Edited by: John Joseph Strouse, Duke University, USA
Reviewed by: William Morello, University of Bologna, Italy; Markus Bender, University Hospital Würzburg, Germany
Specialty section: This article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The use of central venous catheters (CVCs) in children is escalating, which is likely linked to the increased incidence of pediatric venous thromboembolism (VTE). In order to better understand the specific risk factors associated with CVC-VTE in children, as well as available prevention methods, a literature review was performed. The overall incidence of CVC-VTE was found to range from 0 to 74%, depending on the patient population, CVC type, imaging modality, and study design. Throughout the available literature, there was not a consistent determination regarding whether a particular type of central line (tunneled vs. non-tunneled vs. peripherally inserted vs. implanted), catheter material, insertion technique, or insertion location lead to an increased VTE risk. The patient populations who were found to be most at risk for CVC-VTE were those with cancer, congenital heart disease, gastrointestinal failure, systemic infection, intensive care unit admission, or involved in a trauma. Both mechanical and pharmacological prophylactic techniques have been shown to be successful in preventing VTE in adult patients, but studies in children have yet to be performed or are underpowered. In order to better determine true CVC-VTE risk factors and best preventative techniques, an increase in large, prospective pediatric trials needs to be performed.
Central venous catheters (CVCs) are the single largest risk factor for pediatric venous thromboembolism (VTE) in all pediatric populations. The incidence of VTE in children is increasing, most likely secondary to advances in care of critically ill children and the increased insertion rate of CVCs (
We identified English articles using Medline (1975–August 2016) and Scopus (1975–August 2016). The search strategies comprised “venous thromboembolism,” “risk,” “children,” central venous line, central venous catheter, and venous access device, with multiple subject headings and text words per concept. Selectively exploding subject headings, with relevant subcategories, permitted ever-increasing specificity. We included systematic reviews, meta-analyses, randomized controlled trials, prospective cohorts, and retrospective cohorts. Case reports and case series were excluded.
We excluded studies of patients older than 21 years based on the definition of pediatric age from the National Institute of Child Health and Human Development. For studies that included pediatric and adult patients, we excluded those without clear sub-analyses for patients under 21 years. Similarly, we excluded studies on arterial thromboembolism unless cases of VTE were included and clearly delineated in sub-analyses. Studies were identified as narrative reviews, commentaries, single case reports, retrospective case series, cross-sectional studies, case–control studies, cohort studies (retrospective and prospective), registry studies, or clinical trials, the first three of which were excluded.
This review included only pediatric CVC-related VTE with an aim to identify additional risk factors and populations at risk. An overview of the literature regarding different types and locations of CVCs, populations at risk, and prophylactic mechanisms will be discussed.
Incidences of CVC-VTE in children reported in the literature vary largely, ranging between 0 and 74% for patients with CVCs (
| CVC characteristic associated with increased VTE incidence | Reference |
|---|---|
| Externally tunneled CVCs (vs. internal CVCs, such as port-a-caths) | ( |
| CVCs placed in the femoral vein (vs. upper extremity) | ( |
| CVCs placed on the upper left side, in the subclavian vein (vs. jugular), and percutaneous technique (vs. cut-down) | ( |
| Peripherally inserted central catheters (vs. tunneled lines) | ( |
| Increased time CVC is in place, especially over 4 years | ( |
| Multi-lumen CVC (vs. single lumen) | ( |
| Polyurethane CVC material (vs. silicone estomer) | ( |
| Blind approach technique for insertion (vs. ultrasound guidance) | ( |
There are three distinct types of catheters: non-tunneled, which includes peripherally inserted central catheters (PICCs) and acute short-term lines; tunneled (Broviacs and Hickmans); and totally implanted CVCs (port-a-caths). The ideal type of CVC to minimize CVC-VTE is unknown. Although the populations described in systematic reviews and meta-analyses are heterogeneous in terms of patient location [e.g., neonatal or pediatric intensive care unit (ICU)] or underlying diagnoses (e.g., malignancy, sepsis), identification of additional risk factors (risk stratification) has not been carried out. As a result, determining the sole impact of the catheter type/location to the development of CVC-VTE is challenging. Furthermore, differing statistical analysis within studies of similar patient cohorts makes comparison of results across studies challenging. In a systematic review, 15,979 children with CVC were reviewed (
There are varied catheter compositions, although polyurethane and silicone elastomer is typically used, with silicone catheters reported to be the least thrombogenic (
In terms of insertion technique among adults, ultrasound-guided approach vs. blind approach to line insertion resulted in decreased complications (
Venous thromboembolism in children can also occur as a secondary complication of severe primary diseases (Table
| Primary disease states with an increased VTE incidence |
|---|
|
Malignancy with any type of CVC. For patients with a port-a-cath: increased risk in younger females with left-sided CVCs placed for a prolonged duration Neonates in an intensive care unit Critically ill children, especially those with a CVC-associated bloodstream infection or requiring mechanical ventilation Congenital heart disease Systemic infection Intestinal failure requiring total parental nutrition Trauma, especially those with a high injury severity score, received a blood product transfusion or an adolescent |
