Neonatal epicutaneo-cava catheter-related thrombosis: a comprehensive overview

Abstract

Epicutaneo-cava catheters(n-PICC) are widely used in neonates for long-term nutritional support and medication administration, reducing the need for frequent invasive punctures. However, catheter-related thrombosis (CRT) is a serious complication of n-PICC placement. Due to the developmental immaturity of the neonatal coagulation system, neonates are at an increased risk of thrombosis. Currently, there is no standardized protocol for the diagnosis and management of CRT in neonates. This review summarizes the current understanding of risk factors, diagnostic approaches, treatment strategies, and preventive measures for CRT in neonates, aiming to provide clinical guidance.

Introduction

Epicutaneo-cava catheters(n-PICC) is a device inserted via peripheral venipuncture, with its catheter tip positioned in the superior vena cava or inferior vena cava to provide access for nutritional support, drug infusion, blood purification, and treatment monitoring [1], which solves the need for long-term venous access in critically ill neonates and preterm infants, successfully establishing a lifeline for neonatal care. However, with the widespread use of n-PICC in neonates, the incidence of catheter-related thrombosis (CRT) has increased significantly due to its developmental coagulation function [2, 3]. N-PICC-related thrombosis refers to the formation of blood clots on the inner wall of the vessel and adherent to the catheter surface, caused by multiple factors including direct vascular endothelial injury from puncture or catheterization, as well as the patient’s underlying physiological state, following n-PICC placement. According to relevant studies, the incidence of n-PICC associated thrombosis in neonates is 1.68%, primarily occurring with catheters placed in the lower extremity veins [4]. Furthermore, the high-risk period for CRT remains unknown [5]. Early and timely identification and management is the key to treatment. Yet, there are no large-scale studies and methods for early identification and treatment of CRT. Diagnosis primarily relies on clinical manifestations and ultrasound examination [6], while treatment is mainly based on limited case reports and adult guidelines. Consequently, CRT diagnosis is often missed or delayed, and treatment lacks precision. Therefore, this review focuses on the risk factors, prevention, diagnosis, and treatment of CRT in neonates, aiming to provide robust support for the early diagnosis and intervention of neonatal CRT in clinical practice, thereby reducing the incidence of sequelae and mortality rates, and ultimately lowering healthcare costs.

Risk factors for CRT in the neonatal period

The three elements of thrombosis are endothelial injury, altered blood flow and hypercoagulability. When n-PICC is inserted, it produces endothelial injury and the resulting reduction in peripheral blood flow. This leads to the activation of coagulation factor XII. Activated FXII further cleaves coagulation factor XI into its activated form, thereby supporting downstream activation of the coagulation cascade, ultimately leading to thrombosis formation and propagation [6]. We discuss the risk factors for CRT in the neonatal period by categorizing them into catheter-related, neonatal-related and maternal-related factors.

Catheter-related factors

Catheter type, material and process

Past studies have shown that the role of catheter type and material as risk factors for CRT remains controversial. Due to their higher insertion success rates and relatively lower incidence of catheter-related bloodstream infections (CRBSI) compared to non-tunneled central venous catheters, n-PICC has become the preferred choice in clinical practice [7]. A systematic study indicated that compared to other central venous catheters (CVC), n-PICC was associated with an increased risk of venous thromboembolism (VTE) [8]. Similarly, a study by Julie Jaffray et al. demonstrated that peripherally inserted central catheters(PICC) was associated with a significantly elevated risk of venous thromboembolism in pediatric patients [9], although another study had reached the opposite conclusion [10]. In a study by Pinghu Wang and Jasmin et al. [11, 12], it was concluded that polyurethane materials were more likely to cause PICC-related venous thrombosis than silicone materials, which may be due to the higher stiffness of polyurethane materials, mechanical irritation of the vessel wall, and increased risk of thrombophlebitis [13]. However, a study comparing silicone and polyurethane materials for CRT in PICC found that polyurethane catheters had a significantly lower CRT incidence than silicone catheters which have high risk of mechanical complications (dislocations, breakages, tip migrations) due to the greater fragility of the material [14]. In contrast, another systematic review concluded that catheter material did not significantly influence thrombus formation [15]. A prospective study strongly demonstrated the hypothesis that an insertion bundle with standardized operating procedures for central venous catheterization was highly effective in optimizing the safety of the maneuver, reducing immediate, early, and late complications, which included seven evidence-based strategies: preprocedural ultrasound evaluation, appropriate aseptic technique, ultrasound-guided venipuncture, intraprocedural tip location by non-radiological methods, proper choice of the exit site by tunneling, sutureless securement, and protection of the exit site using glue and transparent membranes [16].

