https://doi.org/10.1177/1129729820947594 The Journal of Vascular Access 1 –8
© The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1129729820947594 journals.sagepub.com/home/jva
JVA
The Journal ofVascular Access
Introduction
Central venous access devices (CVADs) have become rou-tine part of the management of hospitalized patients for the administration of chemotherapy, antimicrobial therapy, and parenteral nutrition and for blood sampling.1 Despite being
perceived as essential tools, their use is also inevitably asso-ciated with early and late complications. Catheter-related thrombosis (CRT), defined as a mural thrombus extending from the catheter into the lumen of a vessel,2 represents one
of the most common complications following central venous access insertion, potentially leading to local signs and symp-toms, catheter removal, delay in treatment, post-thrombotic syndrome, and very rarely, life-threatening events such as pulmonary embolism.3–5 Despite the amount of available
studies, many aspects surrounding CRT remain controver-sial. First, its actual incidence is difficult to define, since the rate of CRT ranges from 0% to 71.9%,6–15 due to
heteroge-neity in study settings in terms of type of CVAD, definition of thrombosis, diagnostic criteria, and inclusion/exclusion of asymptomatic thrombotic events. Furthermore, albeit
playing a pivotal role in CRT occurrence, CVAD insertion technique is often neglected in many clinical studies.
Thirteen years ago, the Italian Study Group for Long Term Central Venous Access (GAVeCeLT) developed a nationwide Consensus16 in order to clarify some key aspects
on this topic. However, the knowledge around CRT has greatly evolved over the last decade, with a natural evolution in terms of catheter technologies, insertion techniques, and management bundles. The aim of this editorial is to read-dress the same eight fundamental questions of the 2007 GAVeCeLT Consensus, on the basis of current knowledge.
Reconsidering the GAVeCeLT
Consensus on catheter-related
thrombosis, 13 years later
Fulvio Pinelli
1, Paolo Balsorano
1, Benedetta Mura
2and Mauro Pittiruti
3Abstract
Catheter-related thrombosis represents one of the most common complications following central venous access insertion. Despite the amount of available studies, many aspects surrounding catheter-related thrombosis remain controversial. Thirteen years ago, the Italian Study Group for Long Term Central Venous Access (GAVeCeLT) developed a nationwide Consensus in order to clarify some key aspects on this topic. Despite most of them still remain valid, however, knowledge around catheter-related thrombosis has greatly evolved over the last decade, with a natural evolution in terms of catheter technologies, insertion techniques, and management bundles. Aims of this editorial are to readdress conclusions of the 2007 GAVeCeLT Consensus in the light of the new relevant evidences that have been added in the last 13 years and to analyze some unsolved issues that still remain debated.
Keywords
Central venous catheter, catheter-related thrombosis, central venous catheter thrombosis, venous thromboembolism, deep vein thrombosis
Date received: 25 April 2020; accepted: 8 July 2020
1 Department of Anesthesia and Intensive Care, Careggi University
Hospital, Florence, Italy
2 School of Human Health Science, University of Florence, Florence,
Italy
3Department of Surgery, Catholic University Hospital, Rome, Italy
Corresponding author:
Fulvio Pinelli, Department of Anesthesia and Intensive Care, Careggi University Hospital, Largo Brambilla 3, 50012 Florence, Italy. Email: fulvio.pinelli@me.com
Old answers and relative recommendations will be presented as they originally appeared in the 2007 Consensus. Our answers to the questions will update and integrate the old answers providing recent evidence. Finally, a few unsolved issues related to CRT will be discussed so as to highlight some areas where further studies are warranted.
By which mechanisms may a catheter cause
venous thrombosis? Which is the difference
between CRT and fibrin sheath?
2007 GAVeCeLT Consensus: There are multiple mecha-nisms, always including an acute and/or chronic endothe-lial damage to the vein wall, produced by a foreign intravascular body. Although mechanisms of fibrin sheath formation are well-known, their relationship with the thrombotic event is not yet clear.16
Recent findings confirm that pathogenesis of thrombosis is multifactorial.17 In this context, factors involved in the
pathogenesis of CRT traditionally include vessel wall injury as a result of needle insertion, venous stasis or occlusion as a result of the relationship between catheter and vein diameter, and patient-related hypercoagulability. While some technical factors may be modified in order to reduce the risk of CRT, hypercoagulability is inevitably related to the patient’s char-acteristics and comorbidities (hypercoagulable states, malig-nancies, sepsis, pregnancy or peri-partum, left ventricular dysfunction, prolonged immobility, etc.), thus being suscep-tible to be modulated only to a limited extent.
