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Vitamin K antagonists in children with central

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Pediatr Nephrol
DOI 10.1007/s00467-015-3293-1
ORIGINAL ARTICLE
Vitamin K antagonists in children with central venous catheter
on chronic haemodialysis: a pilot study
Fabio Paglialonga 1 & Andrea Artoni 2 & Simon Braham 2 & Silvia Consolo 1 &
Alberto Giannini 3 & Giovanna Chidini 3 & Luisa Napolitano 3 & Ida Martinelli 2 &
Giovanni Montini 1 & Alberto Edefonti 1
Received: 28 August 2015 / Revised: 2 December 2015 / Accepted: 3 December 2015
# IPNA 2015
Abstract
Background To date, no study has investigated the use of
vitamin K antagonists (VKA) in children undergoing chronic
haemodialysis (HD) with a central venous catheter (CVC).
Methods Consecutive patients aged <18 years with a newly
placed tunnelled CVC for chronic HD were enrolled over a 3-
year period. Children with active nephrotic syndrome or a
history of venous thrombosis received warfarin (VKA group)
with therapeutic target international normalised ratios of be-
tween 2.0 and 3.0. Patients at standard risk of CVC malfunc-
tion were not treated with VKA (standard group). The primary
end-point was overall CVC survival.
Results The VKA group consisted of nine patients (median
age 10.6 years; range 1.215.3 years) with 11 CVC, and the
standard group comprised eight patients (11.8 years; 6.117.3
years) with ten CVC. The 6- and 12-month CVC survival was
significantly longer in the VKA group than in the standard
group (100 vs. 60 % and 83.3 vs. 16.7 %, respectively;
p<0.05), with a median survival of 369 and 195 days, respec-
tively (p<0.05). None of the CVC in the VKA group required
removal due to malfunction, as compared to four in the stan-
dard group. No major bleeding episodes occurred in either
group.
* Fabio Paglialonga
fabiopaglialonga@alice.it
1
Pediatric Nephrology and Dialysis Unit, Fondazione IRCCS Ca
GrandaOspedale Maggiore Policlinico, Via Commenda 9,
20122 Milan, Italy
2
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione
IRCCS Ca GrandaOspedale Maggiore Policlinico, Milan, Italy
3
Pediatric Intensive Care Unit, Fondazione IRCCS Ca Granda
Ospedale Maggiore Policlinico, Milan, Italy
Conclusions Therapy with VKA would appear to be safe in
children on chronic HD and may improve CVC survival in
patients at increased risk of CVC thrombosis.
Keywords Oral anticoagulants . Paediatric haemodialysis .
Tunnelled central venous catheter . Vitamin K antagonists .
Warfarin
Introduction
Arteriovenous fistula (AVF) is widely considered to be the
optimal vascular access for patients on chronic haemodialysis
(HD). This strategy is recommended by the National Kidney
Foundation/Kidney Disease Outcome Quality Initiative
(NKF/KDOQI) guidelines as the first-choice option in pa-
tients with end-stage renal disease (ESRD), as well as in chil-
dren weighing >20 kg [17]. Nevertheless, in routine practice
central venous catheter (CVC) remains the most common
form of vascular access (6080 %) in children with ESRD
[813]. The choice of CVC as access is likely due to the
expected short period of maintenance dialysis preceding kid-
ney transplantation in the paediatric patient population, the
possibility to avoid the pain caused by AVF puncture and
the technical difficulties involved in creating AVFs, especially
in children with a low body weight.
The use of a CVC in HD patients can however be associated
with serious complications. In the short term there is a higher
incidence of access malfunction and infections compared to
AVF, and in the long-term recurrent CVC placement frequently
leads to central vein thrombosis, which can have a dramatic
impact on patient health [14]. To date, there are few therapeu-
tic options available to avoid the complications of CVC use in
patients on chronic HD. Given that thrombosis accounts for
most cases of CVC mechanical failure [6], defined as the failure

to sustain a blood pump speed adequate for dialysis, vitamin K
antagonists (VKA) have been proposed as a therapeutic strate-
gy to reduce the incidence of CVC malfunction. This option
was not supported by a meta-analysis of five randomised con-
trolled trials (RCTs) which failed to show a beneficial effect of
VKA on catheter malfunction [1419]. However, a statistically
significant heterogeneity was identified among the trials includ-
ed in the meta-analysis which could not be accounted for by the
different doses of VKA used [14]. Notably, these studies in-
cluded adult patients only and were not limited to patients at
higher risk of CVC malfunction who may receive the greatest
benefit from an anticoagulant treatment.
