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original article
The
new england journal
of
medicine
n engl j med 360;1 nejm.org january 1, 2009
20
Decontamination of the Digestive Tract
and Oropharynx in ICU Patients
A.M.G.A. de Smet, M.D., J.A.J.W. Kluytmans, M.D., Ph.D., B.S. Cooper, Ph.D.,
E.M. Mascini, M.D., Ph.D., R.F.J. Benus, M.D., T.S. van der Werf, M.D., Ph.D.,
J.G. van der Hoeven, M.D., Ph.D., P. Pickkers, M.D., Ph.D., D. Bogaers-Hofman, I.C.P.,
N.J.M. van der Meer, M.D., Ph.D., A.T. Bernards, M.D., Ph.D., E.J. Kuijper, M.D., Ph.D.,
J.C.A. Joore, M.D., M.A. Leverstein-van Hall, M.D., Ph.D., A.J.G.H. Bindels, M.D., Ph.D.,
A.R. Jansz, M.D., R.M.J. Wesselink, M.D., Ph.D., B.M. de Jongh, M.D., Ph.D.,
P.J.W. Dennesen, M.D., Ph.D., G.J. van Asselt, M.D., Ph.D., L.F. te Velde, M.D.,
I.H.M.E. Frenay, M.D., Ph.D., K. Kaasjager, M.D., Ph.D., F.H. Bosch, M.D., Ph.D.,
M. van Iterson, M.D., S.F.T. Thijsen, M.D., Ph.D., G.H. Kluge, M.D., Ph.D.,
W. Pauw, M.D., J.W. de Vries, M.D., Ph.D., J.A. Kaan, M.D., J.P. Arends, M.D.,
L.P.H.J. Aarts, M.D., Ph.D., P.D.J. Sturm, M.D., Ph.D., H.I.J. Harinck, M.D., Ph.D.,
A. Voss, M.D., Ph.D., E.V. Uijtendaal, Pharm.D., H.E.M. Blok, M.Sc.,
E.S. Thieme Groen, M.D., M.E. Pouw, M.D., C.J. Kalkman, M.D., Ph.D.,
and M.J.M. Bonten, M.D., Ph.D.
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. de Smet at the Division of Periopera-
tive and Emergency Care, University Med-
ical Center Utrecht, Q04.2.313, P.O. Box
85500, 3508GA Utrecht, the Netherlands,
or at a.desmet@umcutrecht.nl.
N Engl J Med 2009;360:20-31.
Copyright © 2009 Massachusetts Medical Society.
Abstract
Background
Selective digestive tract decontamination (SDD) and selective oropharyngeal decon-
tamination (SOD) are infection-prevention measures used in the treatment of some
patients in intensive care, but reported effects on patient outcome are conf licting.
Methods
We evaluated the effectiveness of SDD and SOD in a crossover study using cluster
randomization in 13 intensive care units (ICUs), all in the Netherlands. Patients with
an expected duration of intubation of more than 48 hours or an expected ICU stay of
more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and stan-
dard care) were applied in random order over the course of 6 months. Mortality at day
28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and
topical applicat ion of tobramycin, colistin, and amphotericin B in t he orophar ynx and
stomach. SOD consisted of oropharyngeal application only of the same antibiotics.
Monthly point-prevalence studies were performed to analyze antibiotic resistance.
Result s
A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care,
1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%,
26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age,
sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation
status, and medical specialty used as covariates, odds ratios for death at day 28 in the
SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% con-
fidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively.
Conclusions
In an ICU population in which the mortality rate associated with standard care
was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points
with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials num-
ber, ISRCTN35176830.)
The New England Journal of Medicine
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Decontamination of the Digestive Tract and Oropharynx in ICU Patients
n engl j med 360;1 nejm.org january 1, 2009
21
I
nfections acquired in the intensive
care unit (ICU) are important complications
of the treatment of critically ill patients, in-
creasing morbidity, mortality, and health care
costs.
1
Reductions in the incidence of respiratory
tract infections have been achieved with the use
of prophylactic antibiotic regimens, such as se-
lective decontamination of the digestive tract
(SDD)
2,3
and selective oropharyngeal decontam-
ination (SOD).
