Preliminary results of a phase I trial of prophylactic
ethanol-lock administration to prevent mediport
catheter-related bloodstream infections☆,☆☆
Mark L. Kayton MDa, Edward G. Garmey MDb, Nicole M. Ishill MSc,
Nai-Kong V. Cheung MD, PhDb, Brian H. Kushner MDb, Kim Kramer MDb,
Shakeel Modak MDb, Carol Rossetto RN, MSNb, Courtney Hennelly RN, MSb,
Melissa Parra Doyle RN, MSNb, Shoshana Rosenberg MPHa,
Olga Santoro BSa, Michael P. La Quaglia MDa,⁎
aDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
bDepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
cDepartment of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Received 15 February 2010; revised 12 May 2010; accepted 13 May 2010
Central venous catheter;
Background: Catheter-related bloodstream infections remain costly with no simple prevention. We
report preliminary results of a phase I trial of ethanol-lock administration to prevent mediport catheter-
related bloodstream infections in children.
Methods: Twelve patients receiving intravenous antibody treatments for neuroblastoma were enrolled.
On 4 days of each 5-day antibody cycle, 70% ethanol was administered instead of heparin to dwell in
each patient's mediport overnight. We used clinical monitoring/questionnaires to assess symptoms and
measured blood ethanol levels and liver functions. Patients were tracked for positive blood cultures.
Time to infection for ethanol-lock–treated patients was compared with historical controls.
Results: We administered 123 ethanol-locks. No adverse symptoms attributable to ethanol occurred;
one patient's urticaria worsened. Blood ethanol levels averaged 11 mg/dL. The study was voluntarily
suspended after 3 patients' catheters became occluded, 1 of which fractured. A positive blood culture
occurred in 1 (8%) of 12 patients, but suspension of the study precluded statistical power to detect
impact on time to infection.
☆Financial disclosure: The authors have no financial relationships relevant to this article to disclose.
☆☆Support for this study was provided by a grant from the Society of Memorial Sloan-Kettering.
⁎Corresponding author. Pediatric Surgical Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Tel.: +1
212 639 7002; fax: +1 212 717 3373.
E-mail address: firstname.lastname@example.org (M.P. La Quaglia).
0022-3468/$ – see front matter © 2010 Published by Elsevier Inc.Published by Elsevier Inc.
Journal of Pediatric Surgery (2010) 45, 1961–1966
Conclusions: Although children with mediport catheters exhibited nontoxic blood ethanol levels and a
low rate of bloodstream infections following prophylactic ethanol-lock use, there was a high incidence
of catheter occlusion. Adjustments are necessary before adopting ethanol-locks for routine prophylaxis
against catheter infections in children.
© 2010 Published by Elsevier Inc.Published by Elsevier Inc.
Central venous catheter infections are now in the
crosshairs in the debate about reimbursement for nosocomial
infections. Hospital costs rise by more than $39,000 for
every episode of nosocomial bloodstream infection in
pediatric intensive care unit patients . Among pediatric
oncology patients, catheter-related bloodstream infections
represent more than half of all nosocomial infections  and
continue to occur at rates of 22% to 25% in contemporary
series of children treated for cancer using long-term central
venous access devices [3,4].
Recent strategies have been devised to address this
problem, including the use of multipoint checklists for
central line insertion and maintenance in hospital intensive
care units  and the introduction of antibiotic flushes .
But no inexpensive, single-faceted strategy exists that averts
the risk of development of resistant organisms while
remaining easy to implement in a population of pediatric
oncology patients, much of whose care is performed in the
Ethanol has long been accepted as an intravenous antidote
against poisoning with methylene glycol, the active
ingredient found in antifreeze [7,8]. In children with central
venouscatheters, ethanol-locking solutions (“ethanol-locks”)
have been administered for purposes ranging from the
clearance of luminal occlusions to the treatment of
established, refractory, catheter-related bloodstream infec-
tions [9-11]. No study has examined the use of prophylactic
ethanol-locks in pediatric oncology or directly measured
the systemic absorption of ethanol following its use as a
We undertook the first prospective phase I trial of ethanol-
lock administration for the prevention of central venous
catheter infections in pediatric oncology patients. The study
was designed to demonstrate that the ethanol-lock strategy
would be safe and well tolerated in the prophylactic setting.
