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Need for tissue plasminogen activator for central venous catheter malfunction and its association with occurrence of vVenous thromboembolism

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Need for tissue plasminogen activator for central venous catheter malfunction and its association with occurrence of vVenous thromboembolism

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NEED FOR TISSUE PLASMINOGEN ACTIVATOR FOR CENTRAL VENOUS
CATHETER MALFUNCTION AND ITS ASSOCIATION WITH OCCURRENCE OF
VENOUS THROMBOEMBOLISM

by

Xiaofan Zhu

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)

May 2023

Copyright 2023
Xiaofan Zhu
ii

Acknowledgements
First, I sincerely thank my professor Ji Lingyun, who instructed me to complete this thesis.
She has taught me how to analyze data and use STATA to analyze these variables. When I
encountered difficulties in completing this thesis, she always guided me in the right direction
patiently and responsibly.
Second, I thank Professor Wendy Jean Mack and Professor Ming Li. They have helped me
review my thesis and given me a lot of valuable suggestions and timely feedback. Their
feedback made my thesis more professional and rigorous.
Finally, I would like to thank my family and friends, who gave me a lot of encouragement
and support during my thesis completion. Their help also made me finish my thesis smoothly.
iii

TABLE OF CONTENTS
Acknowledgements ...................................................................................................................................... ii
List of Tables ................................................................................................................................................ iv
Abstract .......................................................................................................................................................... v
Introduction .................................................................................................................................................. 1
Chapter 1: Methods ..................................................................................................................................... 4
Study design and data source ............................................................................................................... 4
Study aims ................................................................................................................................................ 4
Study inclusion and exclusion criteria ............................................................................................... 4
Study procedure ...................................................................................................................................... 5
The characteristics of data .................................................................................................................... 6
Statistical analysis .................................................................................................................................. 6
Chapter 2: Results ....................................................................................................................................... 8
The characteristics of included CVCs ................................................................................................ 8
VTE events in PICCs and TLs ........................................................................................................... 12
CVC malfunction and VTE events ................................................................................................... 14
TPA administration and VTE events ............................................................................................... 14
Multivariable mixed effect logistic regression analysis ............................................................... 18
Chapter 3: Discussion ............................................................................................................................... 20
References ................................................................................................................................................... 25

iv

List of Tables
Table 1 Demographics characteristics of included CVCs ............................................................... 9
Table 2 Description of number of TPA administration required by Malfunction #1 ..................... 16
Table 3 Description of number of TPA administration required by Malfunction #2 ..................... 16
Table 4 Description of number of TPA administration required by Malfunction #3 ..................... 16
Table 5 Description of number of TPA administration required by Malfunction #4 ..................... 16
Table 6 Occurrences of outcome indicators for each CVC ........................................................... 17
Table 7 Univariable and multivariable mixed effect logistic regression analysis ......................... 19
v

Abstract
Background: In response to the important role of Central venous catheters (CVC) in
the treatment of medically complex conditions and critical care in children, it is of great
clinical significance to evaluate the relationship among the occurrence of CVC
malfunction and corresponding administration of tissue plasminogen activator (TPA)
and the incidence of venous thromboembolism (VTE) in children.
Methods: In this prospective study, patients between 6 months and 18 years were
enrolled to evaluate the relationship among the occurrence of CVC malfunction and
corresponding application of TPA and the incidence of VTE with mixed effect logistic
regression analysis.
Results: 1257 peripherally inserted central catheters (PICCs) and 710 tunneled lines
(TLs) were enrolled on the study among which 76 (6.1%) VTE and 19 (2.7%) VTE
were diagnosed, respectively. 247 (19.6%) PICCs and 197 (27.7%) TLs were identified
to have had malfunctions. The proportions of VTE within 6 months after CVC
placement in PICCs with malfunction was higher than TLs with malfunction (9.7% v.s.
2.5%). Three hundred and twenty-four CVCs received at least one TPA treatment due
to CVC malfunction, among which 29 (8.9%) were subsequently diagnosed with VTE.
CVCs which received at least one TPA treatment had higher risk of the occurrence of
VTE than CVCs which did not receive TPA treatment (8.9% v.s. 4.0%). Mixed effects
logistic regression analysis revealed that the risk of VTE was strongly associated with
CVCs that required 2 or more doses of TPA for CVC malfunction. The number of CVC
vi

malfunctions or the number of malfunctions requiring TPA did not independently
associate with VTE diagnosis after adjusting for number of TPA treatments.
Conclusion: A statistically significant association was found between higher doses of
TPA therapy and the occurrence of VTE, which was possibly due to the occurrence of
obvious symptom and clinical indications of pre-existing thromboembolism.
Keywords: Pediatric, Venous Thromboembolism, Central Venous Catheter,
Malfunction, Tissue plasminogen activator
1

