Xie et al. BMC Pediatrics(2024) 24:534
https://doi.org/10.1186/s12887-024-05008-2

BMC Pediatrics

RESEARCH

Open Access

Development and validation of a nomogramfor catheter-related thrombosis prediction
in children with central venous catheter:a retrospective observational study
Wangfang Xie1, Bin Xu2*, Xiaofang Lou3, Jihua Zhu3 and Sheng Ye1
Abstract
Background Catheter-related thrombosis (CRT) is a thrombotic complication associated with using central venous
catheters (CVCs). Although risk factors for CRT were identified in children, no nomograms or predictive tools areavailable for the pediatric population with CVCs. This study aimed to develop and validate a prediction model ofasymptomatic CRT in children with CVCs.
Methods This retrospective observational study included consecutive pediatric patients who admitted to theChildren’s Hospital Zhejiang University School of Medicine and received CVCs between October and December 2021.
Results This study included 669 patients, 553 (314 males, aged 22.00 [0.36, 180.00] months, 62 with CRT) were in the
training set, and 116 (62 males, aged 15.00 [1.13, 156.00] months, 16 with CRT) were in the validation set. Multivariate
logistic regression showed that a catheter time of 0–3 days (OR = 0.201, 95%CI: 0.081–0.497, P = 0.001), catheter timeof 4–7 days (OR = 0.412, 95%CI: 0.176–0.964, P = 0.041), male (OR = 3.976, 95%CI: 1.864–4.483, P < 0.001), congenital
heart diseases (OR = 0.277, 95%CI: 0.078–0.987, P = 0.048), postoperative (OR = 0.161, 95%CI: 0.072–0.360, P < 0.001),
and femoral CVC (OR = 2.451, 95%CI: 1.129–5.318, P = 0.002) were independently associated with CRT. The nomogram
incorporating these variables showed relatively good discrimination (AUC = 0.77, 95%CI: [0.65, 0.90]) and calibration
abilities in the validation set, and the decision curve analysis (DCA) yielded a clinical net benefit.
Conclusion A prediction model for CRT in children with CVC was established based on catheter time, sex, diseases,
postoperative, and catheter vein. The nomogram based on logistic regression model showed favorable predictive
performance.
Keywords Catheter-related thrombosis, Central venous catheter, Children, Prediction model*Correspondence:
Bin Xuxbzjhz@zju.edu.cn
1Comprehensive Intensive Care Unit, Children’s Hospital, Zhejiang
University School of Medicine, National Clinical Research Center for Child
Health, Hangzhou 310003, Zhejiang, China

2

Department of Ultrasound, Children’s Hospital, Zhejiang University
School of Medicine, National Clinical Research Center for Child Health,Hangzhou 310003, Zhejiang, China
3
Department of Nursing, Children’s Hospital, Zhejiang University Schoolof Medicine, National Clinical Research Center for Child Health,Hangzhou 310003, Zhejiang, China© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Xie et al. BMC Pediatrics(2024) 24:534

BackgroundA central venous catheter (CVC) is a catheter whose tip
resides within the proximal third of the superior vena
cava, right atrium, or inferior vena cava [1, 2]. CVCs
include catheters typically inserted in the internal jugular, subclavian, or femoral vein or peripherally inserted
central catheters (PICCs) [1, 2]. The types of catheters
include non-tunneled centrally inserted catheters and
PICCs, tunneled, and implantable catheters [1, 2]. CVCs
provide short- or long-term access to central veins for
drug delivery, hemodynamic monitoring and interventions, and communication with extracorporeal blood
circuits [1, 2]. In children, CVCs are useful to avoid
repeated punctures in small, hard-to-find veins and toprovide long-term fluids, medications, and nutrients [3].
Catheter-related thrombosis (CRT) is a thrombotic
complication associated with using CVCs [4–7]. CRT
typically refers to deep vein thrombi in the vein wherea catheter is placed [4, 5]. About 70-80% of all upper
extremity thromboses and about 10% of all venous
thromboembolism (VTE) incidences are reported to becatheter-related [5, 8]. Symptomatic deep vein thrombosis (DVT) is reported in 1-5% of patients with CVCs,
while asymptomatic DVT is reported in 19-41% of
patients with CVCs, depending on the detection method[4, 8]. The risk factors for CRT in the general population(irrespective of age) include the type of catheter (especially a peripherally inserted central catheter [PICC]),
the catheter insertion site, the insertion technique, andpatient-related risk factors (e.g., cancer, a previous history of VTE, and the type of therapy administered, andsystemic or catheter-related infection) [4, 8]. In children,a large registry study reported a higher risk of CRT inchildren with cancer, cardiac disease, infection, trauma,short gut or depending upon parenteral nutrition, renal
failure, surgery, and bronchopulmonary dysplasia [9].
Another study in children showed that the risk factors for
CRT were < 1-year-old, mechanical ventilation, cardiac
catheterization, PICC, and percutaneous CVC [10]. Li etal. [11] reported that age < 1 year, use of 20% mannitol or
glycerol fructose, CVC placement by a pediatric intensive
care unit physician, length ≥ 9 cm, and elevated D-dimer
levels were risk factors for CRT in children. The complications include pulmonary embolism, recurrent DVT,
postthrombotic syndrome, and sepsis [4, 8]. The early
detection of CRT is important to prevent complications[4, 8].
Still, there are fewer studies on children than on adults.
In 2012, the American College of Chest Physicians(ACCP) published guidelines for managing thrombosis
in children [12]. The American Society of Hematology
published its guidelines in 2018 [13]. European guidelines are now available specifically on thrombosis inchildren on home parenteral nutrition [14]. Although

