Anda di halaman 1dari 11

Review Article

Chlorhexidine-Impregnated Dressing for


Prevention of Catheter-Related Bloodstream
Infection: A Meta-Analysis*
Nasia Safdar, MD, PhD1,2; John C. O’Horo, MD3; Aiman Ghufran, MD2; Allison Bearden, MD, MPH2;
Maria Eugenia Didier, MD2; Dan Chateau, PhD4; Dennis G. Maki, MD2

Objective: To assess the efficacy of a chlorhexidine-impregnated infection (random effects relative risk, 0.60; 95% CI, 0.41–0.88,
dressing for prevention of central venous catheter–related p = 0.009). The prevalence of catheter colonization was also
colonization and catheter-related bloodstream infection using markedly reduced in the chlorhexidine-impregnated dressing
­meta-analysis. group (random effects relative risk, 0.52; 95% CI, 0.43–0.64; p
Data Sources: Multiple computerized database searches supple- < 0.001). There was significant benefit for prevention of catheter
mented by manual searches including relevant conference pro- colonization and catheter-related bloodstream infection, including
ceedings. arterial catheters used for hemodynamic monitoring. Other than
Study Selection: Randomized controlled trials evaluating the effi- in low birth weight infants, adverse effects were rare and minor.
cacy of a chlorhexidine-impregnated dressing compared with Conclusions: Our analysis shows that a c ­ hlorhexidine-impregnated
conventional dressings for prevention of catheter colonization and dressing is beneficial in preventing catheter colonization and,
catheter-related bloodstream infection. more importantly, catheter-related bloodstream infection and war-
Data Extraction: Data were extracted on patient and catheter rants routine use in patients at high risk of catheter-related blood-
characteristics and outcomes. stream infection and central venous catheter or arterial catheter
Data Synthesis: Nine randomized controlled trials met the inclu- colonization. (Crit Care Med 2014; 42:1703–1713)
sion criteria. Use of a chlorhexidine-impregnated dressing Key Words: catheter-related infection; chlorhexidine; nosocomial
resulted in a reduced prevalence of catheter-related bloodstream infection

I
*See also p. 1742.
ntravascular catheters are often needed in patients of all
1
William S. Middleton Memorial Veterans Hospital, Madison, WI.
ages requiring intensive care, parenteral alimentation, can-
2
Section of Infectious Diseases, Department of Medicine, University of
Wisconsin School of Medicine and Public Health, Madison, WI.
cer chemotherapy, organ transplantation, home antibiotic
3
Department of Medicine, Division of Pulmonary and Critical Care therapy, or hemodialysis (1–3). An estimated 5 million U.S.
­Medicine, Mayo Clinic, Rochester, MN. patients require either short-term or prolonged central venous
4
Biostatistical Consulting Unit, Department of Community Health Sci- access each year (4–7).
ences, University of Manitoba, Winnipeg, MB. Although vital to care, these devices are associated with risk
Supplemental digital content is available for this article. Direct URL cita- of catheter-related bloodstream infection (CRBSI) (3, 6, 7).
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/ CRBSIs directly increase antibiotic exposure, length of stay, and
ccmjournal). healthcare costs and may increase mortality (8–11). CRBSI is
Presented, in part, at the Annual Meeting of the Society for Healthcare increasingly recognized as a preventable ­healthcare-associated
Epidemiology, Atlanta, GA, 2010.
infection (12), prompting the United States Centers for
Dr. Safdar is supported by grant number AG40669 from the National
Institute on Aging, National Institutes of Health, and a VA MERIT grant.
Medicare and Medicaid Service to cease reimbursing health-
The remaining authors have disclosed that they do not have any potential care institutions for these complications as of October 2008.
conflicts of interest. There is an urgent need for effective strategies to prevent
Address requests for reprints to: Nasia Safdar, MD, PhD, Department of CRBSI (13, 14).
Medicine, University of Wisconsin Medical School, MFCB 5221, 1685
Highland Avenue, Madison, WI 53705. E-mail: ns2@medicine.wisc.edu The most common route of infection occurs at inser-
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott tion when skin organisms invade the percutaneous tract
Williams & Wilkins extraluminally via capillary action. During regular use, con-
DOI: 10.1097/CCM.0000000000000319 tamination of the hub and lumen can occur whenever the

