Intensive Care Med

DOI 10.1007/s00134-014-3565-4 SYSTEMATIC REVI EW

Akira Kuriyama
Noriyuki Umakoshi
Impact of closed versus open tracheal
Jun Fujinaga suctioning systems for mechanically ventilated
Tadaaki Takada
adults: a systematic review and meta-analysis

Received: 1 June 2014 Abstract Purpose: Whether
Accepted: 12 November 2014 closed tracheal suctioning systems
(CTSS) reduce the incidence of ven-
Ó Springer-Verlag Berlin Heidelberg and tilator-associated pneumonia (VAP)
ESICM 2014
compared with open tracheal suc-
Electronic supplementary material tioning systems (OTSS) is
The online version of this article inconclusive. We conducted a sys-
(doi:10.1007/s00134-014-3565-4) contains tematic review and meta-analysis of
supplementary material, which is available
to authorized users. randomized controlled trials that
compared CTSS and OTSS. Meth-
ods: PubMed, the Cochrane Central
Register of Controlled Trials, the
Web of Science, Google Scholar, and
a clinical trial registry from inception
to October 2014 were searched with-
out language restrictions.
Randomized controlled trials of
A. Kuriyama ()) CTSS and OTSS that compared VAP
Department of General Medicine, Kurashiki in mechanically ventilated adult
Central Hospital, 1-1-1 Miwa, Kurashiki,
Okayama 710-8602, Japan patients were included. The primary
e-mail: nrk40448@nifty.com outcome was the incidence of VAP.
Secondary outcomes were mortality
N. Umakoshi
J. Fujinaga and length of mechanical ventilation.
Department of Emergency Medicine, Data were pooled using the random
Kurashiki Central Hospital, Kurashiki, effects model. Results: Sixteen tri-
Okayama, Japan als with 1,929 participants were
included. Compared with OTSS,
T. Takada
Department of Emergency and Critical Care CTSS was associated with a reduced
Medicine, Urasoe General Hospital, Urasoe, incidence of VAP (RR 0.69; 95 % CI
Okinawa, Japan 0.54–0.87; Q = 26.14; I2 = 46.4 %).
Compared with OTSS, CTSS was not
associated with reduction of mortality
(RR 0.96; 95 % CI 0.83–1.12;
Q = 2.27; I2 = 0.0 %) or reduced
length of mechanical ventilation
(WMD -0.45 days; 95 % CI -1.25
to 0.36; Q = 6.37; I2 = 5.8 %). Trial
sequential analysis suggested a lack
of firm evidence for 20 % RR
reduction in the incidence of VAP.
The limitations of this review inclu-
ded underreporting and low quality of
the included trials, as well as varia-
tions in study procedures and
characteristics. Conclusions: Based
on current, albeit limited evidence, it
is unlikely that CTSS is inferior to
OTSS regarding VAP prevention;
however, further trials at low risk of
bias are needed to confirm or refute
this finding.
Keywords Endotracheal suctioning

