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Heparin-bonded catheters for prolonging the patency of

central venous catheters in children (Review)

Shah PS, Shah N

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 3
http://www.thecochranelibrary.com

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) i
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Heparin-bonded catheters for prolonging the patency of


central venous catheters in children

Prakeshkumar S Shah1 , Niketa Shah2


1 Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto,
Canada. 2 Department of Pediatrics, New Jersey Hospital, Jersey City, New Jersey, USA

Contact address: Prakeshkumar S Shah, Department of Paediatrics and Department of Health Policy, Management and Evaluation,
Rm 775A, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1XB, Canada. pshah@mtsinai.on.ca.

Editorial group: Cochrane Peripheral Vascular Diseases Group.


Publication status and date: Edited (no change to conclusions), published in Issue 3, 2011.
Review content assessed as up-to-date: 20 August 2007.

Citation: Shah PS, Shah N. Heparin-bonded catheters for prolonging the patency of central venous catheters in children. Cochrane
Database of Systematic Reviews 2007, Issue 4. Art. No.: CD005983. DOI: 10.1002/14651858.CD005983.pub2.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Central venous catheters (CVCs) are a mainstay in the management of critically ill children. However, these catheters are associated
with mechanical and infectious complications which reduce their life span. Heparin bonding of catheters has shown promise in animal
studies and in adults.
Objectives
The primary objective was to determine the effect of heparin-bonded CVCs on the duration of catheter patency in children. Secondary
objectives were to determine the effect of heparin-bonded catheters on catheter-related thrombosis, occlusion, sepsis and side effects.
Search strategy
The Cochrane Peripheral Vascular Diseases (PVD) Group searched their trials register (last searched 8 August 2007) and the Cochrane
Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2007, Issue 3). We also searched MEDLINE
(1966 to March 2007).
Selection criteria
We included randomized and quasi-randomized controlled trials of heparin-bonded catheters versus non heparin-bonded catheters or
antibiotic-impregnated catheters that reported on any of the prespecified outcomes, without language restriction.
Data collection and analysis
We assessed the methodological quality of the trials using the information provided in the studies and by contacting authors. We
extracted data and estimated the effect size and reported as risk ratio (RR), risk difference (RD) or number needed to treat (NNT), as
appropriate.
Main results
We included two eligible studies with a total of 287 patients; both had good methodological quality. There was no difference in the
duration of catheter patency between heparin-bonded and non heparin-bonded catheters (median duration seven days versus six days)
reported in one study. There was no difference in the risk of catheter-related thrombosis (RR 0.71, 95% CI 0.44 to 1.15; RD -0.05,
Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 1
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
95% confidnce interval (CI) 0.13 to 0.02; I2 = 79%). Data from one study revealed a statistically significant reduction in the risk of
catheter occlusion (RR 0.06, 95% CI 0.00 to 1.07; RD -0.08, 95% CI -0.13 to -0.02; NNT 13, 95% CI 8 to 50), catheter-related
infections (RR 0.06, 95% CI 0.01 to 0.41; RD -0.17, 95% CI -0.25 to -0.10; NNT 6, 95% CI 4 to 10) and catheter colonization
(RR 0.21, 95% CI 0.06 to 0.71; RD -0.11, 95% CI -0.19 to -0.04; NNT 9, 95% CI 5 to 25) in the heparin-bonded catheter group.

Authors’ conclusions

Two eligible studies on the use of heparin-bonded catheters versus placebo in children were identified. The use of heparin-bonded
catheters is a promising therapy but warrants further studies.

PLAIN LANGUAGE SUMMARY

Heparin-bonded catheters for prolonging the patency of central venous catheters in children

Central venous catheters are used for prolonged intravenous therapy in the management of critically ill children, for parenteral nutrition,
medication and monitoring. Having these catheters in place can cause blood clots in or around the end of the catheter as well as
infection, either local or a blood stream infection. As a result, the catheter becomes blocked, eventually to the point that it is occluded
and can no longer be used to give fluids. Anticoagulant drugs such as heparin can be given to prolong the usefulness of the catheter
or the catheters coated with heparin (heparin-bonded catheters). Heparin can cause side effects such as bleeding, allergic reactions,
induced thrombocytopenia (an abnormal drop in the number of platelets in the blood) and osteoporosis with long-term use.

The review authors identified two good quality controlled trial that randomized 287 children aged one day to 16 years to either a
heparin-bonded catheter or a standard catheter. The median duration of time that the catheter could be used to give fluids (its patency)
was not clearly different with the two types of catheter, seven days in the heparin-bonded catheter group and six days in the standard
catheter group. There was a trend towards the heparin-bonded catheter reducing the risk of catheter-related thrombosis over the time
the catheter was in and a trend towards reduction in the risk of catheter occlusion in the first week after catheter placement.

The risk of catheter-related infections and bacterial colonization of the catheter were significantly reduced using the heparin-bonded
catheter, with a longer time to develop infection (delayed in the heparin-bonded catheter group). There was no significant difference
in risk of thrombocytopenia after catheter placement.

