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Vitamin K antagonists in children with central


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Article in Pediatric Nephrology December 2015


DOI: 10.1007/s00467-015-3293-1

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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 Conclusions Therapy with VKA would appear to be safe in


Background To date, no study has investigated the use of children on chronic HD and may improve CVC survival in
vitamin K antagonists (VKA) in children undergoing chronic patients at increased risk of CVC thrombosis.
haemodialysis (HD) with a central venous catheter (CVC).
Methods Consecutive patients aged <18 years with a newly Keywords Oral anticoagulants . Paediatric haemodialysis .
placed tunnelled CVC for chronic HD were enrolled over a 3- Tunnelled central venous catheter . Vitamin K antagonists .
year period. Children with active nephrotic syndrome or a Warfarin
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- Introduction
tion were not treated with VKA (standard group). The primary
end-point was overall CVC survival. Arteriovenous fistula (AVF) is widely considered to be the
Results The VKA group consisted of nine patients (median optimal vascular access for patients on chronic haemodialysis
age 10.6 years; range 1.215.3 years) with 11 CVC, and the (HD). This strategy is recommended by the National Kidney
standard group comprised eight patients (11.8 years; 6.117.3 Foundation/Kidney Disease Outcome Quality Initiative
years) with ten CVC. The 6- and 12-month CVC survival was (NKF/KDOQI) guidelines as the first-choice option in pa-
significantly longer in the VKA group than in the standard tients with end-stage renal disease (ESRD), as well as in chil-
group (100 vs. 60 % and 83.3 vs. 16.7 %, respectively; dren weighing >20 kg [17]. Nevertheless, in routine practice
p<0.05), with a median survival of 369 and 195 days, respec- central venous catheter (CVC) remains the most common
tively (p<0.05). None of the CVC in the VKA group required form of vascular access (6080 %) in children with ESRD
removal due to malfunction, as compared to four in the stan- [813]. The choice of CVC as access is likely due to the
dard group. No major bleeding episodes occurred in either expected short period of maintenance dialysis preceding kid-
group. 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
* Fabio Paglialonga in children with a low body weight.
fabiopaglialonga@alice.it The use of a CVC in HD patients can however be associated
with serious complications. In the short term there is a higher
1
Pediatric Nephrology and Dialysis Unit, Fondazione IRCCS Ca
incidence of access malfunction and infections compared to
GrandaOspedale Maggiore Policlinico, Via Commenda 9, AVF, and in the long-term recurrent CVC placement frequently
20122 Milan, Italy leads to central vein thrombosis, which can have a dramatic
2
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione impact on patient health [14]. To date, there are few therapeu-
IRCCS Ca GrandaOspedale Maggiore Policlinico, Milan, Italy tic options available to avoid the complications of CVC use in
3
Pediatric Intensive Care Unit, Fondazione IRCCS Ca Granda patients on chronic HD. Given that thrombosis accounts for
Ospedale Maggiore Policlinico, Milan, Italy most cases of CVC mechanical failure [6], defined as the failure
Pediatr Nephrol

