Bundle of Coated Devices To Reduce Nosocomial Infections in The Intensive Care Unit: CRITIC Pilot Randomized Controlled TrialAnn Am Thorac Soc 2020

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Bundle of Coated Devices to Reduce Nosocomial Infections in the Intensive Care Unit: CRITIC
Pilot Randomized Controlled Trial
Fernando G Zampieri1,2, Neymar Elias de Oliveira3, Antonio Paulo Nassar Jr4, Airton Leonardo de
Oliveira Manoel5, Cintia Grion6, Fábio H Lacerda7, Israel Maia1,8, Marlus Thompson9, Thiago
Simões Giancursi 10, Priscilla de Aquino Martins11, Thiago Lisboa1,12, Tamiris Abait1, Lucas P
Damiani1, Flávia R Machado13, Alexandre B Cavalcanti1 for the BRICNet
1. Research Institute, HCor, São Paulo, Brazil

2. Center for Epidemiological Research, University of Southern Denmark, Odense, Denmark
3. Hospital de Base, São José do Rio Preto, Brazil
4. AC Camargo Cancer Center, São Paulo, Brazil
5. Hospital Paulistano, São Paulo, Brazil
6. Hospital Evangélico, Londrina, Brazil
7. Hospital da Luz, São Paulo, Brazil
8. Hospital Nereu Ramos, Florianópolis, Brazil
9. Hospital Evangélico Cachoeiro de Itapemirim, Cachoeiro do Itapemerim, Brazil
10. Hospital Universitário do Oeste do Paraná, Cascavel, Brazil
11. Hospital Estadual Jayme dos Santos Neves, Serra, Brazil
12. Santa Casa de Porto Alegre, Porto Alegre, Brazil
13. Hospital São Paulo, Federal University of São Paulo, Brazil
Corresponding Author:
Fernando G Zampieri, Research Institute, HCor, São Paulo, Brazil
Address: Rua Abílio Soares 250, 12th floor
e-mail: fzampieri@hcor.com.br
Running Title: CRITIC Pilot study
Author Contributions: FGZ, ABC, LPD: Wrote the initial proposal, obtained funding, drafted that
manuscript. FGZ, LPD, TCL: Performed statistical analysis. Remaining authors: Randomized
patients and collected data, reviewed the manuscript for intellectually important content. All
authors approved the final submitted version.
Conflicts of Interest: This study was sponsored by Bactiguard, Sweden, the manufacturer of the
devices used for the coated devices group. The grant for the trial was received by FGZ and ABC.
All other authors report no conflicts of interest.
Role of the Funding Source: This is an investigator-initiated trial. The investigators (FGZ, ABC)
proposed the trial in its form to the sponsor (Bactiguard, Sweden). The sponsor reviewed and
agreed on the design and endpoints. The sponsor was not involved in any aspect of the trial
other than funding and supplying of devices and did not have access to individual patient data
nor on the decision to publish or not the results. As per contract agreement, the sponsor
received a version of this manuscript before submission and agreed with its contents.
ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

Copyright © 2020 by the American Thoracic Society
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Keywords: coated devices; healthcare-associated infections; ventilator-associated pneumonia;

sepsis
List of Participating (Collaborators at each site):

Hospital de Base (Livia Pereira Miranda Prado; Ricardo Costa Nuevo); AC Camargo Cancer
Center (Silvana Soares dos Santos); Hospital Paulistano; Hospital Evangélico; Hospital da Luz
(Eliana Viera do Nascimento); Hospital Nereu Ramos (Cássio Zandonai); Hospital Evangélico
Cachoeiro de Itapemirim; Hospital Universitário do Oeste do Paraná; Hospital Estadual Jayme
dos Santos Neves (Thaís Fonseca e Gobbo, Érica Juliane da Silva Pereira, Christiane Tokiko
Marçal Uka);Santa Casa de Porto Alegre; Hospital São Paulo (Maria Aparecida de Souza)