Catheter tip position

A systematic review on the incidence and risk factors of CRT in neonates indicated that n-PICC tip placement position was a risk factor for CRT formation [17]. This finding was also corroborated by a retrospective study from Aditya et al. [18] that predicted CRT in hospitalized critically ill infants. When n-PICC is placed, its tip should be positioned within the superior vena cava or inferior vena cava near the entrance to the right atrium. Appropriate catheter tip positioning is crucial for reducing the incidence of CRT.

Catheter insertion position

Xiuwen Che et al. [17] indicated that catheter insertion in the lower extremity veins was a risk factor for CRT. This difference may be related to hemodynamics and changes in activity. A single-center observational study in neonates found that femoral vein catheterization was associated with neonatal CRT occurrence [19]. However, a systematic review in children showed similar rates of deep vein thrombosis (DVT) occurrence between the upper and lower extremities [20]. Therefore, current evidence on the CRT high-incidence sites remains limited and varies considerably depending on study design, patient selection, catheter type, and other factors. Current guidelines recommend ultrasound-guided placement of CVC [21] to avoid life-threatening complications and to confirm appropriate catheter tip position [22].

Catheter placement diameter

International evidence-based guidelines stated [22] that to reduce the risk of CRT, the catheter diameter should not exceed one-third of the venous luminal diameter. The available diameters for PICC range from 1.1 to 3 Fr (1 Fr = 1/3 mm), with 1.1 to 2 Fr being the most commonly used. Currently, 1.9 Fr is commonly used in China. A systematic review on the risk of CRT formation with different PICC diameters demonstrated [23] that using the smallest diameter PICC met the patient’s clinical needs which helped reduce CRT occurrence and save costs, while larger diameter PICC may increase the incidence of symptomatic CRT. Therefore, selecting an appropriate catheter diameter is equally critical for CRT prevention. Neonates, with their small vessel diameter and difficult access, benefit significantly from ultrasound-guided insertion. It allows assessment of the catheter-to-vein diameter ratio, visualization of the vessel and surrounding tissue relationships, selection of appropriately sized catheters, and reduction in the number of insertion attempts.

Catheter placement time

Current studies do not have uniform recommendations at home and abroad regarding the high-risk period for the occurrence of CRT after n-PICC catheterization. A study on thrombosis in n-PICC in preterm infants indicated occurrence within 1 week after catheter insertion [24]. Currently there is no established optimal time point for monitoring during the high-risk window period for CRT.

Number of catheter placements

Whether an increased number of insertion attempts is a risk factor for CRT requires further investigation. Retrospective studies in adults suggested that more insertion attempts increased the risk of CRT, particularly with PICC placement [25]. However, a meta-analysis indicated that technically difficult insertions did not increase thrombosis risk [26]. Similarly, studies in children with PICC found no statistically significant difference in CRT occurrence related to the number of insertion attempts [27]. Although current research has not yet established a relationship between the number of catheter insertion attempts and n-PICC catheter-related thrombosis in neonates, relevant studies suggested that increased insertion attempts may elevate the risk of central line-associated bloodstream infection [28]. In clinical practice, when central venous catheterization is required and ultrasound equipment is available, ultrasound-guided insertion should be strongly recommended early on. A systematic review confirmed the superiority of ultrasound-guided insertion due to its ability to reduce associated risks like CRT and pneumothorax [29]. A meta-analysis further indicated that ultrasound guidance significantly reduced the number of puncture attempts [30].

Neonatal-related factors

The formation of CRT also involves neonatal factors, and multiple studies provide a theoretical basis. Research by Ji Hye Hwang et al. [31] found hypercalcemia to be an independent risk factor for umbilical vein CRT. A meta-analysis by Xiuwen Chen et al. [17] identified 12 risk factors for CRT formation in neonates with n-PICC. Among these, gestational age < 28 weeks, abdominal pathology, fresh frozen plasma transfusion > 5 days (dose > 50 mL/kg), infection, cardiac insufficiency, and being the donor twin in twin-twin transfusion syndrome were identified as high-risk populations for CRT. Research by Maria et al. [10] also concluded that a history of cardiovascular surgery was a high-risk factor for neonatal CRT. Although a single-center retrospective study suggested [19] that gestational age was not a statistically significant risk factor for CRT, it found that most CRTs occurred in neonates aged 29–31 weeks. Additionally, the study by Marwa et al. [19] indicated that red blood cell transfusion via n-PICC was the strongest factor associated with CRT. It is evident that the risk factors for neonatal CRT are diverse and complex. Any disruption in the balance between neonatal coagulation and anticoagulation can promote CRT formation. However, monitoring for CRT occurrence in neonates is challenging. Establishing predictive models for CRT may be a direction for future research.