to sustain a blood pump speed adequate for dialysis, vitamin K according to the International Society of Thrombosis and
antagonists (VKA) have been proposed as a therapeutic strate- Haemostasis criteria [30]: major bleeding was defined as (1)
gy to reduce the incidence of CVC malfunction. This option any fatal bleeding and/or (2) symptomatic bleeding in a criti-
was not supported by a meta-analysis of five randomised con- cal area or organ, such as intracranial, intraspinal, intraocular,
trolled trials (RCTs) which failed to show a beneficial effect of retroperitoneal, intraarticular or pericardial or intramuscular
VKA on catheter malfunction [1419]. However, a statistically with compartment syndrome and/or (3) bleeding causing a fall
significant heterogeneity was identified among the trials includ- in haemoglobin level of 2 g/dL or leading to transfusion of
ed in the meta-analysis which could not be accounted for by the two or more units of whole blood or red cells.
different doses of VKA used [14]. Notably, these studies in- HD adequacy (HD blood flow and Kt/V), the frequency of
cluded adult patients only and were not limited to patients at urokinase use and the incidence of CVC-related infections
higher risk of CVC malfunction who may receive the greatest were also assessed. The following parameters were calculated
benefit from an anticoagulant treatment. as median values for each CVC in order to assess HD adequa-
Several risk factors for thrombosis are recognised in pa- cy: blood flow rate (Qb)/body weight (mL/min/kg), single-
tients with ESRD, such as hyperhomocysteinemia and an im- pool Kt/V (spKt/V) and equilibrated Kt/V (eKt/V). SpKt/V
balance between pro- and anti-thrombotic factors. In particu- and eKt/V were calculated according to standard formulae
lar, patients with active nephrotic syndrome (NS) have an [6]. Data related to all HD sessions were used to calculate
acquired thrombophilic state [2028]. Additionally, a prior median Qb, and all available pre-and post-dialysis blood urea
thrombosis increases the risk of a subsequent one [29]. Based nitrogen values (at least 1 per month per patient) were used to
on these observations it can be surmised that this patient pop- calculate spKt/V and eKt/V
ulation would benefit the most from an anticoagulant therapy. The CVC placed in each patient was a cuffed catheter
The aim of this study was to investigate the effect of war- (Medcomp, Harleysville, PA), French size (Fr) 8 or 10. Each
farin, a VKA, on the survival of tunnelled CVC and to assess CVC was placed in an internal jugular or subclavian vein
the rate of complications in children with active NS or previ- under general anesthesia using percutaneous cannulation un-
ous central vein thrombosis undergoing chronic HD. 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
Subjects and methods 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
This study included consecutive patients aged <18 years in were placed in all other patients.
whom a tunnelled CVC had been placed for chronic HD be- Unfractionated heparin (5000 U/mL) was standardly used
tween 1 June 2011 and 30 March 2014. Patients with active as a lock solution at the end of each HD session, with the
NS (serum albumin<2.5 g/dL and urine protein/creatinine exception of a blood flow rate (Qb) reduction of >20 % from
ratio>2 mg/mg) or a previous CVC thrombosis were consid- baseline, a pre-pump arterial pressure of 250 mmHg or a
ered to be at high risk of CVC thrombosis. In these patients failure to draw blood from the access, in which cases a 5000
sodium warfarin was added to the standard treatment, starting U/mL urokinase lock was used. In both patient groups heparin
at 0.3 mg/kg/day (maximum 5 mg/day) and then adjusted to was used as anticoagulant during the HD session according to
maintain an international normalised ratio (INR) of prothrom- our local protocol: 2025 U/kg as bolus injections, followed
bin time of between 2.0 and 3.0 (VKA group). Patients in by 2025 U/kg/h as continuous infusion, with monitoring of
whom a CVC was placed for chronic HD without NS or pre- the activated clotting time (ACT) values. Routine exit site care
vious CVC thrombosis were considered to be at standard included a strictly sterile use of the CVC by only trained
thrombotic risk and did not receive warfarin treatment (stan- nurses, sterile gloves and surgical masks whenever the CVC
dard group). The two groups were compared for CVC survival was accessed, gauze dressings at the exit site and no systemic
(primary end-point) and for the incidence of CVC removal antibiotic prophylaxis.
due to malfunction and the occurrence of bleeding complica- The warfarin dose was modified according to the INR
tions (secondary end-points). Patients were censored at the values by two haematologists. Standard 5 mg warfarin tablets
time of transplantation if the CVC was still functioning or in were used whenever possible, whereas 0.5 mg powders were
case of death. In all other cases the observational period ended prepared in the case of small children who needed smaller
at the time of CVC removal, and the reasons for CVC removal doses. In order to avoid the effect of heparin on the INR, blood
and the time from placement to removal were recorded. CVC samples for INR measurements were routinely taken from the
malfunction was defined as the inability to perform HD due to HD circuit immediately after the start of the treatment and not
failed aspiration or the infusion of blood through the CVC. At from the CVC lumen. No patients received anti-platelet agents.
every dialysis session, relatives and nurses were asked if any The incidence of exit-site infections, tunnel infections and
bleeding complication had occurred. Bleeding was defined catheter-related bloodstream infections, diagnosed in
Pediatr Nephrol

Table 1 Characteristics of
patients and central venous Baseline characteristics Warfarin group (n = 11 CVC) Standard group (n = 10 CVC)
catheter
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 1.22. Two CVC in the VKA group were removed because of
assessed in both groups [6]. CVC breaks (micro-holes).
The control (standard) group consisted of ten cuffed CVC
Statistical analysis 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
Data were expressed as median values and ranges and was the CVC site in five patients. Eight CVC in the control
analysed using the MannWhitney test for continuous vari- group were removed because of malfunction (n=4) or dis-
ables and the chi-square test for dichotomous variables. placement (n=4).
KaplanMeier analysis was used to evaluate CVC survival. As shown in Fig. 1, the 6- and 12-month CVC survival
A p value of <0.05 was considered to be statistically rates were significantly higher in the warfarin group (100 vs.
significant. 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
Results