Closed tracheal suctioning systems

Adults
Ventilator-associated
pneumonia
Meta-analysis

Systematic review
Trial
sequential analysis

Introduction
Ventilator-associated pneumonia (VAP) is one of the com-
mon nosocomial infections in intensive care units (ICUs). It
is reported that 6–52 % of mechanically ventilated patients
develop VAP [1–4]. VAP is associated with prolonged ICU
and hospital stays [5, 6] and mortality [7, 8]. The annual cost
for VAP is considerable and approximated $3.0 billion USD
[9]. Thus, the prevention of VAP has substantial merits from
the clinical and societal perspectives.
Currently, two types of endotracheal suctioning sys-
tems are available: closed tracheal suction systems
(CTSS) and open tracheal suction systems (OTSS). CTSS
allow multiple episodes of endotracheal suctioning with-
out disconnecting the patient from the ventilator. Their
suggested advantages compared with OTSS use include
limited environmental and personnel contamination [10],
maintained positive end expiratory pressure, lung volume,
and oxygenation [11, 12], and fewer physiologic distur-
bances during suctioning such as decreased arterial
deoxygenation, increased heart rate, and increased mean
arterial pressure [13, 14].
Another potential advantage of CTSS use is the pre-
vention of VAP. Previous systematic reviews and meta-
analyses have concluded that CTSS use has no benefit
over OTSS use in preventing VAP [13, 15–20]. However,
they were based on a relatively small number of trials, and
some even suggested a potential publication bias [13, 20].
Trials published in some non-English languages were not
included.
Therefore, we conducted a systematic review and
meta-analysis to reassess the efficacy of CTSS use to
prevent VAP in mechanically ventilated adult patients, in
comparison with OTSS use. Recent trials and trials pub-
lished in non-English languages were included, and trial
sequential analysis was conducted to challenge the
robustness of the available evidence.
Materials and methods
Study selection
The study protocol was pre-specified as a protocol and
followed the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) Statement for
reporting on systematic reviews [21]. We searched Pub-
Med, the Cochrane Central Register of Controlled Trials,
and the Web of Science. The search strategy was listed in
the protocol (Supplementary File). Clinicaltrial.gov, Go-
ogle Scholar, and the references of retrieved articles and
previous systematic reviews were reviewed for potentially
relevant trials. No language restrictions were placed on
the search. The last search was conducted on October 27,
2014.
Eligibility criteria
Randomized controlled trials that compared CTSS and
OTSS use in adult patients (aged 18 years or over) on
mechanical ventilation in ICUs were included. Trials
published in abstracts were also included if pertinent data
on patients’ characteristics and outcomes of interest were
available. Crossover trials and trials conducted on neo-
nates and infants were excluded.
Data abstraction and risk of bias assessment
At least two of the reviewers (A.K., N.U., and J.F.)
independently extracted the following information in
duplicate: (1) study characteristics (the types of ICUs,
sample size, inclusion or exclusion of patients with
pneumonia at admission to ICUs, and definitions of
VAP); (2) participants’ demographics (age and sex); (3)
interventions (CTSS brand names, the cycle of CTSS
exchange, industry sponsorship); and (4) outcomes of
interest. Attempts were made to contact the original
authors for more details. The authors were considered
unresponsive, when three e-mails were sent and no reply
was obtained. At least two of the authors (A.K., N.U., and
J.F.) independently assessed the risk of bias, using the
Risk of Bias tool recommended by the Cochrane Col-
laborations [22], as well as the sponsorship. Any
disagreement was resolved through discussion.
Statistical analysis
The primary outcome was the incidence of VAP. Any
definitions of VAP were allowed. Secondary outcomes
were mortality and length of mechanical ventilation.
When trials had more than one arm for the intervention,
the data were pooled into a single group [22]. When trials
had zero events in either arm, continuity corrections were
applied with addition of 0.5 to each cell of 2 9 2 tables
from the trial [23]. Dichotomous outcomes were com-
bined and presented as risk ratios (RRs) with associated
95 % confidence intervals (CIs). Length of mechanical
ventilation was combined using weighted mean differ-
ences (WMD). We a priori knew that the included
populations would be clinically heterogenous, and thus
data were pooled using the DerSimonian and Laird ran-
dom-effects model [24]. Statistical heterogeneity was
assessed with the I2 and Q statistics [25]. When significant
heterogeneity was identified (I2 C 50 % or p \ 0.1),
meta-regression analysis was conducted to investigate the
potential sources of heterogeneity. We performed sub-
group analysis stratified by the ICU population, as done in
the Cochrane review [19] and on our hypothesis that there
is no difference in the effect size among subgroups. A
subgroup analysis stratified by the cycle of exchanging