Introduction
Use of Central venous catheters (CVC) was a milestone in the medical field
because of its advantages of monitoring central venous pressure, administering large
amounts of fluids in a short time, avoiding injury of peripheral blood vessels caused by
stimulant drugs, and reducing pain caused by repeated vein puncture. CVCs have been
widely used in treating critically ill patients, acute massive bleeding, hemorrhagic shock,
chemotherapy, total parenteral nutrition, very low weight premature infants and heart
disease (1, 2). CVCs play a particularly prominent role due to poor vein puncture
coordination, poor peripheral venous tolerance and changes in pediatric conditions. The
application of CVC not only reduces the frequent vein puncture in children, but also
alleviates the stimulation of drugs on veins and vessels and the associated pain and fear
(1, 2). Therefore, CVC is an essential clinical tool in the care of children with medically
complex and acute diseases. The incidence of venous thromboembolism (VTE) in
children, once extremely low, is now increasing. The incidence of venous thrombosis
in children has increased by 70 to 200 percent over the past 20 years (1, 3-5). Most of
these VTEs were associated with central venous catheterization in children. Central
venous catheterization has become the primary and independent risk factor for catheter-
related thrombosis in children (6).
CVC malfunction is believed to be closely associated with the occurrence of
adverse catheter-related outcomes in children. Cohort studies of children have shown
that CVC malfunction is closely associated with increased risk for CVC thrombosis and
2

reduced overall survival (7, 8). Interventions for CVC malfunction include use of
thrombolytic agents instilled directly into the catheter lumen. Tissue plasminogen
activator (TPA) is one type of thrombolytic agent that has been shown to be effective
in treating and preventing CVC thrombosis. It is usually applied to restore the opening
of CVC during the onset of CVC malfunction in clinical practice. Although TPA is
frequently used to manage CVC malfunction in children (9-11), there is a lack of
research on whether CVC malfunction and the use of TPA are associated with the
occurrence of VTE in children.
The CIRCLE (Clot Incidence Rates in Central Lines) study was a multicenter,
prospective, observational cohort study in children between six months and 18 years
(12). The study enrolled 1257 peripheral central catheters (PICCs) and 710 tunnel lines
(TLs), and monitored the lines prospectively via electronic medical record review for
the development of a VTE or CVC malfunction. A previous publication from this
prospective study demonstrated that CVC malfunction was an independent risk factor
for formation of VTE in children (12). Previous analyses also indicated that the
incidence of CVC malfunction in peripherally inserted central catheters (PICCs) was
significantly higher than that of tunneled lines (TLs) (HR = 2.0, 95%CI: 1.6-2.4).
However, previous analyses have not investigated independent associations between
incidence of VTE and occurrences of CVC malfunctions vs. usage of TPA following
CVC malfunctions in the clinical application of PICCs and TLs (12).
Given the important role of CVC in the treatment of medically complex and
critically ill children, it is of great clinical significance to evaluate the relationship
3

among the occurrence of CVC malfunction and corresponding application of TPA and
the incidence of VTE in children using CVCs. In this thesis, we aimed to conduct
further analyses based on the original CIRCLE study to explore the clinical impact of
number of episodes of CVC malfunctions and doses of TPA administration following
CVC malfunctions on VTE occurrence.
4

Chapter 1: Methods
Study design and data source
The study design and data source of this study were presented in the previous
publication on the CIRCLE study (12). The data were collected from children who met
inclusion criteria at four tertiary care centers: Nationwide Children's Hospital,
Children's Hospital Los Angeles, Children's Hospital of Philadelphia, and Texas
Children's Hospital between October 2013 and June 2018. These ensure the accuracy
and completeness of the data. Based on the risk factors for the formation of CVC-related
VTE in children, this thesis will further analyze whether CVC malfunctions and
subsequent usage of TPA are independent risk factors for the occurrence of VTE.

Study aims
In this thesis, we assess whether CVC malfunctions and TPA treatment following
CVC malfunctions in PICCs and TLs are independent risk factors for occurrence of
CVC-related VTE, and describe the relative contribution of the number of malfunctions
of PICCs and TLs vs. doses of TPA treatments in relation to VTE.

