand frames per second. Consequently, the multiparametric ultrafast platforms manage new imaging algorithms as high-frequency ultrasound, contrast-enhanced ultrasound, shear wave elastography, vector flow, and local pulse wave imaging. These advances allow better ultrasound performances, more detailed blood flow visualization and vessel walls’ characterization, and many future applications for vascular viscoelastic properties evaluation.

In this paper, we provide an overview of each new technique’s principles and concepts and the real or potential applications of these modalities on the study of the artery and venous anatomy and pathophysiology of the upper limb before and after creating a native or prosthetic arterio-venous fistula. In particular, we focus on high-frequency ultrasound that could predict cannulation readiness and its potential role in the venous valvular status evaluation before vascular access creation; on contrast-enhanced ultrasound that could improve the peri-operative imaging evaluation during US-guided angioplasty; on shear wave elastography and local pulse wave imaging that could evaluate preoperative vessels stiffness and their potential predictive role in vascular access failure; on vector flow imaging that could better characterize the different components of the vascular access complex flow.

Keywords

Multiparametric ultrasound, shear wave elastography, high-frequency ultrasound, vector flow imaging, local pulse wave velocity, vascular access

Date received: 19 June 2020; accepted: 6 May 2021

Introduction

Ultrasound (US) is the first-line imaging modality for screening, diagnosis, and monitoring treatment in cardio- circulatory pathology because of its safeness, non-inva- siveness, wide availability, and low cost. Conventional ultrasound modalities as B-mode, color Doppler, and spec- tral analysis allow the recognition of vessel wall and bloodstream changes, depicting the site of vascular sten- oses and occlusions.1,2 Consequently, US plays a pivotal role also in hemodialysis vascular access creation and surveillance.

Conventional platforms have a limited frame rate (images/second) because they use the line-by-line scanning acquisition method. This technical approach provides a lim- ited temporal resolution. Recent ultrafast platforms acquire

image information at frame rates of several thousand Hz, while conventional ultrasound systems acquire images at only 70–100 frames per second. The higher temporal and spatial resolution of this technical approach allows manag- ing all the new imaging algorithms as high-frequency

1Institute of Life Sciences, S. Anna School of Advanced Studies, Pisa, Italy

2Institute of Life Sciences, S. Anna School of Advanced Studies, Department of Internal Medicine, University of Pisa, Pisa, Italy

3Radiodiagnostic and Interventional Radiology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Corresponding author:

Petrucci Ilaria, Institute of Life Sciences, S. Anna School of Advanced Studies, Piazza Martiri della Libertà, 33, Pisa 56127, Italy.
Email: i.petrucci@santannapisa.it

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© The Author(s) 2021
Article reuse guidelines: sagepub.com/journals-permissions hDttOpsI://1d0o.i1.o1r7g/71/01.1127977/1219289272191802210110250150 journals.sagepub.com/home/jva

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ultrasound (HFUS), contrast-enhanced ultrasound (CEUS), shear wave elastography, vector flow, and local pulse wave imaging. Ultrafast imaging allows better US performance, with more detailed visualization of blood flow, better char- acterization of vessel walls, and many applications in vascu- lar viscoelastic properties evaluation.

The availability of these technologies allows coining the term “high resolution” and “multiparametric ultra- sound” (MPUS) to define the current imaging applications on the top-line machine.3

Regarding vascular applications, the technological advances with potential applications in vascular access planning and surveillance are HFUS, CEUS, shear wave elastography, vector flow, and local pulse wave imaging.3–5

In this paper, we provide an overview of the principles and concepts of high resolution and MPUS, and we describe the actual or potential applications on the study of the artery and venous anatomy and pathophysiology of the upper limb before and after the creation of a native arterio- venous fistula (AVF) or a graft.

High-frequency ultrasound

High-frequency ultrasound refers to the US probe fre- quency of more than 10 MHz. High-frequency transducers were introduced in the pre-clinical setting and were mainly used in animal models to monitor tumor growth and to evaluate changes in micro-vascularization of neoplastic masses after antineoplastic therapy.4 The US transducers used in clinical practice operate at 22–100 MHz. These frequencies have short wavelengths and are more easily absorbed, so they improve spatial resolution with a reduced depth of penetration. HFUS could be applied to evaluate normal and diseased skin and superficial vessels.