4,5
The SDD approach
6,7
consists of prevention of
secondary colonization with gram-negative bacte-
ria, Staphylococcus aureus, and yeasts through appli-
cation of nonabsorbable antimicrobial agents in
the oropharynx and gastrointestinal tract, preemp-
tive treatment of possible infections with commen-
sal respiratory tract bacteria through systemic
administration of cephalosporins during the pa-
tient’s first 4 days in the ICU, and maintenance of
anaerobic intestinal flora through selective use
of antibiotics (administered both topically and
systemically) without antianaerobic activity.
7
De-
spite the beneficial effects of SDD on infection
rates, most studies have lacked sufficient statis-
tical power to detect effects on survival. In meta-
analyses and in three single-center, randomized
studies, the use of SDD, including a short course
of systemic antibiotics, was associated with im-
proved survival.
2,3,8-10
SOD (application of topical antibiotics in the
oropharynx only) has been postulated as an al-
ternative to SDD for the prevention of ventilator-
associated pneumonia.
4,5
Although several studies
have identified the pivotal role of oropharyngeal
colonization in the pathogenesis of ventilator-
associated pneumonia
11,12
and the efficacy of SOD
in preventing ventilator-associated pneumonia ap-
pears to be similar to the efficacy of SDD,
13,14
a
head-to-head comparison of the two strategies is
needed. Because of methodologic issues,
15,16
such
as single-center study designs with limited gen-
eralizability, and concern about increased selec-
tion of antibiotic-resistant pathogens,
17,18
the
routine use of SDD and SOD has remained con-
troversial and has not been recommended in in-
ternational guidelines.
19,20
Methods
Study Design
We performed a controlled, crossover study using
cluster randomization in 13 ICUs between May
2004 and July 2006. The participating ICUs dif-
fered in size and teaching status, reflecting all
levels of intensive care in the Netherlands. (More
information on the ICUs can be found in the Sup-
plementary Appendix, available with the full text
of this article at NEJM.org.) Since the interven-
tions included ecologic changes in the ICU, an
individualized, randomized design would have al-
lowed the treatment of a patient in one study
group to influence the treatment of a patient in
another group. Therefore, cluster randomization
was used, a nd a ll three study regimens (SDD, SOD,
and standard care) were administered to all eli-
gible patients over the course of 6 months, with
the order of regimens randomly assigned. A cross-
over design was used to control for unit-specific
characteristics. Randomization was performed by
a clinical pharmacist who was not involved in
patient care in any of the participating units and
who was unaware of t he identit y of each ICU. The
order in which the regimens were assigned was
randomly generated by computer software (De-
sign, version 2.0, a Systat Module), with alloca-
tion to the wards in consecutive order of study
start. St udy periods were preceded by washout and
wash-in periods (for more information see the
Supplementary Appendix). The antibiotics used
were purchased by t he hospitals. All aut hors vouch
for the completeness and accuracy of the data
presented.
Patients admitted to the ICU with an expected
duration of mechanical ventilation of more than
48 hours or an anticipated ICU stay of more than
72 hours were eligible. Eligibility was assessed by
physicians responsible for patient care in each unit.
Pregnant patients and patients with documented
or presumed allergy to any component of the anti-
microbial study regimens were excluded.
The study protocol was approved by the insti-
tutional review board at each participating hos-
pital. After reviewing the protocol, the boards
waived the requirement for informed consent. Per-
mission to use patient-specific medical data for
analysis was obtained from patients or their rep-
resentatives.
Inclusion rates were determined for each ICU
and each study period. Research nurses visited
each center regularly (at least twice per study pe-
riod) and evaluated up to 50 consecutively admit-
ted patients per visit (starting from a randomly
chosen date) for eligibility and study inclusion.
The SDD regimen, which consisted of 4 days
The New England Journal of Medicine
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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
The
new england journal
of
medicine
n engl j med 360;1 nejm.org january 1, 2009
22
of intravenous cefotaxime and topical application
of tobramycin, colistin, and amphotericin B in the
oropharynx and stomach, was identical to the
regimen used by de Jonge et al.