Study inclusion and exclusion criteria
Inclusion criteria: The study subjects were children aged 6 months to 18 years who
had CVC placement at the four tertiary care centers (as given in Study design and data
5

source) from October 2013 to June 2018. CVCs were monitored prospectively for 6
months or until line removal via electronic medical record review for development of a
VTE or CVC malfunctions. CVC malfunctions and the corresponding TPA usage that
occurred within 6 months of CVC insertion but before diagnosis of VTE were of interest
to analyses conducted in this thesis. Hence, for a CVC to be included in the CIRCLE
study, CVC malfunctions prior to PICCs and TLs placement or after VTE diagnosis
were excluded from our analyses.
Exclusion criteria: Children younger than 6 months were excluded from the study.
Children whose PICCs and TLs malfunction occurred after VTE diagnosis were
excluded from analyses.

Study procedure
The four medical institutions placed the CVC according to their standard of care,
and collected the corresponding information of the enrolled children according to the
data registration form. From the date of placement of the CVC, the CIRCLE study
prospectively examined the occurrence of CVC malfunction, the usage of TPA, and the
incidence of VTE through electronic medical record review. All diagnoses of VTE were
confirmed by clinical radiological diagnosis. CVC malfunctions included blockage,
broken wiring, misalignment, and mechanical damage (e.g., fibrin sheath, drug
precipitant). Information on TPA required for CVC malfunction was documented.

6

The characteristics of data
Study data included demographic characteristics, medical history, CVC
characteristics (including type, size, number of cavities, catheter material and brand),
and details of CVC placement. The features of CVC malfunction (the number, date and
type of malfunction), the usage of TPA and the incidence of VTE and adverse events
were documented. Medical practices like the placement of CVC, TPA treatment and the
occurrence of VTE were accomplished by the medical team of the four research
institutions.

Statistical analysis
Stata 15.1 software was used for statistical description and analysis. We compared
the incidence rate of malfunction associated with PICCs and TLs and investigated
whether the number of CVC malfunctions and the number of TPA treatments required
by CVC malfunction are associated with the incidence of VTE. A VTE was considered
to be associated with the CVC if the VTE occurred before or within 30 days of line
removal. A CVC malfunction that appeared before CVC placement or after the
occurrence of VTE was excluded from statistical analysis. Instead of analyzing patients,
statistical analysis was conducted using data from each CVC insertion and subsequent
follow-up. Therefore, each subject could contribute data on one or more CVCs. This
intrapatient correlation was handled with mixed-effect logistic regression analysis (13).
The association between CVC malfunctions in PICCs and TLs and the occurrence of
7

VTE, and the relationship between the number of TPA treatments for malfunction and
the incidence of VTE were first assessed with mixed-effect univariable logistic
regression analysis. Variables with p value less than 0.10 in univariable logistic
regression analysis were included in a mixed-effect multivariable logistic regression
model, backward selection was used to remove variables which were not significantly
associated with the incidence of VTE at the significance level of 0.10 to obtain an
appropriate mixed-effect multivariable model (14). All p values were two-sided.
8

Chapter 2: Results
The characteristics of included CVCs
Consistent with the previously published paper of the CIRCLE study, a total of
1967 CVC placed in 1742 unique subjects were included in this study. Among them,
183 (10.5%) subjects had 2 or more CVCs placed during the study period. The 1967
CVCs included 1257 PICCs and 710 TLs (12). The patient demographic characteristics
and clinical features of the included CVCs are shown in Table 1. Details on the types
and locations of TLs and PICCs placed were demonstrated in the previously published
paper (12).
9

Table 1 Demographics characteristics of included CVCs.
Variables
PICC (n=1257)
Total
TL (n=710)
Total
No malfunction
(n=1010)
With malfunction
(n=247)
No malfunction
(n=513)
With malfunction
(n=197)
Median or n % Median or n % Median or n % Median or n %
Age at CVC insertion (years)
7.4
(0.5-17.9)

4.8
(0.5-17.8)

7.1
(0.5-17.8)
5.3
(0.7-17.4)

5.4
(0.6-17.7)