Critical Care Medicine www.ccmjournal.org 1703


Safdar et al

catheter is manipulated, such as when an infusion is started, of CRBSI and catheter colonization were as provided by the
or when the central venous catheter (CVC) is manipulated individual studies.
with a guidewire. Finally, organisms can be carried hema-
togenously to the implanted device from remote sources of Data Extraction
infection, for example, pneumonia or urinary tract infec- Three investigators (N.S., A.G., J.O.) independently abstracted
tion (15–19). data on the size of the study sample, patient population, type
Understanding these mechanisms of CRBSI, pathogenesis of vascular devices, dressing, cutaneous antiseptic used, device
has led to specific preventive strategies, including the creation use duration, prevalence of catheter colonization, and preva-
of best practice guidelines and evidence-based “bundles” such lence of CRBSI. The authors of studies that did not report
as those developed by the Institute for Healthcare Improvement prevalence data for analysis were contacted for additional
(4, 20, 21). These include an emphasis on hand hygiene, the use information.
of full-barrier precautions during catheter insertion, skin anti- We evaluated the included studies for methodological
sepsis using chlorhexidine, preferential use of the subclavian/ quality using the recommendations outlined in the Cochrane
internal jugular sites for nontunneled catheters, and daily evalu- Handbook of Systematic Review (40). The risk of bias in each
ation of catheter necessity with prompt removal of unnecessary study was assigned as either low or high. Three authors (N.S.,
catheters (4, 20). A.G., J.O.) independently reviewed each report identified by
Strict adherence to evidence-based best practices clearly the above-mentioned search strategy. Disagreements among
reduces CRBSI rates (3, 12, 22–26). Individual interventions abstracters regarding values or analysis assignments were
that can make CRBSI prevention simpler and more cost resolved by discussion.
effective merit further investigation. A promising interven-
tion directed at reducing the extraluminal route of infec- Statistical Analysis
tion is a chlorhexidine gluconate–impregnated dressing Pooled estimates of the relative risk (RR) and 95% CI were
placed at the time of CVC insertion (27–29), which releases obtained using the DerSimonian and Laird random effects
chlorhexidine onto the skin for a 10-day period (30). Studies model (41). Some studies included patients who had more
on the efficacy of a chlorhexidine-impregnated dressing than one vascular catheter during the study period. For these
for reducing CRBSI have had conflicting results (31–38). studies, we inflated the variance of the risk ratio to adjust for
We undertook a meta-analysis to examine the efficacy of a within-patient correlation (42, 43). Heterogeneity was assessed
­chlorhexidine-impregnated dressing compared with con- using the Cochran Q statistic and I 2 (40). Negative values of I 2
ventional site care for prevention of CRBSI and catheter are conventionally equal to 0% so I 2 values can range between
colonization. 0% and 100%. Zero percent indicates no observed hetero-
geneity and larger values indicate increasing heterogeneity.
Subgroup analyses were used to explore possible reasons for
METHODS heterogeneity. Publication bias was assessed using a funnel
plot and Eggers statistical test (44, 45). Statistical analyses were
Search Strategy performed using Stats Direct (2002, Cheshire, United King-
This study was performed in accordance with the Preferred dom) and Review Manager software (2008, Nordic Cochrane
Reporting Items for Systematic Reviews and Meta-Analysis Center).
(39). The search strategy was developed with the assistance of
an expert librarian (for search details, see online supplemen-
tary material, Supplemental Digital Content 1, http://links. RESULTS
lww.com/CCM/A880). Study Selection
The database search retrieved 505 unique citations of which
Inclusion Criteria seven met our inclusion criteria, described in Figure 1 (31,
Included studies were prospective randomized trials compar- 33–38). Manual search of references of included studies identi-
ing a chlorhexidine-impregnated dressing with conventional fied two additional studies (32, 46). Excluded studies fell into
site care. Included studies had to provide microbiologically one or more of the following exclusionary categories: nonran-
based definitions for CRBSI and systematically report the domized trial (n = 8), chlorhexidine solution or impregnated
prevalence of CRBSI in both comparator and control arms. catheters rather than dressing (n = 108), chlorhexidine for
Authors of potentially relevant studies were contacted for indications other than intravascular devices (n = 126), review
further information if some of these data were unpublished. article (n = 42), editorial or letter (n = 13), study population or
Case-control, case reports, reviews, retrospective studies, and outcome not meeting selection criteria (n = 7), or unrelated to
nonrandomized prospective trials were excluded. intravascular device use (n = 194).

Outcome Measures Study Characteristics


The primary outcome measure was CRBSI. Catheter coloni- The nine trials enrolled 6,067 patients with a total of 11,214
zation was identified as a secondary outcome. The definitions catheterizations; 5,586 catheters in 2,984 patients received a

1704 www.ccmjournal.org July 2014 • Volume 42 • Number 7


Review Article

and 5-day intervals for one study (38). One study varied the
interval by assignment, with 7-day changes in the experimen-
tal group and 2-day intervals in the control group (32). Two
studies were randomized control trials with both 3- and 7-day
dressing change intervals (35, 46).
The majority of patients analyzed in this meta-analysis were
patients in ICUs, both pediatric and adult patients in seven of
the nine included trials (31–33, 35, 36, 38, 46). Duration of
catheterization ranged from 5.6 (33) to 71.5 days (34).

Details of Randomization
Block randomization was used in seven trials (31–33, 35–37,
46). In the remaining two studies, the method of randomiza-
tion was not given (34, 38). Single blind methodology was
employed in review of cultures and/or data in four studies (33,
35, 36, 46). Intention-to-treat analysis was described in five tri-
als (31, 32, 34, 35, 46).

Study Quality
Two of the included studies were determined to have a high
risk of bias due to high baseline infections and nonstandard
Figure 1. Literature search and selection of studies. RCT = randomized
controlled trial. infection control practices (34, 37), whereas the remaining
seven studies were classified as low risk. The risk assessments
of the individual studies are listed in Table 1.
chlorhexidine-impregnated dressing and 5,628 catheters in Three large studies (32, 35, 47) accounted for 83% of the
3,083 patients received conventional site care. Two large studies included patients. All three of these studies were designated as
accounted for more than half the patient population (35, 46). having a low risk of bias.
Two studies were conducted in neonates, infants, or children
(31, 33), two in adult patients with malignancy (34, 37), and Diagnosis of Catheter Colonization and CRBSI
five in adult medical-surgical and cardiothoracic ICUs (32, 35, The authors used various definitions for catheter coloniza-
36, 38, 46). tion and CRBSI in the included studies (Table 1). One study
The characteristics of the nine randomized controlled tri- provided no definition for catheter colonization, other studies
als are summarized in Table 1. Five studies (32, 34, 36, 38, 46) defined it as catheter tip culture yielding greater than 15 colo-
recorded catheter colonization and CRBSI using the catheter nies or greater than or equal to 1,000 colony-forming units per
as the unit of analysis, while three of the included trials (31, 33, milliliter (CFU/mL). Another two used a lower cutoff of 100
37) reported the data using the patient as the unit of analysis. CFU/mL using the Sherertz technique (35, 46). Roberts and
One study reported the outcome measures for both patients Cheung (38) defined catheter colonization nonquantitatively
and catheters (35). as isolation of the same organism from exit site and catheter
The mean duration of catheterization varied between the tip without obvious signs of infection.
studies but was similar within the control and intervention CRBSI was defined by Chambers et al (34) as positive blood
groups of each individual trial. These are reported in Table 2. cultures drawn in the presence of fever with no other recog-
All studies used standard aseptic technique in inserting nized focus of infection, causing premature removal of the
catheters, including cutaneous antisepsis. The different topical catheter and the catheter tip, yielding greater than 15 CFU/
antisepsis agents are summarized in Table 1. One study used dif- mL of the same organism. Similar definitions were used in the
ferent skin preparations for the comparator ­(povidone-iodine) studies by Arvaniti et al (36), Garland et al (31), Levy et al (33),
and treatment (70% isopropyl alcohol) arms (31). and Maki et al (32). Roberts and Cheung (38) identified CRBSI
The subclavian or internal jugular sites were the preferred as any infection yielding the same organism from the CVC tip/
central venous access site in most studies (32, 33, 35, 37, 46). exit site and a blood culture isolate and associated with fever
Only one study used the femoral site predominantly (36), and elevated WBC count. Ruschulte et al (37) used blood cul-
and one used primarily peripherally inserted central catheters tures drawn both percutaneously and from the catheter, with
(PICCs) (31). Two studies did not specify the sites used (34, a differential time to positivity of greater than 2 hours. Timsit
38). The trial by Maki et al (32) included central venous, PICCs, et al (35, 47) used the following definition: positive blood
pulmonary artery, and peripheral arterial catheterizations. cultures sampled 48 hours before or 48 hours after catheter
With the exception of one study that used no dressing removal with a quantitative catheter tip culture yielding the
(34), all the other trials used occlusive dressings as the com- same microorganisms or a differential time to positivity of
parator. Dressing changes were conducted at 7-day intervals in blood cultures greater than or equal to 2 hours, without any
three studies (31, 33, 37), 3-day intervals for one study (36), other focus of infection.