Thrombosis and fibroblastic sleeve
The fibroblastic sleeve which surrounds the catheter is not a thrombotic event. This sleeve, erroneously named “fibrin sleeve” or “fibrin sheath,” is a physiological phenomenon which occurs when a foreign body is in prolonged contact with the blood fluid, inside the vessels. The sleeve is made of connective tissue, and it starts with the early deposition of circulating fibronectin over the catheter within 24 h after insertion, with subsequent proliferation of fibroblastic cells and collagen deposition.1 Experimental evidence in rats
sug-gests the hypothesis of a migration of smooth muscle cells from the endothelium, with redifferentiation as fibro-blasts.18,19 On the contrary, thrombosis starts from tissue
fac-tors released after the endothelial injury;20 the thrombus is a
tissue generated by aggregated platelets mixed with a mesh of specialized coagulation proteins (including fibrin). Even if mechanisms of fibroblastic sleeve and thrombosis formation are well-known, their relationship remains still unclear.21
Is there an ideal insertion technique for
minimizing the risk?
2007 GAVeCeLT Consensus: To date, to our knowledge, no randomized trials have investigated the relationships
between insertion techniques in the long-term setting (e.g. percutaneous vs venous cut-down, US-guided vs anatomic landmark techniques) and central venous thrombosis rate. Prospective, non-randomized studies have suggested a relationship between minimal insertion damage to vein wall, as obtained with US guidance, and low rate of subse-quent thrombotic events.16
US guidance is nowadays considered a standard of care for catheter insertion and appropriate vein choice.22
Since 2008, an extensive body of evidence has demon-strated that real-time ultrasound-guided venipuncture reduces the risk of CRT.23 US guidance has shown to
reduce puncture attempts, technical failures, and mechan-ical complications, thus minimizing vessel wall trauma, a key element in CRT development. A recent meta-analysis8
which included only studies where catheter insertion had been performed according to good clinical practice (US-guided venipuncture, appropriate catheter size choice, and proper verification of tip location) showed a low incidence of CRT. As a result, US guidance is cur-rently recommended in all bundles aimed at catheter-related complication prevention.23,24
Is there any device or material that may
intrinsically reduce the risk?
2007 GAVeCeLT Consensus: Silicone and second- and third-generation polyurethane catheters are less thrombo-genic than polyethylene or polyvinylchloride. A lower diameter catheter and a single lumen might be protective against the risk of central venous thrombosis. When the number of therapies demands a multiple-lumen catheter, the number of lumens used should be minimized.16
The choice of the device in terms of type of venous approach, material, and size plays an important role in order to minimize thrombotic risk and ensure good cathe-ter performance.22
Type. Type of central venous approach results in different risks of CRT. Femorally inserted central catheters (FICCs) have the highest risk of CRT, with a rate of 5%–15% in adult patients. Furthermore, lower limb CRT is associated with a fourfold increase in risk of pulmonary embolism.6
No hard data about the actual incidence of venous throm-bosis related to centrally inserted central catheters (CICCs) are available, with reported rates ranging between 3% and 5%, depending on catheter size, cannulation route, and insertion technique. As for peripherally inserted central catheters (PICCs), current evidence shows that if they are inserted respecting the proper indications and paying attention to a few technical aspects, the rate of sympto-matic CRT is 3% or less in both oncologic and non-onco-logic patients and a little higher (5%–6%) in hematonon-onco-logic patients.7 Moreover, PICC-related pulmonary embolism is
thrombosis-related morbidity and mortality, the use of PICCs should be recommended over CICCs and FICCs.13,14
Materials. Experimental and clinical evidence confirmed that polytetrafluoroethylene and polyethylene are more thrombogenic compared with silicone and second-/third-generation polyurethane.25
In recent years, two different types of medicated PICCs have been released into the market, with supposed antithrom-bogenic activity: Angiodynamics BioFlo® PICCs with
Endexo® technology and Arrow PICCs with Chloragard
technology®. Endexo® is a low-molecular-weight
fluorine-oligomeric additive that self-locates in the first few nanom-eters of the surface of the material. It is not a catheter coating, but rather it is incorporated into the polyurethane. As a result, antithrombogenic properties are located on the internal, external, and cutting surfaces of PICC. This substance inhib-its platelet adhesion, suppresses the formation of protein pro-coagulants, and reduces thrombus formation.26
Nevertheless, at present, there is scarce evidence sug-gesting the effectiveness of Endexo® technology in
reduc-ing the risk of CRT and no convincreduc-ing evidence of its cost-effectiveness.26,27
As regards chlorhexidine-coated PICCs (Chloragard®),
in one recent experimental study, they have been associ-ated with a non-significant reduction of fibroblastic sleeve, with no effect on CRT.28
Therefore, at the moment, no conclusion can be drawn from available evidences about the role of medicated cath-eters in CRT reduction.