BACKGROUND
placement. Infections can be caused by bacteria or fungi. Addi-
Central venous catheters (CVCs) are important for the manage- tionally, thromboses can also act as a nidus (breeding ground) for
ment of prolonged intravenous therapy in children who need par- infection (Timsit 1998).
enteral nutrition, medication or hemodynamic monitoring (Klerk
2003). However, these catheters are associated with mechanical Several measures have been employed to prevent CVC-related
and infectious complications. Mechanical complications include thrombosis. These include anticoagulants such as unfractionated
thrombosis (clotting) (Andrew 1994; Massicotte 1998), extrava- heparin at prophylactic or therapeutic dosages (Abdelkefi 2004;
sation (leakage of blood or lymph, intravenous drugs, or intra- Bailey 1979; Brismar 1982); low molecular weight heparins (for
venous nutrition from a vein into the surrounding tissue), occlu- example dalteparin); warfarin; heparin-bonded catheters; infusion
sion (blockage) and dislodgement of the catheter. The incidence of nitroglycerin (Jacobs 2001); vitamin C (Rabe 2002). In a sys-
of CVC-related thrombosis is reported to be 10% to 26% (Beck tematic review of six studies of prophylactic or therapeutic use of
1998) or 3.5 per 10,000 pediatric admissions (Massicotte 1998) heparin flushes or antithrombotic agents in adults, Klerk (Klerk
and is higher in patients with malignancy. Several factors have been 2003) concluded that the addition of heparin to parenteral flu-
implicated in the causation of thrombosis. These include patient ids did not reduce the incidence of CVC-related thrombosis. In
characteristics, for example younger age and infusion-related char- a randomized controlled trial of 152 children, heparinization was
acteristics such as low flow states, rate of infusion (Beck 1998), site found to reduce the risk for non-patency of arterial catheters but
of catheter placement (Massicotte 1998) and duration of catheter not for CVCs (de Neef 2002). However, another meta-analysis
Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 2
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of 11 studies of heparin infusion or heparin bonding for CVCs 1. CVC-related thrombosis (determined by colour-coded
reported a reduction of CVC-related venous thrombosis (relative Doppler ultrasonography or venography).
risk 0.43, 95% confidence interval 0.23 to 0.78) with prophylactic
2. Occlusion of CVCs (defined as inability to infuse fluids
heparinization (Randolph 1998). A review of the effectiveness of
through the catheter due to blockage).
antibiotic-impregnated and heparin-bonded catheters in prevent-
ing infections reported a significant reduction in the incidence of 3. Episodes of CVC-related sepsis and CVC-related
infection. However, only one study of heparin-bonded catheters colonization (CVC-related sepsis was defined as the presence of
was included in this review (Marin 2000). Carrasco 2004 com- symptoms and signs suggestive of sepsis, accompanied by
pared heparin-coated catheters with chlorhexidine and silver sul- positive blood cultures obtained from a normally sterile site
fadiazine-coated CVCs in adult intensive care units and reported different to the CVC and from the CVC or CVC tip, each
reduced colonization by gram-positive cocci and Candida species growing the same micro-organism; CVC-related colonization
in the latter group. was defined as the presence of micro-organisms in the CVC only
and not from another sterile site).
Thrombosis was observed within 24 hours of placement of in-
travenous catheters and by 72 hours thrombi started to detach 4. Number of additional CVC insertions.
(Hofbauer 2000). Bonding of the catheter surface with heparin
5. Abnormality of coagulation profile.
benzalkonium was shown to reduce thrombogenicity and throm-
bophlebitis in rabbits by reducing damage to the intima (the inner 6. Allergic reactions to heparin.
layer of a blood vessel) and by reducing platelet aggregation (Di
7. Heparin-induced thrombocytopenia (HIT) (development
Costanzo 1984). Heparin bonding of catheter in which heparin is
of thrombocytopenia after insertion of a heparin-bonded CVC
impregnated and thus slowly released on continuous basis should
in an infant with a previously normal platelet count after
be differentiated from heparin flushes which involves intermittent
exclusion of all other causes of thrombocytopenia, and a positive
infusion of heparin alongside other infusate. Heparinization was
antibody test).
also shown to reduce adherence by coagulase negative Staphylo-
coccus aureus when compared with catheters without hepariniza- 8. Hemorrhage from any site in the body.
tion (Appelgren 1996). Heparin coating was believed to reduce fi-
bronectin (a substance that interacts with extracellular substances 9. Osteoporosis with long-term use.
such as fibrin) adhesion on catheters and thereby reduce bacterial 10. Mortality.
attachment (Appelgren 1996). However, Bennegard 1982 demon-
strated an increased incidence of thrombophlebitis in the first four
days after catheterization in heparin-coated polyethylene catheters
METHODS
with no reduction in the incidence of thrombotic complications.
Mollenholt 1987 cautioned against overestimation of the protec-
tive effects of heparin bonding of pulmonary arterial catheters be-
cause effectiveness was found to decrease with time. Additionally, Criteria for considering studies for this review
heparin is associated with side effects such as bleeding, allergic reac-
tions and heparin-induced thrombocytopenia (HIT) (Warkentin
1990). These side effects could be aggravated in critically ill chil- Types of studies
dren if they have other intravascular devices in place or are receiv- We included randomized controlled trials of heparin-bonded
ing additional heparin. CVCs in children with CVCs and also studies that used alterna-
This review assessed the effectiveness and safety of heparin-bonded tive methods of randomizations such as alternate days of the week,
CVCs in children. odd or even dates of birth or hospital number (quasi-randomized).
We did not include studies that used historical controls. For any
studies in which the unit of randomization was the catheter, we
contacted the primary authors to obtain data for the first catheter
OBJECTIVES after randomization and only those data were planned to be in-
The primary objective of this review was to determine the effect cluded. If authors were unable to provide the data or could not be
of heparin-bonded CVCs on the duration of catheter patency in contacted, we described the study and included only data on side
children. effects and long-term outcomes such as hemorrhage or mortality.
Secondary objectives were to determine the effect of heparin-
bonded catheters on the following. Types of participants
Children (from birth to 18 years) who required CVCs.