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these guidelines identify risk factors for CRT in children,
they do not have predictive tools specific to children.
Although risk factors for CRT were identified in children[9–11], no nomograms or predictive tools are available
for the pediatric population.
Therefore, the present study investigated the development and validation of a prediction model of CRT in children with CVC.

Methods
Study design and patients

This retrospective observational study included consecutive pediatric patients who admitted to the Children’s
Hospital Zhejiang University School of Medicine andreceived CVC between October and December 2021.
The inclusion criteria were (1) 0–15 years of age, and (2)received a CVC for > 24 h. The exclusion criteria for the
study were (1) incomplete clinical information or (2) ahistory of thrombosis before receiving a CVC. The Medical Ethics Committee of the Children’s Hospital Zhejiang University School of Medicine approved this study(2018-IRBAL-081), and the Medical Ethics Committee
exempted requirement of informed consent for this retrospective study.
Data collection

Demographic characteristics (age, sex, and weight),
clinical characteristics (primary disease and underwent
surgery or not), and catheterization characteristics (position, type of catheter, and time) were collected from theelectronic medical record system. As part of our comprehensive monitoring protocol, routine ultrasoundexaminations were performed to assess the integrity andfunction of the catheters at predetermined intervals after
catheter placement. Specifically, ultrasound examinations
were scheduled at 3 days, 7 days, before catheter removal,
and upon patient transfer to another department. This
proactive screening protocol is informed by evidence
suggesting the initial 48 h after catheterization are a peak
period for thrombus formation, with additional risks
extending into the first week. During these examinations,cases of CRT were incidentally identified. It is important
to note that all CRTs were asymptomatic and detected
while the catheters were confirmed to be functioning
normally. The diagnosis of asymptomatic CRT was madebased on the ultrasound findings: (1) the segment of thevein is noncompressible in compression ultrasound evaluation, or (2) venous blood flow is absent, or if the normal biphasic flow is altered in Doppler ultrasound [8, 15].
These ultrasound criteria are used specifically to detect
asymptomatic CRT, as these patients do not present withtypical thrombotic symptoms such as pain or swelling.
The patients were divided into the asymptomatic CRT

Xie et al. BMC Pediatrics(2024) 24:534

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and non-CRT groups according to whether they eventually developed CRT or not.
Statistical analysis

SPSS 21.0 (IBM, Armonk, NY, USA) and R 4.0.0 (The R
Project for Statistical Computing, www.r-project.org)
were used for statistical analysis. Continuous data that
conformed to the normal distribution were presented
as means ± standard deviation (SD) and analyzed using
student’s t-test. The continuous data that conformed toskewed distribution were presented as medians (ranges)
and analyzed using the Mann-Whitney U-test. Categorical data were presented as n (%) and analyzed using thechi-square test. According to the patients of catheterization date, the patients catheterized between OctoberTable 1 Characteristics of the patients
Characteristics
Age, months
3
3–6
6–12
12–24
24–36
36–120
> 120
Sex
Male
FemaleWeight, kg
0–10
10–20
> 20
Postoperative
Yes
No
DiseaseNeurological
Digestive system
Neoplastic hematologic
Congenital heart
Disease of respiratory
Septic shock
OthersCatheter vein
Femoral vein
Jugular vein
Catheter time, days
0–3
4–7
>7
CatheterSingle-lumen
Double-lumen
Data are shown as n (%)