Several risk factors for thrombosis are recognised in pa-
tients with ESRD, such as hyperhomocysteinemia and an im-
balance between pro- and anti-thrombotic factors. In particu-
lar, patients with active nephrotic syndrome (NS) have an
acquired thrombophilic state [2028]. Additionally, a prior
thrombosis increases the risk of a subsequent one [29]. Based
on these observations it can be surmised that this patient pop-
ulation would benefit the most from an anticoagulant therapy.
The aim of this study was to investigate the effect of war-
farin, a VKA, on the survival of tunnelled CVC and to assess
the rate of complications in children with active NS or previ-
ous central vein thrombosis undergoing chronic HD.
Subjects and methods
This study included consecutive patients aged <18 years in
whom a tunnelled CVC had been placed for chronic HD be-
tween 1 June 2011 and 30 March 2014. Patients with active
NS (serum albumin<2.5 g/dL and urine protein/creatinine
ratio>2 mg/mg) or a previous CVC thrombosis were consid-
ered to be at high risk of CVC thrombosis. In these patients
sodium warfarin was added to the standard treatment, starting
at 0.3 mg/kg/day (maximum 5 mg/day) and then adjusted to
maintain an international normalised ratio (INR) of prothrom-
bin time of between 2.0 and 3.0 (VKA group). Patients in
whom a CVC was placed for chronic HD without NS or pre-
vious CVC thrombosis were considered to be at standard
thrombotic risk and did not receive warfarin treatment (stan-
dard group). The two groups were compared for CVC survival
(primary end-point) and for the incidence of CVC removal
due to malfunction and the occurrence of bleeding complica-
tions (secondary end-points). Patients were censored at the
time of transplantation if the CVC was still functioning or in
case of death. In all other cases the observational period ended
at the time of CVC removal, and the reasons for CVC removal
and the time from placement to removal were recorded. CVC
malfunction was defined as the inability to perform HD due to
failed aspiration or the infusion of blood through the CVC. At
every dialysis session, relatives and nurses were asked if any
bleeding complication had occurred. Bleeding was defined
Pediatr Nephrol
according to the International Society of Thrombosis and
Haemostasis criteria [30]: major bleeding was defined as (1)
any fatal bleeding and/or (2) symptomatic bleeding in a criti-
cal area or organ, such as intracranial, intraspinal, intraocular,
retroperitoneal, intraarticular or pericardial or intramuscular
with compartment syndrome and/or (3) bleeding causing a fall
in haemoglobin level of 2 g/dL or leading to transfusion of
two or more units of whole blood or red cells.
HD adequacy (HD blood flow and Kt/V), the frequency of
urokinase use and the incidence of CVC-related infections
were also assessed. The following parameters were calculated
as median values for each CVC in order to assess HD adequa-
cy: blood flow rate (Qb)/body weight (mL/min/kg), single-
pool Kt/V (spKt/V) and equilibrated Kt/V (eKt/V). SpKt/V
and eKt/V were calculated according to standard formulae
[6]. Data related to all HD sessions were used to calculate
median Qb, and all available pre-and post-dialysis blood urea
nitrogen values (at least 1 per month per patient) were used to
calculate spKt/V and eKt/V
The CVC placed in each patient was a cuffed catheter
(Medcomp, Harleysville, PA), French size (Fr) 8 or 10. Each
CVC was placed in an internal jugular or subclavian vein
under general anesthesia using percutaneous cannulation un-
der fluoroscopic guidance and ultrasonographic vein
localisation and tunnelled through the subcutaneous tissue,
with the tip positioned at the atrio-caval junction or just inside
the right atrium, as confirmed on X-rays. 8 Fr CVC were
placed in children with a body weight of<12 kg; 10 Fr CVC
were placed in all other patients.