CTSS and meta-regression analysis to examine the rela-
tionship between the cycle and the effect size were also
conducted. The test-of-interaction was performed in
subgroup analyses [26]. Sensitivity analyses were con-
ducted by excluding trials that included patients with
pneumonia at admission, and by excluding trials with
unclear or high risk of bias in any domain of sequence
generation, allocation concealment, or blinding of out-
come assessors. Publication bias was tested using Egger’s
method [27]. All these analyses were conducted with
Stata v.11.2 (Stata, College Station, TX, USA).
A meta-analysis may suffer from the type I error due to
an increased risk of random error due to sparse data, and due
to repeated significance testing when meta-analyses are
updated with new trials [28]. Sensitivity analysis with trial
sequential analysis (TSA) on our primary outcome (VAP)
was additionally performed to adjust for random error and
repetitive testing. Meta-analysis monitoring boundaries
and required information size (cumulated sample size of
included trials) were calculated, with D2 (diversity adjusted
information size) and adjusted 95 % CIs. The idea behind
TSA is that if the cumulative Z-curve crosses the boundary,
a sufficient level of evidence is reached and no further trials
are needed. If the Z-curve does not cross the boundary and
the required information size is not been reached, evidence
is insufficient to allow investigators to conduct further trials
for a conclusion. We conducted TSA to maintain a type I
error of 5 %, and calculated the required information size
with an anticipated intervention size of 20 % relative risk
reduction (RRR), at a power of 80 % [29]. We conducted
TSA with TSA 0.9 (The Copenhagen Trial Unit, Copen-
hagen, Denmark).
Results
The search produced 400 articles (Supplementary Fig. 1).
After application of inclusion and exclusion criteria, 16
randomized, controlled trials that compared CTSS and
OTSS were identified [14, 30–44]. Two major CTSS sales
companies were contacted, but no new information was
obtained. A total of 1,929 mechanically-ventilated
patients was included in the analysis (Table 1). The mean
age of participants was 48.3 years, and 29 % was women.
The median sample size was 74. The follow-up periods
were reported in six trials, and ranged from 7 to 31 days
[30, 33, 34, 37, 41, 44]. Four trials were conducted in
medical ICUs [32, 35, 36, 40], four in surgical ICUs [14,
30, 31, 38], and six in mixed (medico-surgical) ICUs [33,
34, 37, 39, 43, 44]; the remainder was unclear. Six trials
used Trach Care, two Steri Cath, two Hi Care, and one Ty
Care as the CTSS; the CTSS brand was unclear in five
trials. The cycle of CTSS exchange varied considerably;
nine trials exchanged CTSS every 24 h [14, 30, 31, 34,
35, 38, 40, 42, 44], one every 72 h [37], one every 168 h
[32], and one trial included groups that exchanged CTSS
every 24 and 48 h [43], respectively. All trials except two
excluded patients with pneumonia at the onset of the
studies [32, 41]. Fourteen trials set VAP as the primary
outcome [14, 31–40, 42–44], four of which a priori cal-
culated the sample size [32–34, 37]. Twelve trials were
reported in English, two in Chinese [43, 44], one in
Korean [37], and one in Arabic [42].
Study quality
Overall, four trials (25 %) had adequate sequence gen-
eration, whereas two (13 %) had adequate concealed
allocation (Supplementary Table 1). Outcome assessors
were judged to be adequately blinded in four trials
(25 %). Only one trial was assessed as overall low risk of
bias [32]. Two studies (13 %) disclosed the involvement
of industry sponsorship; CTSS was provided for one trial,
and a support grant was given for the other trial.
Primary outcome analysis
Use of CTSS was associated with a reduced incidence of
VAP compared with OTSS (RR 0.69; 95 % CI 0.54–0.87;
Q = 26.14; df = 14; I2 = 46.4 %, p = 0.03) (Fig. 1).
The point estimates of the effect size were similar across
the subgroups (test-of-interaction p = 0.95) (Table 2). No
publication bias was evident (p = 0.13). The pooled data
had moderate heterogeneity. Meta-regression analysis
showed that sample size (p = 0.06), age (p = 0.35), sex
(p = 0.50), publication date (p = 0.53), publication type
(p = 0.65), single- or multicenter study (p = 0.75) and
any risk of bias were not the source of the heterogeneity.
Compared to OTSS use, the use of CTSS was not asso-
ciated a reduced incidence of VAP in the only one trial
with overall low risk of bias (RR 0.56; 95 % CI
0.27–1.14), whereas pooled results from the trials with
overall unclear or high risk of bias showed beneficial
effect (RR 0.70; 95 % CI 0.54–0.90; Q = 25.51; df = 13;
I2 = 49.0 %, p = 0.02).
Secondary outcome analysis
Compared with use of OTSS, use of CTSS was not
associated with reduction of mortality (RR 0.96; 95 % CI
0.83–1.12; Q = 2.27; df = 6; I2 = 0.0 %; p = 0.89)
(Supplementary Fig. 2) or a shorter length of mechanical
ventilation (WMD -0.45 days; 95 % CI -1.25 to 0.36;
Q = 6.37; df = 6; I2 = 5.8 %; p = 0.38) (Supplemen-
tary Fig. 3). No publication bias was evident in mortality
(p = 0.94) or length of mechanical ventilation
(p = 0.90).
Table 1 Characteristic of the included trials