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 3
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions (last searched The Cochrane Library 2007, Issue 3) for publica-
Heparin-bonded CVCs versus control (CVCs without heparin tions describing randomized or quasi-randomized controlled tri-
bonding or CVCs impregnated with antibiotics) without restric- als of heparin-bonded CRCs in children. The PVD Group’s Tri-
tion to the amount of heparin released. als Register contains citations of trials identified through elec-
tronic searches of MEDLINE (1966 to August 2007); EMBASE
(1980 to August 2007); and CINAHL (1982 to August 2007);
Types of outcome measures and through handsearching journals and conference proceedings.
The full list of journals that have been handsearched, as well as the
Studies that reported on one or more of the following outcomes search strategies for the electronic databases, are described in the
amongst all those participants randomized. ’Search strategies for the identification of studies’ section within
the editorial information about the Cochrane PVD Group in
The Cochrane Library see http://www.mrw.interscience.wiley.com/
Primary outcomes cochrane/clabout/articles/PVD/frame.html. For details of the
Days of catheter patency (duration of patency of first catheter, in search strategy used to search CENTRALfor this review see Ap-
days). pendix 1
The review authors also searched MEDLINE (1966 to March
2007); the search strategy is detailed in Appendix 2.
Secondary outcomes
1. Thrombosis of the catheter (along the length or at the tip of
the catheter, or at adjacent sites) as determined clinically and con- Searching other resources
firmed by Doppler ultrasonography or contrast venography. This
was determined as dichotomous data (yes or no) and the time du- In addition, we searched the reference lists of identified trials.
rations of catheter-related thrombosis were: There was no restriction on language of publication.
(a) within one week of catheter placement; We excluded letters, editorials, commentaries, reviews and lectures
(b) within two weeks of catheter placement; that did not contain original research data.
(c) within four weeks of catheter placement;
(d) after four weeks of catheter placement.
2. Occlusion of the catheter (identified by inability to infuse flu-
ids). This was determined as dichotomous data (yes or no) and Data collection and analysis
the time durations of occlusion of the catheter were:
(a) within one week of catheter placement;
(b) within two weeks of catheter placement;
(c) within four weeks of catheter placement; Selection of studies
(d) after four weeks of catheter placement. Both authors independently assessed all published articles iden-
3. Episodes of CVC-related sepsis and CVC-related colonization tified as potentially relevant by the literature search for inclusion
(children with one or more episodes). in the review. In order to be included the trial had to meet the
4. Number of additional CVCs needed. following criteria:
5. Side effects of heparin (allergic reactions, hemorrhage, heparin- • the study population was children;
induced thrombocytopenia (HIT), abnormal coagulation profile, • the intervention was heparin-bonded CVCs compared with
osteoporosis). standard catheters or antibiotic-impregnated catheters;
6. Mortality. • the study was a randomized or quasi-randomized controlled
7. Any other reported adverse outcome (not prespecified). trial;
• one or more of the primary or secondary outcome measures
were reported.
Search methods for identification of studies

Data extraction and management


Electronic searches Both authors independently extracted data from the retrieved ar-
The Cochrane Peripheral Vascular Diseases (PVD) Group ticles. We contacted the primary authors of any articles for which
searched their Trials Register (last searched 8 August 2007) and there was inadequate information, or if relevant data could not be
the Cochrane Central Register of Controlled Trials (CENTRAL) extracted. Any discrepancies were resolved by consensus.