Maternal-related factors

Studies indicated [17] that neonates born to mothers with autoimmune diseases during pregnancy were more susceptible to CRT after n-PICC insertion. This may be related to maternal autoantibodies affecting neonatal coagulation function, although the specific mechanism remains unclear. Furthermore, preeclampsia and gestational diabetes mellitus may also influence neonatal CRT occurrence. However, the degree of impact of specific maternal comorbidities during pregnancy on CRT development still needs to be elucidated [32].

Diagnosis of CRT

Symptomatic diagnosis

Symptoms of CRT can include swelling and discoloration at the insertion site, phlebitis, and catheter malfunction. The specific manifestations vary depending on the degree of obstruction, the location of the thrombus, and the type of vein involved. However, CRT is most often asymptomatic [6].

Laboratory diagnosis

D-dimer (D-D) is a soluble degradation product generated by the fibrinolysis of fibrin. Its elevation results from the degradation of vascular thrombi by the fibrinolytic system. In adults, D-D is useful as an adjunct for the diagnosis of VTE and disseminated intravascular coagulation (DIC), monitoring the optimal duration of anticoagulation in VTE patients, and identifying medical patients at high risk for VTE [33]. Some studies in children have also found [5, 34, 35] that elevated D-D levels were a significant risk factor for CRT and could predict the recurrence of post-thrombotic syndrome. However, other studies indicated [36] that D-D had poor discriminatory and predictive power for DVT in children, with its primary application being the diagnosis of pulmonary embolism (PE) in this population [37]. Currently, there is limited research and application of D-D specifically for neonatal CRT. The potential role of D-D in neonatal CRT remains unclear and requires further exploration.

Research by Nei et al. [34] found that elevated levels of coagulation factor VIII at the time of thrombus diagnosis could serve as a predictor of poor thrombotic prognosis. Furthermore, Edward et al. [38] investigated coagulation factor VIII for predicting CRT formation in critically ill children. Their preliminary findings suggested that coagulation factor VIII activity might be useful for stratifying CRT risk. A coagulation factor VIII activity level greater than 100 IU/dL may help identify children requiring pharmacological intervention for thromboprophylaxis. However, studies specifically examining coagulation factor VIII in neonatal CRT have not yet been conducted, and further analysis of its potential value is needed.

Thrombomodulin and thrombin-antithrombin III (TAT) complexes have also shown promise in the diagnosis and prognosis of VTE in adults [39, 40]. These markers hold potential as novel predictive indicators for the diagnosis and prognosis of CRT in children and neonates. It is worth noting that the detection of these coagulation markers requires a relatively large blood volume, which means it cannot be routinely performed in neonates, especially premature infants, necessitating new technologies or markers to address this challenge.

Imaging diagnosis

While venography has historically been the gold standard for diagnosing VTE, its invasive nature and radiation risks have led to its gradual replacement by the non-invasive and effective alternative of ultrasound. When CRT is suspected, ultrasound is the first-line imaging modality, with a sensitivity of 91% and specificity of 93% [41]. However, ultrasound has poor visualization of bony structures, due to acoustic shadowing from the clavicle, sternum, and lung tissue, though it is reliable for examining jugular, subclavian veins and inferior vena cava [42]. Additionally, it is important to differentiate CRT from a fibrin sheath on ultrasound. CRT typically appears anechoic or hypoechoic, whereas a fibrin sheath appears hyperechoic [43]. Furthermore, the detection of the CRT needs careful visualization of all the veins in which the catheter was localized after its removal. The fibrin sheath covering the catheter changes into CRT quickly after catheter removal. Although routine ultrasound monitoring of catheters is not universally recommended, ultrasound remains the only reasonable and effective method for visualizing CRT. However, achieving optimal catheter monitoring is particularly challenging in preterm infants, the very population that benefits most from n-PICC. Frequent ultrasound assessments carry the potential for disturbance or physiological instability in this vulnerable group. As such, the decision to pursue closer CRT monitoring requires careful consideration of these risks.