Unfractionated heparin (5000 U/mL) was standardly used
as a lock solution at the end of each HD session, with the
exception of a blood flow rate (Qb) reduction of >20 % from
baseline, a pre-pump arterial pressure of 250 mmHg or a
failure to draw blood from the access, in which cases a 5000
U/mL urokinase lock was used. In both patient groups heparin
was used as anticoagulant during the HD session according to
our local protocol: 2025 U/kg as bolus injections, followed
by 2025 U/kg/h as continuous infusion, with monitoring of
the activated clotting time (ACT) values. Routine exit site care
included a strictly sterile use of the CVC by only trained
nurses, sterile gloves and surgical masks whenever the CVC
was accessed, gauze dressings at the exit site and no systemic
antibiotic prophylaxis.
The warfarin dose was modified according to the INR
values by two haematologists. Standard 5 mg warfarin tablets
were used whenever possible, whereas 0.5 mg powders were
prepared in the case of small children who needed smaller
doses. In order to avoid the effect of heparin on the INR, blood
samples for INR measurements were routinely taken from the
HD circuit immediately after the start of the treatment and not
from the CVC lumen. No patients received anti-platelet agents.
The incidence of exit-site infections, tunnel infections and
catheter-related bloodstream infections, diagnosed in
Pediatr Nephrol

Table 1 Characteristics of
patients and central venous
catheter
Baseline characteristics Warfarin group (n = 11 CVC) Standard group (n = 10 CVC)
Number of patients 9 8
Age (years) 10.6 (1.215.3) 11.8 (6.117.3)
Sex (male/female) 5/4 5/3
Type of CVC 10 Fr split catheter: 8 10 Fr split catheter: 10
8 Fr dual-lumen catheter: 3
Body weight (kg) 23.5 (75-40) 21.9 (15.838)
Height (cm) 130.0 (70160) 130.5 (106138)
CVC site
Right jugular vein 1 3
Left jugular vein 2 2
Right subclavian vein 5 2
Left subclavian vein 3 3
Primary kidney disease
FSGS 7 1
Renal dysplasia 1 4
Oxalosis 1 0
Other 0 3

Data are presented as the median with the range in parenthesis, or as the number of patients
CVC, central venous catheter; FSGS, focal segmental glomerulosclerosis; Fr, French size

accordance with the NKF/KDOQI guidelines, was also
assessed in both groups [6].
Statistical analysis
Data were expressed as median values and ranges and
analysed using the MannWhitney test for continuous vari-
ables and the chi-square test for dichotomous variables.
KaplanMeier analysis was used to evaluate CVC survival.
A p value of <0.05 was considered to be statistically
significant.
Results
1.22. Two CVC in the VKA group were removed because of
CVC breaks (micro-holes).
The control (standard) group consisted of ten cuffed CVC
placed in eight patients with a median age of 11.8 (range 6.1
17.3) years. No patient weighed <15 kg. The subclavian vein
was the CVC site in five patients. Eight CVC in the control
group were removed because of malfunction (n=4) or dis-
placement (n=4).
As shown in Fig. 1, the 6- and 12-month CVC survival
rates were significantly higher in the warfarin group (100 vs.
60 % and 83.3 vs. 16.7 %, respectively; p<0.05), with a me-
dian survival of 369 and 195 days, respectively (p<0.05). The
difference remained statistically significant when only the

A total of 38 patients aged <18 years underwent chronic HD in

our Unit during the study period, of whom 15 (39.5 %) had at
least one tunnelled CVC placed and were enrolled in our
study. Baseline characteristics of the enrolled patients and
CVC are shown in Table 1.