Author Year Type of ICU Sample size Age Type of Hours of Pneumonia Diagnosis of VAP
(country) (%, female) closed suction closed system use excluded?

Conrad (US) 1989 NS 33 (NS) NS Trach Care 24 Yes Fever, leukocytosis, new pulmonary infiltrate
Deppe 1990 Surgical ICU 84 (42.9) 53.2 Trach Care 24 Yes Purulent sputum, T C 38.1 °C or B 35.9 °C, new or progressive
(USA) infiltrate on chest X-ray, WBC [ 12,000/mm3 or \3,000/mm3,
time after admission [48 h
Johnson 1994 Trauma ICU 35 (25.7) 43.1 Trach Care 24 Yes New or progressive pulmonary infiltrate in radiograph and at least
(USA) two of the following criteria; purulent sputum, T C 38.1 °C
without any extrapulmonary source, or leukocytosis [12,000/
mm3
Adams 1997 Liver-transplant 20 (60) 52.6 Trach Care 24 Yes Temperature, endotracheal secretion, abnormal gas exchange,
(UK) ICU presence of infiltration on chest X-ray and leucocytosis
Welte (Germany) 1997 NS 52 (NS) 49.9 Trach- NS
Care
NS Positive BAL
culture with
infiltrate on
chest X-ray,
fever,
leucocytosis
Combes 2000 Neurosurgical 104 (29.8) 43.4 Steri-Cath 24 Yes New and persistent infiltrate on chest X-ray, purulent endotracheal
(France) ICU aspirate with positive sputum culture, BT [ 38C, and WBC
[10,000/mm3 or 4,000/mm3
Zeitoun 2003 Medical and 47 (NS) NS NS NS Yes T [ 37.8C, radiographic appearance of new or progressive
(Brazil) surgical ICU pulmonary infiltrate, leukocytosis (WBC C10,000/mm3) and
purulent tracheobronchial secretions or change in their
characteristics
Lee (South 2004 Emergency ICU 70 (22.9) 57.5 NS 72 Yes Physician-based diagnosis, based on positive TA culture and chest
Korea) X-ray
Topeli 2004 Medical ICU 78 (46.2) 64.1 Steri-Cath Not routine Yes New and persistent infiltration in the chest X-ray and presence of
(Turkey) any two of three criteria; T [38 °C or \35.5 °C, WBC
[10,000/mm3 or \3,000/mm3, and purulent tracheobronchial
secretions or at least 10 WBC/high power field in a Gram stain
of TA
Rabitsch 2004 Medical 24 (37.5) 63.5 Trach Care 24 Yes A new or progressive radiographic infiltrate developed with one of
(Austria) the following signs: radiographic evidence of cavitation;
histological evidence of pneumonia; a positive blood culture
finding without another source of infection; a purulent tracheal
aspirate; or a positive pleural fluid culture finding with 2 of the
following symptoms or signs: T [ 38.0 °C, WBC \3,000/mm3,
or [10,000/mm3
Lorente 2005 Medical-surgical 443 (31.4) 58.8 Hi Care 24 Yes All of the following criteria were met: new onset of bronchial
(Spain) purulent sputum, T [ 38 °C or \35.5 °C, WB °C [10,000/
mm3 or \4,000/mm3, chest X–ray showing new or progressive
infiltrates, and culture of significant respiratory secretions or
blood culture coinciding with the culture of the respiratory
secretion
 NS not stated, T temperature, TA tracheal aspirate, BAL bronchoalveolar lavage, VAP ventilator-associated pneumonia, WBC white blood cell, CPIS clinical pulmonary
Subgroup analysis stratified by the cycle of CTSS