Critical Care Medicine www.ccmjournal.org 1705


Safdar et al

Table 1. Descriptive Characteristics of the Nine Included Studies


Population, Setting, Definition of Catheter
References and Inclusion Criteria Catheter Type Colonization Definition of CRBSI

Roberts and Adult ICU patients CVC Same organism from CVC Clinical infection with same
Cheung requiring CVC during tip and exit site, no clinical organism isolated from
(38) a 7-wk period infection catheter tip (and/or exit site)
and blood
Maki et al Adult patients requiring CVC, pulmonary > 15 CFUs by roll plate Isolation of the same organism
(32) CVC, pulmonary artery, or method from peripheral blood and
artery or peripheral peripheral catheter tip, hub, or infusate
arterial catheters arterial
catheter

Garland et al Neonates admitted to CVC and Semiquantitative catheter Clinical infection with same
(31) level III ICU with CVC tunneled colony count > 15 CFU organism isolated from
expected to remain (Broviac) CVC catheter tip and blood
in place a minimum
of 48 hr

Chambers Adult patients in Long-term, NR Fever and positive blood cultures


et al (34) hematology tunneled, without alternative infection
unit undergoing cuffed CVC source and catheter tip culture
chemotherapy with > 15 colonies of the
same organism

Levy et al Pediatric cardiac ICU Short-term, > 15 CFU by the roll-plate Bacteremia with isolation of the
(33) patients requiring nontunneled technique, no signs of same organism from CVC tip
CVC for minimum of CVC infection and blood
48 hr

Ruschulte Adults with hematologic Short-term, NR Clinical evidence of infection and


et al (37) or oncologic nontunneled time-to-positivity method used
malignancy with catheter with CVC and peripherally
catheter expected for impregnated drawn blood cultures
minimum of 5 d on the exterior
surface
with silver
sulfadiazine-
chlorhexidine

Timsit et al Adult ICU patients CVC and/ Quantitative CVC tip culture Clinical infection without
(35) requiring catheter or arterial ≥ 1,000 CFUs/mL alternative source, peripheral
minimum of 48 hr catheter blood drawn immediately
prior to or within 48 hr
following catheter removal and
quantitative catheter tip culture
isolating the same organism,
or confirmed using differential
time to positivity test
Arvaniti et al Adult ICU patients CVC Quantitative CVC tip culture Quantitative CVC tip culture
(36) requiring catheter at with > 1,000 CFU/mL and with > 1,000 CFU/mL with
least 72 hr no systemic signs of sepsis systemic signs of sepsis

Timsit et al Adult ICU patients CVC Quantitative CVC tip culture Correlation between peripheral
(47) expected to require > 1,000 CFU/mL and no blood culture and quantitative
catheter for at systemic signs of sepsis tip culture without other likely
least 48 hr source
CRBSI = catheter-related bloodstream infection, CVC = central venous catheter, CFU = colony-forming units, NR = not reported, ITT = intention to treat.

1706 www.ccmjournal.org July 2014 • Volume 42 • Number 7


Review Article

Dressing Replacement
Skin Antiseptic Interval Risk of Bias and Comments

Chlorhexidine 0.5% in Every 5 d or as needed Low risk


70% alcohol
Underpowered to detect differences in catheter colonization and
CRBSI between groups

NR Control: every 2 d Low risk


Treatment group: every Abstract only
7d
Additional information (catheterization duration, CVC insertion
site) obtained by reviewing publications based on the same
study population and from study author
Control group: 10% Every 7 d (twice weekly Low risk
povidone-iodine in surgically placed
CVC with control Study halted before recruitment goal met (funding constraints and
dressing) low CRBSI rates)
Treatment group: 70% Different skin antisepsis used in two groups
alcohol
Underpowered to detect difference in CRBSI between groups
Alcohol-povidone-iodine Treatment group: High risk
10% weekly or as needed
Control group: no Control group had no dressing once exit site dry/free of ooze
dressing
This may not represent a healed site and could increase risk of
tunnel and exit site infection, and ultimately increased risk for
CRBSI, in control group
Chlorhexidine As needed Low risk
No established interval for dressing change
Underpowered to detect CRBSI difference
Alcohol spray Every other week or as High risk
needed
High baseline rate of infection
Short-term rather than long-term CVCs used in population of
oncologic patients
81% of CVC placed in internal jugular rather than subclavian site
Alcohol spray used as skin antiseptic
62% of CRBSI caused by coagulase-negative staphylococci
without molecular epidemiology to confirm source
4% aqueous povidone- Every 3 d or every Low risk
iodine scrub solution 7 d (based on
followed by 5% randomized group Modified ITT analysis: those who withdrew consent after
povidone-iodine in assignment) randomization were not included in denominator of ITT analysis
70% alcohol solution 60% of CVCs were at jugular or femoral sites, 41% of peripheral
arterial catheters were at femoral site

NR Every 3 d or as needed Low risk


Had third arm (antibiotic-impregnated catheters) excluded for this
analysis
Alcohol-povidone or Every 3–7 d according Low risk
alcohol chlorhexidine to center/assignment
or as needed Randomized control trial using intention-to-treat analysis

Critical Care Medicine www.ccmjournal.org 1707


Safdar et al

Figure 2. Relative risk of catheter colonization with chlorhexidine-impregnated dressing and comparator using a random effects model.