The VKA group consisted of 11 tunnelled CVC placed in
nine children with a median age of 10.6 (range 1.215.3)
years. Of these nine children six had active NS (6 catheters)
with a median albumin level of 1.5 (range 1.11.8) g/dL and a
median urinary protein/creatinine ratio of 21.03 (8.8
60.8) mg/mg and three (5 catheters) had previous central vein
thrombosis due to CVC placement. The subclavian vein was
the CVC site in eight patients. Four patients had a body
weight of <15 kg. The median time within the therapeutic Fig. 1 Overall central venous catheter (CVC) survival in the vitamin K
range was 51.0 % (range 764 %). The mean INR was 2.02 antagonist (VKA) group and the control (standard) group

Fig. 2 Malfunction-free survival of central venous catheters (CVC) in the
vitamin K antagonists (VKA) group and standard group
removals due to malfunctions were considered: the 6- and 12-
month CVC malfunction-free survival rates were 100 vs.
76.2 % and 100 vs. 50.8 %, respectively (p<0.05) (Fig. 2)
As shown in Table 2, there were no differences in blood
flow/body weight, dialysis adequacy (using spKT/V and eKt/
V) or urokinase use among the two groups. Nine exit-site
infections and three tunnel infections were observed, equally
distributed between the two groups.
No major bleeding complications occurred in both groups
over a cumulative treatment period of 2489 days.
Discussion
The results of our study show that CVC survival is longer in
children at high risk of CVC thrombosis due to active NS or
previous CVC thrombosis when treated with VKA than in
children at standard thrombotic risk not treated with VKA.
Central line malfunction is a common problem in patients
undergoing HD through a CVC; after a successful first use,
thrombosis is the most common cause of mechanical failure.
Warfarin has therefore been proposed as a strategy to improve
Table 2 Dialysis blood flow,
dialysis adequacy, urokinase use Parameters of haemodialysis
and infections in the vitamin K
antagonists (VKA) and standard
groups Qb (mL/kg/min)
spKt/V
eKt/V
Urokinase (% sessions)
Exit-site infoection (n/1000 CVC days)
Tunnel infectionI (n/1000 CVC days)
Bloodstream infection (n/1000 CVC days)
Data are presented as the median, with the range given in parenthesis, unless indicated otherwise
Qb, Blood flow rate to the dialyzer; spKt.V, single-pool Kt/V ; eKt/V, equilibrated Kt/V; CVC, central venous catheter
Pediatr Nephrol
central line survival in adult patients on chronic HD, but the
results have been conflicting. Since the use of VKA is associ-
ated with a potential risk of bleeding, in our study we chose to
restrict warfarin treatment to those patients whom we consid-
ered to be at high risk of CVC malfunction due to catheter
thrombosis and, therefore benefit the most from anticoagulant
treatment, namely, children with active NS or with a previous
episode of CVC thrombosis.
The most important finding of this study is that CVC sur-
vival and malfunction-free survival rates were significantly
higher in the VKA group, even if these patients had additional
risk factor(s) for thrombosis, such as the presence of more
patients with a body weight of <15 kg and with more subcla-
vian vein CVC [3134]. Available studies focusing on the use
of tunnelled CVC in children on HD have reported a median
survival time of between 91 and 322 days and a 1-year sur-
vival ranging from 0 to 62 % [5, 3538]. Among our patients,
median tunnelled CVC survival was 369 days in the VKA
group and 195 days in the control group, with a 1-year sur-
vival of 83 and 16.7 %, respectively. As there were no other
differences in CVC management between the two groups, we
can surmise that the longer CVC survival in patients receiving
VKA is at least partly due to warfarin treatment. More specif-
ically, the longer CVC survival in the VKA group can be
attributed to the significant reduction in the frequency of
CVC removal secondary to malfunction. This benefits of war-
farin regarding CVC survival was observed despite the rela-
tively low median INR in the therapeutic range (between 2.0
and 3.0): INR values were<2.0 in most of the cases, which
should be taken into account in the evaluation of the bleeding
risk of these patients.
We did not observe any major bleeding episodes. The
risk of major bleeding in children treated with oral anti-
coagulants has been reported to be as high as 0.5 % per
patient-year [39], but observation periods longer than our
observation period are clearly required to assess the risk
of bleeding associated with the use of warfarin in paedi-
atric patients on HD.