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 4
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of risk of bias in included studies publication. For further details please see tables “Characteristics
We used standard methods of the Cochrane PVD Group to assess of included studies” and “Characteristics of excluded studies”.
the methodological quality of studies. Anton 2005 was a single-center study. A total of 90 patients were
Both authors independently assessed the quality of included stud- recruited but two patients did not have ultrasound examination
ies using the following criteria: and one patient did not get CVC, thus 87 patients were evaluated.
• masking of randomization; Children less than one year of age with congenital heart disease
• masking of intervention; who required a short term central venous line for standard clinical
• completeness of follow up; care were randomized to receive either a heparin-bonded catheter
• masking of outcome measurement. or non heparin-bonded catheter. The catheters were identical in
appearance. The primary outcome of the study was incidence of
thrombosis as diagnosed by ultrasound. All ultrasounds were re-
Assessment of heterogeneity viewed by a blinded central adjudication committee. No further
details on any of the other outcomes were available from the ab-
We applied tests for between-study heterogeneity including the I
2 stract.
test to assess the appropriateness of combining studies.
Pierce 2000 was a single-center study. A total of 209 patients be-
tween ages of day one and 16 years were randomized to either
heparin-bonded catheter or non heparin-bonded catheters. The
Data synthesis
authors reported that at the end of the study data were available
Statistical methods included risk ratio (RR), risk difference (RD), for 97 patients randomized to heparin-bonded catheters and 103
number needed to treat (NNT) and weighted mean difference patients randomized to non heparin-bonded catheters for anal-
(WMD), where appropriate, using the methods recommended by yses. Both types of catheter were made from polyurethane. The
the Cochrane PVD Review Group. We used a fixed-effect model catheters were either size 4F in diameter; double or triple lumen;
for meta-analyses. and 5 cm, 8 cm or 15 cm in length. The catheters had similar ap-
pearance and construction. The decision to remove a catheter was
made by the attending team. All patients had colour Doppler ul-
Subgroup analysis and investigation of heterogeneity trasound examination within three days of insertion of the catheter
The following subgroup analyses were planned according to con- and then every three days until the removal of the catheter. Throm-
trol intervention: bosis was defined as the presence of an echogenic mass within the
(1) heparin-bonded CVCs versus standard CVCs (without any lumen disrupting the blood flow. The radiologist reviewing the
coating); ultrasonography was unaware of the treatment allocation. All pa-
(2) heparin-bonded CVCs versus antibiotic-impregnated CVCs. tients had blood cultures taken from the central venous catheter
and another site on insertion of the catheter and then every three
days until the removal of the catheter. Additional blood cultures
were obtained when clinically indicated. Infections were consid-
ered significant when the same organism was grown from two sets
RESULTS of cultures from two different sites and the organism was differ-
ent from the one isolated from the start of catheter placement.
Catheter-related blood stream infections were considered when
Description of studies the same organism was isolated from two sets of cultures from two
separate sites. The microbiologist reporting infection was unaware
See: Characteristics of included studies; Characteristics of excluded
of treatment allocation.
studies.
After an extensive detailed search seven studies were retrieved for
further evaluation (Appelgren 1996; Bennegard 1982; Carrasco
2004 Hoar 1981; Krafte-Jacobs 1995; Mangano 1982; Pierce
Risk of bias in included studies
2000). Five studies were excluded because the studies included Anton 2005: The study was described as triple blind study, but
adult patients only (Appelgren 1996; Bennegard 1982; Carrasco detail information on certain aspects was not available from the
2004; Hoar 1981; Mangano 1982). One study was excluded be- abstract. The method of randomization and treatment allocation
cause it was not randomized (Krafte-Jacobs 1995). Two eligible could not be determined from the abstract. The ultrasound exam-
studies (Anton 2005; Pierce 2000) were included in this review. inations were reviewed by a masked radiology adjudication com-
One study was published as an abstract (Anton 2005); the authors mittee. Data on 87 patients were available; however a total 90 pa-
were contacted for further details but were unable to provide fur- tients were recruited.
ther details on their study in that the manuscript is submitted for Pierce 2000: Randomization was performed by selecting consec-

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 5
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
utively numbered opaque envelopes. The investigators were un- contact authors declined to provide further data at this stage as
aware of treatment allocation. The radiologist reporting results their manuscript is under preparation for submission.
of ultrasound Doppler and the microbiologist reporting results (a) At any time during catheter stay: (Outcome 01.01)
of infection were unaware of allocation. The attending physi- Both studies reported on this data. There were no statistically sig-
cian deciding about the removal of a catheter was also unaware nificant beneficial effects of heparin-bonded catheters in reducing
of treatment allocation. Nine patients (five patients in the hep- the risk of catheter-related thrombosis (RR 0.71, 95% CI 0.44 to
arin-bonded catheter group and four patients in the non heparin- 1.15; RD -0.05, 95% CI -0.13 to 0.02; I2 = 79%).
bonded catheter group) were removed from the study after ran-
domization (one patient needed to be changed to a different type (b) Within one week of catheter placement (Outcome 01.02)
of catheter for hemofiltration and in the other eight patients the Only Pierce 2000 provided data on this outcome. There was no
catheters were removed before microbiological data could be col- statistically significant reduction in catheter-related thrombosis in
lected). the first week after catheter placement (RR 0.10, 95% CI 0.01 to
1.72; RD -0.05, 95% CI -0.09 to 0.00).
(c) After the first week of catheter placement (Outcome 01.03)
Effects of interventions Only Pierce 2000 furnished data on this outcome. There was no
statistically significant reduction in catheter-related thrombosis
after the first week of catheter placement (RR 0.14, 95% CI 0.01
Heparin-bonded CVCs versus standard CVCs to 2.58; RD -0.07, 95% CI -0.15 to 0.02).