The pathogenesis of thrombosis in patients with cancer is multifactorial. This includes the affect of the disease, in which tumor cells interfere with the hemostatic system by secreting procoagulant molecules and cytokines, as well as the invasion or compression of blood vessels my malignant cells (
Sickle cell disease has been demonstrated to have features associated with hypercoagulability, including increased levels of endothelial and platelet microparticles (
In a recent review, Park et al. reported an incidence of 9.2% of CVC-VTE in patients in the neonatal ICU (
Children with CHD often have disruptions in the balance of hemostasis, which paradoxically could result in bleeding, thrombosis, or both. Cyanotic CHD is more commonly reported to have known hemostatic abnormalities compared with acyanotic CHD. Reported differences include abnormalities in coagulation proteins, platelets number and function, and red cell number and function altering hemostasis. These abnormalities can result in bleeding and/or thrombosis, with many having >1 abnormalities present (
Systemic infection has been identified as an additional risk factor in all high-risk populations, although no studies have specifically evaluated systemic infection and CVC-VTE. However, in severe sepsis, dysregulation of the hemostatic system may lead to disseminated intravascular coagulation and result in micro-vascular thrombosis that may contribute to CVC-VTE (
One retrospective study reported 53 children with intestinal failure (
The presence of a CVC continues to be the single greatest risk factor for VTE in pediatric trauma patients (OR 64, CI: 68.8–243.9) with a reported incidence of 0.2% for symptomatic CVC-VTE (
There are two main categories of prophylactic measures for children who are at risk for a CVC-VTE. These include mechanical prophylaxis, which consists of graduated compression stockings (GCSs) or intermittent pneumatic compression devices (IPCs), and pharmacological prophylaxis, such as systemic anticoagulation, ethanol locks, or fibrinolytics.
Graduated compression stockings and IPCs improve venous blood return from the lower extremities by providing circumferential or intermittent pressure. Theoretically, the use of GCSs and IPCs may not prevent CVC-VTEs, especially in the upper extremity where many CVCs are placed, but there could be some benefit by improving overall venous blood flow and activating systemic fibrinolysis (
Studies regarding the efficacy and safety of prophylactic anticoagulation in pediatric patients are limited. Meta-analysis on the use of antithrombotic agents (unfractionated heparin, low molecular weight heparin, warfarin, and antithrombin concentrate) and nitroglycerin did not demonstrate any significant efficacy with prophylaxis of CVC-VTE, although the studies were underpowered and closed early due to poor accrual (
Ethanol lock therapy has been demonstrated to decrease the rate of central venous line-associated blood infections (CLABSI) in a number of pediatric populations with CVC. There are no anticoagulant properties associated with ethanol; however, ethanol decreases infection and there may be an interrelationship between bacteremia and CVC-VTE (
Tissue plasminogen activator (TPA) is the main fibrinolytic drug used for clot lysis and restoration or maintenance of catheter patency. A literature review focusing on pediatric patients with CVCs and the use of TPA revealed that 50–90% of catheters were cleared of thrombosis when TPA was instilled, with improved efficacy when doses where higher and dwell times were longer (
Venous thromboembolism is a serious and potentially life-threatening condition that has lead to increased morbidity and mortality in pediatric patients. CVCs remain a predominant risk factor for VTE in children, and their use and rate of insertion continue to climb. Data evaluating the incidence and specific risk factors for CVC-VTE with various CVC types and medical conditions are limited. Most studies are predominantly retrospective, single institution, and focused on a single central catheter type. This article sought to provide a brief review of the literature regarding pediatric CVC-related VTE in order to highlight various risk factors linked to catheter characteristics and the patients’ medical history.
The overall incidence of CVC-VTE in pediatrics varies greatly due to differences in patient population, catheter type, detection methods (screening vs. requiring clinical symptoms), and imaging modality. CVC type and its effect on VTE incidence remain the most significant question. PICCs, which are usually placed into vessels of smaller caliber with a longer intravascular course, are being placed even more readily than other forms of CVCs (
Various patient populations have been shown to have an increased risk of VTE. There is difficulty determining if these populations are more at risk for VTE overall or CVC-related VTE specifically. Children with the highest risk of CVC-VTE are those with malignancy, systemic infection, CHD, gastrointestinal failure, sickle cell disease, those in an ICU, and those with a traumatic injury. Besides having a CVC, some of these patients have many other compounding risk factors, such as being in an inflammatory state, having decreased mobility, and being exposed to thrombogenic medications such as steroids or asparaginase.
Preventative measures, such as mechanical or pharmacological prophylaxis, have not been largely studied in pediatric patients, and thus, their utility in CVC-VTE prevention is unknown. Recurrent TPA locks have been shown to improve catheter flow in patients with CVCs obstructed by thrombosis.
In conclusion, our review illustrates the need for large prospective pediatric studies to truly evaluate catheter types, insertion techniques, and clinical characteristics to create guidelines for our patients prior to receiving a CVC. We hope that this review of the current literature will lead to a better understanding of the risk factors linked with CVC-VTE, which will promote the needed prospective evaluation.
JJ assisted in writing and editing the manuscript. MB assisted in performing the review and writing the manuscript. PM assisted in performing the review and writing and editing the manuscript. JJ and PM addressed the reviewer comments.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.