It was also designed to gather preliminary data on whether
the ethanol-lock strategy reduces the occurrence of positive
blood cultures in pediatric cancer patients with central
This prospective clinical trial was approved by the
Institutional Review Board of Memorial Sloan-Kettering
Cancer Center and was registered at http://www.clinical-
trials.gov (identifier NCT00471679). Informed consent was
obtained from each participant or parent. Enrollment was
limited to patients with high-risk neuroblastoma who were
receiving protocol therapy (clinicaltrials.gov NCT00450307)
with the 3F8 monoclonal antibody, which binds to the GD2
ganglioside of neuroblastoma cells . To qualify for 3F8
treatment, patients must have already undergone treatments
that had rendered them free of residual disease or else had
residual disease in bone marrow only. This population was
selected because it represents a homogeneous group of
patients who have completed cytotoxic chemotherapy and
are not experiencing bouts of protracted neutropenia. Most of
these children have long-term central venous access devices.
Because the antibody treatment is conducted in a day
hospital setting, central lines are accessed and deaccessed 5
days a week during protocol-specified treatment weeks,
followed by a break of 2 to 4 weeks (with occasional
extensions if human anti-mouse antibody titers preclude
treatment), with repetition of such cycles for upwards of 6
months. During the years 2002–2005, we treated 145
neuroblastoma patients with surgically implanted central
venous catheters (52 with mediports and 93 with tunneled
Broviac-type catheters), using comparable 3F8 antibody
protocols. These patients served as the historical control
Patients with tunneled (Broviac-type) external catheters
and those with implanted mediports with reservoirs were
eligible to enroll in the ethanol-lock study. We did not
enroll anyone with a titanium port because we did not feel
that there were adequate preclinical data examining the
interaction of ethanol with titanium. Protocol-specified
exclusion criteria included age younger than 6 months;
history of seizure disorder; serum bilirubin at least 1.5
times the upper limit of normal within the week before
enrollment; serum aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase elevations at least
2.5 times the upper limit of normal within the week before
enrollment; or the presence of prior infection in the central
venous catheter to be treated.
This study was an open-label, single-armed study.
Ethanol was obtained as a 98% solution and diluted with
sterile water in the pharmacy to obtain a 70% solution. This
was then sterile filtered and dispensed in prefilled, labeled
syringes in volumes corresponding to the filling volumes of
each patient's central venous catheter and reservoir. At the
conclusion of the day's scheduled 3F8 antibody therapy and
before ethanol-lock administration, a 10-mL saline flush was
given to clear residual solutes from the line. The ethanol-lock
solution was then instilled into the catheter to dwell
overnight. The external component of each catheter's access
tubing was labeled with a brightly colored sticker to clearly
1962 M.L. Kayton et al.
signal to caregivers that ethanol dwelled in the line. Vital
signs were monitored for 1 hour after each patient's first
exposure to the ethanol-lock and for 15 minutes on each
successive administration. Patients were then discharged
from the day hospital with the ethanol dwelling in the
A member of the study team withdrew the ethanol-lock
solution from the catheter lumen the next morning and
flushed the catheter with saline. If the ethanol-lock solution
proved too sluggish to withdraw, all or part of it was
flushed through followed by a saline flush. On the few
occasions when a clinical event mandated use of the line
before the next morning (eg, a fever requiring the drawing
of blood cultures through the central venous catheter), the
ethanol-lock was withdrawn early to enable use of the
central venous catheter.
Morning blood ethanol levels and liver function tests were
obtained on each treatment week. Hepatotoxicity was graded
according to the NCI Common Terminology Criteria for
Adverse Events (version 3.0). Blood cultures were obtained
only if indicated for clinical criteria (eg, fever, rigors, or
clinical deterioration of the patient). In keeping with our
established clinical practice for pediatric cancer patients,
blood cultures were drawn from the central line and not
peripherally. We felt a that requirement to separately culture
the central line and peripheral blood would have deterred
families from enrolling in and complying with this study. As
such, any positive blood culture drawn from the central
venous catheter was construed as a study failure and resulted
in removal of the patient from the study. Other off-study
criteria defined in the protocol included seizures, pain
resulting from the ethanol-lock, unremediable occlusion or
failure of the central venous catheter, withdrawal of consent
by the patient/parent, any grade 4 or higher toxicity
attributable to ethanol-lock use, or termination of the
patient's participation in the 3F8 antibody treatment
protocol. In the absence of these events, ethanol-lock
treatments were continued during all scheduled treatment
weeks for 6 months.
To evaluate the efficacy of ethanol-lock treatments in
prolonging time to infection, we took each patient's
infection-free duration from the date of enrollment on the
ethanol-lock study to the date of first positive blood
culture, with censoring performed if protocol participation
ended for other (non-infection–related) reasons. For
historical controls, time to infection was calculated as the
duration during which each patient received 3F8 antibody
protocol therapy through a central venous catheter until the
date of the first positive blood culture. If there was not a
positive blood culture, control patients were censored at
either the date on which the patient ended antibody
protocol therapy or the date (if earlier) on which the
central venous catheter was removed for an elective or
noninfectious reason. Two patients whose central venous
catheters were removed at outside institutions on unknown
dates were censored at the latest date on which we could
find confirmation in our medical records that the catheter
was still in place.