Prevalence of Catheter Colonization catheter care, and definitions of colonization. I 2 for colo-
Seven of the nine studies provided data on colonization nization was moderate at 54%. For CRBSI, heterogeneity
(31–33, 35, 36, 38, 46). Overall, 361 of 5,281 catheters (6.8%) was low (I 2 = 17%).
were colonized in the chlorhexidine-impregnated dressing Only two studies failed to demonstrate a reduction in colo-
group compared with 743 of 5,200 (14.3%) in the comparator nization with impregnated sponges. The first had a small sam-
arm. The chlorhexidine-impregnated dressing was associated ple size, and authors stated that the study was not adequately
with an RR of 0.52 (95% CI, 0.43–0.64; p < 0.001). This is illus- powered to make a definitive statement about chlorhexidine
trated as a forest plot in Figure 2. dressing efficacy (38). The second study attributed the lack
of effect to avoidance of femoral catheterization sites, smaller
Prevalence of CRBSI percentage of trauma patients, and use of povidone-iodine
Overall, 1.1% of patients (64 of 5,639) developed CRBSI in skin antisepsis prior to cannulation (36).
the treatment group compared with 2.1% of patients (120 of
5,608) in the comparator group. Six of the nine trials had results Subgroup Analysis
favoring the chlorhexidine-impregnated dressing for reducing To explore the reasons for heterogeneity, we undertook three
CRBSI. The RR for CRBSI comparing the chlorhexidine and subgroup analyses limited to studies assessing the efficacy of
comparator groups in the meta-analysis was 0.60 (95% CI, the chlorhexidine-impregnated dressing for 1) prevention of
0.41–0.88; p = 0.009), depicted as a forest plot in Figure 3. CRBSI in patients with malignancy, 2) in adult ICU patients
only, and 3) in PICU patients only.
Publication Bias Using a random effects model to analyze data from the
Funnel plots (Fig. 4) did not indicate publication bias to be two studies in patients with hematologic malignancy (34,
likely. Eggers test was not statistically significant (p = 0.15). 37), we found a statistically significant benefit with the use of
chlorhexidine-impregnated dressing. The RR was 0.53 (95%
Assessment of Heterogeneity CI, 0.32–0.89; p = 0.02).
There was substantial clinical heterogeneity in the included Five studies were limited to adult ICU populations (32,
studies with differing patient populations, protocols for 35, 36, 38, 46) and the chlorhexidine-impregnated dressing
was associated with an RR of
0.45 (95% CI, 0.28–0.72). In
the pediatric population, the
chlorhexidine-impregnated
dressing was not associated
with a statistically significant
reduction in bloodstream
infection (BSI) (RR, 1.21; 95%
CI, 0.60–2.44) (31, 33).
Duration of catheteriza-
tion was reported in all but
two studies. Catheterization
averaged longer than 2 weeks
in three studies (31, 34, 37). In
Figure 3. Relative risk of catheter-related bloodstream infection with chlorhexidine-impregnated dressing and that subgroup, there was not
comparator using a random effects model. an appreciable impact on rates

1708 www.ccmjournal.org July 2014 • Volume 42 • Number 7


Review Article

Adverse Effects of
Chlorhexidine
Contact dermatitis from the
chlorhexidine-impregnated
dressing was the most com-
mon adverse effect reported
in studies (31, 35, 46). Timsit
et al (35) found the prevalence
of severe contact dermatitis
requiring catheter removal
to be 5.3 per 1,000 catheters.
The second study by Timsit
et al (47) found a similar low
event rate of contact derma-
titis (5.0 of 1,000 catheters)
and no systemic reactions.
Garland et al (31) reported
a much higher prevalence of
19 of 335 neonates (5.7%).
Birth weight of all seven neo-
nates who developed contact
dermatitis in the initial 15
months of the study was 880 g
or less with a gestational age
less than 27 weeks with CVCs
placed on day 8 of life or ear-
lier. The observation of an
adverse reaction in prema-
ture babies with extremely
low birth weights led to a
change in the inclusion crite-
ria for the study, and thereaf-
ter, infants less than 26 weeks
of gestation were enrolled in
the study only if CVC was
inserted after the first week of
life. Overall, in the treatment
group, 15 of 98 neonates
(15%) with birth weight less
than 1,000 g developed con-
Figure 4. Funnel plot to evaluate for publication bias for colonization (top) and catheter-related bloodstream
tact dermatitis versus four of
infection (bottom). Publication bias is not evident. RR = relative risk. 237 neonates (1.5%) greater
than or equal to 1,000  g
of BSI (RR = 0.68; 95% CI, 0.36–1.30). In the remaining five (p < 0.0001). Garland et al (31) also reported pressure necro-
studies (33, 35, 36, 38, 46), the benefit of chlorhexidine dress- sis in two cases. No systemic reactions to chlorhexidine were
ings was more pronounced (RR = 0.52; 95% CI, 0.30–0.90). observed.