Clinical applications

Nowadays, HFUS is used in neonatal and pediatric pathol- ogies to evaluate nerves, hand transplants, thyroid, lymph nodes, male reproductive organs, dermatological patholo- gies (melanoma, lipoma, hair follicles), and also musculo- skeletal and oral pathologies.6

The vascular applications of this technique are mainly on the smallest vascular anatomy: arteries and veins in pediatric and neonatal patients, measurement of Intima- Media Thickness (IMT) and characterization of carotid plaques for research and assessment of cardiovascular health, assessment of peripheral vessels in diabetes and other circulatory condition and visualization of flow pat- terns in atherosclerotic or abnormal vessels.

Vascular access applications

Jaberi et al.7 have hypothesized that venous wall thickness and circumferential stress measured with HFUS could

Figure 1. Cephalic vein valve and IMT evaluated with HFUS. Valve flaps are very well distinguishable (white arrows) and IMT (red line) is measurable at the far wall of the vessel.

predict cannulation readiness in AVFs. They have scanned an excised AVF specimen with a 55-MHz probe, and they have correlated the US findings with histological features. Then, they measured with HFUS the IMT of the near-field AVF venous wall of 20 patients with newly created AVFs within one week of cannulation. Cannulation readiness was defined as no extravasation during the first dialysis treatment. The mean IMT of the no extravasation group was greater than that of the extravasation group (p < 0.001). A minimum threshold IMT of 0.13 mm (p < 0.001) was associated with successful cannulation. The mean cir- cumferential stress of the no extravasation group was lower than that of the extravasation group (p < 0.001). A maximum circumferential stress threshold of 248 kPa was associated with successful cannulation (p = 0.009). They concluded that venous IMT and circumferential stress assessed with HFUS could predict cannulation readiness in AVFs clinically considered mature.

High-frequency US could also be useful in evaluating venous valves (Figure 1) during the preoperative mapping before AVF creation, and further studies are needed to evaluate its real utility.

Contrast-enhanced ultrasound

CEUS is an imaging modality based on microbubbles, made up of a hydrophilic shell surrounding a gas core, using their property of resonant volumetric oscillations in response to the acoustic pressure variations of the ultra- sound waves.

Ultrasound contrast enhancers are administered intra- venously in an aqueous solution as a bolus followed by a flush saline solution. Microbubbles have a mean size of 3 μm, and in general 95% of the bubbles pooling is smaller than 10 μm. They remain in the bloodstream, do not pass into the interstitial fluid and easily cross the pulmonary

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and peripheral capillaries without causing thrombotic complications. They are able to make “bright” the vessel, allowing an accurate study of the micro and macro-vascu- lature.8 Microbubbles are then disrupted by the acoustic US pulse and exhaled with breathing. CEUS imaging per- mits the evaluation of the vascular abnormalities, estimates blood flow parameters, and identifies and quantifies the neovascularization.9,10

Clinical applications

In literature, the use of CEUS has recently obtained many established and emerging applications.11 CEUS is rou- tinely employed for the differential diagnosis in focal parenchymal lesions, especially in the liver and in the kid- ney, for screening and early diagnosis of hepatocellular carcinoma in cirrhotic livers.12 Microbubbles allow to assess of the contrast enhancement due to malignant angi- ogenesis and identify the “wash-out” in the late phases.

CEUS imaging is also used to evaluate abdominal aortic aneurysm after endovascular aneurysm repair as an alterna- tive to computed tomography angiography, especially in contrast allergy or in patients with impaired renal function avoid excessive radiation exposure during follow-up.13 CEUS can accurately detect and characterize eventual endoleak, showing the persistence of contrast enhancement into the aneurysmal sac, which may lead to progressive aneurysmal enlargement and secondary rupture. CEUS is even superior to tomography angiography to detect the pres- ence and type of endoleaks in some cases. It is not affected by metallic artifacts of the graft, and it is a dynamic imaging modality allowing to visualize the inflow vessels source of endoleak. Limitations are similar to conventional US imag- ing: operator dependence and image quality impairment depending on body habitus and bowel gas presence.14 The risk of anaphylactic reaction after ultrasound contrast agent administration is very rare (1 on 100.000 cases).

CEUS imaging is also spreading in the Emergency Department, where this method permits the identification of aortic dissection and post-traumatic parenchymal inju- ries and finds eventual focal sources of bleeding.15

CEUS imaging allows an accurate measurement of the degree and length of stenosis and better evaluates plaque morphology, thickness, and vulnerability. For these rea- sons, many studies applied this imaging modality to assess the extracranial carotid occlusive disease and estimate the carotid plaque. It was demonstrated the possibility to detect and quantify intraplaque angiogenesis, which is a marker of plaque growth.16 Thus, CEUS may be used for risk stratification of patients with atherosclerotic disease and predict the risk of cerebrovascular accident.