6.4
(0.6-17.6)
Age group (years)
0.5-1 81 8 20 8 101 21 4 15 8 36
>1-5 292 29 106 43 398 232 45 80 41 312
>5-10 262 26 38 15 300 104 21 44 22 148
>10-18 375 37 83 34 458 156 30 58 29 214
Sex
Female 486 48 117 47 603 228 45 89 45 317
Male 524 52 130 53 654 285 55 108 55 393
Ethnicity
Hispanic/Latino 325 32 104 42 429 173 34 58 29 231
Non-Hispanic 428 43 80 32 508 226 44 76 38 302
Not Listed 257 25 63 26 320 114 22 63 33 177
Race
White 481 48 104 42 585 271 53 104 53 375
Asian 55 6 16 6 71 40 8 14 7 54
Black or African American 127 13 30 12 157 54 11 16 8 70
Native Hawaiian/Pacific Islander,
American Indian or Native Alaskan
1 <1 2 <1 3 3 <1 1 <1 4
American Indian/ Native Alaskan 2 <1 1 <1 3 11 2 1 <1 12
10

Variables
PICC (n=1257)
Total
TL (n=710)
Total
No malfunction
(n=1010)
With malfunction
(n=247)
No malfunction
(n=513)
With malfunction
(n=197)
Median or n % Median or n % Median or n % Median or n %
Other 331 33 90 36 421 132 26 61 31 193
Unknown 13 1 4 1 17 2 <1 0 0 2
Medical History
Current infection 338 34 84 32 423 71 14 24 12 95
Previous CVC 267 28 108 41 375 203 41 90 45 291
Recent surgery 216 22 70 27 287 107 21 38 19 145
Cancer 173 17 94 35 268 380 75 151 73 534
Parental nutrition dependence 158 16 49 19 207 64 13 38 18 101
Congenital heart disease 83 9 35 13 118 10 3 1 <1 11
History of thrombosis 71 8 18 9 93 33 7 15 8 49
Cystic fibrosis 77 8 7 2 84 7 2 1 <1 8
Metabolic/mitochondrial disorder 53 5 16 6 69 12 3 12 6 24
Inflammatory bowel disease 28 3 6 3 34 3 <1 2 <1 5
Nephrotic syndrome 9 <1 2 <1 11 3 <1 1 <1 4
Lupus/juvenile rheumatoid arthritis 8 <1 0 <1 8 1 <1 1 <1 2
None/other 208 21 27 9 230 29 6 12 6 41
Type of TL
Port-a-cath® - - - - - 368 72 116 59 484
Broviac® - - - - - 76 15 49 25 125
Hickman® - - - - - 39 8 23 12 62
Medcomp® - - - - - 13 3 5 2 18
Powerline® - - - - - 0 0 3 1 3
11

Variables
PICC (n=1257)
Total
TL (n=710)
Total
No malfunction
(n=1010)
With malfunction
(n=247)
No malfunction
(n=513)
With malfunction
(n=197)
Median or n % Median or n % Median or n % Median or n %
Unknown/other - - - - - 17 3 1 <1 18
Number of malfunctions
1 - - 167 68 167 - - 122 62 122
2 - - 35 14 35 - - 43 22 43
3 - - 22 9 22 - - 12 6 12
4 - - 9 4 9 - - 9 5 9
> 4 - - 14 6 14 - - 11 6 11
Diagnosed with VTE 50 5 26 11 76 12 2 7 4 19
12

VTE events in PICCs and TLs
A total of 95 VTE events occurred in this study within 6 months of CVC insertion,
of which 76 were in PICCs (incidence rate: 6.0%) and 19 were in TLs (incidence rate:
2.7%) (Figure 1). The median time between diagnosis of CVC-associated VTE and
CVC placement in PICCs was 14 days (range: 1-160 days), while the median time
between placement of TL and diagnosis of VTE was 42 days (range: 1-162 days).
According to univariable mixed effect logistic regression analysis, the risk of CVC-
associated VTE was significantly higher in PICCs than in TLs (odds ratio (OR): 2.26,
95% confidence interval (CI): 1.32-3.98).
13

Figure 1 Cumulative incidence of VTEs
14

CVC malfunction and VTE events
A total of 444 CVC malfunctions were observed in 402 children (Table 1). Among
these malfunctions, 247 CVC malfunctions were PICCs and 197 CVC malfunctions
were TLs. There were 167 (67.6%), 35 (14.2%), 22 (8.9%), 9 (3.6%), and 14 (5.7%)
PICCs with one, two, three, four and more than four times of CVC malfunction. Also,
122 (61.9%), 43 (21.8%), 12 (6.1%), 9 (4.6%), 11 (5.6%) TLs had 1, 2, 3, 4 and greater
than 4 CVC malfunction. In total, twenty-six PICCs with malfunctions were diagnosed
as VTE (incidence rate: 9.7%). Among these, 13 (54.2%), 1 (4.2%), 3 (12.5%), 1 (4.2%)
and 6 (25.0%) lines were with 1, 2, 3, 4 and ≥ 4 CVC malfunctions. In comparison,
only five TLs with malfunctions were diagnosed with VTE (incidence rate: 2.5%). In
univariable mixed effect logistic analysis, a statistically significant relationship
between CVC malfunction and VTE occurrence was only observed when the number
of CVC malfunctions requiring TPA was 3 or greater.