Microbiology and Resistance to Chlorhexidine DISCUSSION


Staphylococcus epidermidis was the most common organ- In this meta-analysis, a chlorhexidine-impregnated dressing
ism isolated, followed by Staphylococcus aureus, other was significantly more effective than traditional site care for
­Gram-positive cocci, and Escherichia coli. None of the studies preventing vascular catheter colonization and CRBSI. The rel-
reported prevalence of resistance to chlorhexidine. However, ative risk reduction was 45% for CRBSI and 48% for catheter
routine surveillance by Chambers et al (34) before and after colonization. The pooled absolute risk reduction in CRBSI was
catheterization grew one isolate of micrococcus at 1 month 1.3%, making the number needed to treat 77.
in 0.01% chlorhexidine broth but did not grow at subsequent Our findings suggest that a chlorhexidine-impregnated
concentrations. dressing can provide considerable value in reducing the

Critical Care Medicine www.ccmjournal.org 1709


Safdar et al

Table 2.Prevalence of Catheter Colonization and Catheter-Related Bloodstream


Infection With Chlorhexidine-Impregnated Dressing

Mean Duration of
No. of Patients/Catheters Catheterization (d)

References CHG Dressing Control CHG Dressing Control

Roberts and Cheung (38) 17/17 16/16 7 6


Maki et al (32) 301/665 366/736 NR NR
Garland et al (31)b 335/335 370/370 17.7 17.4
Chambers et al (34) 52/58 43/54 71.5 62.5
Levy et al (33) 74/74 71/71 5.75 5.6
Ruschulte et al (37) 300/300 301/301 16.62 15.76
Timsit et al (35) 817/1,953 819/1,825 6c 6c
Arvaniti et al (36) 150/150 156/156 7.03 7.38
Timsit et al (47) 938/2,108 941/2,055 8.21 8.29

Total 2,984/5,586 3,083/5,628


CHG = chlorhexidine-impregnated dressing, RR = relative risk, NR = not reported.
a
Variance estimate inflated to adjust for correlation.
b
21 chlorhexidine-dressed catheters and 56 control catheters were not cultured and were excluded from the analyses.
c
Median reported in place of mean.
d
As reported in the study after adjusting for correlation.

risk of CRBSI in patients with central vascular catheters. A and dressing disruption have been well described with a
­chlorhexidine-impregnated dressing is expected to be of great- sponge dressing (48). At our institution, we have been using
est benefit in a setting where the extraluminal route of infec- the sponge dressing for over a decade and continue to witness
tion is expected to predominate such as short-term catheters. wrong placement of the dressing. An integrated chlorhexidine
Garland et al, in a subcohort analysis, found that the differences dressing obviates this problem but may have its own limita-
in catheter tip colonization, an accepted surrogate for CRBSI, tions such as difficulty in removal.
between the treatment and control groups were most evident To our knowledge, ours is the first meta-analysis to exam-
for neonates whose catheters were in situ less than or equal to ine the impact of a chlorhexidine dressing including both
14 days (11% vs 25%; p = 0.0007); there were no differences a sponge dressing and an integrated dressing. Ho et al (49)
between the treatment and control groups when the catheter previously demonstrated a nonstatistically significant trend
was in situ longer than 14 days (23% vs 20%; p = 0.53) (3). toward reduction in CRBSI with the use of chlorhexidine-
This analysis suggests that there may be little or no advantage impregnated sponge dressings. This analysis includes seven
to using a chlorhexidine-impregnated dressing on a catheter studies evaluated by this previous analysis and includes
in place beyond 14 days. This likely corresponds to a change in two additional, recently published large studies. This study
the pathogenesis of CRBSI from the extraluminal route (27) excluded one included in Ho et al (49), which evaluated
associated with short-term CVCs to the intraluminal route skin colonization as its endpoint, because it did not evalu-
(17). The benefits of chlorhexidine-impregnated dressings ate catheter colonization or CRBSI, the main outcomes for
would not be expected to have as much impact on CRBSI rates this analysis.
when the intraluminal route is the primary source of infection, Chlorhexidine-impregnated dressings must be viewed as an
as is the case with long-term devices and any CVC after the adjunct to the sum total of essential preventive measures shown
first or second week of insertion with routine dressing changes. to reduce CRBSI and do not replace insertion and mainte-
Most studies in our analysis used a c­ hlorhexidine-impregnated nance best practices. But even if a high rate of compliance with
sponge dressing (Biopatch, Johnson and Johnson, New best practices has been achieved, two of the most recent trials
Brunswick, NJ), and one study used an integrated chlorhexi- found a substantial and highly statistically significant reduc-
dine dressing (3M Tegaderm Chlorhexidine Dressing, 3M, St tion in CRBSI, with a very low baseline rate of CRBSI.
Paul, MN) (46). We included both types in our analyses as the It is important to ascertain whether the benefit of the
mechanism of activity would be expected to be similar. The chlorhexidine-impregnated dressing is confined to a par-
Biopatch dressing comes as a round sponge that is placed cir- ticular type of vascular catheter. In the three studies that
cumferentially around the insertion site. Errors in placement included arterial catheters (32, 35, 46), the beneficial effect

1710 www.ccmjournal.org July 2014 • Volume 42 • Number 7


Review Article

Catheter Colonization Catheter-Related Bloodstream Infection

n/N (%) n/N (%)

CHG Dressing Control RR (95% CI) CHG Dressing Control RR (95% CI)

2/17 (12) 1/16 (6) 1.88 (0.19–18.80) 1/17 (5) 0/16 (0) 2.83 (0.26–13.59)
109/665 (16) 216/736 (29) 0.55 (0.36–0.85) a
8/665 (1) 24/736 (3) 0.37 (0.07–1.95)a
47/314 (15) 82/341 (24) 0.62 (0.45–0.86) 12/314 (4) 11/341 (3) 1.18 (0.53–2.65)
NR NR NR 2/58 (3) 7/54 (13) 0.27 (0.06–1.22)a
11/74 (15) 21/71 (29) 0.50 (0.26–0.97) 4/74 (5) 3/71 (4) 1.28 (0.30–5.51)
NR NR NR 19/300 (6) 34/301 (11) 0.56 (0.33–0.96)
97/1,953 (4) 213/1,825 (12) 0.36 (0.28–0.46)b 6/1,953 (0) 17/1,825 (0) 0.33 (0.13–0.83)d
20/156 (13) 24/156 (15) 0.91 (0.53–1.56) 3/150 (4) 2/156 (6) 0.69 (0.25–1.90)
75/2,108 186/2,055 (9.0) 0.39 (0.30–0.51) 9/2,108 (0.4) 22/2,055 (1.0) 0.40 (0.18–0.86)
(3.5)
361/5,281 743/5,200 0.52 (0.43–0.64) 64/5,639 120/5,608 0.59 (0.38–0.93)