Size. The presence of the catheter itself inside the vein invariably reduces blood flow. Retrospective observations reported a greater risk of CRT when using larger catheters, especially when inserted in small veins, as it occurs with PICCs and with any CVAD in children.29,30 In the
ultra-sound era, the possibility of measuring the vein diameter has introduced the concept of catheter/vein ratio. In vitro and in vivo studies have confirmed that catheter/vein ratio may be more relevant than catheter diameter per se. An ideal catheter/vein ratio has not yet been defined. On the basis of the in vitro study by Nifong et al.,19 many
institu-tions have adopted the rule of 33%. Similarly, the interna-tional WoCoVA-GAVeCeLT-WINFOCUS Consensus suggests that the external diameter of the catheter should not exceed one-third of the internal diameter of the vein.23
The rule of the 33% has also the advantage of being easy to remember, easy to teach, easy to learn, and easy to apply. In fact, in practical terms, according to that rule, for a 3 mm vein, one will choose a 3 Fr catheter, for a 4 mm vein a 4 Fr catheter, for a 5 mm vein a 5 Fr, and so on. Micro-introducers. Vessel wall trauma as a result of catheter insertion is one of the main mechanisms at the basis of CRT occurrence. Therefore, the use of small introducer kits (21G
echogenic needle, atraumatic 0.018″ nitinol guidewire, 3 or 4 Fr micro-introducers) represents an obvious benefit during catheter insertion in order to limit vessel injury. The use of micro-introducers has been included in evidence-based insertion bundles10,31–33 for catheter-related complication
prevention, and their widespread use reflects recent advances in terms of technical development and awareness of factors related to catheter-related thrombotic events. Proper securement. Catheter stabilization has emerged as an important aspect in minimizing catheter-related complica-tions.34 Inadequate securement is associated not only with
the risk of dislodgment but also with in and out movements of the catheter at the exit site, which may cause prolonged trauma to the vein wall trauma and enhance bacterial con-tamination by the extraluminal route.35 Strategies of proper
securement include (a) appropriate choice of the exit site, with mid-upper arm and infraclavicular area being the pre-ferred catheter exit sites, (b) use of sutureless36 devices or
subcutaneously anchored systems (SAS) and (c) semiper-meable transparent dressing.34 Proper catheter securement
techniques have shown to reduce phlebitis, local infection, catheter migration, and dislodgement, all known risk fac-tors for CRT.37 However, the impact of securement
tech-niques on CRT has not been fully demonstrated yet. Some authors have shown that securement devices help reducing catheter-related bloodstream infections (CRBSI) and improve cost-effectiveness in patients with non-tunneled CVADs, including PICCs.38 Finally, a recent
meta-analy-sis39 showed that transparent dressing might reduce CRBSI.
It is possible that this type of dressing, improving the stabil-ity of the catheter, may also be helpful in reducing CRTs.
What are the patient’s risk factors?
2007 GAVeCeLT Consensus: Neoplastic disease and chem-otherapy are recognized risk factors for the development of central venous thrombosis in patients with a central venous catheter. Pathophysiology includes direct release of throm-bogenic factors by neoplastic cells, decrease of antithrom-botic natural factors induced by the tumor, and the procoagulant activity of many antineoplastic drugs. In non-randomized studies, mutations of Factor V Leiden and/or the prothrombin gene and low antithrombin III levels have been found to be related to a higher incidence of central venous thrombosis in cancer patients with a central venous catheter. Hereditary screening procedures for thrombo-philia are not presumably cost-effective.16
particular, the tumor itself produces procoagulant and anti-fibrinolytic factors, such as plasminogen activation inhibi-tor-1, tissue factor, and podoplanin,41 and these substances,
through the expression of adhesion molecules and the release of cytokines and angiogenic factors, cause an increase in thrombin and fibrin formation, therefore lead-ing to a hypercoagulable state.40,42 In addition, many
anti-tumor drugs exert a clotting activation.43,44
Not all oncology patients have the same thrombotic risk. In fact, patients with certain types of tumors such as gastric and pancreatic adenocarcinoma, ovarian cancer, and espe-cially, onco-hematological diseases are at increased risk for CRT.
