Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis

Accepted Manuscript Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis

Noa Mandel-Shorer, Shimrit Tzvi-Behr, Elizabeth Harvey, Shoshana Revel-Vilk PII: DOI: Reference:

S0049-3848(18)30593-0 https://doi.org/10.1016/j.thromres.2018.10.031 TR 7190

To appear in:

Thrombosis Research

Received date: Revised date: Accepted date:

3 August 2018 1 October 2018 29 October 2018

Please cite this article as: Noa Mandel-Shorer, Shimrit Tzvi-Behr, Elizabeth Harvey, Shoshana Revel-Vilk , Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis. Tr (2018), https://doi.org/10.1016/ j.thromres.2018.10.031

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ACCEPTED MANUSCRIPT Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis

Noa Mandel-Shorer1, Shimrit Tzvi-Behr2, Elizabeth Harvey3, Shoshana Revel-Vilk4

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick

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1

Division of Pediatric Nephrology, Shaare Zedek Medical Center, affiliated with

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2

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Children and University of Toronto, Toronto, Canada

Hadassah- Hebrew University Medical School, Jerusalem, Israel Division of Pediatric Nephrology, Department of Pediatrics, The Hospital for Sick

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3

Children and University of Toronto, Toronto, Canada Pediatric Hematology/Oncology Unit, Department of Pediatrics, Shaare Zedek Medical

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4

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Center, affiliated with Hadassah- Hebrew University Medical School, Jerusalem, Israel

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ACCEPTED MANUSCRIPT Abstract: Despite the high rate of central venous catheter (CVC)-related venous thromboembolic (VTE) complications and long-term sequelae, CVCs remain a vital component of patient care in children with complex underlying diseases. In this review, we focus on CVC-related VTE in children with end-stage renal disease (ESRD) undergoing hemodialysis, a population in whom the provision of renal replacement

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therapy is a lifelong undertaking. Occlusion of the CVC and thrombosis underlie most

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instances of access malfunction and failure in children on chronic hemodialysis. Frequent

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CVC replacements are required, resulting in increased risk of central vein thrombosis and stenosis, precluding adequate hemodialysis in years to come. As recurrent CVC

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malfunction may constitute the sole sign of CVC-related VTE, a high index of suspicion is required for its investigation and the consequent institution of anticoagulation

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treatment, attempting to salvage the CVC and minimize recurrent line exchanges and venous cannulations and their sequelae. Hemodialysis access planning should take into

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account potentially modifiable prothrombotic risk factors in order to preserve vascular

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access. Effective strategies for maintenance of catheter patency and survival are needed for the conservation of future hemodialysis access. Further investigation aiming for

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identification of predictors of CVC-related VTE in children undergoing hemodialysis will aid in the design and application of much needed multicenter prospective studies

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examining the benefit and the safety of thromboprophylaxis.

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ACCEPTED MANUSCRIPT Introduction The last decade has witnessed a significant increase in the incidence of pediatric venous thromboembolism (VTE) [1]. In addition to the availability of better diagnostic methods and increasing awareness of VTE in children, this increasing frequency of VTE can be explained by the ongoing advances in pediatric critical and complex patient care, allowing

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for the survival of children who in the past would have succumbed.

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The use of central venous catheters (CVCs), both acute and chronic, is an essential

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component of advanced pediatric care, allowing for the administration of intravenous therapy, such as fluids, medications, total parenteral nutrition (TPN), and blood

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products, as well as for the provision of hemodialysis and plasmapheresis [2–4]. The presence of a CVC is the single most important risk factor for VTE in the pediatric

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population [5].

The reported incidence of pediatric CVC-related VTE varies widely, ranging from 1-80%

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in children with CVCs [2,6]. This remarkable variation in reported rates stems from

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differences in study design (e.g. inclusion of symptomatic vs. asymptomatic events; differing imaging modalities employed), and heterogeneity of patient populations

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included in the different studies [2,7,8]. Although most CVC-related VTEs remain asymptomatic [9–11], significant morbidity

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and mortality are associated with their occurrence, with reports of a 2-4% mortality rate in hospitalized children [12,13]. Acute/short-term complications of CVC-related VTE include pulmonary embolism (PE), SVC syndrome, chylothorax, paradoxical embolic stroke through intracardiac right-to-left shunting, cardiac arrest, CVC-related infection and sepsis, and repeated loss of CVC patency requiring local thrombolytic therapy or CVC replacement [9,13,14]. Long-term consequences of CVC-related VTE include the development of post-thrombotic syndrome (PTS), recurrent thrombosis, and loss of future

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ACCEPTED MANUSCRIPT venous access [13–16]. The severity of PTS has been reported to evolve and worsen over time, and to be associated with a decreased health-related quality of life (HRQoL) [17,18]. Chronic venous alterations following deep vein thrombosis (DVT), including persistent partial and complete venous occlusion, make the involved venous structures especially susceptible to re-thrombosis at the time of future disease or hypercoagulable

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state (3%-21% in different studies) [13,19,20]. Chronic venous occlusion may hamper

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future attempts for venous access, and consequently compromise the delivery of essential

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medical care [16].