TPA administration and VTE events
The distribution of doses of TPA administration required for each occurrence of
CVC malfunction is shown in Tables 2, 3, 4 and 5. In this study, a total of 324 CVCs
received at least one TPA administration due to CVC malfunction, among which 29
CVCs (8.9%) were eventually diagnosed with VTE (Table 6). Sixty-six of 1643 lines
(4.0%) that did not receive TPA administration for CVC malfunction were eventually
diagnosed with VTE. This difference was statistically significant (P ＜0.001). Subgroup
15

analysis based on different catheter types was not conducted due to the small number
of TLs receiving TPA with a subsequent VTE event. In univariable analysis, CVCs
requiring two or more TPA administrations following malfunctions had statistically
significantly higher risk of VTE occurrence (2 TPA administration in comparison to no
TPA administration: OR = 5.47, 95%CI: 3.04-9.88; ≥ 3 TPA administration in
comparison to no TPA administration: OR = 5.58, 95%CI: 2.16-14.86).
16

Table 2 Description of number of TPA administration required by Malfunction #1,
for CVCs with 1, 2, 3, 4, or >4 malfunctions, respectively
Number of TPA
administration required
for Malfunction #1
Total number of malfunctions
for a CVC
1 2 3 4 > 4
0 102 9 5 3 1
1 148 51 20 10 13
2 30 15 7 5 9
3 8 3 1 0 1
4 1 0 0 0 1
> 4 0 0 1 0 0

Table 3 Description of number of TPA administration required by Malfunction
#2, for CVCs with 1, 2, 3, 4, or >4 malfunctions, respectively
Number of TPA
administration required
for Malfunction #1
Total number of malfunctions
for a CVC
1 2 3 4 > 4
0 11 8 3 0
1 49 19 8 17
2 13 7 7 7
3 3 0 0 1
4 1 0 0 0
> 4 1 0 0 0

Table 4 Description of number of TPA administration required by Malfunction
#3, for CVCs with 1, 2, 3, 4, or >4 malfunctions, respectively
Number of TPA
administration required
for Malfunction #1
Total number of malfunctions
for a CVC
1 2 3 4 > 4
0 4 3 0
1 23 12 15
2 5 3 7
3 2 0 3
4 0 0 0
> 4 0 0 0

Table 5 Description of number of TPA administration required by Malfunction
#4, for CVCs with 1, 2, 3, 4, or >4 malfunctions, respectively
Number of TPA
administration required
for Malfunction #1
Total number of malfunctions
for a CVC
1 2 3 4 > 4
0 3 3
1 7 11
2 7 7
3 0 2
4 1 2
> 4 0 0

17

Table 6 Occurrences of CVC malfunctions, CVC malfunctions requiring TPA
administration, and total times of TPA administration for each CVC.
PICC (n=1257) TL (n=710) Total
Variables
VTE
Yes
(n=76)
VTE
No
(n=1181)
VTE
Yes
(n=19)
VTE
No
(n=691)
VTE
Yes
(n=95)
VTE
No
(n=1872)
n % n % n % n % n % n %
Number of CVC malfunctions occurred
0 50 66 960 81 12 63 501 73 62 65 1461 78
1 15 17 152 13 4 21 118 17 19 20 270 14
2 1 1 34 3 1 5 42 6 2 2 76 4
3 3 4 19 2 0 0 12 2 3 3 31 2
4 1 1 8 1 2 11 7 1 3 3 15 1
> 4 6 8 8 1 0 0 11 2 6 6 19 1
Number of CVC malfunctions requiring TPA administration
0 52 68 1006 85 14 74 571 83 66 69 1577 84
1 13 17 103 9 2 11 69 10 15 16 172 9
2 1 1 37 3 1 5 30 4 2 2 67 4
3 3 4 18 2 0 0 8 1 3 3 26 1
4 1 1 7 1 2 11 5 1 3 3 12 1
> 4 6 8 10 1 0 0 8 1 6 6 18 1
Total times of TPA administration
0 52 68 1006 85 14 74 571 83 66 69 1577 84
1 13 17 120 10 1 5 90 13 14 15 210 11
2 6 16 38 4 4 21 23 4 10 16 61 4
3 2 3 13 1 0 0 6 1 2 2 19 1
4 1 1 4 1 0 0 1 1 1 1 5 1
> 4 2 3 0 0 0 0 0 0 2 2 0 0
18