Warfarin group Standard group p value
(n =11 CVC) (n = 10 CVC)
3.4 (2.713.0) 5.2 (3.37.2) 0.06
1.6 (0.82.3) 1.4 (1.01.9) 0.45
1.4 (0.72.0) 1.2 (0.91.6) 0.40
2.9 1.7 0.06
2.0 1.7 0.83
0.8 0.4 0.48
0 0 0.99
Pediatr Nephrol
At first sight our results appear to conflict with those
reported in adults. A meta-analysis of five RCTs investigating
the efficacy of oral anticoagulants to prevent CVC
malfunction found that patients treated with warfarin had no
significant advantage over those on placebo (relative risk
0.59, 95 % confidence interval 0.281.22) [14]. However, a
more in-depth examination of three major trials included in
the meta-analysis reveals that in one trial with 85 patients
warfarin was ineffective at a fixed dose of 1 mg daily
(although a decrease in thrombosis was found in the
subgroup that achieved INR>1.0) and in another trial with
174 patients which used a target INR of 1.51.9. On the
contrary, the percentage of patients experiencing thrombosis
at 1 year in a randomised trial of 144 adults on HD was 12 %
in those treated with warfarin with a target INR of 1.82.5,
which is closer to our target INR than that of the other studies,
and 52 % in controls. More importantly, the thrombotic risk
of children on HD can be different from that of adults due to a
relative disproportion between the caliber of the CVC and the
veins.
Notwithstanding the benefits associated with the use of
VKA in our population, the median access survival was still
lower than that commonly observed with AVF. Taking into
account all of the proven advantages of AVF over CVC, it
remains essential to encourage early AVF creation in paediat-
ric patients needing chronic HD.
Some limitations and strengths of this study need to be
addressed. First, this is a pilot study that included a relatively
small number of patients and, therefore, our results need
confirmation. Second, we were not able to assess the
incidence of central vein thrombosis (whereas this should be
the true end-point of any study of anticoagulant therapy in
patients on chronic HD). Third, we compared two different
groups of patients, and the choice of the standard risk group as
the control group may be open to debate: given that a histor-
ical cohort of patients at high risk of thrombosis not treated
with VKA was not available, we used as controls all of the
CVC of the same type, placed in the same study period in the
same Unit. Even if the CVC survival in the VKA group was
higher than that reported in most of the published studies [5,
3538], only a randomized control trial (RCT) study enrolling
a homogeneous population of children with the same throm-
botic risk could show the true benefits of VKA in children.
The use of subclavian vein in most of the patients is another
limitation of the study. It can be partially explained by the
presence of jugular vein thrombosis in some children in the
VKA group; moreover, the child with the highest number of
subclavian CVC had a severe cardiac malformation, which
contraindicated the creation of an AVF. Although subclavian
vein remains a common site of CVC placement according to
many reports [3538], it should be avoided whenever possi-
ble, given the high risk of thrombosis with the subsequent
impossibility to perform an AVF.
The benefits of this study is that it is the first to analyse the
use of oral anticoagulants in children undergoing chronic HD,
and it shows that oral anticoagulation should be considered in
selected paediatric patients. The selection of patients at high
risk of CVC thrombosis who may benefit most from warfarin
therapy is a novel approach. Although our data are far from
being conclusive, they could provide the rationale for a well-
designed multicentre RCT on this issue.
In conclusion, our study shows that treatment with warfarin
led to better CVC survival and a reduced need for CVC re-
placement in paediatric HD patients with active NS or previ-
ous central vein thrombosis than in HD patients without these
risk factors who were not treated with oral anticoagulants. The
use of sodium warfarin was safe in our paediatric patients.
Further randomised prospective studies are needed to confirm
our results, as well as to assess the long-term safety of warfarin
therapy, identify the patients who can benefit most from
anticoagulation therapy and investigate the possible effect of
oral anticoagulants on central vein patency in children on
chronic HD.
Compliance with ethical standards
Ethics statement The study was approved by the local Ethical Com-
mittee and conforms with the Declaration of Helsinki. All parents gave
written informed consent
Conflict of interest The authors declare no conflict of interest.
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