Thus, effective strategies for the prevention of CVC-related thrombosis are highly

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desirable, especially for those patients that require long term vascular access. The identification of potentially modifiable risk factors for CVC-related VTE is important,

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particularly those factors that can be modified without compromising clinical care. Various CVC-related factors have been associated with increased risk for CVC-related

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VTE (Table 1). However, due to the heterogeneity of patient populations, as well as

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different statistical analyses employed in different studies, contradictory reports are often found, making it difficult to characterize an "ideal” CVC that would be associated with

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minimal risk of thrombosis [7].

The main patient-related VTE risk factors in children are age, underlying diagnosis, and

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personal and/or family history of thrombosis [1,13,20,30,33–36]. All these apply also when CVC-related VTE is concerned. The significance of personal and family history of thrombosis as prothrombotic risk factors is reflected in their incorporation into risk stratification algorithms in various pediatric hospital-acquired VTE prophylaxis guidelines [37–40].

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ACCEPTED MANUSCRIPT Although inherited and acquired thrombophilia has been shown to constitute an important risk factor for VTE in children [20,41], the contribution of thrombophilia to CVC-related VTE is negligible, and thus testing for thrombophilia in patients with CVC-related VTE is not recommended [42–47]. While the single most important risk factor for pediatric VTE is the presence of a CVC,

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the risk for CVC-related VTE may be influenced by the patient's underlying medical

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condition and its treatment [2,11].

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A recent review discussed in detail specific patient populations at increased risk for CVCrelated VTE, including children with hematologic and malignant diseases, critically ill

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neonates and children, and pediatric patients with congenital heart disease, systemic infection, intestinal failure, and traumatic injury [7]. We chose to focus this review on

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children with end-stage renal disease (ESRD) requiring hemodialysis – a patient population that has also been shown to be at increased risk for CVC-related VTE [34].

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Prevention or minimization of CVC-VTE in this patient population is of utmost

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importance, not only for prevention of acute and chronic complications of VTE, but also for the maintenance of reliable venous access, without which long-term survival may be

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impossible.

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Central Venous Catheter (CVC)-Related VTE in Hemodialysis Patients While pre-emptive renal transplantation constitutes the renal replacement modality of choice, and while peritoneal dialysis is the preferred modality of dialysis in younger children, according to the 2016 Annual Data Report of the United States Renal Data System (USRDS), hemodialysis is the most commonly used renal replacement modality in patients aged 0-21 years awaiting a kidney transplant [48].

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ACCEPTED MANUSCRIPT Vascular access options for hemodialysis include arteriovenous fistula (AVF) or subcutaneously tunneled CVC and synthetic AV grafts [49]. Both American and European Guidelines emphasize permanent vascular access in the form of AVF is preferable to CVC for children requiring chronic hemodialysis [50,51]. This is in light of a significantly increased rate of CVC-related complications, including infection, fibrin

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sheath formation potentially leading to catheter malfunction and failure, and venous

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thrombosis and stenosis with the potential loss of future venous access [3,52,53].

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However, despite efforts to increase the utilization of AVFs (the Fistula First Breakthrough Initiative [54]), the use of CVCs as hemodialysis access continues to

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predominate among children [48,55], as reflected in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 2011 annual dialysis report, in which CVCs

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constitute 79% of 3,363 reported hemodialysis access devices [56]. One possible explanation for CVC preference is that clinicians anticipate that the venous access will be

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required for a short duration (i.e., short dialysis course prior to living or deceased donor

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transplant), while an AVF requires weeks to months to mature and its creation poses a technical challenge, especially in young children (under 10-15 kg) [49]. An additional

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factor is the perceived reluctance of children to endure the pain associated with access cannulation. CVCs are an acceptable vascular access option for children who require a

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bridge to peritoneal dialysis or to the maturation of an AVF, for those in whom prompt renal transplantation is anticipated, and for those who require urgent hemodialysis. CVC may also be the best access choice for a child who has extremity contractures, bony deformities, or other mobility limiting conditions [3].