of the ­ chlorhexidine-impregnated dressing extended also (53). The investigators found that the zones of inhibition to
to peripheral arterial catheters, suggesting that use of the chlorhexidine were similar for organisms recovered from both
­chlorhexidine-impregnated dressing on arterial catheters war- the antiseptic and control catheters. However, in vitro studies
rants consideration. of Pseudomonas stutzeri exposed to slowly increasing concen-
Consideration of adverse effects of topical prolonged expo- trations of chlorhexidine found emergence of resistance to
sure to chlorhexidine is essential and adverse effects were chlorhexidine and several classes of therapeutic antimicrobial
explicitly addressed in three published clinical trials included agents (55). None of the published clinical trials included in
in our meta-analysis (31, 35, 46). Reported adverse effects of our analysis adequately assessed emergence of resistance to
cutaneous use of chlorhexidine include contact dermatitis and chlorhexidine among isolates recovered from blood or cath-
pressure necrosis. These adverse reactions were encountered in eter segments. Although low-level bacterial chlorhexidine
approximately 15% of cases in a randomized trial of a chlorhex- resistance (56) and resistance genes encoding chlorhexidine
idine-impregnated sponge dressing in premature neonates resistance (57) have been identified, there have been no reports
with birth weight less than 1,000 g and suggest that a chlorhex- of clinically relevant chlorhexidine resistance to date (57,
idine-impregnated dressing should be used with caution in 58), despite the widespread use of chlorhexidine for cutane-
this population. Generally, chlorhexidine-impregnated dress- ous disinfection vascular access sites and surgical sites, and in
ings for prevention of CRBSI appear to be safe and well toler- recent years, total body bathing of patients in critical care units
ated; however, clinicians should remain vigilant for erythema (59–61). The increasing use of chlorhexidine makes continued
and dermatitis at the site of the ­chlorhexidine-impregnated surveillance for developing resistance important (57), but, as
dressing. the microbial populations beneath a chlorhexidine dressing
Another potential concern associated with the prolonged are minute following cutaneous disinfection, it seems unlikely
use of antiseptic agents is the emergence of microbial resis- that the use of chlorhexidine sponge dressings for prevention
tance (50). Frequent exposure to chlorhexidine may result in of vascular catheter-related BSI will contribute materially to
development of resistance to biocides (51, 52). However, in the emergence and spread of chlorhexidine-resistant nosoco-
clinical trials of chlorhexidine-impregnated vascular devices, mial pathogens.
resistance to chlorhexidine has not been detected (53, 54). A There are several limitations to our analyses that war-
recent well-designed trial comparing a ­ second-generation rant consideration. Although one of the studies blinded the
CVC impregnated with chlorhexidine and silver sulfadia- investigators evaluating the data (32), and two blinded asses-
zine with a standard uncoated catheter for prevention of sors (35, 46), none of the included studies were truly double
CRBSI included rigorous efforts to detect antiseptic resistance blind, increasing risk of bias. Two studies reported that blinded