following in association with a new and persistent radiographic

purulent sputum, T [ 38 °C or \35.5 °C, WBC [10,000/mm3

infiltrates, and culture of significant respiratory secretions or

All of the following criteria were met: new onset of bronchial
exchange

CPIS [6, or clinical criteria; the presence of at least 2 of the

blood culture coinciding with the culture of the respiratory
or \4,000/mm3, chest X–ray showing new or progressive

extrapulmonary infectious source, (ii) WBC [10,000 or

An analysis of each outcome stratified by the cycle of

infiltrate: (i) T [ 38 °C or \36 °C without obvious

CTSS exchange was conducted (Table 3). Use of CTSS
was associated with a reduced incidence of VAP in the
subgroup with 24-h and 72-h cycles, and reduced length
of mechanical ventilation in the subgroup with a 48-h
cycle. No significant differences were found in the other
subgroups. Meta-regression analyses showed that there
was no relationship between the cycle of CTSS exchange
and VAP (p = 0.50), mortality (p = 0.33), or length of
mechanical ventilation (p = 0.78).
Pneumonia Diagnosis of VAP

\4,000/mm3 Sensitivity analyses

secretion

Of the 16 trials, 2 trials included 252 patients with

CPIS [6

CPIS [6

CPIS [6

pneumonia at the initiation of the studies [32, 41]. When

these two trials were excluded, use of CTSS was associ-
ated with a reduced incidence of VAP (RR 0.71; 95 % CI
0.54–0.94; Q = 24.08; df = 12; I2 = 50.2 %; p = 0.02),
closed suction closed system use excluded?

but it was not associated with reduced mortality (RR 1.03;

95 % CI 0.86–1.23) or shorter length of mechanical
Yes

Yes

Yes

Yes

No

ventilation (WMD -0.47 days; 95 % CI -1.43 to 0.50).

Meta-regression analysis failed to find the source of het-
erogeneity in the pooled outcome of VAP.
We additionally conducted sensitivity analyses on all
Not routine

outcomes (Supplementary Table 2). Use of CTSS tended

Hours of

24 or 48

to lower the incidence of VAP in all sensitivity analyses,

168

but the statistical significance disappeared due to a limited

24

24

number of trials and less statistical power. The results of

sensitivity analyses on mortality and the length of
mechanical ventilation were consistent with the secondary
Ty Care
Sample size Age Type of

59.4 Hi Care

outcome analysis.
NS

NS

NS

We reanalyzed the data using TSA. The required

diversity (D2 = 53 %, model variance-based) adjusted
NS

information size of 4331 participants was calculated,

60

60

43

based on 26 % events in the control group, a type I

(%, female)

457 (30.4)

error of 5 %, a power of 80 %, and an RRR of 20 %.

156 (NS)
67 (23.9)

200 (48)
80 (30)

The cumulative Z-curve did not cross the trial sequen-

tial monitoring boundary for benefit, or the required
information size was not reached (Fig. 2). This implies
the lack of evidence of CTSS use on the incidence of
2006 Medical-surgical

VAP.
2011 Medical ICU
Year Type of ICU

2007 Mixed ICU

2010 Mixed ICU

2010 NS

Discussion
Table 1 continued

infection score

Our traditional meta-analysis showed that use of CTSS

was associated with a 30 % reduction in VAP develop-
(China)
(Spain)
(country)

(India)

ment, compared with use of OTSS. While each subgroup

(Iran)
Lorente

(China)
Author

Fakhar

David
Wang

by the type of ICU included a small number of trials, and

thus had a wide confidential interval and moderate
Li
Table 2 Subgroup analyses by the type of ICU populations

Outcome Population Summary estimate (95 % CI) Heterogeneity

Q df I2 (%)