Frequency of CVC-related VTE in pediatric hemodialysis patients

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ACCEPTED MANUSCRIPT Children with ESRD requiring hemodialysis have an increased risk for hospital-acquired VTE, both related and unrelated to the presence of a CVC [34,35]. The exact frequency of CVC-related VTE in children with ESRD requiring hemodialysis is difficult to assess, as most literature regarding thrombosis in these children is limited primarily to retrospective nephrology and surgical experience, where many reports did not specifically note CVC-

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related VTE. Nevertheless, it is widely accepted that fibrin sheath formation and

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thrombosis leading to catheter occlusion account for most cases of CVC malfunction,

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defined as inability of the CVC to obtain and maintain extracorporeal blood flow sufficient to perform hemodialysis, which in turn underlies a large proportion of catheter

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failures requiring replacement [51,55,57]. Thus, in the current review, the data on CVC related VTE was extrapolated from reports also on the incidence of catheter occlusion,

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malfunction, and replacement (Table 2). The lower rates are generally considered underestimation of the true occurrence, as most cases are asymptomatic, and patients are

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not regularly screened. Specifically, with regards to subclavian CVC, the National Kidney

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Foundation has quoted data suggesting the occurrence of subclavian vein stenosis in over

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80% of pediatric patients [51].

Risk Factors for hemodialysis-CVC-related VTE

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Catheter-related risk factors: Catheter size- The increased risk for thrombosis in children undergoing hemodialysis has been partly attributed to the larger catheter size used. A similar association between an increased ratio of catheter-to-vessel size and CVC-related thrombosis has been described in some cohorts of children with CVC-related VTE [13], but not in others [28,34]. Hemodialysis catheter size is in part related to adapting machines designed for adults for use in children. Two new machines specifically designed for renal replacement therapy in

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ACCEPTED MANUSCRIPT neonates and small infants (<10 kg) are now available, requiring significantly smaller accesses [71,72]. Double-lumen CVCs- Compared with single lumen CVCs, higher rates of CVC-related VTE have been associated with double-and multi-lumen CVCs, commonly employed for hemodialysis. This association has been reported in studies focusing on PICCs, tunneled

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CVCs, and ports [21–23]. The higher frequency of thrombosis associated with multi-

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lumen CVC may as well be attributed to their larger size as compared with single-lumen CVCs.

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Type of CVC – Findings of pediatric studies as well as recent systematic reviews have

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been contradictory. Some have reported PICCs and non-tunneled CVCs to be associated with higher rates of thrombotic complications as compared with tunneled and totally

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implanted CVCs [26]. Others have found the opposite [6]. A recent study by Kanin and Young found no difference between PICCs and tunneled CVCs with regards to the rate of

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CVC-related thrombotic complications [27]. Particularly pertinent for children with

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ESRD, given the high rates of hemodialysis catheter use in this population, is a reported association between previous exposure to CVC and a nearly two-fold increase in the risk

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of developing thrombosis/stenosis following PICC placement [73]. Catheter insertion site- Subclavian vein catheterization has been reported to be

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associated with a particularly high risk of thrombosis, long-term stenosis and shorter catheter days [9,51,74]. Left jugular vein catheterization has also been associated with higher rates of stenosis and thrombosis as compared with right-sided catheter placement [9]. Catheter insertion technique - Ultrasound guided approach to CVC placement has been associated with significantly lower rates of occlusion and VTE as compared with the anatomical landmark approach [31]. Generally, lower rates of mechanical complications

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ACCEPTED MANUSCRIPT have been reported with the ultrasound-guided approach as compared with surgical venous cutdown or venography guided approach to CVC placement [75]. Thus, the use of ultrasound is becoming the standard of care for CVC insertion [76,77] .

Patient-Related Risk Factors:

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ESRD in itself constitutes a well-acknowledged prothrombotic state.

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As depicted in Table 3, the increased thrombosis risk associated with ESRD stems from

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alterations affecting the coagulation cascade, platelet function, the endothelium, as well as microparticles. Taken together, with possible additional contribution on the part of

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antiphospholipid antibodies, these changes lead towards the creation of a prothrombotic hemostatic state [78].

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An underlying diagnosis of nephrotic syndrome (NS) constitutes an established significant risk factor for thrombosis in patients with ESRD [79].

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Several prothrombotic mechanisms have been identified in patients with NS.

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The most acknowledged of these is the urinary loss of the natural anticoagulants, predominantly antithrombin, as well as free protein S. At the same time, increased

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synthesis of thrombosis-promoting factors, including factors V and VIII and fibrinogen, further shifts the hemostatic balance towards a prothrombotic one [80,81].