Vascular access applications

Ramnarine et al.17 reported the use of CEUS in 11 patients in ultrasound guided AVFs balloon angioplasty procedures

for failing or non-maturing AVFs. The procedure was under the guidance, and CEUS was used initially to evalu- ate the fistula morphology and after balloon angioplasty to confirm the stenosis treatment and reveal intra-operative complications. They conclude that CEUS improves peri- operative imaging evaluation because it provides a higher spatial resolution for narrow stenotic segments. It is more sensitive in demonstrating potential complicating extrava- sation, avoiding the use of iodinated contrast, and being a viablealternativetofluoroscopyforAVFintervention.The main limitations are that more proximal lesions may be difficult to visualize due to depth limitation.

Tissue elastography

Mechanical tissue properties change in many different dis- ease processes that lead to fibrosis, inflammation, and neo- vascularization. US elastography evaluates the tissue stiffness based on Young’s modulus, a physical property that relates applied force per unit area (stress) and the conse- quent relative change in tissue dimension (strain). Ultrasonographic methods to evaluate tissue elastography may be strain-based, in which the probe pressure applies the force, or shear wave-based, in which the force is produced by the imaging system.18 Strain elastography only allows semi-quantitative assessments of stiffness that are difficult to compare longitudinally. Shear wave propagation velocity is directly correlated with tissue stiffness, and in most ultra- sound systems, compressive acoustic waves are used to induce and track shear waves all along with the ultrasound probe, permitting shear wave velocity estimation.

US elastography has been successfully applied to eval- uate many tissues and organs, including liver, breast, thy- roid, kidney, spleen, prostate, lymph nodes, tendons, and vessels.18,19

Clinical applications

Strain elastography is an accurate technique to distinguish liver fibrosis stages and benign from malignant liver masses. Shear wave elastography (SWE) is used since the early stages of liver fibrosis caused by HBV, HCV, alco- holic liver disease, hepatic toxicity, and autoimmune hepa- titis. In patients with chronic kidney disease (CKD), strain values are higher than in healthy volunteers, and strain elastography can also detect early renal graft interstitial fibrosis, suggesting an organ rejection. SWE has shown significant differences between CKD grades, and it could also represent a marker for diabetic kidney disease.18 Moreover, strain-imaging studies to assess focal renal masses have shown promising results. SWE has improved the differential diagnosis between benign and malignant breast, thyroid, pancreas, and prostate lesions, and encour- aging results are growing about the use of SWE in the dif- ferential diagnosis between benign and malignant lymph nodes, endoscopic spleen evaluation in chronic liver

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disease, and cirrhosis.19 The cardiovascular system is a new potential field of application of SWE, especially in the risk stratification of carotid plaques3 and in the evalua- tion of carotid stiffness in patients with acute ischemic stroke.20 Arterial stiffness measured with SWE has been evaluated in patients with CKD, and the results show that their brachial artery is stiffer than in healthy subjects.21 At present, there is only limited evidence available for the application of SWE in the evaluation of peripheral veins, in particular on thrombus characterization.3

Vascular access applications

Inabilities to prevent non-maturation or avoid early fail- ure of AVFs are due to an incomplete understanding of preexisting arterial and venous conditions. Small-diameter at anastomosis sites, old age, diabetes mellitus, arterio- sclerotic pathologies of the artery, and preexisting low- quality vein wall are all risk factors of non-maturation and early failure of vascular access.22 Whether preexisting vascular pathologies associated with or aggravated by CKD can impair the necessary adaptive remodeling of blood vessels after vascular access placement is still an open question. There is some evidence that the elastic modulus measurements are significantly higher in patients undergoing preoperative mapping for hemodialysis access than in healthy volunteers.23 The arterial stiffness could be a possible biomarker for AVF failure due to the lower arterial ability to dilate.24–26 However, the studies pub- lished to date on the arterial stiffness evaluation before or after AVFs creation are not conclusive because they have used very heterogeneous methods, not including SWE that could potentially be able to evaluate the local arterial stiffness.27–29 MacDonald et al.30 have retrospectively analyzed the preoperative and postoperative data of 33 patients indicated for fistula creation. Vessels diameters at the B-mode ultrasound, SWE of the brachial artery, and demographic data were considered to find if any of these variables were related to the outcome of the AVF 3 months after creation. Shear wave velocity decreased after AVF creation, indicating increased compliance, but there were no parameters associated with AVF failure. Further stud- ies with a larger number of patients and a longer follow- up period are needed to assess the utility of SWE evaluation of arterial and or venous vessels before and after AVF (Figure 2) or AVG creation (Figure 3).