CRT (n = 66) Non-CRT (n = 487) P
0.355
9 (14.52)
2 (3.23)
9 (14.52)
6 (9.68)
7 (11.29)
23 (37.10)
6 (9.68)

56 (11.41)
59 (12.02)
73 (14.87)
68 (13.85)
56 (11.41)
145 (29.53)
34 (6.92)

Results< 0.00149 (79.03)
13 (20.97)

265 (53.97)
226 (46.03)

19 (30.65)
23 (37.10)
20 (32.26)

218 (44.40)
193 (39.31)
80 (16.29)

29 (46.77)
33 (53.23)

452 (92.06)
39 (7.94)

26 (41.94)
5 (8.06)
8 (12.90)
9 (14.52)
6 (9.68)
1 (1.61)
7 (11.29)

68 (13.85)
61 (12.42)
56 (11.41)
258 (52.55)
26 (5.30)
6 (1.22)
16 (3.26)

47 (75.81)
15 (24.19)

289 (58.86)
202 (41.14)

0.006< 0.001< 0.0010.010

298 (60.69)
123 (25.05)
70 (14.26)

48 (77.42)
14 (22.58)

257 (52.34)
234 (47.66)

Characteristics of the patients

This study included 669 patients: 553 (62 with asymptomatic CRT) were in the training set, and 116 (16 withasymptomatic CRT) were in the validation set. Detailed
catheter usage was as follows: 2 instances of CRT
occurred with port catheters, both in patients with hematologic malignancies; PICC lines were used in 6 instancesof CRT, with 2 in patients with gastrointestinal diseases
and 4 in patients with hematologic malignancies. In the
training set, the patients were mostly 36–120 months old.
Compared with the non-CRT group, the CRT group displayed a higher proportion of males (79.03% vs. 53.97%,
P < 0.001), were heavier (> 20 kg, 32.26% vs. 16.29%,
P = 0.006), did not undergo surgery (53.23% vs. 7.94%,
P < 0.001), had neurological diseases (41.94% vs. 13.85%,
P < 0.001), had femoral vein catheter (75.81% vs. 58.86%,
P = 0.010), had a catheter for 7 days (43.55% vs. 14.26%,
P < 0.001), and had single-lumen CVCs (77.42% vs.
52.34%, P < 0.001) (Table 1).
Establishment of prediction model< 0.00117 (27.42)
18 (29.03)
27 (43.55)

1 and December 15 were in the training set, and thosecatheterized between December 16 and December 31
were in the validation set.
In the training set, the XgBoost machine learning algorithm and multivariate logistic regression were used toestablish the prediction model. The XgBoost machinelearning algorithm included all the variables collected in
the study. The multivariate logistic regression used stepwise regression methods to select the variables. And anomogram was established based on the results of multivariate logistic regression analysis.
For the XgBoost model and the logistic regression
model, the received operating characteristics (ROC)
curves were plotted in the development and validation
sets, and the diagnostic efficiency was evaluated using
the area under the ROC curves (AUC) and were compared using the Delong test. The performance of nomogram was assessed for discrimination and calibration.
Discrimination was assessed using the AUC, and thecalibration was assessed with the calibration slope andcalibration plot. And the net benefit of the models wasevaluated using a decision curve analysis (DCA). A twosided P < 0.05 was considered as statistic difference.

< 0.001

Multivariate logistic regression showed that catheter
time of 0–3 days (OR = 0.201, 95%CI: 0.081–0.497,
P = 0.001), catheter time of 4–7 days (OR = 0.412, 95%CI:
0.176–0.964, P = 0.041), male (OR = 3.976, 95%CI:
1.864–4.483, P < 0.001), congenital heart diseases(OR = 0.277, 95%CI: 0.078–0.987, P = 0.048), postoperative (OR = 0.161, 95%CI: 0.072–0.360, P < 0.001), andfemoral CVC (OR = 2.451, 95%CI: 1.129–5.318, P = 0.002)