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Abstract
Rationale: Coated devices may reduce biofilm formation and reduce occurrence of device-
related infections in critically ill patients. A bundle of coated devices (endotracheal tube - ETT,
central venous catheter - CVC, urinary catheter - UC) simultaneously inserted may optimize
benefits of coated devices in most severe patients.
Objectives: To assess feasibility of a randomized controlled trial on simultaneous insertion of
gold-silver-palladium coated devices versus uncoated devices in severely ill patients required
sequential insertion of all three devices (ETT, CVC and UC) for support in intensive care unit
(ICU).
Methods: Multi-center randomized controlled pilot trial. Patients that required simultaneous
insertion of ETT, CVC and UC were randomized to coated versus uncoated devices which were
used as necessary for up to 28 days. Primary endpoint was feasibility, defined as the trial being
able to enroll enough sample size for its secondary primary endpoint (estimating sepsis
incidence in this population) in less than one year and estimating the number of admitted
patients that require simultaneous insertion of all three devices. Secondary endpoints included
incidence of sepsis and device-associated infections (ventilator associated pneumonia [VAP],
catheter related bloodstream infection [CRBI] and catheter related urinary tract infection
[CRUTI]) within each group and number of days alive free of antibiotics during ICU stay. All
events were adjudicated.
Results: 103 patients (48 coated and 55 uncoated group) were included in the per-protocol
analysis. Inclusion period was eight months. There were 13 septic events in each group (26 in
total), with an approximate incidence of sepsis of 32.3 (95% credible interval 22.4-44.9) per 100

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patient-days. Overall incidence of VAP, CRUTI and CRBI were 15.2 (95% credible interval 7.8-
26.4), 6.3 (95% credible interval 2.4-13.7), and 7.9 (95% credible interval 3.6-15.1) per 1,000
patient-days, which were not statistically different between groups. Patients in the coated
group had more days alive free of antibiotics in the ICU (28.97 days versus 19.62 per 100
patient-days, mean ratio of 1.48, 95% credible interval 1.16-1.89).
Conclusion: Use of a bundle of coated devices as initial management of severely ill patients is
feasible. Coated devices may be associated with more days alive and free of antibiotics.
Clinical trial registered with ClinicalTrials.gov (NCT03868241)

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Critically ill patients frequently require invasive devices in order to receive appropriate
monitoring and/or support to organ failure. Endotracheal tubes (ETT), urinary catheters (UC)
and central venous catheters (CVC) are among the most used devices in intensive care medicine
[1-4]. Despite lifesaving, invasive devices represent a rupture of the natural protections of the
human body to microorganisms and are an important risk factor for infection [5,6]. In fact,
infection related to the extensive use of invasive devices represents an important public health
issue since it increases costs, increases antibiotic use (contributing to the emergence of multi-
drug resistant pathogens) and may be related to higher mortality [7,8]. While the most obvious
way to decrease infection related to invasive devices is through avoiding their use, invasive
device may be necessary in the most severe patients. Therefore, strategies that could reduce
infection related to invasive devices must be sought [7,9].
The development of coated devices that can inhibit bacterial adhesion to the invasive
device has been suggested to reduce biofilm formation and the development of infection
[10,11]. Despite their use, evidence for a clear benefit are lacking. Some studies using gold-
silver-palladium coated devices reported a positive effect in reducing device-related infection
[11], while other reported null results for short term catheterization [12]. However, the
feasibility of a strategy involving simultaneous insertion of coated-only devices in critically ill
patients has not been studied so far. Theoretically, benefits of coating would be maximized if
the highest possible number of devices inserted were coated. However, the simultaneous
insertion of ETT, CVC and UC may be challenging since many patients receive one or more of
these devices outside the intensive care unit (ICU) setting, such as emergency room or wards
[13].

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We therefore performed a pilot feasibility randomized controlled trial involving coated
devices (ETT, CVC and UC covered by an alloy of gold-silver-palladium) in severely ill patients
admitted to the ICU to confirm the feasibility of a bundle intervention (simultaneous insertion
of all three coated devices for patients who needed it) and to obtain estimates of incidence of
events, including sepsis, ventilator associated pneumonia (VAP), catheter related bloodstream
infection (CRBI) and catheter related urinary tract infection (CRUTI) for larger trials.
Methods
Study Design
Pilot, single-blinded, randomized controlled trial on 12 ICUs in Brazil.
Inclusion and Exclusion Criteria
All patients admitted to the intensive care unit which would require simultaneous insertion of
all three devices (endotracheal tube, central venous catheter and urinary catheter) due to
illness severity as defined by the attending physician were considered for enrollment. Patients
admitted with indication for urgent surgery, including organ transplantation, could be enrolled
if they were planned to remain on mechanical ventilation after the procedure. In this specific
case, patients could receive the devices in the operating theater. We excluded patients
admitted to the intensive care unit for more than 48 hours or admitted in the hospital for more
than seven days; patients already on use of any of the invasive devices (endotracheal tube,
central venous catheter or urinary catheters) before randomization and absence of the