Critically ill patients are also at increased risk for CRT. In fact, in addition to general venous thromboembolism risk factors, intensive care unit (ICU) patients are exposed to ICU-acquired risk factors, such as prolonged sedation, immobilization, and vasopressors use. In particular, the incidence of CRT in the ICU setting is higher in the elderly, in septic patients, and in patients with FICCs, especially if placed in emergency.6,40
What is the role of central venous catheter tip
positioning?
2007 GAVeCeLT Consensus: In many prospective studies, tip positioning emerged as the main independent prognostic factor for malfunction, thrombosis, and reduced duration of the device. In oncology patients, the cavoatrial junction appears to be the optimal position of the catheter, as it mini-mizes the risk of central venous thrombotic events.16
All current guidelines agree that an incorrect tip position is a major risk factor for CRT, arrhythmias, valve, and heart lesions.45 The distal tip of the catheter should be placed at
the junction between superior vena cava and the right atrium.46 Post-operative chest X-ray has been traditionally
considered the gold standard for central catheter’s tip loca-tion for many years. As an alternative, fluoroscopy has been used diffusively worldwide for both tip location and tip navigation. However, recent guidelines47 recommend
non-invasive intra-procedural methods for tip location, such as intracavitary electrocardiography (IC-EKG) or transthoracic echocardiography (TTE).
IC-EKG and TTE have several advantages over radiol-ogy: as opposed to chest X-ray, they are intra-procedural, allowing real-time verification of correct tip position; also, they are more accurate and less expensive,48 especially
com-pared to fluoroscopy.49 Also, they are safer for both patients
and operators, avoiding ionizing radiation exposure.
If thrombosis occurs, when should the catheter
be removed?
2007 GAVeCeLT Consensus: Catheter removal or mainte-nance does not influence the outcome. Although local
thrombolytic treatment may require the presence of the catheter, a poor peripheral vein status could represent a major limiting factor for most therapies, if the catheter has been removed. In case of clinically overt or imaging diag-nosed deep vein thrombosis (DVT), a risk of embolization during or immediately after catheter removal has been clinically confirmed. Catheter should be removed in case of (a) infected thrombus, (b) malposition of the tip, and (c) irreversible occlusion of the lumen.16
International guidelines2,22,46,50 recommend the
mainte-nance of the catheter in the presence of CRT if the catheter is necessary for the patient, still functioning, correctly positioned with the distal tip placed at the cavoatrial junc-tion, and with no signs or symptoms of infection. Increased risk of pulmonary embolism due to mobilization of the thrombus is reported during or immediately after the VAD removal,51,52 in particular when the CRT involves the tip of
the catheter and the thrombus is recent and partially floating.51,52
Should the catheter be removed, it is wise to do it only after a short course of treatment with low-molecular-weight heparin (LMWH; 3–5 days according to the 2015 European Society for Medical Oncology (ESMO) guide-lines).53 In case of a PICC-related thrombosis localized in
the veins of the arm, even if there is no data, removal is probably safe after 72 h of treatment. At the moment, there are no recommendations by available guidelines about the need of ultrasound evaluation before removal of a catheter complicated by thrombosis. In this context, it is notewor-thy to say that the aim of the short course of LMWH before catheter removal is not to dissolve the whole thrombus but to stabilize it, by dissolving only the friable part of the thrombus. However, while not routinely suggested, US evaluation by mean of CUS (compressive ultrasound) technique before catheter removal might be a reasonable option in case of risk factors for clot embolism, such as a floating thrombus.
What is the ideal pharmacological
management?
2007 GAVeCeLT Consensus: Thrombolytic drugs should be used in acute symptomatic cases (diagnosis <24 h after the first symptoms). Efficacy of systemic versus local thrombolysis is still a matter of debate, especially for large thrombi. Chronic symptomatic cases should be treated with a combination of LMWH and then oral anticoagu-lants, or LMWH long term alone, depending on the clini-cal setting. Compared with warfarin, the LMWHs exhibit a superior safety profile and more predictable antithrom-botic effects and can usually be given once daily in a unit dose without the need for dose monitoring.16
regimen does not differ from the one usually adopted for non-CRT of the deep veins of the lower limbs.54 Treatment
starts with parenteral anticoagulants, subcutaneous LMWH, or fondaparinux; some guidelines suggest to shift later to a vitamin K antagonist (warfarin), while others recommend to continue with LMWH.2,55 LMWH is usually preferred to
warfarin in CRT patients with cancer56 due to a more
favora-ble risk profile. Most guidelines recommend LMWH (Dalteparin 200 IU/kg/day o.d., Enoxaparin 1 mg/kg b.i.d.) for at least 3 months (or until removal of the CVAD, should the CVAD stay in place for more than 3 months after the CRT episode).