Both studies included neonates (< 28 days of age) and children (>
28 days of age). Data only on neonates could not be separated. 2. Occlusion of the catheter (identified by inability to infuse
The results reported below include all patients and contains both fluids)
published and unpublished information obtained by contacting These data were provided by the authors in two categories, occlu-
authors. sion within the first week and after the first week.
(a) Within one week of catheter placement (Outcome 01.04)
Pierce 2000 provided data for this outcome. There was a trend
Primary outcome
towards reduction in the risk of catheter occlusion in the first week
after catheter placement in the heparin-bonded catheter group
compared to the non heparin-bonded group (RR 0.06, 95% CI
Days of catheter patency (duration of patency of first
0.00 to 1.07; RD -0.08, 95% CI -0.13 to -0.02). The number of
catheter, in days)
children needed to be treated to prevent catheter occlusion in the
Pierce 2000 reported this data in survival curve format for devel- first week with use of heparin-bonded catheter was 13, (95% CI
opment of infection. The authors provided data that the catheter 8 to 50).
remained patent for > seven days in 47/97 patients in the heparin- (b) After first week of catheter placement (Outcome 01.05)
bonded catheter group versus 45/103 patients in the non heparin- Pierce 2000 reported a significant reduction in risk of catheter
bonded catheter group. There was no significant difference in the occlusion after the first week of catheter placement in the hep-
median duration of catheter patency (seven days in the heparin- arin-bonded catheter group compared to the non heparin-bonded
bonded catheter group versus six days in the non heparin-bonded catheters (RR 0.22, 95% CI 0.07 to 0.72; RD -0.23, 95% CI -
catheter group). 0.37 to -0.08). The number of children needed to be treated to
prevent one catheter occlusion in the first week with the use of
heparin-bonded catheters was 5, (95% CI 3 to 13).
Secondary outcomes

3. Episodes of CVC-related sepsis and CVC-related


1. Catheter-related thrombosis (along the length or at the tip colonization (children with one or more episodes)
of the catheter, or at adjacent sites) as determined clinically (Outcome 01.06 and 01.07)
and confirmed by Doppler ultrasonography or contrast Pierce 2000 reported a significant reduction in the risk of catheter-
venography related infection in the heparin-bonded catheter group compared
Pierce 2000 reported data on any thrombosis during the stay of the to non heparin-bonded catheters (RR 0.06, 95% CI 0.01 to 0.41;
catheter in the published report and provided additional data on RD -0.17, 95% CI -0.25 to -0.10). The number of children
number of infants with thrombosis within the first week of therapy needed to be treated with heparin-bonded catheter to prevent one
and after the first week of therapy. Anton 2005 only reported on catheter-related infection was 6, (95% CI 4 to 10). There was a sig-
catheter-related thrombosis at any time during catheter stay and nificant reduction in risk of catheter colonization in the heparin-