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intention to exchange the devices; age lower than 18 years; known pregnancy; known allergy to
gold, silver and palladium; patients with conditions where subclavian or jugular routes were
considered not advisable (severe chronic pulmonary obstructive disease and irradiation and/or
thrombosis in site selected for catheter insertion); suspected or confirmed brain death; and
patients previously enrolled in the study. All other aspects of care, including the decision to use
other devices (such as dialysis catheters and invasive arterial lines) were left at the discretion of
the attending physician.
Randomization and Trial Intervention
Patients were randomized at 1:1, blocks of two, to receive coated devices (gold-silver-palladium
coated devices, Bactiguard ®) or shelf (uncoated) devices available at participating sites.
Randomization was stratified at sites and according to suspicion of sepsis at randomization and
performed electronically using a secure web-based system by the investigator at the site.
Informed consent form was obtained from the patient or their legal representative. Due to
illness severity and need for immediate intervention, patients could be randomized before
informed consent form; in this scenario, consent form was obtained from patient of their legal
representative as soon as possible. Ethical approval was obtained at the coordinating site and
at all participating sites. After randomization, we recommended that all three devices (ETT, CVC
and UC) were inserted as soon as possible in accordance with main inclusion criteria. Patients
should use devices according to randomization arm up to 28 days, as needed. If device
exchange was needed, the same type of device should be used.

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Study Endpoints and Outcome Measurements
The primary endpoint of this study was feasibility. Feasibility was defined as being able to finish
enrollment for the study´s secondary primary endpoint which was estimating nosocomial sepsis
incidence (up to ICU discharge or death, truncated at 28 days) in this population of very
severely ill patients. We were also interested in other markers of feasibility, such as number of
participants recruited in each center during the trial and the number of participants admitted to
participating intensive care units that required simultaneous insertion of endotracheal tube,
central venous catheter and urinary catheter. Sepsis was defined as an increment in Sequential
Organ Failure Score (SOFA) [14] of two points over baseline coupled with an introduction of
new antimicrobial scheme due to infection suspicion [15]. De-escalation of antibiotic treatment
or culture-guided changes in antibiotic treatment were not considered as new sepsis episode.
We included several secondary endpoints which should all be considered exploratory due to
the pilot nature of this study, including:
1. Incidence of sepsis between groups, following the same definition
2. Incidence of ventilator-associated pneumonia (VAP), central venous catheter-related
bloodstream infection (CRBSI) and urinary catheter-related infection (CRUTI, truncated
at 28 days
3. Rate of composite endpoint of ventilator-associated pneumonia and/or central venous
catheter-related bloodstream infection and/or urinary catheter-related infection
truncated at 28 days
4. Number of days alive and without antibiotics, truncated at 28 days in the ICU
5. ICU, hospital, and 28 days mortality, truncated at hospital discharge, after enrollment

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Secondary endpoints of occurrence of VAP, CRBSI and/or CRUTI were adjudicated by
two physicians that were blinded to treatment group. Adjudicators had access to case report
form inform information, including results of cultures and imaging tests, when available.
Diagnosis criteria are discussed in the electronic supplementary material (ESM) which includes
study protocol (Appendix 1) and statistical analysis plan (Appendix 2). Coated devices are
indistinguishable to inspection on chest radiography. Only ETT without subglottic suctioning
port were used on both groups.
Statistical Analysis
The statistical analysis plan was developed and uploaded to ClinicalTrials.gov before end of
study enrollment and follow-up period and is also available in the ESM. The original protocol
considered an intention-to-treat analysis which was changed before study completion to a per
protocol analysis since patients that would not receive the intervention were not be at risk for
one of the study’s primary endpoints (occurrence of sepsis in patients that require all three
devices); we provide the intention-to-treat results in the ESM. Sample size was set at 100
patients; this sample size was defined to be able to inform 95% credible intervals with an
interval of approximately 3 events per 100 patient-days overall (4 events per patient-day per
group) based on Bayesian Poisson regression model with intercept parameter assuming non-
informative normal prior centered in 8 event per 100 patient-days incidence rate (normal prior
N~(e0.08,5)). This prior was used for the secondary primary endpoint of estimating sepsis
incidence in the population and for the secondary endpoints of comparing incidence of sepsis,
VAP, CRBSI and CRUTI between groups. This prior has a large standard deviation, giving virtually