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Fibrinolytic activity is impaired in the nephrotic state, owing to decreased concentrations of both plasminogen and tissue-plasminogen activator (tPA), while at the same time the inhibitors of fibrinolysis, including plasminogen activator inhibitor-1 andα2-plasmin inhibitor, are increased in concentration. Additionally, NS-associated alterations in fibrin clot structure may confer it with higher resistance to fibrinolysis [80,81]. Reactive thrombocytosis is frequent in NS. However, its prothrombotic consequences in children are generally considered negligible [80]. Nevertheless, there is evidence for 9

ACCEPTED MANUSCRIPT constitutive activation of platelets in NS, which in turn may be associated with increased risk of mainly arterial thrombotic events [80]. Elevated levels of microparticles, which may contribute to the prothrombotic state, have been identified in children with idiopathic NS [80]. Lastly, red blood cell hyperaggregability has been reported in NS, possibly stemming

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from volume contraction and sodium retention, leading to red cell dehydration [80].

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Risk factors associated with VTE in children with NS include age (infants <1 year and

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adolescents ≥12 years), worsening proteinuria, and histopathology (membranous nephropathy or focal segmental glomerulosclerosis [FSGS]) [79,80]. Congenital NS,

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presenting over the first months of life, is associated with a further increased risk of VTE. While yet undiscovered disease-specific pathophysiology may underlie the increased VTE

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risk, it is also likely that the increased risk is related to more frequently requiring CVCs, and prolonged periods of protein losing state [79].

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The role of previous history of thrombosis, family history of thrombosis, and inherited

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and acquired thrombophilia have been discussed above.

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Diagnosis

Poor CVC function due to occlusion/thrombosis, followed by CVC-related infection, are

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the two most commonly reported causes of CVC failure requiring revision of hemodialysis access (Table 2). While a frequent cause for line occlusion/malfunction is the formation of a fibrin sheath or an intra-luminal clot, CVC malfunction may also be the sole manifestation of an underlying VTE of the associated vessels [2,82]. Current guidelines recommend investigating an occluded/malfunctioning CVC, especially when the occlusion/malfunction persists despite the local installation of a thrombolytic agent. A chest X-ray can be done for visualization of the CVC position. Unless the

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ACCEPTED MANUSCRIPT catheter is completely occluded, the presence of a fibrin sheath is best diagnosed by a contrast linogram. Importantly, a linogram cannot exclude the presence of asymptomatic large vessel thrombosis, the diagnosis of which will require Doppler ultrasound, conventional venography, or contrast-enhanced magnetic resonance venography (MRV) [82].

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Current pediatric guidelines recommend the use of Doppler ultrasound for initial

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evaluation of the upper venous system. If the result is not diagnostic and thrombosis of

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the central intra-thoracic veins is nevertheless suspected, the generally recommended modality for assessment of the central veins in children is MRV, which is considered

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preferable to CTV for radiation exposure considerations [8,82]. However, in patients with advanced kidney disease, MRV with gadolinium should be avoided due to the risk of

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nephrogenic systemic fibrosis (NSF) [74]. If deemed necessary, newer gadolinium preparations should be considered and patients informed of the potential risks of NSF.

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Treatment

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hemodialysis CVC.

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Figure 1 depicts a suggested algorithm for the investigation of a malfunctioning

Catheter occlusion: Management of catheter occlusion in hemodialysis patients is

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recommended as employed in non-hemodialysis patients. Local thrombolytic agents such as tissue plasminogen activator (t-PA) or urokinase (UK) should be instilled in the catheter for 30-60 minutes. If the catheter's patency is not restored, a second dose of t-PA/ UK can be administered. If the catheter remains occluded following two doses of local thrombolytic agent, imaging studies should be obtained to rule-out CVC-related VTE (see above) [83].

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ACCEPTED MANUSCRIPT Generally, efforts should be made to salvage CVCs, thereby reducing line exchanges and reinsertions with their associated increased risk of venous thrombosis and stenosis. In a study by Quinlan et al., reporting a median CVC survival of 390 days, a key contributor to these outstanding results may have been the use of anticoagulation for the management of CVC thrombi, and culture of "working with the CVC rather than moving quickly to

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replacement" [69].

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Catheter-related DVT: Management of hemodialysis catheter-related DVT is recommended as per the management of CVC-related DVT in non-hemodialysis patients.

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If the catheter is no longer functional, it should be removed following 3-5 days of therapeutic anticoagulation, aiming to diminish the risk of embolization at the time of

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removal. This may necessitate temporary vascular access to achieve dialysis. After removal of the catheter, anticoagulation should be continued for duration of 6 weeks to 3

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months. If the catheter remains functional, it may remain in-situ. Therapeutic

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anticoagulation is recommended for a duration of 6 weeks to 3 months, after which prophylactic dosing of anticoagulation is recommended for as long as the catheter is in

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situ [83].