Critical Care Medicine www.ccmjournal.org 1711


Safdar et al

laboratory personnel performed cultures, and one study used a 9. Arnow PM, Quimosing EM, Beach M: Consequences of intravascular
catheter sepsis. Clin Infect Dis 1993; 16:778–784
blinded case report review; however, the influence of the pres-
10. Collignon PJ: Intravascular catheter associated sepsis: A common
ence of the dressing on the clinician’s suspicion and decision problem. The Australian Study on Intravascular Catheter Associated
to investigate CRBSI is unknown (33, 35). Only two studies Sepsis. Med J Aust 1994; 161:374–378
performed a comprehensive epidemiologic evaluation of the 11. Rello J, Ochagavia A, Sabanes E, et al: Evaluation of outcome of intra-
CRBSI source by sampling the catheter hub and performing venous catheter-related infections in critically ill patients. Am J Respir
Crit Care Med 2000; 162:1027–1030
molecular identification of isolated coagulase-negative staphy- 12. Pronovost P, Needham D, Berenholtz S, et al: An intervention to
lococci to establish concordance between strains found in the decrease catheter-related bloodstream infections in the ICU. N Engl
blood, catheter tip, and hub (31, 32). Additional limitations J Med 2006; 355:2725–2732
include the varied populations, settings, catheter types, and 13. Mattie AS, Webster BL: Centers for Medicare and Medicaid Services’
“never events”: An analysis and recommendations to hospitals. Health
reasons for use. Care Manag (Frederick) 2008; 27:338–349
Another significant limitation is the variable rates 14. Clancy CM: CMS’s hospital-acquired condition lists link hospital pay-
of ­ catheter-related infections seen across studies, with ment, patient safety. Am J Med Qual 2009; 24:166–168
control-group CRBSI rates ranging from 0% to 13%.
­ 15. Marrie TJ, Costerton JW: Scanning and transmission electron micros-
copy of in situ bacterial colonization of intravenous and intraarterial
Differences in local practice and prevention guideline imple- catheters. J Clin Microbiol 1984; 19:687–693
mentation over time may account for this difference. 16. Cooper GL, Schiller AL, Hopkins CC: Possible role of capillary action
These limitations notwithstanding, our results have impor- in pathogenesis of experimental catheter-associated dermal tunnel
tant implications for clinicians involved in the care of patients infections. J Clin Microbiol 1988; 26:8–12
with intravascular catheters and highly support the use of a 17. Sitges-Serra A, Linares J, Garau J: Catheter sepsis: The clue is the
hub. Surgery 1985; 97:355–357
chlorhexidine-impregnated dressing. Our analyses support the
18. Maki DG, Jarrett F, Sarafin HW: A semiquantitative culture method for
routine use of a chlorhexidine-impregnated dressing for the identification of catheter-related infection in the burn patient. J Surg
prevention of CRBSI as part of a comprehensive approach to Res 1977; 22:513–520
reducing CRBSI. Future research needs to undertake compara- 19. Crnich CJ, Maki DG: The promise of novel technology for the pre-
vention of intravascular device-related bloodstream infection. II.
tive effectiveness and cost-effectiveness studies to determine ­Long-term devices. Clin Infect Dis 2002; 34:1362–1368
which of the available multiple novel technologies and pre- 20. Haraden CP: What is a bundle? 2006. Available at: http://www.ihi.
vention strategies, alone or in combination, provide the most org/IHI/Topics/CriticalCare/IntensiveCare/ImprovementStories/
impact for reducing CRBSI and better identify subgroups of WhatIsaBundle.htm. Accessed August 8, 2008
patients most likely to benefit. 21. Yokoe DS, Mermel LA, Anderson DJ, et al: A compendium of strate-
gies to prevent healthcare-associated infections in acute care hospi-
tals. Infect Control Hosp Epidemiol 2008; 29(Suppl 1):S12–S21
22. Eggimann P, Harbarth S, Constantin MN, et al: Impact of a prevention
REFERENCES strategy targeted at vascular-access care on incidence of infections
1. Climo M, Diekema D, Warren DK, et al: Prevalence of the use of cen-
acquired in intensive care. Lancet 2000; 355:1864–1868
tral venous access devices within and outside of the intensive care
unit: Results of a survey among hospitals in the prevention epicenter 23. Berenholtz SM, Pronovost PJ, Lipsett PA, et al: Eliminating
program of the Centers for Disease Control and Prevention. Infect ­catheter-related bloodstream infections in the intensive care unit. Crit
Control Hosp Epidemiol 2003; 24:942–945 Care Med 2004; 32:2014–2020
2. Shlaes DM, Gerding DN, John JF Jr, et al: Society for Healthcare 24. Zingg W, Imhof A, Maggiorini M, et al: Impact of a prevention strat-
Epidemiology of America and Infectious Diseases Society of America egy targeting hand hygiene and catheter care on the incidence of
Joint Committee on the Prevention of Antimicrobial Resistance: catheter-related bloodstream infections. Crit Care Med 2009;
­
Guidelines for the prevention of antimicrobial resistance in hospitals. 37:2167–2173; quiz 2180
Clin Infect Dis 1997; 25:584–599 25. Warren DK, Zack JE, Mayfield JL, et al: The effect of an education pro-
3. Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the gram on the incidence of central venous catheter-associated blood-
diagnosis and management of intravascular catheter-related infection: stream infection in a medical ICU. Chest 2004; 126:1612–1618
2009 Update by the Infectious Diseases Society of America. Clin 26. Coopersmith CM, Zack JE, Ward MR, et al: The impact of bedside
Infect Dis 2009; 49:1–45 behavior on catheter-related bacteremia in the intensive care unit.
4. O’grady NP, Alexander M, Dellinger EP, et al; Healthcare Infection Arch Surg 2004; 139:131–136
Control Practices Advisory Committee: Guidelines for the prevention 27. Safdar N, Maki DG: The pathogenesis of catheter-related blood-
of intravascular catheter-related infections. Am J Infect Control 2002; stream infection with noncuffed short-term central venous catheters.
30:476–489 Intensive Care Med 2004; 30:62–67
5. Mermel LA, Farr BM, Sherertz RJ, et al; Infectious Diseases Society 28. Mermel LA, McCormick RD, Springman SR, et al: The pathogenesis
of America; American College of Critical Care Medicine; Society for and epidemiology of catheter-related infection with pulmonary artery
Healthcare Epidemiology of America: Guidelines for the management Swan-Ganz catheters: A prospective study utilizing molecular subtyp-
of intravascular catheter-related infections. Clin Infect Dis 2001; ing. Am J Med 1991; 91:197S–205S
32:1249–1272 29. Bjornson HS, Colley R, Bower RH, et al: Association between micro-
6. Safdar N, Crnich CJ, Maki DG: The pathogenesis of organism growth at the catheter insertion site and colonization of the
­ventilator-associated pneumonia: Its relevance to developing effective catheter in patients receiving total parenteral nutrition. Surgery 1982;
strategies for prevention. Respir Care 2005; 50:725–739; discus- 92:720–727
sion 739–741 30. Banton J: Techniques to prevent central venous catheter infections:
7. Safdar N, Crnich CJ, Maki DG: Nosocomial infections in the intensive Products, research, and recommendations. Nutr Clin Pract 2006;
care unit associated with invasive medical devices. Curr Infect Dis 21:56–61
Rep 2001; 3:487–495 31. Garland JS, Alex CP, Mueller CD, et al: A randomized trial compar-
8. Pittet D, Tarara D, Wenzel RP: Nosocomial bloodstream infection in ing povidone-iodine to a chlorhexidine gluconate-impregnated dress-
critically ill patients. Excess length of stay, extra costs, and attributable ing for prevention of central venous catheter infections in neonates.
mortality. JAMA 1994; 271:1598–1601 Pediatrics 2001; 107:1431–1436