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
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-
Fig. 2 Malfunction-free survival of central venous catheters (CVC) in the vian vein CVC [3134]. Available studies focusing on the use
vitamin K antagonists (VKA) group and standard group of tunnelled CVC in children on HD have reported a median
survival time of between 91 and 322 days and a 1-year sur-
removals due to malfunctions were considered: the 6- and 12- vival ranging from 0 to 62 % [5, 3538]. Among our patients,
month CVC malfunction-free survival rates were 100 vs. median tunnelled CVC survival was 369 days in the VKA
76.2 % and 100 vs. 50.8 %, respectively (p<0.05) (Fig. 2) group and 195 days in the control group, with a 1-year sur-
As shown in Table 2, there were no differences in blood vival of 83 and 16.7 %, respectively. As there were no other
flow/body weight, dialysis adequacy (using spKT/V and eKt/ differences in CVC management between the two groups, we
V) or urokinase use among the two groups. Nine exit-site can surmise that the longer CVC survival in patients receiving
infections and three tunnel infections were observed, equally VKA is at least partly due to warfarin treatment. More specif-
distributed between the two groups. ically, the longer CVC survival in the VKA group can be
No major bleeding complications occurred in both groups attributed to the significant reduction in the frequency of
over a cumulative treatment period of 2489 days. 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
Discussion 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
The results of our study show that CVC survival is longer in risk of these patients.
children at high risk of CVC thrombosis due to active NS or We did not observe any major bleeding episodes. The
previous CVC thrombosis when treated with VKA than in risk of major bleeding in children treated with oral anti-
children at standard thrombotic risk not treated with VKA. coagulants has been reported to be as high as 0.5 % per
Central line malfunction is a common problem in patients patient-year [39], but observation periods longer than our
undergoing HD through a CVC; after a successful first use, observation period are clearly required to assess the risk
thrombosis is the most common cause of mechanical failure. of bleeding associated with the use of warfarin in paedi-
Warfarin has therefore been proposed as a strategy to improve atric patients on HD.

Table 2 Dialysis blood flow,


dialysis adequacy, urokinase use Parameters of haemodialysis Warfarin group Standard group p value
and infections in the vitamin K (n =11 CVC) (n = 10 CVC)
antagonists (VKA) and standard
groups Qb (mL/kg/min) 3.4 (2.713.0) 5.2 (3.37.2) 0.06
spKt/V 1.6 (0.82.3) 1.4 (1.01.9) 0.45
eKt/V 1.4 (0.72.0) 1.2 (0.91.6) 0.40
Urokinase (% sessions) 2.9 1.7 0.06
Exit-site infoection (n/1000 CVC days) 2.0 1.7 0.83
Tunnel infectionI (n/1000 CVC days) 0.8 0.4 0.48
Bloodstream infection (n/1000 CVC days) 0 0 0.99

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

At first sight our results appear to conflict with those The benefits of this study is that it is the first to analyse the
reported in adults. A meta-analysis of five RCTs investigating use of oral anticoagulants in children undergoing chronic HD,
the efficacy of oral anticoagulants to prevent CVC and it shows that oral anticoagulation should be considered in
malfunction found that patients treated with warfarin had no selected paediatric patients. The selection of patients at high
significant advantage over those on placebo (relative risk risk of CVC thrombosis who may benefit most from warfarin
0.59, 95 % confidence interval 0.281.22) [14]. However, a therapy is a novel approach. Although our data are far from
more in-depth examination of three major trials included in being conclusive, they could provide the rationale for a well-
the meta-analysis reveals that in one trial with 85 patients designed multicentre RCT on this issue.
warfarin was ineffective at a fixed dose of 1 mg daily In conclusion, our study shows that treatment with warfarin
(although a decrease in thrombosis was found in the led to better CVC survival and a reduced need for CVC re-
subgroup that achieved INR>1.0) and in another trial with placement in paediatric HD patients with active NS or previ-
174 patients which used a target INR of 1.51.9. On the ous central vein thrombosis than in HD patients without these
contrary, the percentage of patients experiencing thrombosis risk factors who were not treated with oral anticoagulants. The
at 1 year in a randomised trial of 144 adults on HD was 12 % use of sodium warfarin was safe in our paediatric patients.
in those treated with warfarin with a target INR of 1.82.5, Further randomised prospective studies are needed to confirm
which is closer to our target INR than that of the other studies, our results, as well as to assess the long-term safety of warfarin
and 52 % in controls. More importantly, the thrombotic risk therapy, identify the patients who can benefit most from
of children on HD can be different from that of adults due to a anticoagulation therapy and investigate the possible effect of
relative disproportion between the caliber of the CVC and the oral anticoagulants on central vein patency in children on
veins. chronic HD.
Notwithstanding the benefits associated with the use of
VKA in our population, the median access survival was still Compliance with ethical standards
lower than that commonly observed with AVF. Taking into
Ethics statement The study was approved by the local Ethical Com-
account all of the proven advantages of AVF over CVC, it mittee and conforms with the Declaration of Helsinki. All parents gave
remains essential to encourage early AVF creation in paediat- written informed consent
ric patients needing chronic HD.
Conflict of interest The authors declare no conflict of interest.
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
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