The major safety concern associated with the use of anticoagulation is bleeding. There is

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no data pertaining specifically to the frequency of anticoagulation-associated bleeding in the pediatric hemodialysis / ESRD population. Nevertheless, as low-molecular-weightheparin (LMWH) elimination is primarily renal, significant renal insufficiency may result in drug accumulation leading to increased risk of bleeding. Bioaccumulation of Enoxaparin with the resultant increased risk of bleeding is known to occur when it is used in standard therapeutic doses in patients with severely impaired renal function (glomerular filtration rate < 30ml/min/1.73 m2). The recommendation is thus to reduce the LMWH

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ACCEPTED MANUSCRIPT dose by approximately 25% and to monitor anti-Xa levels [84,85]. Peak and trough antiXa levels are needed to ensure safety and efficacy of anticoagulation. Another consideration is the clearance of Enoxaparin during dialysis sessions, which is higher with high-flux dialysis membranes. Hence patients dialyzed with high-flux membranes may require greater doses of Enoxaparin [86]. Administration of Enoxaparin after each dialysis

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session is a possible solution.

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While data regarding Dalteparin use in pediatric patients with renal insufficiency is scant,

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it does suggest that significant dose reductions are required in order to avoid bioaccumulation [87].

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Of note, there is evidence to suggest that the risk of bioaccumulation is lower with Tinzaparin; thus it may be a safer alternative in the presence of renal insufficiency

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[84,85].

A rare, yet potentially grave complication of anticoagulation is heparin induced

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thrombocytopenia (HIT). Studies of HIT in children are sparse, with a reported incidence

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in the range of 0-2.3%, mainly with the use of therapeutic doses of UFH [88,89]. There have been no systematic studies concerning the occurrence of HIT in the pediatric

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hemodialysis / ESRD population. Of note, when stratifying pediatric patients into high and low risk groups for HIT, pediatric hemodialysis patients have been included in the

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low risk group [89].

No data are available on the safety and efficacy of direct oral anticoagulants (DOACs) in children undergoing hemodialysis.

Prevention Vascular access creation in children with ESRD should constitute a part of a long-term dialysis access strategy. Special attention and careful planning of device placement are

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ACCEPTED MANUSCRIPT required to meet the patients' access requirements without compromising future access sites. Interventions that may potentially compromise future vascular access, mostly as a result of central vein thrombosis and stenosis, should be avoided. Once a CVC is deemed to be the best access option for a patient, as per the NKF/KDOQI (National Kidney Foundation Kidney Disease Outcomes Quality Initiative) guidelines,

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standard dual lumen, twin, and split catheters are all considered adequate options for

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children on chronic hemodialysis. The NKF/KDOQI strongly recommends against the use

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of PICCs due to their increased frequency of venous thrombosis and stenosis, in patients with chronic kidney disease [51].

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Given the high rates of subclavian vein stenosis following subclavian vein catheter placement, and its potential to permanently preclude the use of the ipsilateral limb vessels

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for AV fistulae or grafts, its cannulation should be avoided. The NKF guidelines recommend internal jugular vein catheter placement. The right internal jugular vein is

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preferred over the left. Femoral access can be used when upper anatomy venous access is

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no longer available [51]. In children, the femoral vein is mainly used as temporary access, both for hygiene reasons, and since potential associated damage to the inferior vena cava

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may complicate future transplantation. Right atrial catheter tip positioning is recommended, as it has been associated with lower

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risk of catheter occlusion, while allowing for the high flow rates required for dialysis [51]. With regards to CVC insertion technique, ultrasound-guided approach has become the standard of care for CVC insertion [31,32,76,77].

Maintaining Patency of Hemodialysis CVCs Most pediatric centers use intraluminal heparin as a CVC-locking solution with a wide variation of concentrations (1,000 U/ml, 2,500 U/ml, 5,000 U/ml) [57]. Still, CVC

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ACCEPTED MANUSCRIPT malfunction attributed to catheter occlusion frequently occurs [57]. In adults undergoing long-term hemodialysis through newly inserted tunneled CVCs, the use of once-weekly tPA (1 mg in each lumen) as a catheter locking solution significantly reduced the incidence of both catheter malfunction and bacteremia as compared with heparin 5000units/mL instilled three times per week [90]. In children, the use of alteplase (t-PA) 1

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mg/mL was more effective compared with heparin 5,000 units/mL in reducing

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intraluminal clot formation between hemodialysis sessions [91]. Evaluation of the impact

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of the use of t-PA as a routine line lock on CVC-associated thrombotic and infectious

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complications requires multicenter randomized pediatric studies.