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 6
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
bonded catheter group compared to non heparin-bonded catheters risk group of children with congenital heart disease. Presence of
(RR 0.21, 95% CI 0.06 to 0.71; RD -0.11, 95% CI -0.19 to - congenital heart disease in itself is a predisposing factor for vascu-
0.04). The number of children needed to be treated with heparin- lar thrombosis, second to polycythemia associated with cyanotic
bonded catheters to prevent one catheter colonization with mi- heart disease. A slower, altered circulatory state and increased like-
crobes was 9, (95% CI 5 to 25). The authors reported the sur- lihood of undergoing surgery is higher in this group of infants,
vival function for time to development of infection. There was a increasing probability of thrombosis. Anton 2005 appears to be
statistically significant difference in the time to develop infection a negative result study where as Pierce 2000 reports positive re-
(delayed in the heparin-bonded catheters group) with an adjusted sults study as far as the efficacy of heparin-bonded catheters in
hazard ratio of 0.14 and P < 0.001. preventing vascular thrombosis and its associated complications
are concerned. These studies reflect a fair amount of clinical and
statistical heterogeneity.
4. Number of additional CVCs needed
Heparin-bonded catheters have been well-studied in the adult
This outcome was not reported in any of the studies.
population in different types of catheters. Appelgren 1996 re-
ported reduced colonization by staphylococcal organisms in hep-
5. Side effects of heparin (allergic reactions, hemorrhage, arin-bonded-catheters. Bennegard 1982 did not identify any ad-
heparin-induced thrombocytopenia (HIT), abnormal vantage of heparin-bonded catheters in preventing thrombotic
coagulation profile, osteoporosis) complications. Carrasco 2004 reported reduced colonization with
(Outcome 01.08) antibiotic-impregnated catheters compared with heparin-bonded
Only data on incidence of thrombocytopenia were available from catheters.
Pierce 2000. There was no significant difference in risk of throm- Hoar 1981 reported reduced thrombogenicity with heparin-
bocytopenia after catheter placement (RR 0.73, 95% CI 0.38 to bonded pulmonary catheters when examined at 24 hours of age
1.39; RD -0.05, 95% CI -0.15 to 0.05). Patients were not in- during bypass surgery. Mangano 1982 reported that heparin-
vestigated for heparin-induced thrombocytopenia. No other side bonded catheters provided protection from thrombosis when ex-
effects were reported. amined at 24 hours of age during atriotomy. Krafte-Jacobs 1995
prospectively evaluated 50 consecutive but non-randomized pe-
diatric patients who had heparin-bonded (n = 25) and non hep-
6. Mortality
arin-bonded (n = 25) catheters. They reported thrombotic com-
This outcome was not reported. plications in 44% of patients in the non heparin-bonded catheter
group versus 8% of patients in the heparin-bonded catheter group
(P = 0.004). The incidence of positive blood culture was 24% in
the non heparin-bonded catheter group versus none in the hep-
DISCUSSION arin-bonded catheter group (P = 0.009). None of these studies
reported a higher incidence of complications associated with the
After an extensive literature review we identified only two stud-
use of heparin-bonded catheters.
ies which have evaluated this intervention. Pierce 2000 is a very
well-conducted single-center study with adequate methodological Thrombophlebitis, hemorrhage and heparin-induced thrombocy-
quality. Anton 2005 also appears to be a well conducted single- topenia are major concerns with the use of heparin. An animal
center study; however, further details will only be available after study (Di Costanzo 1984) showed that heparin-benzalkonium-
publication of the full article. Pierce 2000 reported a trend towards bonded silicone catheters provided protection against throm-
a reduction in the risks of catheter-related thrombosis and catheter bophlebitis due to less damage to intima and slowed aggregation
occlusion in the heparin-bonded catheter group whereas Anton of platelets. Nichols 1984 revealed that heparin-bonded catheters
2005 reported no significant difference in the risk of catheter-re- prevented catheter-induced platelet alpha granule release and fib-
lated thrombosis. There was a significant reduction in the risks of rin formation on catheter surfaces, which thus may prevent throm-
catheter-related infection and catheter colonization in the study bus formation.
by Pierce 2000. The incidence of catheter occlusion was reduced
Gilbert 2003 reported that, despite the study by Pierce 2000, the
in the heparin-bonded catheter group within the first week of
use of heparin-bonded catheters is not prevalent in the UK due to
catheter placement according to Pierce 2000. There was no in-
licensing issues. Only the center where the study was conducted
crease in the risk of thrombocytopenia associated with the use of
is using these types of catheters with full legal responsibility and
heparin-bonded catheters according to Pierce 2000. A major dif-
on a named-patient basis.
ference in the clinical characteristics of these two studies is the
population. Pierce 2000 enrolled all patients admitted to NICU Due to variability in the results, the findings of the study by Anton
irrespective of diagnosis while Anton 2005 only enrolled a high- 2005 and Pierce 2000 need to be confirmed in other studies before

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 7
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
specific recommendations can be made. Exposure to inadvertent arin-bonded catheters; however, further research is needed to es-
use of heparin for pediatric patients needs to be studied carefully, tablish safety and efficacy.
especially with emerging reports of heparin-induced thrombocy-
topenia and associated thrombosis in adult and pediatric patients Implications for research
(Schmugge 2002). Exposure at this early age may lead to sensi-
Further research in the form of a randomized controlled trial,
tization and could render an individual prone to further compli-
preferably a multicenter study, is needed to evaluate the safety and
cations in later life. There was no difference in the duration of
efficacy of heparin-bonded central venous catheters. This study
catheter patency in this study, which usually is the effect com-
should only include one catheter per patient; report on duration of
monly seen with heparin. The authors have also not documented
catheter patency among censored (catheters removed due to com-
the clinically important and significant outcome of mortality in
plications) and non-censored (catheters removed electively) obser-
either studies. Further multicenter evaluation of heparin-bonded
vations (mean, SD, median, range), catheter-related infection, oc-
catheters is warranted. We also await the complete results of Anton
clusion, catheter-related thrombosis; and incidence of heparin-in-
2005 study.
duced thrombocytopenia, hemorrhage, allergic reactions, throm-
bophlebitis and overall all-cause mortality prior to discharge from
units.

AUTHORS’ CONCLUSIONS

Implications for practice ACKNOWLEDGEMENTS


Heparin-bonded central venous catheters may have a role in pe- We would like to thank Dr C Pierce for providing additional data
diatric patients in reducing catheter-related infections and col- on her group’s study. We would also like to thank the Cochrane
onizations; however, there was no statistically significant differ- Consumer Network for providing a plain language summary and
ence in the catheter-related thrombosis or duration of catheter pa- the Cochrane Peripheral Vascular Diseases Group for their exten-
tency. Currently available data indicate possible benefits of hep- sive assistance in the first published version of this review.