Thrombolysis represents a therapeutic option only in specific cases. It may be considered in case of very acute presentation with severe symptoms refractory to conven-tional therapy and/or thrombosis extension in superior vena cava, in patients with low bleeding risk.2,57,58
Can we prevent catheter-related central venous
thrombosis?
2007 GAVeCeLT Consensus: Although some open-label, early trials suggested a benefit of oral, low-dose daily warfarin or daily subcutaneous dose of LMWHs, more recent randomized, double-blind, placebo-controlled, and sufficiently powered trials did not find any advantages for either of these prevention strategies. The choice to start a prophylaxis of venous thromboembolic events in all oncol-ogy patients bearing a central venous catheter, either with LMWHs or with mini-dose warfarin, remains unsupported by evidence-based medicine. GAVeCeLT suggests consid-ering prophylaxis with a daily single dose of LMWH 100 IU/kg only in high-risk population (including those who have a family history or previously suffered from idi-opathic venous thrombotic events of the upper or lower vena cava district).16
Several randomized trials have evaluated LMWH, low-dose warfarin, or unfractionated heparin as an attempt to reduce the risk of CRT in adult patients with cancer or critical illness. However, a clinical benefit coming from these interventions has not been proven yet. A recent meta-analysis59 including 13 randomized controlled trials
(RCTs) on 3420 patients found a moderate evidence that LMWH prophylaxis may reduce CRT if compared to con-trols. However, the analysis did not confirm or exclude a beneficial or detrimental role of prophylactic LMWH on mortality, major and minor bleeding. In the same meta-analysis, low-dose warfarin did not show any beneficial or detrimental effect on symptomatic CRT compared to con-trols. Furthermore, the evidence was not conclusive for the effect of LMWH on mortality and risk of symptomatic CRT if compared to warfarin.
As a result, based on the current lack of evidence in terms of meaningful clinical endpoints, experts do not rec-ommend routine pharmacological prophylaxis in cancer
patients with indwelling central VAD to prevent CRT. However, LMWH prophylaxis can be considered in high-risk patients, including those who have hereditary anoma-lies associated with thrombophilia or previously suffered from CRT or DVT related to the neoplastic disease. In these patients, clinicians should balance the possible ben-efit of reduced thromboembolic complications with the possible arms of anticoagulation.
Unanswered issues
Asymptomatic CRT natural history
The natural history of asymptomatic thrombosis is an often neglected aspect surrounding CRT, which may play an essential role in terms of diagnostic and therapeutic approaches. At the moment, an extensive body of literature is available for symptomatic events where the presence of symptoms allows early diagnosis and treatment, leading to a low rate of serious adverse events, such as pulmonary embolism and post-thrombotic syndrome. However, little is known about asymptomatic events in adult patients, which mostly appear to be incidental findings during diag-nostic screening procedures. In this context, asymptomatic CRT natural history in pediatric patients has been elegantly evaluated by Jones et al.60 In their study, thrombus
exten-sion, clinical pulmonary embolism, and post-thrombotic syndrome appeared to be uncommon events when asymp-tomatic thrombotic events were not treated. Further inves-tigation is warranted in adult patients, so as to determine whether asymptomatic upper extremity CRT should be screened and treated or whether it represents an unevent-ful, not clinically relevant event.
Length of treatment
Recommendations on anticoagulation for CRT (i.e. 3 months of treatment) are mainly extrapolated from data on non-CRT of deep veins of the lower limb. However, the latter phenomenon is quite different from CRT in terms of pathophysiology. Prolonged anticoagulation is not devoid of risks, while the optimal duration of treatment following CVAD removal is not clear, due to lack of good quality data. In this context, length of treatment is often variable between different institutions, reflecting personal prefer-ences and believes. Therefore, also in this field, further studies are warranted in order to reach a more coherent and uniform approach.