1712 www.ccmjournal.org July 2014 • Volume 42 • Number 7


Review Article

32. Maki D, Mermel L, Kluger D, et al: The efficacy of a chlorhexidine 47. Timsit JF, Mimoz O, Mourvillier B, et al: Randomized controlled trial of
impregnated sponge (Biopatch) for the prevention of intravascu- chlorhexidine dressing and highly adhesive dressing for preventing
lar catheter-related infection—A prospective randomized controlled catheter-related infections in critically ill adults. Am J Respir Crit Care
multicenter study [abstract 1430]. Programs and Abstracts of the Med 2012; 186:1272–1278
Fortieth Interscience Conference on Antimicrobial Agents and 48. Ye X, Rupnow M, Bastide P, et al: Economic impact of use of
Chemotherapy, Toronto, 2000; Washington, DC, American Society for chlorhexidine-impregnated sponge dressing for prevention of central
Microbiology, p 422 line-associated infections in the United States. Am J Infect Control
33. Levy I, Katz J, Solter E, et al: Chlorhexidine-impregnated dressing for 2011; 39:647–654
prevention of colonization of central venous catheters in infants and 49. Ho KM: Comment on: Use of chlorhexidine-impregnated dressing to
children—A randomized controlled study. Pediatr Infect Dis J 2005; prevent vascular and epidural catheter colonization and infection: A
24:676–679 meta-analysis. J Antimicrob Chemother 2010; 65:811–814
34. Chambers ST, Sanders J, Patton WN, et al: Reduction of exit-site infec- 50. Tambe SM, Sampath L, Modak SM: In vitro evaluation of the risk of
tions of tunnelled intravascular catheters among neutropenic patients developing bacterial resistance to antiseptics and antibiotics used in
by sustained-release chlorhexidine dressings: Results from a prospec- medical devices. J Antimicrob Chemother 2001; 47:589–598
tive randomized controlled trial. J Hosp Infect 2005; 61:53–61 51. McDonnell G, Russell AD: Antiseptics and disinfectants: Activity,
35. Timsit JF, Schwebel C, Bouadma L, et al; Dressing Study Group: action, and resistance. Clin Microbiol Rev 1999; 12:147–179
Chlorhexidine-impregnated sponges and less frequent dress- 52. Penna TC, Mazzola PG, Silva Martins AM: The efficacy of chemical
ing changes for prevention of catheter-related infections in criti- agents in cleaning and disinfection programs. BMC Infect Dis 2001;
cally ill adults: A randomized controlled trial. JAMA 2009; 301: 1:16
1231–1241
53. Rupp ME, Lisco SJ, Lipsett PA, et al: Effect of a second-generation
36. Arvaniti K, Lathyris D, Clouva-Molyvdas P, et al; Catheter-Related venous catheter impregnated with chlorhexidine and silver sulfadia-
Infections in ICU (CRI-ICU) Group: Comparison of Oligon catheters zine on central catheter-related infections—A randomized, controlled
and chlorhexidine-impregnated sponges with standard multilumen trial. Ann Intern Med 2005; 143:570–580
central venous catheters for prevention of associated colonization
and infections in intensive care unit patients: A multicenter, random- 54. Maki DG, Stolz SM, Wheeler S, et al: Prevention of central
ized, controlled study. Crit Care Med 2012; 40:420–429 venous catheter-related bloodstream infection by use of an
antiseptic-impregnated catheter. A randomized, controlled trial.
­
37. Ruschulte H, Franke M, Gastmeier P, et al: Prevention of central venous Ann Intern Med 1997; 127:257–266
catheter related infections with chlorhexidine gluconate impregnated
wound dressings: A randomized controlled trial. Ann Hematol 2009; 55. Tattawasart U, Maillard JY, Furr JR, et al: Development of resistance to
88:267–272 chlorhexidine diacetate and cetylpyridinium chloride in Pseudomonas
stutzeri and changes in antibiotic susceptibility. J Hosp Infect 1999;
38. Roberts BL, Cheung D: BIOPATCH—A new concept in antimicrobial 42:219–229
dressings for invasive devices. Aust Crit Care 1998; 11:16–19
56. Cookson BD, Bolton MC, Platt JH: Chlorhexidine resistance in
39. Liberati A, Altman DG, Tetzlaff J, et al: The PRISMA statement for ­methicillin-resistant Staphylococcus aureus or just an elevated MIC?
reporting systematic reviews and meta-analyses of studies that evalu- An in vitro and in vivo assessment. Antimicrob Agents Chemother
ate health care interventions: Explanation and elaboration. Ann Intern 1991; 35:1997–2002
Med 2009; 151:W65–W94
57. Horner C, Mawer D, Wilcox M: Reduced susceptibility to chlorhexi-
40. Higgins JPT, Green S, Cochrane Collaboration: Cochrane Handbook dine in staphylococci: Is it increasing and does it matter? J Antimicrob
for Systematic Reviews of Interventions. Chichester, England; Chemother 2012; 67:2547–2559
Hoboken, NJ, Wiley-Blackwell, 2008
58. Johnson MD, Schlett CD, Grandits GA, et al: Chlorhexidine does not
41. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin select for resistance in Staphylococcus aureus isolates in a commu-
Trials 1986; 7:177–188 nity setting. Infect Control Hosp Epidemiol 2012; 33:1061–1063
42. Donner A, Klar N: Design and Analysis of Cluster Randomization 59. O’Horo JC, Silva GL, Munoz-Price LS, et al: The efficacy of daily
Trials in Health Research. Wiley, London, 2000 bathing with chlorhexidine for reducing healthcare-associated blood-
43. Chaiyakunapruk N, Veenstra DL, Lipsky BA, et al: Chlorhexidine com- stream infections: A meta-analysis. Infect Control Hosp Epidemiol
pared with povidone-iodine solution for vascular catheter-site care: A 2012; 33:257–267
meta-analysis. Ann Intern Med 2002; 136:792–801 60. Derde LP, Dautzenberg MJ, Bonten MJ: Chlorhexidine body washing
44. Egger M, Davey Smith G, Schneider M, et al: Bias in meta-analysis to control antimicrobial-resistant bacteria in intensive care units: A
detected by a simple, graphical test. BMJ 1997; 315:629–634 systematic review. Intensive Care Med 2012; 38:931–939
45. Sterne JA, Egger M: Funnel plots for detecting bias in meta-analysis: 61. Climo MW, Sepkowitz KA, Zuccotti G, et al: The effect of daily
Guidelines on choice of axis. J Clin Epidemiol 2001; 54:1046–1055 bathing with chlorhexidine on the acquisition of methicillin-resis-
46. Schwebel C, Lucet JC, Vesin A, et al: Economic evaluation of tant Staphylococcus aureus, vancomycin-resistant Enterococcus,
chlorhexidine-impregnated sponges for preventing catheter-related and healthcare-associated bloodstream infections: Results of
infections in critically ill adults in the Dressing Study. Crit Care Med a ­ quasi-experimental multicenter trial. Crit Care Med 2009;
2012; 40:11–17 37:1858–1865

Critical Care Medicine www.ccmjournal.org 1713