Primary Thromboprophylaxis for Hemodialysis CVCs

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Currently, no study has proven the efficacy of thromboprophylaxis against CVC-related VTE in children [6]. Thus, available pediatric guidelines generally do not recommend the

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use of routine systemic thromboprophylaxis for children with short-term or medium-term

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CVCs. However, when specifically addressing children undergoing hemodialysis via a CVC, the routine use of vitamin K antagonists (VKAs) or LMWH was suggested for

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thromboprophylaxis (grade 2c recommendation) [83]. This strategy is not widely employed by pediatric dialysis units [57].

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A systematic review in adult hemodialysis patients failed to show a beneficial effect of VKAs on rates of CVC malfunction [92]. A recent study by Paglialonga et al. evaluated the effect of warfarin on tunneled CVC survival and related complications in children with ESRD undergoing chronic hemodialysis. Patients with active NS (serum albumin<2.5 g/dL and urine protein/creatinine ratio>2 mg/mg) or a previous CVC thrombosis were considered at high risk for CVC thrombosis, and were treated with warfarin (targeting international normalized ratio (INR) of 2.5 with a range of 2-3).

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ACCEPTED MANUSCRIPT Despite having more patients with body weight < 15 kg and subclavian vein CVC placement, CVC survival and malfunction-free survival rates were significantly higher in the warfarin-treated patient group, with no increased risk of bleeding [93]. Further studies are required to evaluate and confirm the benefit and the safety of primary thromboprophylaxis in children undergoing hemodialysis. Risk stratification of patients

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may be important to identify the patient populations more likely to benefit from long-term

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primary thromboprophylaxis.

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Despite the identification of established risk factors for VTE in patients with NS, the appropriateness of prophylactic anticoagulation aimed at the prevention of NS-associated

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VTE remains the subject of ongoing debate [79,94]. The current practice at The Hospital for Sick Children and Shaare Zedek Medical Center is that in children with a history of

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NS-associated VTE, anticoagulation is restarted as soon as significant proteinuria recurs. Children with congenital NS are started on prophylactic anticoagulation even in the

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absence of a previous thrombotic event. Full dose anticoagulation is commenced in the

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presence of additional prothrombotic risk factors, including placement of a CVC [95]. Of note, with decreasing glomerular filtration rate, NS patients become less proteinuric

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and thus less hypercoagulable. Consequently, if a patient is severely oliguric or anuric at

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the time of dialysis, anticoagulation may no longer be required.

Special considerations Long-term Complications CVC occlusion and thrombosis, not always amenable to local installation of fibrinolytic agents or systemic anticoagulation, may result in interruption of treatment, repeated CVC insertions (with potential acute insertion related complications [11,58,59,96] ) and

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ACCEPTED MANUSCRIPT stenosis of the central vessels, potentially compromising future vascular access [53,73,74]. Central vein stenosis, affecting the major intrathoracic veins (subclavian vein, brachiocephalic vein, and SVC), is often asymptomatic, especially if the stenosis is not critical, or there is development of adequate collateral flow and is usually diagnosed at

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times of newly attempted CVC insertion or following the construction of an AVF in the

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ipsilateral extremity. Findings of a dilated fistula or elevated venous pressures precluding

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effective hemodialysis then unmask the impediment to increased blood flow. Even then, clinical signs may be subtle, with the only indication of access dysfunction being

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inadequate dialysis [74]. However, at times central vein stenosis may be associated with SVC-syndrome, potentially leading to life- or organ-threatening conditions, requiring

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prompt recognition and treatment [97].

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Small Children

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In small children (body weight < 15 kg) with ESRD, preemptive or early renal transplant is considered the best treatment option. If transplant is not feasible, peritoneal dialysis is

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preferred. However, under certain circumstances, such as previous abdominal surgery including gastrostomy insertion, refractory peritonitis, abdominal masses or bleeding, or

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when peritoneal dialysis fails or is inappropriate for psychosocial reasons, hemodialysis is the only possible option [67,72,98,99]. Over the past 20 years, major technological advances have turned maintenance hemodialysis into a viable treatment option for small children with ESRD [62,69,98]. Nevertheless, the provision and maintenance of adequate vascular access remain the single greatest obstacle to successful hemodialysis in these patients [67,98,100]. The smaller and younger patients are also the ones reported to

17

ACCEPTED MANUSCRIPT harbor the highest rates of CVC malfunction and failure, potentially increasing the rate of central VTE and stenosis with associated compromise of future vascular access (Table 2). Special attention should thus be given to this specific population of pediatric hemodialysis patients, exploring strategies for optimization of catheter survival. One such strategy, as discussed earlier, may be the use of machines designed explicitly for neonates and small

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infants, incorporating lower blood flow and allowing for the use of smaller accesses,

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which in turn may allow for significant prolongation of catheter survival [71,72].