Conclusion
In the last decade, our understanding of CRT risk fac-tors has greatly improved.40 Based on new evidence, the
implementation of insertion and management bundles have been shown to be effective in reducing catheter-related complications.34 In fact, CRT rates have been
steadily decreasing over the years, thanks to the adoption of appropriate strategies, such as ultrasound guidance, proper selection of vein and catheter size, adequate tip placement, and adequate catheter securement.8,23
Understanding the clinical relevance of CRT is another key challenge today. Since the natural history of sympto-matic CRT is well-known, we can intervene with prompt diagnosis and effective treatment and ensure a positive clinical outcome. On the contrary, the natural history of asymptomatic thrombosis is quite mysterious, so that a precautionary behavior still influences our approach toward this poorly understood phenomenon.60,61
Also, some pharmacological aspects in the manage-ment of CRT are not yet well defined.2,55 The actual length
of treatment is not known. The indications to prophylaxis with LMWH are still controversial. The reduction of CRT rates “at any cost” may not necessarily lead to better clini-cal outcomes. However, pharmacologic prophylaxis might be considered in high-risk patients after careful considera-tion of related risks and benefits.59
While many of the recommendations of the original GAVeCeLT Consensus on CRT are still valid, new relevant evidences have been added in the last 13 years. These new insights have greatly improved our knowledge surrounding CRT prevention and risk minimization, leading us to a new perspective, where CVAD insertion should reflect actual clinical needs, without fearing iatrogenic complications.
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.
ORCID iDs
Fulvio Pinelli https://orcid.org/0000-0002-9926-2128 Paolo Balsorano https://orcid.org/0000-0003-0706-734X Mauro Pittiruti https://orcid.org/0000-0002-2225-7654
References
1. McGee DC and Gould MK. Preventing complications of central venous catheterization. New Engl J Med 2003; 348: 1123–1133.
2. Debourdeau P, Farge D, Beckers M, et al. International clinical practice guidelines for the treatment and prophy-laxis of thrombosis associated with central venous catheters
in patients with cancer. J Thromb Haemost 2013; 11(1): 71–80.
3. Geerts W. Central venous catheter-related thrombosis.
Hematology 2014; 2014: 306–311.
4. Baumann Kreuziger L, Cote L, Verhamme P, et al. A RIETE registry analysis of recurrent thromboembolism and hemorrhage in patients with catheter-related thrombosis. J
Vasc Surg Venous Lymphat Disord 2015; 3(3): 243–250.
5. White D, Woller SC, Stevens SM, et al. Comparative thrombosis risk of vascular access devices among critically ill medical patients. Thromb Res 2018; 172: 54–60. 6. Minet C, Potton L, Bonadona A, et al. Venous
thrombo-embolism in the ICU: main characteristics, diagnosis and thromboprophylaxis. Crit Care 2015; 19: 287.
7. Chopra V, Anand S, Hickner A, et al. Risk of venous throm-boembolism associated with peripherally inserted central catheters: a systematic review and meta-analysis. Lancet 2013; 382: 311–325.
8. Balsorano P, Virgili G, Villa G, et al. Peripherally inserted central catheter-related thrombosis rate in modern vascular access era-when insertion technique matters: a systematic review and meta-analysis. J Vasc Access 2019; 21: 45–54. 9. Zochios V, Umar I, Simpson N, et al. Peripherally inserted
central catheter (PICC)-related thrombosis in critically ill patients. J Vasc Access 2014; 15(5): 329–337.
10. Pittiruti M, Brutti A, Celentano D, et al. Clinical experience with power-injectable PICCs in intensive care patients. Crit
Care 2012; 16: R21.
11. Malinoski D, Ewing T, Bhakta A, et al. Which central venous catheters have the highest rate of catheter-associated deep venous thrombosis: a prospective analysis of 2,128 catheter days in the surgical intensive care unit. J Trauma
Acute Care Surg 2013; 74(2): 454–460.
12. Poletti F, Coccino C, Monolo D, et al. Efficacy and safety of peripherally inserted central venous catheters in acute cardiac care management. J Vasc Access 2018; 19(5): 455– 460.
13. Nolan ME, Yadav H, Cawcutt KA, et al. Complication rates among peripherally inserted central venous catheters and centrally inserted central catheters in the medical intensive care unit. J Crit Care 2016; 31(1): 238–242.