Multivariable mixed effect logistic regression analysis
CVC type, the number of CVC malfunctions requiring TPA administration, and the
total number of TPA treatments were included in a multivariable mixed-effect logistic
regression model to investigate their association with the occurrence of VTE. Due to
multicollinearity, the number of CVC malfunctions 3 or greater and the number of CVC
malfunctions requiring TPA administration 3 or greater were dropped from the
multivariable logistic regression model. Results of the final multivariable model are
presented in Table 7. PICC had a higher risk of VTE than TL (OR = 2.31, 95%CI: 1.34-
4.09). Compared to CVCs with malfunctions that did not require TPA treatment, CVCs
requiring one TPA administration had a higher risk of occurrence of VTE (OR = 1.84,
95%CI: 1.02-3.33), and the risk of occurrence of VTE was dramatically higher with
CVCs that required ≥ 2 times of TPA treatment (2 TPA administrations: OR = 5.52,
95%CI: 3.00-10.16; ≥ 3 TPA administrations: OR = 5.36, 95%CI: 2.15-14.10).
19

Table 7 Univariable and multivariable mixed effect logistic regression analysis of
association between occurrences of CVC malfunctions, TPA administration and
VTE occurrence.
Variables
Number
of lines
Number
of lines
with
VTEs
Univariable analysis Multivariable analysis
Odds ratio (95%
CI)
p
Odds ratio (95%
CI)
p
Types of CVCs
TLs 710 19 Reference - Reference -
PICCs 1257 76 2.26 (1.32, 3.98) 0.001 2.31 (1.34, 4.09) 0.001
Number of occurrences of CVC malfunctions
0 1523 62 Reference - - -
1 289 19 1.53 (0.82, 2.68) 0.204 - -
2 78 2 0.52 (0.10, 2.21) 0.391 - -
≥ 3 77 12 3.93 (2.01, 7.68) < 0.001 - -
Number of CVC malfunctions requiring TPA administration
0 1643 66 Reference - - -
1 187 15 2.02 (0.81, 4.05) 0.214 - -
2 69 2 0.73 (0.22, 2.72) 0.612 - -
≥ 3 68 12 4.42 (2.23, 8.68) < 0.001 - -
Total times of TPA administration
0 1643 66 Reference - Reference -
1 224 14 1.72 (0.94, 3.17) 0.077 1.84 (1.02, 3.33) 0.045
2 71 10 5.47 (3.04, 9.88) < 0.001 5.52 (3.00, 10.16) < 0.001
≥ 3 29 5 5.58 (2.16, 14.86) < 0.001 5.36 (2.15, 14.10) < 0.001
20

Chapter 3: Discussion
Previous publication from the CIRCLE study indicated that PICCs were more
prone to CVC malfunction than TLs (PICCs: 41% v.s. TLs: 29%) (12). PICCs also have
a higher risk of VTE than TLs. Taking advantage of the large sample size and
prospective study design of the CIRCLE study, we aimed to investigate whether higher
rates of CVC malfunction and the number of TPA administrations for CVC malfunction
are associated with higher incidence of VTE. Analyses in this thesis suggested that the
greater the number of TPA administration required for CVC malfunction, the higher the
risk of VTE. In addition, this study emphasized the clinical significance of the number
of TPA administration required for CVC malfunction in the treatment of children with
complex medical and serious diseases because of its significant correlation with VTE
risk.
Over the past 20 years, PICCs have become the first choice for venous access in
complex diseases in children due to their ease of operation and low insertion
complications(5). However, with the increasing incidence of VTE in children and the
fact that most VTEs in children are associated with the placement of CVC, it is not
difficult for researchers to hypothesize whether the use of PICCs is closely related to
the increasing incidence of VTE in children. Previous publications from the CIRCLE
showed a higher risk of VTE in PICCs compared to TLs (12). VTE in children not only
requires anticoagulant therapy, but also increases the cost of hospitalization and the
likelihood of death. Considering the important role of CVC in the treatment of
21