Xie et al. BMC Pediatrics(2024) 24:534

were independently associated with asymptomatic CRT(Table 2). The ROC analysis showed that the logistic
regression model had AUC of 0.872, with 77.8% sensitivity and 83.90% specificity (Table S1 and Fig. 1). The
logistic regression model and XgBoost model had an area
under curve (AUC) of 0.778 and 0.812 in external validation, respectively (Table S1). Delong’s test showed no significant differences of diagnostic efficiency between thetwo models.
A nomogram based on the logistic regression results
was established (Fig. 2A). Figure 2B presents a patientwith asymptomatic CRT. The patient was male (75points), not postoperative (100 points), with neurological disease (88 points), femoral vein catheter (48 points),
and catheterization for 4 ~ 7 days (39 points). The total
score was 350, indicating a risk of asymptomatic CRT of
73%. Figure 2C presents a patient without asymptomatic
CRT. The patient was female (0 points), postoperative (0points), with neoplastic hematologic disorder (32 points),
femoral vein catheter (0 points), and catheterized for 4–7
days (39 points). The total score was 17, corresponding toa risk of asymptomatic CRT of 1-5%.
The nomogram incorporating these variables showed
relatively good discrimination (AUC = 0.77, 95%CI: [0.65,
0.90]) and calibration abilities (Figure S1A) in the validation set, and the decision curve analysis (DCA) yielded aclinical net benefit (Figure S1B).

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Table 2 Logistic regression of CRT-related factors
Characteristics
Catheter time (vs. >7 days)
0–3 days
4–7 days
Male sex (vs. female)
Disease types (vs. other diseases)
Neurological disease
Digestive system disease
Neoplastic hematologic disorder
Congenital heart disease
Disease of the respiratory system
Septic shock
Postoperative (vs. not)Catheter placement: femoral vein (vs.
internal jugular vein)

OR
—
0.201
0.412
3.976
—
1.414
0.306
0.495
0.277
0.282
0.318
0.161
2.451

95%CI
—
(0.081,0.497)(0.176,0.964)(1.864,8.483)—(0.427,4.688)(0.069,1.363)(0.129,1.901)(0.064,0.987)(0.064,12.238)(0.026,3.827)(0.072,0.36)(1.129,5.318)

P
0.001
0.041
< 0.001
0.571
0.120
0.306
0.048
0.094
0.367
< 0.001
0.002

OR: odds ratio; CI: confidence interval

Discussion
In this study, a nomogram to predict asymptomatic CRT
in children with CVC was successfully constructed andvalidated based on catheter time, sex, diseases, postoperative, and femoral CVC. The results might help predict the occurrence of CRT and identify patients needingcloser monitoring and prophylaxis.
The predictive value of both models in the external
validation was worse than in the internal validation. In
addition, the predictive value of the logistics regression
method was slightly worse than the value of the XgBoost
algorithm. Nevertheless, the purpose of the model was to
identify children with a higher risk of thrombosis in theFig. 1 The received operating characteristics (ROC) curves of the logistic regression model for internal and external validation

Xie et al. BMC Pediatrics(2024) 24:534

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Fig. 2 The nomogram and its application. A). The nomogram based on the logistic regression model. B). Use of the nomogram for a patient in thecatheter-related thrombosis (CRT) group. Male: 75 points. Not-postoperative: 100 points. Neurological disease: 88 points. Femoral vein catheter: 48 points.
Catheterization time 4 ~ 7 days: 39 points. Total: 350, corresponding to a risk of 73%. C). Use of the nomogram for a patient in the no catheter-related
thrombosis (no-CRT) group. Female: 0 points. Postoperative: 0 points. Neoplastic hematologic disorder: 32 points. Femoral vein catheter: 0 points. Catheter time of 4–7 days: 39 points. Total: 71, corresponding to a risk of 1-5%

future and to implement preventive measures in advance,
which means that the model should have a better ability
to correctly predict positive patients (i.e., patients with
CRT); therefore, sensitivity should be preferred over
specificity, and it is why the logistic model was selected in
the presented study because of its high sensitivity. Nevertheless, the specificity of the prediction of the logistic
model in this study is not ideal, and the predictive ability
for negative samples (negative) is low, which might leadto overtreatment and result in some risks associated withthe superfluous treatments. Hence, studies are still necessary to improve the predictive ability of predictive models for CRT in children.
In this study, surgery was a protective factor against
CRT, meaning that children who were operated on had
a lower risk of CRT than those who did not undergo surgery. These results may initially appear counter-intuitive
as surgical procedures typically elevate postoperative
coagulation factors, which theoretically increase the riskof thrombosis. However, the lower incidence of CRT

in surgical patients can be attributed to the routine useof anticoagulation prophylaxis, particularly in patients
undergoing cardiovascular surgeries for congenital heartdiseases. This prophylactic treatment effectively mitigates
the heightened thrombotic risk associated with increased
coagulation factors [16]. Furthermore, the comparison group, often comprising children with hematological cancers, presents a naturally higher baseline risk ofthrombosis due to inherent hypercoagulability [17–19].
Catheter-related factors are also associated with CRT.
Longer catheterization times are associated with anincreased risk of CRT in adults [20]. In children, it wasreported that CRT occurred mainly after 14 days [11]. A
study showed that a longer placement length was a risk
factor for CRT in children [11], and femoral CVCs often
require longer lengths to reach their target. In the present study, males had a higher risk of CRT than females.
A previous study reported no differences in CRT occurrence in male vs. female children [11]. Discrepant results