2
(for more infor-
mation see the Supplementary Appendix). The use
of antibiotics with antianaerobic activity, such as
amoxicillin, penicillin, amoxicillin–clavulanic acid,
and carbapenems, was discouraged during the
SDD period. Surveillance cultures of endotracheal
aspirates and oropharyngeal and rectal swabs were
obtained on admission and twice weekly there-
after.
SOD consisted of oropharyngeal application of
the same paste used for SDD, with surveillance
cultures of endotracheal aspirates and oropharyn-
geal swabs obtained on admission and twice
weekly thereafter; there were no restrictions on
physicians’ choices of systemic antibiotic therapy.
During the period of standard care, no surveil-
lance cultures were obtained from patients, and
there were no restrictions on physicians’ choices
of systemic antibiotic therapy.
Antibiotic resistance was monitored with the
use of point-prevalence studies on the third Tues-
day of each month. On these days, rectal swabs
and endotracheal aspirates or throat swabs for
surveillance cultures were obtained from all ICU
patients, whether or not they were included in
the study. The prevalence of specific pathogen-
resistance combinations was determined. (Details
on the processing of surveillance cultures during
SDD and SOD and on the monthly point-preva-
lence studies are available in the Supplementary
Appendix.)
Approaches to infection control (other than the
regimens being studied) did not change during
the period of the study in any of the ICUs. (Oropha-
ryngeal care is described in the Supplementary
Appendix.)
Statistical Analysis
The original analysis plan, which specified in-
hospital death as the primary end point, did not
take into account analysis of cluster effects and
failed to specify how to address imbalances in
baseline characteristics between study groups.
However, the study design did not preclude post-
randomization selection bias.
21
It was subsequent-
ly recognized that such an analysis plan failed to
conform to the Consolidated Standards for the
Reporting of Trials (CONSORT) guidelines for
reporting cluster-randomization trials.
22
Failure
to account for cluster effects (e.g., with the use of
a random-effects model) would have increased
the chance of reporting spuriously significant find-
ings, and in the event of selection bias, failure to
adjust for baseline characteristics could have led
to bias in either direction.
21,23
When confronted
with these problems, we consulted a panel of ex-
perts in the field of clinical epidemiology and
data analysis with no prior involvement in the
study and no knowledge of outcome data. The
panel unanimously recommended a revised anal-
ysis plan that overcame these problems. This plan
specified mortality at day 28 as the primary end
point (because it was thought that knowledge of
the intervention being applied at any given time
could have inf luenced discharge policies, compro-
mising the reliability of hospital discharge as an
end point) and the use of a random-effects logis-
tic-regression model to adjust for all available
covariates (the score on the Acute Physiology and
Chronic Health Evaluation [APACHE II], intuba-
tion status, medical specialt y [classif ied as surgical
or other], age, and sex).
This plan was adopted, with no further revi-
sions, and day 28 mortality data were subsequent-
ly collected through hospital and government sys-
tems (these data had not been available when the
analysis plan was formulated). In-hospital mortal-
ity, prevalence of antibiotic resistance, and dura-
tion of mechanical ventilation, ICU stay, and hos-
pital stay for surviving patients were secondary
end points. (Details on the power calculation and
statistical analysis of secondary end points are
available in the Supplementary Appendix.)
Results
Characteristics of the Patients
From May 2004 t hrough July 2006, a total of 5939
patients were enrolled in 13 participating cen-
ters: 1990 received standard care, 1904 received
SOD, and 2045 received SDD. Permission for use
of patient-specific medical data could not be ob-
tained for 12 patients (11 in the SDD group and
1 in t he standard-care group), who were excluded
from all analyses except those for unadjusted mor-
tality; 44 patients were discharged alive from the
hospital but were lost to follow-up at day 28. Over-
all, 48 patient s crossed over to a subsequent study
period. The total number of patients included in
The New England Journal of Medicine
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Decontamination of the Digestive Tract and Oropharynx in ICU Patients
n engl j med 360;1 nejm.org january 1, 2009
23
Table 1. Baseline Characteristics of the Patients.*
Characteristic
SDD
(N = 2045)
SOD
(N = 1904)
Standard Care
(N = 1990) P Value
SDD vs.