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no importance to its average choice, which was established assuming a slightly worse scenario
than was described for a European population of approximately 5 events per 100 patient-days
[8]. Results for incidence are reported as cases per 100 patients at risk-day for incidence
outcomes and compared using relative risks with their respective 95% credible intervals (CrI).
Mortality was compared between groups using a Bayesian regression model with flat priors and
reported as relative risks (obtained through simulation from the model´s odds ratio) and 95%
credible intervals. We reported both unadjusted and baseline SOFA adjusted results (see ESM
for details). Number of days alive without antibiotics was defined as number of days patients
were alive inside the ICU without use of antibiotics; patients that died in the ICU received zero
days alive and free of antibiotics if they received at least one dose of antibiotics during ICU stay,
otherwise they received the number of days they spent in the ICU until death. For this analysis,
the ratio of the mean number of days alive and free of antibiotics is reported. The only planned
subgroup was presence/absence of sepsis at enrollment.
Analyses were conducted using R Project Version 3.6.0 [16] with brms package [17]. This
report follows the CONSORT (CONsolidated Standards of Reporting Trials) 2010 guidelines [18]
(supplied in the ESM Appendix 3).
Results
Overall Results and Primary Endpoint
A total 127 patients were screened and 118 (93%) were randomized at 11 sites from April until
November 2019 (8 months). The study flowchart is shown in Figure 1, overall patient features

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are shown in Table 1, and the number of patients randomized at each site are shown in
Supplementary Table 1 (sTable 1). Fifteen patients (13%, 11 in the coated group and four in the
uncoated group) did not receive the intervention and were not included in the per protocol
analysis for reasons shown in flowchart. Most patients were enrolled after medical admission
and were severely ill (mean SOFA score of approximately 6 and average Simplified Acute
Physiology Score 3 – SAPS 3 [19] – of 60 points). Sepsis was suspected in over 80% of all
included patients. The total number of patients-days on follow-up was 1,458 in hospital and
985 patient-days for ICU stay. Information on follow-up time and number of days in use of each
device are shown in Table 2. There were 13 septic events in each group (26 in total), with an
approximate incidence of sepsis of 32.3 (95% CrI 22.4-44.9) per 1,000 patient-days in the whole
population.
Secondary Endpoints
Incidence of sepsis was 37.8 (95% CrI 22.7 – 56.8) and 26.9 (95% CrI 15.4 – 43.0) for coated and
uncoated devices, respectively. The number of suspected events were 58 VAP, 7 CRUTI and 14
CRBSI (31, 3 and 5 for coated and 27, 4 and 9 for uncoated devices, respectively). After
adjudication, the number of confirmed events were 10 VAP, 5 CRUTI and 7 CRBSI (6, 2 and 2 for
coated and 4, 3 and 5 for uncoated devices, respectively – Table 2). Overall incidence of VAP,
CRUTI and CRBI were 15.2 (95% CrI 7.80-26.4), 6.3 (95% CrI 2.4-13.7), and 7.9 (95% CrI 3.6-15.1)
per 1,000 patient-days. Patients in the coated group had more days alive free of antibiotics in
the ICU (28.97 days versus 19.62 per 100 patient-days, mean ratio of 1.48, 95% CrI 1.16-1.89).
Crude (unadjusted) and SOFA-adjusted secondary outcomes according to study arm are shown

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in Table 3. Cumulative mortality is shown in Figure 2A. Cumulative incidence plot for occurrence
of sepsis and mortality over time is shown in Figure 2B.
Results for the subgroup analysis of patients admitted with sepsis is shown in the ESM
(sTable 2). All device-related infections occurred in the patients admitted with sepsis suspicion.
There were no compliance issues after randomization, including crossovers. Reasons for device
exchange, when needed, are shown in sTable 3. No adverse events were reported.
Results considering the intention-to-treat approach are shown in the ESM, sTable 4,
together with information on excluded patients. Results in the intention to treat were similar to
the modified intention-to-treat.
Discussion
In this pilot feasibility study of use of bundle of coated devices, we obtained important insights
on feasibility and occurrence of important outcomes to guide future trials. This study
distinguishes itself from previous evaluations of coated devices by selecting a higher risk
population and by applying multiple coated devices at the same time in a bundle-fashion
approach, which could theoretically maximize benefits of coating. We were able to randomize
most patients that fulfilled inclusion criteria during study period; however, a significant number
of exclusions after randomization occurred. In a per protocol analysis, there were numerically
less CRUTI and CRBSI in the coated group but more VAP. Credible intervals were wide making
definitive conclusions impossible. Patients in the coated group had more days alive in the ICU
without use of antibiotics.