Vector flow imaging

Vector Flow Imaging (VFI) is an innovative imaging algo- rithm, angle-independent, which provides a multidimen- sional characterization of blood flow in all directions, showing the streamlines and vortices distribution into a vessel as velocity vectors.31

Figure 2. Longitudinal view of a cephalic vein in a distal radio-cephalic AVF using local SWE. The region of interest is adjusted to the IMT of the far wall of the vein. In this case the venous IMT is homogeneous with a stiffness of 47 kPa.

Figure 3. Longitudinal view of the venous anastomosis in a prosthetic arteriovenous fistula using SWE, which shows the different elastic properties and stiffness of the vessel walls. The portion of the graft is much stiffer (represented in red) at the venous anastomosis than the contiguous venous walls.

Commercial US systems primarily developed two methods of estimation based on different principles: trans- verse oscillation method and plane wave imaging. In the transverse oscillation method, the probe emits several con- secutive pulses. Two receiving beamformers are used to estimate the axial and transverse components of the veloc- ity vectors, and the difference from the received signals is compared to calculate the velocity.32,33

In ultrafast plane wave imaging, the transmission is made up of single unfocused beams at several incidence angles. The multidirectional flow estimation is performed through speckle tracking, and the real vector velocity is calculated by compounding velocities returning from a series of steers through a complex angle-compounding algorithm.34–36

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These methods allow a high frame rate, with a dynami- cal and intuitive visualization of complex hemodynamic features. The bloodstream is represented in VFI with many moving-colored arrows, where the color and the length of the vector indicate the velocity magnitude.37 The operator can measure the velocity at any point of the vessel and every instant of the cardiac cycle, revealing even transient flow movements, otherwise not detectable with conven- tional ultrasound.

VFI has some limitations. It is based on pulse repetition frequencies, so it does not permit the correct measure- ments of higher velocities in aliasing areas, and it is a two- dimensional technique, not allowing a 3-D comprehension of the streamlines.

Clinical applications

Several clinical studies based on VFI showed the additional information carried out from this technique analyzing differ- ent flow patterns in the human cardio-circulatory system.

The first in-vivo study with the vector velocity method, based on plane wave acquisition, was published in 2009 by Hansen et al.,38 which reported the visualization of a stable vortex in the bulb of six carotid bifurcations.

VFI was then deployed to demonstrate reversal blood flow from the external to the internal carotid during the sys- tole, suggesting the possible role of retrograde embolism in the case of plaques in the proximal external carotid artery.39

Goddi et al.37 evaluated 60 carotid bifurcations in healthy adults, identified a complex flow in the internal carotid artery, and analyzed the location and the duration of the different blood flow patterns, confirming the rela- tionship between vessel enlargement and flow distur- bances. VFI was also used to assess the normal values of wall shear stress in the common carotid arteries of 79 healthy volunteers, with a good intraclass correlation coef- ficient and inter-observer reproducibility.40

Hansen et al.41 demonstrated the association between the vector concentration in VFI and the stenosis degree percent- age obtained with digital subtraction angiography in 11 patients with stenoses of the superficial femoral artery.

In a rare case of the femoral artery “trifurcation,” where the origin of the lateral circumflex femoral artery arises from the femoral bifurcation, VFI revealed a blood recir- culation rest and retrograde blood flow redistribution dur- ing lower limb compression.42

These preliminary evaluations demonstrate that high frame rate VFI represents an innovative ultrasound appli- cation, with a better and more intuitive flow estimation within the vessel during the cardiac cycle.

Vascular access applications

Hansen et al.43 compared the blood flow volume meas- ured during dialysis sessions with VFI and the ultrasound

Figure 4. Longitudinal view of a radio-cephalic fistula
using VFI, which represents the flow with many colored vectors frame. In this frame at the systolic peak it shows high velocity red vectors at the arterial side just before the fistula anastomosis, with recirculation and reverse flow (1), multidirectional low-velocity green vector against the venous wall on the venous side of the anastomosis (3) and faster vector streamline at the venous side of the fistula (2).

dilution technique in 20 AVFs, evidencing a good corre- lation with these methods. The possible sources of error during the volume flow rate measurement with VFI are related to the off-axis placement of the scan plane com- pared to the vessel’s central axis.44