Standard Care
SOD vs.
Standard Care
SDD vs.
SOD
Age — yr† 62.4±15.9 61.4±16.3 61.4±16.2 0.04 0.88 0.05
Male sex — no. (%) 1244 (61.2) 1213 (63.7) 1220 (61.3) 0.90 0.13 0.09
Mean APACHE II score 19.6±7.8 19.5±8.2 18.6±7.9 0.00 0.001 0.63
APACHE II score ≥20 — no. (%) 969 (47.4) 897 (47.1) 837 (42.1) 0.001 0.002 0.87
Mechanical ventilation — no.(%) 1890 (92.9) 1793 (94.2) 1753 (88.1) 0.00 0.00 0.12
Reason for admission — no. (%)
Surgical 923 (45.4) 866 (45.5) 973 (48.9) 0.03 0.03 0.95
Medical 1111 (54.6) 1038 (54.5) 1016 (51.1)
Specialty of admitting physician —
no. (%)
Surgery 605 (29.7) 551 (28.9) 609 (30.6) 0.56 0.26 0.60
Cardiothoracic surgery 353 (17.4) 284 (14.9) 321 (16.1) 0.31 0.31 0.04
Neurosurgery 105 (5.2) 140 (7.4) 145 (7.3) 0.006 0.95 0.005
Neurology 124 (6.1) 144 (7.6) 128 (6.4) 0.70 0.19 0.08
Internal medicine 382 (18.8) 371 (19.5) 393 (19.8) 0.45 0.84 0.60
Cardiology 159 (7.8) 147 (7.7) 129 (6.5) 0.11 0.13 0.95
Pulmonology 152 (7.5) 138 (7.2) 127 (6.4) 0.19 0.31 0.81
Other 153 (7.5) 126 (6.6) 137 (6.9) 0.47 0.75 0.29
Unknown 1 (<1) 3 (0.2) 0 1.00 0.12 0.36
Previous or preexisting condition —
no. (%)
Cardiovascular disease 1031 (50.7) 899 (47.2) 976 (49.1) 0.31 0.25 0.03
Pulmonary disease 530 (26.1) 448 (23.5) 489 (24.6) 0.29 0.45 0.07
Diabetes mellitus 281 (13.8) 274 (14.4) 302 (15.2) 0.23 0.50 0.61
Chronic renal insufficiency 155 (7.6) 135 (7.1) 119 (6.0) 0.05 0.17 0.54
Malignant solid tumor 220 (10.8) 193 (10.1) 196 (9.9) 0.33 0.79 0.50
Metastasized cancer 71 (3.5) 56 (2.9) 64 (3.2) 0.66 0.64 0.37
Hematologic cancer 56 (2.8) 51 (2.7) 48 (2.4) 0.55 0.61 0.92
Immunodepression or AIDS 60 (2.9) 47 (2.5) 47 (2.4) 0.28 0.84 0.38
Alcohol or drug abuse 112 (5.5) 120 (6.3) 111 (5.6) 0.95 0.34 0.31
Place from which patient was admitted
to ICU — no. (%)
Emergency room 509 (25.0) 475 (24.9) 465 (23.4) 0.23 0.26 0.97
Other ICU 135 (6.6) 121 (6.4) 116 (5.8) 0.30 0.50 0.75
Hospital ward 961 (47.2) 915 (48.1) 943 (47.4) 0.80 0.80 1.00
Other 440 (21.5) 393 (20.5) 466 (23.4) 0.11 0.21 0.77
* Plus–minus values are means ±SD. Permission for use of patient-specific data could not be obtained for 11 patients in the selective diges-
tive tract decontamination (SDD) group and 1 patient in the standard-care group. AIDS denotes acquired immunodeficiency syndrome,
APACHE Acute Physiology and Chronic Health Evaluation, and SOD selective oropharyngeal decontamination.
† Values for age are based on age at the time of hospital admission.
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