Xie et al. BMC Pediatrics(2024) 24:534

might due to the cutoff points used, the study populations, patient selection,
In the logistic regression analysis, age, weight, andthe number of catheter lumens were not associatedwith CRT. The age distribution of pediatric deep venous
thrombosis (DVT) follows a double peak phenomenon(early infancy and adolescence) [21]. In addition, using
CVCs in infants with small blood vessels and thin vessel walls can easily cause mechanical obstruction of
the blood vessels and limbs, which is one of the basic
causes of DVT [21, 22]. In this study, the peaks of CRT
occurrence were observed in the 0-3-month (13.85%)
and > 120-month (15.00%) groups, consistent with the
double-peak phenomenon observed in children [23]. A
double-peak phenomenon was also observed with weightin the present study, but weight in children is directly
related to age. Therefore, it might be necessary to consider these two characteristics as indirect-acting factors
affecting DVT. The number of catheter lumens is considered associated with the risk of CRT because doublelumen CVCs are thicker than single-lumen CVCs, andthicker CVCs, irrespective of the number of lumens, areassociated with a higher risk of CRT [24]. Although thenumber of lumens was not included in the nomogram,the present study showed a higher CRT rate in the singlelumen group. This discrepancy should be related to thefact that single- and double-lumen CVCs are used for different uses or indications and that the number of lumens
could be covariant with another variable (e.g., type of disease). Still, two studies in children with CVCs showed noassociation of CRT with the number of lumens [25].
This study had limitations. The patients were from thesame hospital and from a short study period, resulting ina small sample size. Still, the single-center nature of thestudy guarantees uniform CVC and CRT management
but at the cost of lower generalizability. The consistency
in management across this short study period can be
attributed to the stable implementation of these standardized protocols, which experienced minimal changes
during the study timeframe. However, the retrospective
nature of the study limited the data to those available in
the patient charts and shared by all patients. Additionally,
due to the wide variety of drugs administered to the children and the absence of specific documentation on theuse of anticoagulation or anti-platelet therapy post-CVC
insertion, it was not feasible to analyze the impact ofthese drugs on CRT outcomes. This lack of detailed therapeutic data restricts a comprehensive analysis of how
these treatments might have influenced CRT outcomes,
thereby underscoring the need for prospective, multicenter, large-sample studies that can provide highergrade evidence for the effective management of CRT inchildren.

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Conclusion
In conclusion, this study designed and validated a prediction model to predict CRT in children with CVC, basedon catheter time, sex, diseases, postoperative, and catheter vein.
Abbreviations
CRT	Catheter-related thrombosis
CVCs	Central venous catheters
DCA	Decision curve analysis
PICCs	Peripherally inserted central catheters
VTE	Venous thromboembolism
DVT	Deep vein thrombosis
SD	Standard deviation
ROC	Received operating characteristics
AUC	Area under curves

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s12887-024-05008-2.
Supplementary Material 1
Supplementary Material 2
Supplementary Material 3
Acknowledgements
None.
Author contributions
Wangfang Xie and Bin Xu carried out the studies, participated in collecting
data, and drafted the manuscript. Wangfang Xie and Xiaofang Lou performed
the statistical analysis and participated in its design. Wangfang Xie, Bin Xu,
Xiaofang Lou, Jihua Zhu and Sheng Ye participated in acquisition, analysis, orinterpretation of data and draft the manuscript. All authors read and approved
the final manuscript.
Funding
This study was funded by the Project of the Health Department of Zhejiang
Province in 2019 (Grant No. 2019KY440) to Wangfang Xie and the Project of
the Health Department of Zhejiang Province in 2020 (Grant No. 2020KY613) to
Xiaofang Lou.
Data availability
All data generated or analyzed during this study are included in this article
and supplementary information files.

Declarations
Ethics approval and consent to participate
This work has been carried out in accordance with the Declaration of Helsinki(2000) of the World Medical Association. This study was approved by the
Ethics Committee of the Children’s Hospital, Zhejiang University School of
Medicine [2018-IRBAL-081]. This article is a retrospective study. Therefore, theEthics Committee of the Children’s Hospital, Zhejiang University School of
Medicine waived the requirement to obtain distinct written informed consent
from the patients.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 23 May 2024 / Accepted: 13 August 2024

Xie et al. BMC Pediatrics(2024) 24:534

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