14. Takashima M, Schults J, Mihala G, et al. Complication and failures of central vascular access device in adult critical care settings. Crit Care Med 2018; 46(12): 1998–2009. 15. Cortelezzi A, Moia M, Falanga A, et al. Incidence of
thrombotic complications in patients with haematological malignancies with central venous catheters: a prospective multicentre study. Br J Haematol 2005; 129(6): 811–817. 16. Campisi C, Biffi R and Pittiruti M. Catheter-related
cen-tral venous thrombosis: the development of a nationwide Consensus paper in Italy. J Assoc Vasc Access 2007; 12: 38–46.
17. Bagot CN and Arya R. Virchow and his triad: a question of attribution. Br J Haematol 2008; 143(2): 180–190.
18. Forauer AR, Theoharis CGA and Dasika NL. Jugular vein catheter placement: histologic features and development of catheter-related (fibrin) sheaths in a swine model. Radiology 2006; 240(2): 427–434.
peripherally inserted central venous catheters. Chest 2011; 140(1): 48–53.
20. Guyton AC and Hall JE. Guyton and Hall textbook of
medi-cal physiology. 13th ed. Amsterdam: Elsevier, 2015.
21. Boddi M, Villa G, Chiostri M, et al. Incidence of ultra-sound-detected asymptomatic long-term central vein cath-eter-related thrombosis and fibrin sheath in cancer patients.
Eur J Haematol 2015; 95(5): 472–479.
22. Pittiruti M, Hamilton H, Biffi R, et al. ESPEN guidelines on parenteral nutrition: central venous catheters (access, care, diagnosis and therapy of complications). Clin Nutr 2009; 28(4): 365–377.
23. Lamperti M, Bodenham AR, Pittiruti M, et al. International evidence-based recommendations on ultrasound-guided vascular access. Intensive Care Med 2012; 38(7): 1105– 1117.
24. Franco-Sadud R, Schnobrich D, Matthews BK, et al. Recommendations on the use of ultrasound guidance for central and peripheral vascular access in adults: a position statement of the Society of Hospital Medicine. J Hosp Med 2019; 14: E1–E22.
25. Poli P, Scocca A, Di Puccio F, et al. A comparative study on the mechanical behavior of polyurethane PICCs. J Vasc
Access 2016; 17(2): 175–181.
26. Interface biologics, https://www.interfacebiologics.com/ (accessed 22 February 2020).
27. Kleidon T, Ullman AJ, Zhang L, et al. How does your PICCOMPARE? A pilot randomized controlled trial com-paring various PICC materials in pediatrics. J Hosp Med 2018; 13: 517–525.
28. Sylvia CJ Jr, Wagel MA, Giare-Patel K, et al. Chlorhexidine-coated peripherally inserted central catheters reduce fibro-blastic sleeve formation in an in vivo ovine model. J Vasc
Access 2018; 19(6): 644–650.
29. Menéndez JJ, Verdú C, Calderón B, et al. Incidence and risk factors of superficial and deep vein thrombosis associated with peripherally inserted central catheters in children. J
Thromb Haemost 2016; 14(11): 2158–2168.
30. Koo CM, Vissapragada R, Sharp R, et al. ABO blood group related venous thrombosis risk in patients with peripher-ally inserted central catheters. Br J Radiol 2018; 91(1082): 20170560.
31. Cotogni P, Pittiruti M, Barbero C, et al. Catheter-related complications in cancer patients on home parenteral nutri-tion: a prospective study of over 51,000 catheter days. JPEN
J Parenter Enteral Nutr 2013; 37(3): 375–383.
32. Cotogni P, Barbero C, Garrino C, et al. Peripherally inserted central catheters in non-hospitalized cancer patients: 5-year results of a prospective study. Support Care Cancer 2015; 23(2): 403–409.
33. Pittiruti M, Emoli A, Porta P, et al. A prospective, rand-omized comparison of three different types of valved and non-valved peripherally inserted central catheters. J Vasc
Access 2014; 15(6): 519–523.
34. Loveday HP, Wilson JA, Pratt RJ, et al. Epic3: national evi-dence-based guidelines for preventing healthcare-associated infections in NSH hospitals in England. J Hosp Infect 2014; 86(Suppl 1): S1–S70.
35. Chan RJ, Northfield S, Larsen E, et al. Central venous Access device SeCurement and Dressing Effectiveness for
peripherally inserted central catheters in adult acute hospital patients (CASCADE): a pilot randomised controlled trial.
Trials 2017; 18: 458.
36. Yamamoto AJ, Solomon JA, Soulen MC, et al. Sutureless securement device reduces complications of peripherally inserted central venous catheters. J Vasc Interv Radiol 2002; 13: 77–81.