VAP Overall 0.69 (0.54 to 0.88) 26.10 14 46.4

Mixed ICU 0.63 (0.40 to 0.99) 15.96 5 68.7
Medical ICU 0.79 (0.42 to 1.47) 5.16 3 41.9
Surgical ICU 0.82 (0.53 to 1.25) 1.74 2 0.0
Uncertain 0.56 (0.40 to 0.79) 0.07 1 0.0
Mortality Overall 0.96 (0.83 to 1.12) 2.27 6 0.0
Mixed ICU 1.06 (0.83 to 1.37) 0.50 2 0.0
Medical ICU 0.91 (0.75 to 1.12) 0.89 1 0.0
Surgical ICU 0.91 (0.57 to 1.46) 0.00 1 0.0
Length of mechanical ventilation Overall -0.45 (-1.25 to 0.36) 6.37 6 5.8
Mixed ICU -0.55 (-1.68 to 0.58) 4.55 3 34.1
Medical ICU -0.37 (-2.49 to 1.75) 1.81 2 0.0
VAP ventilator-associated pneumonia, ICU intensive care units

Fig. 1 Comparison of CTSS and OTSS on the incidence of ventilator-associated pneumonia. CTSS closed tracheal suctioning systems,
OTSS closed tracheal suctioning systems

heterogeneity, the point estimate of the effect size was
similar across the subgroups. There was no significant
difference in mortality or length of mechanical ventilation
between CTSS and OTSS use. Use of CTSS tended to
lower the incidence of VAP, but the statistical signifi-
cance disappeared owing to less statistical power due to a
limited number of trials included in the sensitivity anal-
yses. Trials with high risk of bias might have
overestimated the intervention effect of CTSS in the tra-
ditional meta-analysis, and thus the results should be
interpreted cautiously. TSA as sensitivity analysis also
revealed that the evidence is lacking to suggest that use of
CTSS is associated with a lower incidence of VAP, and
further research is needed.
Exogenous bacteria travel to the lower respiratory
tract in mechanically ventilated patients, from the oro-
pharynx along the external surface of the tube to the
trachea, or by inadvertent cross-contamination during the
disconnection of the respiratory circuit for suction, and
they may result in VAP development [35]. Endotracheal
tubes with subglottic secretion might block the former
route [45]. Use of CTSS might reduce the chance of the
Table 3 Summary of pooled outcomes by the cycle of changing the closed tracheal suctioning systems

Cycle Unit 24 h 48 h 72 h 168 h

No. of Outcome No. of Outcome No. of Outcome No. of Outcome
studies (95 % CI) studies (95 % CI) studies (95 % CI) studies (95 % CI)

VAP RR 9 0.70 (0.51, 1 0.44 (0.19, 1.03) 1 0.17 (0.04, 1 0.56 (0.27,
0.96) 0.71) 1.14)
Mortality RR 4 1.03 (0.79, 1 1.14 (0.59, 2.21) NA NA 1 0.84 (0.65,
1.34) 1.10)
Length of mechanical WMD 4 -0.53 (-1.92, 2 -2.70 (-5.22, - NA NA 1 -1.00 (-5.32,
ventilation 0.85) 0.18) 3.32)
None of the subgroup analyses above had heterogeneity of I2 C 50 %
RR risk ratio, WMD weight mean difference, VAP ventilator-associated pneumonia, CI confidence interval