medically complex diseases and emergent conditions in children, it is necessary to study
whether the malfunction of CVC and whether the number of TPA administrations for
CVC malfunction is associated with the occurrence of VTE in children. By studying
the correlation between TPA treatment and VTE due to CVC malfunction, clinicians
may be guided to reduce the incidence of iatrogenic VTE in children in clinical practice.
This helps to optimize the clinical treatment of children with severe or acute illness.
The main strength of this study is that the data were collected from a large cohort
comprehensively, with data collected on CVC placement time, CVC malfunction
occurrence time, TPA treatment time and VTE occurrence time. Longitudinal data
collection could reduce the bias of this study. In addition, data were collected using the
standardized case report forms. The electronic data capture program was used to extract
the electronic medical record data into a data format that was operable and easy to
analyze. This makes the collection of data in this study more comprehensive, less biased,
and increases the clinical adoption and application of the study results.
In this study, 324 (16.4%) patients were treated with TPA for CVC malfunction,
of which 122 received two or more doses of TPA. This is much higher than the
proportion of children with CVC malfunction that need TPA treatment in previous
studies. This might be related to the differences in medical practice guidelines in
different regions and higher incidence of CVC malfunction in this study.
The number of doses of TPA needed for CVC malfunction was significantly
correlated with the occurrence of VTE in children. The correlation between the
malfunction of CVC and the occurrence of VTE in children is an accepted relationship.
22

However, most previous studies were retrospective designs, which could not determine
the temporal order of CVC malfunctions, TPA treatment and VTE occurrence. This
study utilized a prospective design. The placement time of CVC, occurrence of
malfunctions, usage of TPA for each occurrence of malfunctions, and the occurrence
time of VTE were recorded thoroughly. Hence, this study can effectively exclude TPA
treatment that does not conform to the temporal relationship. Therefore, this study
demonstrated that the occurrence of VTE was significantly associated with the dose of
TPA for CVC dysfunction, but not associated with CVC malfunction. This confirms the
previously controversial view that the administration of TPA for CVC malfunction may
make pre-existing thromboembolism symptomatically and clinically obvious.
A study of children with non-central nervous system tumors also showed that the
incidence of VTE was significantly higher in patients with CVC malfunction than
patients without CVC malfunction (23.0% v.s. 8.8%) (15). In addition, Kulkarni et al.
also found in a case-control study that children with tumors with VTE had an increased
number of CVC malfunction treated with TPA compared to children without VTE. Both
of the above studies support the views presented in this thesis (16).
A major limitation of the analyses conducted in this thesis is that the survival time
data of the prospective design were analyzed with logistic regression models, which
ignored the exposure time (i.e., duration in time between occurrence of malfunctions,
TPA treatment, and subsequent VTE diagnosis). This may provide a more conservative
conclusion to the findings of this study. This could partly be the reason why we did not
find an independent significant association between CVC malfunction and the
23

occurrence of VTE after adjusting for the number of TPA treatments. However, the
design and data cleaning of this study are in line with the logic of temporal ordering of
exposures and outcomes. More thorough and comprehensive analyses of the data that
take into consideration the TPA administration and that of VTE diagnosis are ongoing.
This thesis provides persuasive results that the increase of TPA dosage caused by CVC
malfunction is closely related to the occurrence of VTE in children. Despite the
limitation of analyses in this thesis, these results revealed strong association between
TPA administration and VTE diagnosis, and played important roles in our planning of
analyses that are more thorough and systematic.
Another limitation of the analysis is that for number of malfunctions, the number
of CVCs in some categories (e.g., CVCs with two and four malfunctions that were
subsequently diagnosed with VTE) was small. The 95%CI of the estimated odds ratio
in this study was sometimes very wide, which may indicate that the number of children
included in this study was still insufficient. Due to the small sample size in sub-
categories of key variables of interest, our multivariable model did not consider other
potential risk factors (e.g., the types of diseases patients were diagnosed with). It is
probably necessary to further increase the population of children in the study for more
precise effect size estimation, so that results of the study can be more reliably.
A third limitation of the analyses is that we do not yet have an external dataset to
validate the findings of the study. However, investigators of the CIRCLE study have
actively worked on developing other larger registry studies which could potentially be
used to validate findings of the CIRCLE study.
24

In conclusion, our findings showed that the association between the occurrence of
CVC malfunction and the occurrence of VTE was probably due to number of doses of
TPA therapy which subsequently leads to VTE. This suggests that rising TPA treatment
makes pre-existing VTE symptomatically and clinically obvious. More thorough
analyses are in progress.