A recent study reported the use of VFI in 14 AVFs to identify the different components that compound a com- plex flow (Figure 4). The authors found the presence of a disturbed flow, probably related to oscillatory wall shear stress and neointimal hyperplasia development, at the inner wall of the juxta-anastomotic venous side, into the venous aneurysmal tracts and in concomitance of stenosis.45

Pulse wave velocity measurement

Arterial stiffness is a predisposing factor for peripheral vascular disease and represents, in atherosclerosis, an independent risk marker for cardiovascular disease.46 Arterial stiffness can be measured with many different methods, but pulse wave velocity (PWV) is considered the most reliable. PWV is the velocity at which the blood pres- sure pulse propagates through the circulatory system.47 The carotid-femoral PWV is accepted as the standard for measuring aortic stiffness based on a “propagation model” of the arterial tree. However, it has several limitations because it needs a dedicated device, the measurement is not easily feasible and repeatable, and, finally, it does not assess a local arterial stiffness difference.48 Two novel techniques are currently being evaluated for PWV meas- urement: SWE, treated in a previous section, and ultrafast ultrasound imaging or UltraFastEcho (or UltraFast® Imaging), which measures the local PWV at the beginning

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and the end of systole.48 The technological innovation is based on the extremely high imaging frame rate, which is one hundred times faster than conventional ultrasound diagnostic imaging, thus capturing the propagation of the pulse wave in a localized segment of an artery during a single cardiac cycle. The evaluation of local PWV is becoming an important tool because local PWV has emerged as a powerful independent predictor of all-cause and cardiovascular mortalities.5

Clinical applications

Many studies in the literature have proven that global PWV is a predictor of all causes and cardiovascular causes of death in the general population.49 In CKD, the arterial stiffness measured with global PWV is worse in diabetic compared with no diabetic patients. PWV worsens as kid- ney function declines irrespective of the cause of CKD. It correlates with proteinuria in CKD diabetic patients and bone and mineral disorders. PWV is associated with higher central pulse pressures and predicts the onset of heart fail- ure, death, and CKD progression to end-stage renal dis- ease.50 Currently, local PWV measurements are being studied in order to provide localized information on arte- rial stiffness in many fields, such as vessel elasticity abnor- malities of individual target arteries and the prediction of cardiovascular events and end-organ damage, classifica- tion of normal and pathological arteries in hypertensive patients, assessment of coronary artery hemodynamics and determination of acute coronary events, non-invasive assessment of fetal hemodynamics, characterization of the retinal and ocular circulation analysis, and assessment of microvascular stiffness.

Vascular access applications

The role of PWV measurement in vascular access evalua- tion is not encouraging in literature. In the Hemodialysis Fistula Maturation Study on 602 patients undergoing AVF creation, Dember et al.29 that there is a low correlation between global PWV measurement and demographic, clinical, and biochemical factors among the different vas- cular function measures. Allon et al.,51 in the same group of patients, have stated that despite the hypothesis for which the stiffness of the arterial conduit used to create the AVF would restrict arterial outward remodeling, the study failed to find such a relationship. The carotid-femoral PWV showed an inverse relationship with 6-week AVF diameter, but there were no statistically significant rela- tionships between carotid-femoral PWV/carotid-radial PWV and AVF blood flow. Masengu et al.26 and McGrogan et al.52 did not find any statistically significant association between carotid-femoral PWV, brachial-radial PWV, and AVF early failure. However, in the second study, the aortic

Figure 5. Ultrafast measurement of the local PWV of the brachial artery. Ultrafast PWV measurements are obtained at the beginning of systole (BS) and the end of systole (ES). The region of interest is adjusted to the entire field of view of the transducer.

PWV was slower in the primary patency group than the primary failure group, suggesting that stiffer vessels lead to a higher probability of AVF primary failure.

In any case, in all studies, the techniques used for PWV evaluation represent indirect measures of arterial stiffness and are influenced by the global evaluation of several different arteries that may differ in their stiffness. Consequently, local PWV measurement could represent a direct evaluation of brachial and radial artery stiffness (Figure 5). For this reason, it would be very interesting to perform studies on the preoperative evaluation of local arterial stiffness before AVF creation and the correlation with AVF outcomes.

Conclusion

The technological advances encompassed in MPUS have many potential and interesting applications in vascular access planning and surveillance, and only a few of them have already been successfully applied. However, studies with many patients are needed to standardize the parame- ters for the study of the upper limb vascular anatomy and physiopathology before and after AVF/AVG creation and to evaluate their potential correlation with vascular access outcomes.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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ORCID iD

Petrucci Ilaria

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https://orcid.org/0000-0003-1931-1581

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