latter mechanism, thereby reducing VAP development.
However, prior evidence has been inconclusive with
respect to this hypothesis.
Previous systematic reviews and meta-analyses of
randomized trials have concluded that use of CTSS was
not associated with a reduced incidence of VAP compared
with use of OTSS [13, 15–20]. Some also suggested a
potential publication bias. The present traditional meta-
analysis showed that the incidence of VAP was signifi-
cantly reduced by CTSS use. The differences in the
findings between previous reviews and the present review
might be attributed to two factors: (1) the number of
included trials was greater, and (2) all newly included
trials favored CTSS use over OTSS use. There was no
evidence of publication bias in the present analysis.
However, TSA indicated that the current evidence as to
whether the use of CTSS is superior to the use of OTSS in
preventing VAP was still lacking.
Earlier guidelines for the prevention of VAP were
inconclusive about the effectiveness of CTSS as a VAP
prevention measure [46, 47]. Some guidelines have
favored CTSS over OTSS use for cost and safety con-
siderations, despite the scarcity of favorable evidence
supporting CTSS use for the prevention of VAP [48–51].
The present analysis showed that the number needed to
prevent (NNP) with CTSS for reducing one incidence of
VAP was 8.85 (95 % CI 5.62–21.27). However, scarcity
of high-quality trials as well as a lack of firm beneficial
evidence on CTSS rendered this issue inconclusive.
Our study triggered uncertainty regarding the optimal
timing of CTSS exchange. Trials included in the present
review exchanged the CTSS at 24, 48, 72, and 168 h,
respectively. Meta-regression analysis suggested that there
was no relationship between the cycle and the incidence of
VAP. One randomized trial suggested that the incidence of
VAP was not different between the 24-h and 48-h cycles of
CTSS exchange, but it was underpowered [52]. Another
randomized trial compared daily and no routine exchange
of in-line catheters of CTSS [53]. It suggested that, while
the incidence of VAP and hospital mortality were similar
for the two methods, no routine exchange of in-line
catheters reduced the cost. Currently, most manufacturers
recommend daily CTSS exchange, but no direct evidence
supports this. Sufficiently powered trials are needed to
determine the optimal cycle of CTSS exchange. A cost-
effectiveness analysis concerning the cycle of CTSS
exchange, incidence of VAP, and related costs should
subsequently be considered.
Our study has some strengths. First, a comprehensive
search for trials was conducted. During the search, three
Chinese trials that favored CTSS use as a prevention
measure against nosocomial pneumonia were not inclu-
ded, because the diagnostic criteria for nosocomial
pneumonia in mechanically ventilated patients were
unclear. Nevertheless, four trials reported in non-English
languages were included, and the total number of trials
was the largest to date. Second, appropriate and relevant
subgroup and meta-regression analyses were conducted
due to the large number of trials. This made the analysis
more rigorous. Third, the study protocol was preplanned,
as recommended by the Cochrane Collaboration [22].
Finally, the introduction of TSA as well as sensitivity
analyses using the traditional meta-analytic methods led
to our cautious interpretation of the current evidence
about CTSS, which otherwise supported the use of CTSS
as a preventive measure against VAP.
The present study has limitations. First, patients’
characteristics, study protocols including prophylactic
antibiotics and oral care, and the risk of VAP were not
uniform across trials. The pooled analysis of VAP showed
significant heterogeneity in the subgroup of mixed ICUs.
However, a lack of details about these factors precluded
investigating this heterogeneity. Second, many trials un-
derreported their methodology. Of the 16 trials, 13 were
published after 1996, when the CONSORT (Consolidated
Standards of Reporting Trials) statement was developed
to enhance researchers’ complete, clear, and transparent
reporting of randomized trials [54]. More than half of
these trials lacked information on sequence generation,
allocation concealment, and blinding of outcome asses-
sors. Meta-regression analysis showed that these risks
of bias did not affect the pooled outcomes. However,
Fig. 2 Trial sequential analysis comparing CTSS and OTSS on the incidence of ventilator-associated pneumonia. CTSS closed tracheal
suctioning systems, OTSS closed tracheal suctioning systems, RRR relative risk reduction

high-quality trials are still warranted. Third, most trials
included in our analysis was relatively small. It is known
that most large treatment effects emerge from small-sized
trials [55], while meta-regression analysis in our study
barely failed to show that smaller trials tended to show
favorable effectiveness of CTSS (p = 0.06). Thus, when
future trials are conducted with larger sample sizes, the
results may not support our study.
compared with OTSS use. However, sensitivity analyses
including TSA suggested the scarcity of high-quality tri-
als and the lack of firm evidence for the benefit of CTSS
use compared with OTSS use in reducing VAP. This does
not yet support the use of CTSS as a VAP prevention
measure, which was advocated in some current guide-
lines. High-quality trials with a better reporting of trial
results are still needed.

Acknowledgments The authors would like to thank Dr. Arzu

Topeli and Dr. Deepu David for providing relevant information,
and would like to thank Ms. Ryoko Ono for editing the figures.
Conclusion
Conflicts of interest None to declare for any author.
Our traditional meta-analysis suggested that CTSS use
was associated with a reduced incidence of VAP com- Financial disclosures None to declare.
pared with OTSS use. CTSS use showed no differences in
terms of mortality and length of mechanical ventilation

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