The efficacy of a lock solution containing taurolidine, citrate and heparin for the prevention of tunneled central line-associated bloodstream infections in pediatric oncology patients, a randomized controlled, mono-center trial.

Tunneled central venous access devices (CVAD) are fundamental in pediatric
oncology for long-term venous access. The incidence of central line-associated
bloodstream infections (CLABSI) is high and ranges between 0.1-2.3 per 1,000
CVAD-days. In the Princess Máxima Center for pediatric oncology, the incidence
rate of CLABSI was 1.51 per 1,000 CVAD-days. Of all CVADs inserted, 17% were
removed and 5% of the patients were admitted at an intensive care unit due to
CLABSIs. Central venous thrombosis (CVT) is another severe complication of the
CVAD, with an incidence rate of 0.02-0.24 per 1,000 CVAD-days. Different lock
solutions are available to prevent the CVAD from CLABSIs and CVAD-related CVTs.
In the Netherlands, the heparin lock (HL) is the standard of care. The HL
however, does not have an antimicrobial activity and its use is barely
supported by literature. Locks containing taurolidine and citrate, which have
anticoagulant and antimicrobial activities without reported resistance to
taurolidine, appear to be promising in the prevention of CLABSIs. The
taurolidine-citrate(-heparin) lock solution (TCHL) was shown to decrease the
CVAD-infection incidence in haemodialysis patients, total parenteral nutrition
patients, and adult oncology patients compared to heparin, citrate and saline
locks (Rate Ratios (RRs) ranged from 0.00-0.77). In pediatric oncology
patients, six studies have been performed which only included a small number of
patients (n<=180). Therefore, these studies did not deliver enough evidence to
implement the TCHL in pediatric oncology patients. Due to the centralization of
the pediatric oncology care in the Netherlands we are now able to perform an
open labelled randomized controlled trial and include a large number of
patients (n=462), so that we can finally draw conclusions on the efficacy and
safety of the TCHL in pediatric oncology patients. Our goal is to reduce the
CLABSI-rate, CVAD-removal rate, dispense of antibiotics, days of
hospital/intensive care admission, and mortality rate due to CLABSI.

To determine wheter the use of the taurolidine 1.35%, citrate 4%, and heparin
100 IU/ml lock solution (TauroLock*-Hep100) reduces the incidence of first
tunneled central line associated bloodstream inections (CLABSI) compared to the
heparin 100 IU/ml lock solution, in pediatric oncology patients, with a maximum
follow-up of 90 days.

The CATERPILLAR study is designed as a mono-centre, investigator initiated,
open labelled randomized controlled trial (RCT). Patients who receive their
first CVAD or patients who receive a second, third, fourth etc. CVAD after a
CVAD-free interval of more than 12 months, will be asked to participate in this
study. Patients will be randomized into the HL study arm (n=231) or TCHL study
arm (n=231). The lock will be instilled in the Princess Maxima Center with a
maximum of once weekly (if admitted at the hospital or regulary visiting the
hospital) and a minimum of once every three weeks (instillation before going
home or to a different hospital for >1 week). In between, all patients will
receive heparin 100 IU/ml. All patients will be followed up from CVAD insertion
until the first CLABSI episode, CVAD-removal, second CVAD insertion or death
with a maximum study period of 90 days. The maximum study period of 90 days was
chosen since a great deal of the CLABSI episodes occur within the first 90 days
after insertion. All data (incl. shared care hospital data as this is standard
of practice) will be collected in the Princess Máxima Center for Pediatric
Oncology.

One group will receive the TauroLock-Hep100 locks (taurolidine 1.35%, citrate
4.0%, and heparin 100 IU/ml) with a maximum of once weekly and a minimum of
once every three weeks. The other group will receive Heparin locks (heparin
100IU/ml) with a maximum of once weekly and a minimum of once every three
weeks. The locks will be instilled in the central line and will fill the
complete lumen, the lock will stay in situ until the central line is
manipulated again.

Hypothetically, the taurolidine-citrate-heparin lock (TCHL) will reduce the
central line associated bloodstream infection (CLABSI) rate compared to the
heparin lock (HL). Therefore, the TCHL may reduce the administration of
antibiotics, result in lower rates of central venous access device (CVAD)
removal, fewer days of hospital/intensive care unit admission, and a reduced
mortality rate due to CLABSI compared to the HL. Additionally, patients will
benefit directly from reduced and more appropriate antibiotic use, without the
risk of antibiotic resistance development.

The expected side effects are temporarily, caused by a spill-over of citrate,
described if the TCHL is instilled to fast, and if the TCHL is accidentally
flushed instead of aspirated: perioral dysesthesia, discomfort of neck and
chest, dygeusia, nausea and vomiting. Hypocalcaemia events causing arrhythmias
have only been associated with much higher concentrations of citrate, which are
not used in this study. Additionally, hypersensitivity reactions, and heparin
induced thrombocytopenia are possible side-effects, but only in one patient an
anaphylactic-like reaction was observed. Liver-injury is associated with
high-concentrations of systemic taurolidine in mouse-models. The TCHL contains
low-dose taurolidine, which is not associated with liver-injury. A more
frequent dispense of thrombolytics has been associated with lock solutions
containing taurolidine and citrate in haemodialysis patients. However, this was
only observed without the addition of heparin and has not been observed in
pediatric oncology patients. In this study, the lock volumina are adjusted to
the lumen of the CVAD that is inserted, the locks will be aspirated before
instillation of a new lock, the locks will be instilled slowly (<1 ml per
second), heparin is added to the solution for the prevention of the more
frequent dispense of thrombolytics, and an ultrasound of the insertion veins to
detect central venous thrombosis (CVT) will be performed if CVT related
symptoms are observed during the study. The locks will be instilled with a
maximum of once weekly and a minimum of once every three weeks. For a small
number of patients this means that they have to visit the Princess Máxima
Center for Pediatric Oncology 1-2 times more compared to patients that do not
participate in the study. After every study-lock instillation, the patients
will be asked to answer a questionnaire about the experience of possible side
effects.

In conclusion, we think the possible positive effects of the TCHL outweigh the
remaining minimal and rare side effects of the TCHL. We hope to prove that the
TCHL will reduce the CLABSI rate, CVAD-removal rate, dispense of antibiotics,
days of hospital/intensive care unit admission, and mortality rate due to
CLABSI.