Time to infection was estimated by Kaplan-Meier
methods, and differences between the control and treatment
population were determined by the log-rank test, with α =
0.05 chosen to represent significance. The time-to-infection
analysis was based upon the assumption that other reasons
for coming off study, such as progression of disease, did not
reflect an increase in the risk of infection.
2.1. Central venous access devices
Although thestudy was open topatients withmediports as
well as those with tunneled (Broviac-type) catheters, all 12 of
the enrolled patients had mediports. All were single-lumen
Bard MRI implanted ports (Bard Access Systems, Inc, Salt
Lake City, UT; www.bardaccess.com) with plastic reservoirs
and either silicone or polyurethane tubing. Sizes included 6.6
(10 patients), 8 (1 patient), and 9.6 (1 patient) French.
2.2. Blood ethanol levels
Morning blood ethanol levels were sampled once from
each patient each treatment week. The mean blood ethanol
level was 11 mg/dL (range, 0-79.5; n = 31 blood ethanol
samplings). All readings were less than the “legal limit” for
ethanol intoxication (80 mg/dL). On half (52%) of all
occasions, circulating ethanol was 0 mg/dL or less than the
limit of detection.
2.3. Catheter occlusion
Three patients had irremediable occlusion of their
mediports that occurred during ethanol-lock treatment
weeks. One of these 3 patients also developed fracture and
central embolization of the catheter (Fig. 1A, B). All 3
patients required surgical and/or angiographic removal of the
central venous catheters. At explant, catheters in each of
these cases contained dense thrombosis in device reservoirs
or catheter lumens (Fig. 2A, B).
Two patients had no observed perturbations in their liver
function tests. Transient increases in hepatic transaminases
or alkaline phosphatase levels occurred at points during
treatment in the remaining 10 patients. Grade 1 hepatotox-
icity was seen in 7 patients, grade 2 in 1 patient, and grade 3
in 2 patients. One of the grade 3 hepatotoxicities was
attributed to the initiation of total parenteral nutrition during
an episode of adhesive small bowel obstruction. There was
no grade 4 hepatotoxicity.
1963 Ethanol-locks to prevent catheter infections
2.5. Clinical toxicity
Symptoms reported overnight after each of the 123
administrations of the ethanol-lock were self-limited and
mild and included abdominal pain (n = 5 reported events),
vomiting (n = 4), sneezing (n = 4), slurred speech (n = 3),
sleepiness (n = 3), puffiness of the cheeks (n = 3), change
in personality (n = 2), and pain on inspiration (n = 1).
These are typical adverse effects of opioids and anti-
histamines given to counter the adverse effects of 3F8
antibody administration and could not specifically be
attributed to ethanol-lock use.
One patient developed grade 2 cutaneous urticaria
related to 3F8 antibody administration, which is also
common, and subsequently received antihistamines fol-
lowed by placement of the day's scheduled ethanol-lock.
Her urticaria worsened after ethanol administration. She
was removed from study.
2.6. Reasons for ending study participation
Table 1 summarizes the reasons for ending study
participation. Of the 12 patients, 4 completed a full 6 months
on study. Three were removed following catheter occlusion.
Two suffered progression of neuroblastoma and were
removed from 3F8 antibody treatment; on this basis, they
mediport at initial insertion. B, Same patient, after fracture of the
mediport catheter from the subcutaneous reservoir. The catheter
tubing has migrated to the right ventricle.
A, Chest radiograph depicting left subclavian to right atrial
fractured segment, filled with dense thrombus.
A, Fractured mediport after explantation. B, Lumen of
Reasons for ending study participation
Off-study reasonNo. of patients
Completed 6 mo of ethanol-lock study
Progression of neuroblastoma
Positive blood culture
Exacerbation of antibody-related urticaria
1964 M.L. Kayton et al.
no longer qualified for ethanol-lock placement. One patient
was removed from study after a positive blood culture
occurred; and one was removed following exacerbation of
antibody-related urticaria, as previously described. One
patient's consent was withdrawn by the parents, who stated
that the extra time and effort involved in receiving the
ethanol-lock therapy added to the length of their outpatient
visits for antibody therapy.
A positive blood culture occurred in only 1 (8%) of 12
patients on study. The positive blood culture was for Strep-
tococcus pneumoniae and happened during a hospitalization
Among historical controls, positive blood cultures
occurred in 32 (22%) of 145 patients during up to 6 months
of similar 3F8 treatment through an implanted central venous
catheter and 10 (19%) of 52 in the subset of historical
controls with mediports. Because of the low number of
infectious events in both groups, the median time to infection
was not reached in either the ethanol-lock group or the
historical control group. Given the premature suspension of
the study and resulting small sample size, we were
underpowered to detect any significant difference in time
to infection between the groups (data not shown).