Summary

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In pediatric ESRD patients, the provision of renal replacement therapy is a lifelong undertaking. While successful transplantation is achievable even in the young, graft

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survival is limited, and many transplant patients may return to dialysis during their ESRD management. Hemodialysis provision in children is complicated by both the difficulty in

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establishing adequate access and the recognition that future hemodialysis may be limited

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by the loss of access sites sacrificed during childhood. Chronic CVC dependence in hemodialysis patients is associated with a high incidence of access malfunction and

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failure, mainly attributed to CVC occlusion and thrombosis. Recurrent CVC placements are frequently required, resulting in increased risk of central vein thrombosis and stenosis,

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dramatically impacting patient HRQoL and potentially long-term survival. Despite the high rate of complications and long-term sequelae associated with hemodialysis-CVC-related VTE, CVCs remain a vital component of patient care. This calls for evidence-based effective preventive strategies to be adopted and utilized. Awareness of the significant risk of CVC-related VTE in ESRD patients undergoing hemodialysis may affect decision making and treatment planning in this population, especially when it comes to decisions regarding placement of a CVC. Careful planning of

18

ACCEPTED MANUSCRIPT hemodialysis access modality should take into account potentially modifiable catheterrelated risk factors for thrombosis. The establishment of effective strategies for maintenance of catheter patency and survival will aid in the conservation of future hemodialysis access sites. The identification of subpopulations of hemodialysis patients at high risk of CVC-related VTE will aid in the design and application of much needed

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multicenter prospective studies examining the risk and benefit thromboprophylaxis, that

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would optimally be designed and lead in collaboration between nephrologists and

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hematologists.

[1]

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Reference:

L. Raffini, Y.S. Huang, C. Witmer, C. Feudtner, Dramatic increase in venous

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thromboembolism in children’s hospitals in the United States from 2001 to 2007, Pediatrics. 124 (2009) 1001–1008. doi:10.1542/peds.2009-0768. S. Revel-Vilk, Central venous line-related thrombosis in children, Acta Haematol.

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[2]

[3]

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doi:10.1016/j.thromres.2015.05.017. [88] C. Law, L. Raffini, A guide to the use of anticoagulant drugs in children, Pediatr. Drugs. 17 (2015) 105–114. doi:10.1007/s40272-015-0120-x. [89] L. Risch, A.R. Huber, M. Schmugge, Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children, Thromb. Res. 118 (2006) 123–135. doi:10.1016/j.thromres.2004.12.020. [90] B.R. Hemmelgarn, L.M. Moist, C.E. Lok, M. Tonelli, B.J. Manns, R.M. Holden,

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ACCEPTED MANUSCRIPT M. LeBlanc, P. Faris, P. Barre, J. Zhang, N. Scott-Douglas, Prevention of Dialysis Catheter Lumen Occlusion with rt-PA versus Heparin (PreCLOT) Study Group, Prevention of dialysis datheter malfunction with recombinant tissue plasminogen activator, N. Engl. J. Med. 364 (2011) 303–312. doi:10.1056/NEJMoa1011376. [91] N.S. Gittins, Y.L. Hunter-Blair, J.N.S. Matthews, M.G. Coulthard, Comparison of

PT

alteplase and heparin in maintaining the patency of paediatric central venous

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haemodialysis lines: a randomised controlled trial, Arch. Dis. Child. 92 (2007)

SC

499–501. doi:10.1136/adc.2006.100065.

[92] A.Y. Wang, J.N. Ivany, V. Perkovic, M.P. Gallagher, M.J. Jardine, Anticoagulant

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therapies for the prevention of intravascular catheters malfunction in patients undergoing haemodialysis: Systematic review and meta-analysis of randomized,

doi:10.1093/ndt/gft406.

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controlled trials, Nephrol. Dial. Transplant. 28 (2013) 2875–2888.

D

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Napolitano, I. Martinelli, G. Montini, A. Edefonti, Vitamin K antagonists in children with central venous catheter on chronic haemodialysis: a pilot study,

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Frishberg, The outcome of chronic dialysis in infants and toddlers - Advantages and drawbacks of haemodialysis, Nephrol. Dial. Transplant. 23 (2008) 1336–1345.

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401–403. doi:10.1007/s004670050630.