Treatment of CRT

Advances in medical therapy have improved the survival rate of neonates, particularly preterm infants. The widespread use of n-PICC, however, has increased the incidence of thromboembolism and other complications. Treatment for neonates still largely relies on adult thrombosis management protocols and case studies. Crucially, neonatal coagulation function differs from that of adults. The process of neonatal thrombosis formation appears distinct. Approximately 50% of neonatal thrombi resolve without anticoagulation therapy. Consequently, adult thrombosis treatment approaches may not be suitable for managing neonatal CRT and could increase the risk of intraventricular hemorrhage. Therefore, determining the course of neonatal thrombi, assessing the specific site of thrombosis, and identifying risk-free thrombi are essential for deciding whether anticoagulation is necessary for the patient’s future [44]. Current clinical guidelines recommend [45] that for patients with symptomatic CRT who still require venous access support, functional n-PICC should not be removed. However, for patients with symptomatic CRT whose catheter is non-functional or no longer needed, removal is advised. Before catheter removal, several days of anticoagulation therapy with low-molecular-weight heparin or vitamin K antagonists may be administered to reduce the risk of PE or stroke. However, research by Julie et al. [46] found no correlation between the duration of anticoagulation before n-PICC removal and the occurrence of PE. The need for anticoagulation in children with asymptomatic CRT remains controversial. A prospective study of 189 critically ill children showed [47] a low incidence of acute or long-term complications in untreated children with asymptomatic CRT, suggesting that withholding treatment for CRT in critically ill children may be reasonable. Conversely, research by Ling Xiong et al. [48] found that CRT complications occurred most frequently in patients with larger intravascular thrombosis, particularly when the initial thrombus-to-vein diameter ratio exceeded 58%. These patients had a high risk of long-term vascular occlusion or stenosis, suggesting that such neonates should be followed up and anticoagulation should be considered.

Given that most reported CRT cases are asymptomatic, the decision for prophylactic or therapeutic anticoagulation must be carefully weighed against the potential harms of bleeding and other risks associated with anticoagulation. Furthermore, there is currently no large-scale, randomized controlled trial evidence supporting either treatment or non-treatment of asymptomatic thrombosis. Regarding thrombolysis, consensus recommendations suggested it may be considered in specific situations where the benefit outweighed the bleeding risk, such as unresolved symptoms, high risk of post-thrombotic syndrome, or other complications like superior vena cava syndrome [49].

Additionally, there remains no standardized recommendation for the duration of anticoagulation in CRT. Currently, comprehensive assessment of risk factors for CRT, standardized n-PICC insertion, and catheter maintenance can prevent CRT [50]. But no evidence supports the use of pharmacological prophylactic measures to prevent CRT occurrence in children [51]. Heparin in peripherally inserted central catheters did not alter elective removal and complication rates in preterm infants [52]. A randomized controlled trial found that saline, heparin, and vitamin C solutions were equally effective in restoring patency to clotted neonatal central venous catheters. Based on its equivalent efficacy and lower risk of side effects, the use of saline is recommended in newborns [53]. Therefore, the role of prophylactic heparinization in the prevention of catheter-related thrombosis in neonates remains controversial. Numerous dilemmas persist in the treatment of neonatal CRT, necessitating prospective, randomized, large-scale studies for deeper investigation.

Conclusion

In summary, the incidence of neonatal CRT is gradually increasing. CRT has numerous risk factors and is most often asymptomatic. Ultrasound diagnosis can be delayed, and there are currently no specific preventive measures. While preliminary studies suggested potential roles for D-D and coagulation factor VIII in the diagnosis and prognosis of CRT in children, research on these markers in neonatal CRT remains scarce. Consequently, ultrasound detection of CRT in most of the cases should be treated as a preventive measure rather than saved for diagnosis of symptomatic patients. Further research is needed to identify reliable biomarkers and establish predictive models for CRT, providing crucial support for the diagnosis and treatment of neonatal CRT.

Abbreviations

n-PICC

Epicutaneo-cava Catheters

CRT

Catheter-related Thrombosis

CRBSI

Catheter-related Bloodstream Infections

CVC

Central Venous Catheters

VTE

Venous Thromboembolism

PICC

Peripherally Inserted Central Catheters

DVT

Deep Vein Thrombosis

D-D

D-dimer

DIC

Disseminated Intravascular Coagulation

PE

Pulmonary Embolism

TAT

Thrombin-antithrombin III

Author contributions

J. C conceived the original idea and supervised the writing. X. J wrote and revised the manuscript. All authors read and approved the final manuscript.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was supported by Reproductive Health and Maternal and Child Health Security with Grant Numbers 2023YFC2706402.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.