37. Alekseyev S, Byrne M, Carpenter A, et al. Prolonging the life of a patient’s IV: an integrative review of intravenous securement devices. Medsurg Nurs 2012; 21(5): 285–292. 38. Petree C, Wright DL, Sanders V, et al. Reducing blood
stream infections during catheter insertion. Radiol Technol 2012; 83(6): 532–540.
39. Dang FP, Li HJ and Tian JH. Comparative efficacy of 13 antimicrobial dressings and different securement devices in reducing catheter-related bloodstream infections: a Bayesian network meta-analysis. Medicine 2019; 98(14): e14940.
40. Verso M and Agnelli G. Venous thromboembolism associ-ated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003; 21: 3665–3675.
41. Hisada Y and Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood 2017; 130: 1499– 1506.
42. Khorana A, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-asso-ciated thrombosis. Blood 2008; 111: 4902–4907.
43. Zakarija A and Kwaan HC. Adverse effects on hemostatic function of drugs used in hematologic malignancies. Semin
Thromb Hemost 2007; 33(4): 355–364.
44. Ramot Y, Nyska A and Spectre G. Drug-induced thrombo-sis: an update. Drug Saf 2013; 36(8): 585–603.
45. Vesely TM. Central venous catheter tip position: a continu-ing controversy. J Vasc Interv Radiol 2003; 14(5): 527–534. 46. Debourdeau P, Kassab Chahmi D, Le Gal G, et al. 2008
SOR guidelines for the prevention and treatment of throm-bosis associated with central venous catheters in patients with cancer: report from the working group. Ann Oncol 2009; 20(9): 1459–1471.
47. Gorski LA. The 2016 infusion therapy standards of practice.
Home Healthc Now 2017; 35: 10–18.
48. Gao Y, Liu Y, Zhang H, et al. The safety and accuracy of ECG-guided PICC tip position verification applied in patients with atrial fibrillation. Ther Clin Risk Manag 2018; 14: 1075–1081.
49. Pittiruti M, La Greca A and Scoppettuolo G. The electrocar-diographic method for positioning the tip of central venous catheters. J Vasc Access 2011; 12(4): 280–291.
50. Giordano P, Saracco P, Grassi M, et al. Recommendations for the use of long-term central venous catheter (CVC) in children with hemato-oncological disorders: management of CVC-related occlusion and CVC-related thrombosis. Ann
Hematol 2015; 94(11): 1765–1776.
51. Zuha R, Price T, Powles R, et al. Paradoxical emboli after central venous catheter removal. Ann Oncol 2000; 11(7): 885–886.
53. Sousa B, Furlanetto J, Hutka M, et al. Central venous access in oncology: ESMO clinical practice guidelines. Ann Oncol 2015; 26(Suppl 5): v152–v168.
54. Pittiruti M and Scoppettuolo G. Manuale GAVeCeLT dei
PICC e dei Midline. Indicazioni, impianto, gestione. [The GAVeCeLT manual of PICC and midline. indications, inser-tion, management]. Edra, Milan, Italy, 2017.
55. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and pre-vention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Chest 2012; 141(Suppl 2): e419S–e496S.
56. Lee AYY, Peterson EA and Wu C. Clinical practice guide-lines on cancer-associated thrombosis: a review on scope and methodology. Thromb Res 2016; 140(Suppl 1): S119– S127.
57. Schindler J, Bona RD, Chen HH, et al. Regional throm-bolysis with urokinase for central venous catheter-related thrombosis in patients undergoing high-dose chemotherapy
with autologous blood stem cell rescue. Clin Appl Thromb
Hemost 1999; 5(1): 25–29.
58. Pucheu A, Dierhas M, Leduc B, et al. Fibrinolyse des thromboses veineuses profondes sur dispositifs de perfu-sion implantables. A Propos D’une Série Consécutive De 57 Thromboses Et De 32 Fibrinolyses [Fibrinolysis of deep venous thrombosis on implantable perfusion devices. Apropos of a consecutive series of 57 cases of thrombo-sis and 32 cases of fibrinolythrombo-sis]. Bull Cancer 1996; 83: 293–299.
59. Kahale LA, Tsolakian IG, Hakoum MB, et al. Anticoagulation for people with cancer and central venous catheters. Cochrane Database Sys Rev 2018; 6: CD006468. 60. Jones S, Butt W, Monagle P, et al. The natural history of
asymptomatic central venous catheter–related thrombosis in critically ill children. Blood 2019; 133: 857–866.