The occurrence of thrombosis in 2 cases and thrombosis
followed by fracture and central embolization of a mediport
catheter in a third case led to the voluntary suspension of this
study by the investigators. Ex vivo examination of the 3
explanted catheters indicated that the primary event in all 3
cases was intraluminal catheter thrombosis. We believed
catheter fracture to be a secondary event after we attempted
to flush the line in the face of obstruction. Erosion of the
catheter material did not appear to be the primary problem,
which supported existing preclinical data that have found no
deterioration in the integrity or electron-micrographic
appearance of silicone or polyurethane catheters after several
weeks of continuous ethanol exposure [13,14]. None of the
study patients had a history of prothrombotic state or prior
We suspect that residual serum or therapeutic medications
may have been present in the catheter reservoirs, leading to
denaturation, precipitation, and occlusion of the lumens—
despite administration of a generous saline flush before
ethanol-lock placement. It may be important that all 12 of the
enrolled patients had implanted mediports with subcutaneous
reservoirs, unlike previously reported studies of ethanol-lock
therapy in children, in which most had Broviac catheters that
lack reservoirs [9,10]. Alternatively, it is possible that the
catheter thromboses were related to the absence of heparin,
rather than the presence of ethanol. Cesaro et al  reported
that 82% of pediatric cancer patients receiving saline locks
through a positive pressure cap on their Broviac or Hickman
catheters had episodes of occlusion, compared with 40% of
those receiving heparin flushed through a standard cap—a
statistically significant difference—with most episodes
clearing after infusion of urokinase.
Secondary end points in this study revolved around a
reduction in infection rates. Despite the occurrence of
catheter-related adverse events, the rate of bloodstream
infections was surprisingly low. Only 1 positive blood
culture occurred among any of the 12 patients while on
study, with a median follow-up time (time to end of study
participation or line removal, whichever occurred first) of
16 weeks. Although historically, the most common
organisms recovered from central venous catheter cultures
at our institution are staphylococcal, the organism
recovered from the solitary study patient with a positive
blood culture was S pneumoniae, the culture drawn during
a hospital admission for pneumonia. Thus, although our
protocol construed any positive blood culture as a stopping
point for patients on this trial, this particular blood culture
may have reflected hematogenous dissemination from the
lungs rather than a classic catheter-related bloodstream
infection. Owing to the early suspension of the trial and
early removal of several catheters, we were underpowered
to detect any statistically significant difference in infection
rates vs historical controls.
Despite these issues, exposure of children to 70%
ethanol as an indwelling catheter-lock was clinically well
tolerated. Observed symptoms such as vomiting and
sleepiness were rare and were indistinguishable from the
typical symptoms that occur following opioids and
antihistamines administered with the 3F8 antibody. Al-
though perhaps not reflective of true peak exposure to
ethanol, morning blood ethanol levels were undetectable
more than half of the time and were less than the “legal
limit” of intoxication on the remaining occasions. We did
note the occurrence of grade 3 liver function test elevation
in 2 ethanol-lock–treated patients. One of these patients
exhibited the toxicity immediately after initiation of
parenteral nutrition during a bowel obstruction; but in the
second case, the hepatotoxicity could not be easily ascribed
to anything other than exposure to ethanol-lock treatments.
A previous study using ethanol-locks for treatment of
established infections also noted the appearance of low-
grade hepatotoxicity , and this should therefore be
considered as a possible adverse effect of ethanol-lock
administration. However, we did not observe any grade 4
liver toxicity. Likewise, no neurologic disturbances or
seizures were noted. The relative lack of serious systemic
adverse effects seen in this study accords with literature that
has demonstrated successful administration of intravenous
ethanol to children as an antidote to methylene glycol
poisoning at doses several times higher than the maximal
ethanol doses used in the present study .
1965Ethanol-locks to prevent catheter infections
Ethanol-lock treatment of mediports in pediatric patients
appears to be physiologically well tolerated and, in
prophylactic use, is potentially associated with a low rate
of catheter-related bloodstream infection. However, the
occurrence of 3 serious catheter-related adverse events in
the 12 patients enrolled on this trial clearly indicates that
adjustments are needed before adopting the ethanol-lock
strategy for prophylactic use. We believe further use of the
prophylactic ethanol-lock strategy should be predicated upon
changes in the concentration or dwell time of ethanol or
preceded by studies on its compatibility with heparin, citrate,
or other anticoagulants.
This study was presented at the 40th annual meeting
of the American Pediatric Surgical Association, Fajardo,
Puerto Rico, May 2009.
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