REFERENCES

References to studies included in this review antebrachial, polyethylene catheters. Acta Anaesthesiologica
Scandinavica 1982;26(2):112–20.
Anton 2005 {published data only}
Carrasco 2004 {published data only}
Anton N, Cox P, Massicotte P, Dinyari M, Vegh P, Mitchell LG. No
Carrasco MN, Bueno A, de las Cuevas C, Jimenez S, Salinas I,
difference in incidences of thrombosis between heparin bonded
Sartorius A, et al.Evaluation of a triple-lumen central venous
catheters and non heparin bonded catheters in Infants in the critical
heparin-coated catheter versus a catheter coated with chlorhexidine
care unit following surgery for congenital heart disease: a
and silver sulfadiazine in critically ill patients. Intensive Care
randomised controlled triple blind study. Journal of Thrombosis and
Medicine 2004;30(4):633–8.
Haemostasis 2005;3:Abstract # P1726.
Hoar 1981 {published data only}
Pierce 2000 {published and unpublished data}
Hoar PF, Wilson RM, Mangano DT, Avery GJ, Szarnicki RJ, Hill
Pierce CM, Wade A, Mok Q. Heparin-bonded central venous lines
JD. Heparin bonding reduces thrombogenicity of pulmonary-artery
reduce thrombotic and infective complications in critically ill
catheters. New England Journal of Medicine 1981;305(17):993–5.
children. Intensive Care Medicine 2000;26(7):967–72.
Krafte-Jacobs 1995 {published data only}
References to studies excluded from this review Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related
thrombosis in critically ill children: Comparison of catheters with
Appelgren 1996 {published data only} and without heparin bonding. Journal of Pediatrics 1995;126(1):
Appelgren P, Ransjo U, Bindslev L, Espersen F, Larm O. Surface 50–4.
heparinization of central venous catheters reduces microbial
colonization in vitro and in vivo: results from a prospective, Mangano 1982 {published data only}
randomized trial. Critical Care Medicine 1996;24(9):1482–9. Mangano DT. Heparin bonding and long-term protection against
thrombogenesis. New England Journal of Medicine 1982;307(14):
Bennegard 1982 {published data only} 894–895.
Bennegard K, Curelaru I, Gustavsson B, Linder LE, Zachrisson BF.
Material thrombogenicity in central venous catheterization. I. A Additional references
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Abdelkefi 2004 thrombosis: a randomized, controlled trial. Intensive Care Medicine
Abdelkefi A, Ben Othman T, Kammoun L, Chelli M, Romdhane 2001;27(1):187–92.
NB, Kriaa A, et al.Prevention of central venous line-related Klerk 2003
thrombosis by continuous infusion of low-dose unfractionated Klerk CP, Smorenburg SM, Buller HR. Thrombosis prophylaxis in
heparin, in patients with haemato-oncological disease. A patient populations with a central venous catheter: a systematic
randomized controlled trial. Thrombosis and Haemostasis 2004;92 review. Archives of Internal Medicine 2003;163(16):1913–21.
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Marin 2000
Andrew 1994
Marin MG, Lee JC, Skurnick JH. Prevention of nosocomial
Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et
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Massicotte 1998
Bailey 1979
Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central
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Beck 1998
Mollenholt 1987
Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and
Mollenholt P, Eriksson I, Andersson T. Thrombogenicity of
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Nichols 1984
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Brismar B, Hardstedt C, Jacobson S, Kager L, Malmborg AS. Nichols AB, Owen J, Grossman BA, Marcella JJ, Fleisher LN, Lee
MM. Effect of heparin bonding on catheter-induced fibrin
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by intravenous heparin therapy. Archives of Surgery 1982;117(9): formation and platelet activation. Circulation 1984;70(5):843–50.
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de Neef 2002 Rabe C, Gramann T, Sons X, Berna M, Gonzalez-Carmona MA,
de Neef M, Heijboer H, van Woensel JB, de Haan RJ. The efficacy Klehr HU, et al.Keeping central venous lines open: a prospective
of heparinization in prolonging patency of arterial and central comparison of heparin, vitamin C and sodium chloride sealing
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Pediatric Hematology and Oncology 2002;19(8):553–60. 1172–6.
Di Costanzo 1984 Randolph 1998
Di Costanzo J, Sastre B, Choux R, Reynier JP, Noirclerc M, Cano Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of
N, et al.Experimental approach to prevention of catheter-related heparin in central venous and pulmonary artery catheters: a meta-
central venous thrombosis. Journal of Parenteral and Enteral analysis of randomized controlled trials. Chest 1998;113(1):
Nutrition 1984;8(3):293–7. 165–71.
Gilbert 2003 Schmugge 2002
Gilbert R, Howard R, Mok Q. Heparin-bonded lines reduce Schmugge M, Risch L, Huber AR, Benn A, Fischer JE. Heparin-
hospital-acquired bacteraemia. Journal of Hospital Infection 2003;54 induced thrombocytopenia-associated thrombosis in pediatric
(2):163–4. intensive care patients. Pediatrics 2002;109(1):E10.