25

References
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thromboembolism in children's hospitals in the United States from 2001 to
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2. Duesing LA, Fawley JA, Wagner AJ. Central Venous Access in the Pediatric
Population With Emphasis on Complications and Prevention Strategies. Nutr
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3. Sandoval JA, Sheehan MP, Stonerock CE, et al. Incidence, risk factors, and
treatment patterns for deep venous thrombosis in hospitalized children: an
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doi.org/10.1016/j.jvs.2007.11.054
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pediatric hospital-acquired thrombosis cases: The Children's Hospital-
Acquired Thrombosis (CHAT) project. Thromb Res 2018;161:67-72.
doi.org/10.1016/j.thromres.2017.11.019
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Blood Adv 2018;2:1403-1408. doi.org/10.1182/bloodadvances.2017013292
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thrombosis in children: analysis of the Canadian Registry of Venous
Thromboembolic Complications. J Pediatr 1998;133:770-776.
doi.org/10.1016/s0022-3476(98)70149-0
7. Athale UH, Siciliano S, Cheng J, et al. Central venous line dysfunction is an
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8. Deitcher SR, Gajjar A, Kun L, et al. Clinically evident venous
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850. doi.org/10.1016/j.jpeds.2004.05.055
9. Hooke C. Recombinant tissue plasminogen activator for central venous access
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doi.org/10.1053/jpon.2000.8065
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associated with long-term indwelling central venous catheters. Lancet
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11. Chesler L, Feusner JH. Use of tissue plasminogen activator (rt-PA) in young
children with cancer and dysfunctional central venous catheters. J Pediatr
Hematol Oncol 2002;24:653-656. doi.org/10.1097/00043426-200211000-
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lead to a high risk of venous thromboembolism in children. Blood
2020;135:220-226. doi.org/10.1182/blood.2019002260
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Biometrics; 1976.
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doi.org/10.1160/TH14-07-0626

Abstract (if available)

Abstract Background: In response to the important role of Central venous catheters (CVC) in the treatment of medically complex conditions and critical care in children, it is of great clinical significance to evaluate the relationship among the occurrence of CVC malfunction and corresponding administration of tissue plasminogen activator (TPA) and the incidence of venous thromboembolism (VTE) in children.
Methods: In this prospective study, patients between 6 months and 18 years were enrolled to evaluate the relationship among the occurrence of CVC malfunction and corresponding application of TPA and the incidence of VTE with mixed effect logistic regression analysis.
Results: 1257 peripherally inserted central catheters (PICCs) and 710 tunneled lines (TLs) were enrolled on the study among which 76 (6.1%) VTE and 19 (2.7%) VTE were diagnosed, respectively. 247 (19.6%) PICCs and 197 (27.7%) TLs were identified to have had malfunctions. The proportions of VTE within 6 months after CVC placement in PICCs with malfunction was higher than TLs with malfunction (9.7% v.s. 2.5%). Three hundred and twenty-four CVCs received at least one TPA treatment due to CVC malfunction, among which 29 (8.9%) were subsequently diagnosed with VTE. CVCs which received at least one TPA treatment had higher risk of the occurrence of VTE than CVCs which did not receive TPA treatment (8.9% v.s. 4.0%). Mixed effects logistic regression analysis revealed that the risk of VTE was strongly associated with CVCs that required 2 or more doses of TPA for CVC malfunction. The number of CVC malfunctions or the number of malfunctions requiring TPA did not independently associate with VTE diagnosis after adjusting for number of TPA treatments.
Conclusion: A statistically significant association was found between higher doses of TPA therapy and the occurrence of VTE, which was possibly due to the occurrence of obvious symptom and clinical indications of pre-existing thromboembolism.

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Asset Metadata

Creator Zhu, Xiaofan (author)

Core Title Need for tissue plasminogen activator for central venous catheter malfunction and its association with occurrence of vVenous thromboembolism

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Degree Conferral Date 2023-05

Publication Date 05/03/2023

Defense Date 05/02/2023

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag central venous catheter,malfunction,OAI-PMH Harvest,pediatric,tissue plasminogen activator,venous thromboembolism

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Ji, Lingyun (committee chair), Li, Ming (committee member), Mack, Wendy Jean (committee member)

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