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ACCEPTED MANUSCRIPT Table 1: Central venous catheter (CVC) -related factors associated with an increased risk of VTE Double- and multi-lumen catheters [21–23] Catheter material – polyurethane > silicone catheters * [24,25]

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Catheter type - peripherally inserted central catheters > non-tunneled CVCs* [6,26,27]

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Insertion site - subclavian > internal jugular vein; femoral >internal jugular vein [9,28]

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Tip position - SVC > thoracic inlet veins [29,30]

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Upper limb insertion side - left > right [9,10]

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Insertion technique – landmark percutaneous insertion > cut-down [9]; landmark > ultrasound guided [31,32]

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* Conflicting results

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CVC, central venous catheter; SVC, superior vena cava

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ACCEPTED MANUSCRIPT

Table 2: Central venous catheter (CVC) complications and survival in children with end stage renal failure undergoing hemodialysis Ref

Central venous catheters No.1

[52]

17

Failed2

13

193

[59]

b

60 (31%)a

11 (58%)

% 1Y

thrombosis/

problems3

/ occluded

(days)

survival

stenosis4

10 (59%)

6 (35%)

52

NR

NR

13.2%

3/120 (2.5%)

4/120 (3.3%)

a

patients

patients

age (<9Y) and BW (<20kg)

NR

b

split

c

dual lumen

25 (13%)

8 (4%)

159.4

10 (53%)

NR

d

280

NR

SC

NR

NR

PT

NR

failed catheters associated with

14%

NR

NR

d

longer survival when BW >20kg

NR

NR

NR

e

shorter survival when age <1Y

27%

3/23 (13%)

NR

f

D E

45

U N

A M

34%

T P

I R

NR

(median)

(median) 11 c

DVT

Comments

Survival

(mean) 19

Symptomatic

Mechanical Thrombosed

(76%) [58]

Central vein

(median)

[60]

[61]

[62]

59

22

19

31 (53%)

16 (72%)

15 (79%)

28 (47%)

E C

NR

C A

8 (36%)

6 (32%)

NR

4 (21%)

310e (median) 123

patients f

(median) 116.6

NR

NR

NR

NR

1/23 (4.3%)

2/23 (8.7%)

(mean) [63]

40

18 (45%)

13 (32%)

9 (22.5%)

84

35

including also the un-cuffed

ACCEPTED MANUSCRIPT

(mean) [64]

182

100 (55%)

65 (65%)

54 (83%)

219

patients

patients

NR

NR

NR

62%

2/13 (15%)

NR

(median) [65]

33

20 (61%)

14 (42%)

12 (36%)

NR

I R

patients

[66]

16 g

4 (25%)

4 (25%)

NR

322

46%

NR

15h

9 (60%)

4 (27%)

NR

91

[67]

18

NR

NR

NR

A M

0%

(median)

D E

349

NR

NR

[69]

[70]

31

15

112

20 (64%)

6 (40%)

45 (40%)

16 (52%)

6 (40%)

E C

NR

C A

23 (21%)

PT

5 (16%)

NR

110

g

Twin single lumen catheters

NR

h

dual lumen

Children < 2Y with BW < 10kg

patients

NR

3/11 (27%)

(mean) 390

NR

8/21 (38%)

(median)

[68]

SC

U N

(median)

T P

Children with BW < 15kg

patients NR

NR

NR

Children with BW < 10kg

NR

NR

NR

Children < 2Y

(median) 21 (median)

DVT, deep vein thrombosis; Y, year; NR, non-reported; BW, body weight. 1

Number of tunneled CVCs. 2 Failed catheters are those that had to be removed prior to completion of planned treatment. 3 Including

malfunctioned catheters preventing effective hemodialysis. 4 Symptomatic events. 36

ACCEPTED MANUSCRIPT Table 3: Factors underlying the increased thrombosis risk in end stage renal disease [78]

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Antiphospholipid antibodies

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MA

NU

SC

RI

PT

Coagulation cascade Increased levels of fibrinogen tissue factor factor VIII factor XIIa factor VIIa activated protein C complex thrombin-antithrombin complex plasminogen activator inhibitor (PAI)-1 Decreased activity of antithrombin Increased platelet activity Increased levels of phosphatidylserine p-selectin fibrinogen receptor PAC-1 Decreased levels of nitric oxide "Prothrombotic" endothelium Homocysteine-mediated endothelial cell damage Inhibition of the thrombomodulin-dependent activated protein C system Decreased endothelial release of tissue plasminogen activator Interference with subendothelial cell proliferation Increased levels of microparticles Increased presentation of phosphatidylserine Increased levels of tissue factor (membrane-bound and soluble) miRNA effect on platelet function

37

ACCEPTED MANUSCRIPT Highlights -

Children with end stage renal disease require lifelong renal replacement therapy.

-

Central venous catheters (CVCs) are most commonly employed as hemodialysis access. CVC occlusion/thrombosis underlie most catheter failures requiring exchange.

-

Central vein thrombosis/stenosis preclude hemodialysis in years to come.

-

Effective strategies for maintenance of catheter patency and survival are essential.

AC

CE

PT E

D

MA

NU

SC

RI

PT

-

38

Figure 1