Hofbauer 2000 Timsit 1998


Hofbauer R, Moser D, Kaye AD, Dielacher C, Hornykewycz S, Timsit JF, Farkas JC, Boyer JM, Martin JB, Misset B, Renaud B, et
Handler S, et al.Thrombus formation on the balloon of heparin- al.Central vein catheter-related thrombosis in intensive care
bonded pulmonary artery catheters: an ultrastructural scanning patients: incidence, risks factors, and relationship with catheter-
electron microscope study. Critical Care Medicine 2000;28(3): related sepsis. Chest 1998;114(1):207–13.
727–35. Warkentin 1990
Jacobs 2001 Warkentin TE, Kelton JG. Heparin and platelets. Hematology -
Jacobs BR, Barr LL, Brilli RJ, Lyons KA, Wong HR. Intracatheter Oncology Clinics of North America 1990;4(1):243–64.
nitroglycerin infusion fails to prevent catheter-related venous ∗
Indicates the major publication for the study

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 9
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Anton 2005

Methods Randomized controlled trial


I. Masking of randomization - Cannot tell
II. Masking of intervention - Yes
III. Masking of outcome assessment - Yes
IV. Completeness of follow up - No

Participants Inclusion criteria: Children < 1 year of age who had congenital heart disease and needed central venous
catheter access
N = 86; 41 females, 46 males
Mean age: 5.0 ± 3.2 months (SD)

Interventions Group 1: Heparin-bonded central venous catheter


Group 2: Non heparin-bonded central venous catheter

Outcomes Catheter-related thrombosis

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Pierce 2000

Methods Randomized controlled trial


I. Masking of randomization - Yes
II. Masking of intervention - Yes
III. Masking of outcome assessment - Yes
IV. Completeness of follow up - No

Participants Inclusion criteria: Children aged 1 day to 16 years of age who were ventilated and needed central venous
catheter access
Exclusion criteria: Patients with history of recent use of central venous catheter (within the last month),
patients on thrombolytic therapy, patients with history of thrombosis, and post-operative cardiac patients
Group 1:
102 randomized patients (97 patients had complete data and included in the analyses)
Age:
17 patients < 28 days
80 patients > 28 days of age
N = 97 (56 males, 41 females)
Size of catheter

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 10
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pierce 2000 (Continued)

4F:5F = 17:80
Site of catheter
Femoral:Neck = 80:17
Group 2:
107 patients randomized (103 patients had complete data and included in the analyses)
Age:
17 patients < 28 days
80 patients > 28 days
N = 103 (55 males, 48 females)
Size of catheter
4F:5F = 24:79
Site of catheter
Femoral:Neck = 90:13

Interventions Group 1: Heparin-bonded central venous catheter


Group 2: Non heparin-bonded central venous catheter

Outcomes Catheter-related infection


Catheter colonization
Catheter-related thrombosis
Catheter occlusion
Duration of catheter patency
Thrombocytopenia

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

SD = standard deviation

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Appelgren 1996 Adult population only

Bennegard 1982 Adult population only

Carrasco 2004 Adult population only

Hoar 1981 Adult population only

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 11
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Krafte-Jacobs 1995 Not a randomized study


Prospective comparison of two types of catheters

Mangano 1982 Adult population only

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 12
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Heparin bonded catheter versus non-heparin bonded catheters

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Catheter-related thrombosis at 2 287 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.44, 1.15]
any time during catheter stay
2 Catheter-related thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
within one week of catheter
insertion
3 Catheter-related thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
after one week of insertion
4 Occlusion of catheter within one 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
week of catheter insertion
5 Occlusion of catheter after one 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
week of catheter insertion
6 Catheter-related infection 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
7 Colonization of catheter with 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
microbes
8 Thrombocytopenia after catheter 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
insertion

FEEDBACK

Anticoagulant feedback, 14 February 2011

Summary
Feedback received on this review, and other reviews and protocols on anticoagulants, is available on the Cochrane Editorial Unit website
at http://www.editorial-unit.cochrane.org/anticoagulants-feedback.

WHAT’S NEW
Last assessed as up-to-date: 20 August 2007.

Date Event Description

14 February 2011 Amended Link to anticoagulant feedback added

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 13
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HISTORY
Protocol first published: Issue 2, 2006
Review first published: Issue 4, 2007

Date Event Description

30 May 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
PS Shah selected trials, assessed trial quality, extracted data, wrote and edited the final review.
N Shah selected trials, assessed trial quality, extracted data and edited the final review.

DECLARATIONS OF INTEREST
None

SOURCES OF SUPPORT

Internal sources
• Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.
• Department of Hematology and Oncology, Clinical Fellowship Program, The Hospital for Sick Children, Toronto, Canada.

External sources
• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

INDEX TERMS

Medical Subject Headings (MeSH)


Adolescent; Anticoagulants [∗ administration & dosage]; Catheterization, Central Venous [adverse effects; ∗ instrumentation]; Heparin
[∗ administration & dosage]; Infant, Newborn; Randomized Controlled Trials as Topic; Venous Thrombosis [∗ prevention & control]

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 14
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
MeSH check words
Child; Child, Preschool; Humans; Infant

Heparin-bonded catheters for prolonging the patency of central venous catheters in children (Review) 15
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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