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Estimates of incidence of device-related infections in this trial were higher than previous
reports, especially for VAP. One large report from China [9] suggested lower VAP rates, as well
as Brazilian quality improvement trial [20]. Specifically, the VAP rate estimates were of the
magnitude of 3 times higher than other reports [20]. Rates for CRUTI and CRBSI were also
higher than most reports [20-22]. This suggests that the subgroup of patients included on this
study are at extremely high risk of device-related complications when compared with general
population of critically ill. Estimating incidence of sepsis, an important endpoint due to its
associated morbidity, mortality, and costs [23,24], is more cumbersome and there are few
reports available on sepsis incidence in critically ill [8,9]. The results obtained by this pilot study
were lower than an older European study [8] but similar to estimates provided by a point-
prevalence study (SPREAD study [23]) in Brazil. SPREAD study estimated sepsis incidence in the
ICU at 36.3 per 1,000 patient-days using Sepsis 2 definition while we found a very similar value
(32.3, 95% CrI 22.4-44.9 per 100 patient-days) using a different definition (Sepsis 3) [15,23].
Taken together, these results suggest that patients that require simultaneous insertion of ETT,
CVC and UC are at exceedingly high risk for device-related events and constitute an important
group for future trials. This may be due to prolonged duration of device use in these patients,
which potentiate occurrence of infectious complications.
Results for occurrence of events and mortality between groups should be discussed with
caution due to low number of events. There were numerically less CRUTI and CRBSI but more
VAP in coated devices group. Coupled with a numerically lower mortality, the net result was
more days alive in the ICU free of antibiotics in the coated group. This was the only comparison
between groups were credible intervals did not cross the unit, suggesting a benefit of coated

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devices (mean ratio of 1.48, 95% CrI 1.16 - 1.89). This endpoint is particularly interesting
because it combines mortality with antibiotic use, which are both relevant endpoints. In fact,
the sole reduction of antibiotic use may be enough to justify coated devices adoption
considering that costs are only slightly higher for coated devices and that antibiotics represent
an important part of daily ICU cost [25]. Whether this finding is due to chance, real or may
derive from cognitive bias at the center level (including lowering suspicion of infections in
patients with coated devices) can only be answered with larger studies with blinding and in a
larger number of ICUs. Results for the intention-to-treat analysis were mostly similar to the
mITT. Taken our findings together, we believe that a larger trial would be feasible and that days
alive and free of antibiotic therapy would be an interesting primary endpoint that encompasses
both mortality and antibiotic use in a single measurement.
This study has several limitations that should be interpreted in the context of a pilot
study. The large proportional number of patients excluded after randomization represents an
important barrier for future individual randomization studies and may have introduced bias in
the comparison of the incidence of infections between groups due to a larger number of
exclusions in coated (11) than in the uncoated group (4). After excluding patients that refused
to participate, there were 7 exclusions in the intervention group and 4 in the control group; of
those, 4 represented the exclusion of patients that did not required devices (2 canceled
surgeries and 2 patients that rapidly improved) in the coated group. It is conceivable that if
those patients with lower illness severity were kept in an intention-to-treat analysis results
would have been even more biased towards favoring coated devices. Additionally, patients that
did not receive the devices (such as ETT, for example) were not at risk of device-associated

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infection. However, caution is warranted when interpreting our results, especially because we
cannot exclude that exclusions were related to being randomized to coated devices in the
context of an unblinded trial, specially consent refusals. An additional important limitation is
use of uncoated devices for dialysis catheters and arterial lines in both groups.
Conclusion
Use of a bundle of coated devices as initial management of severely ill patients is feasible and
may be tested in a larger trial. Coated devices may be associated with more days alive and free
of antibiotics, although these findings should be preliminary in the context of a pilot study.
Acknowledgments
The authors are thankful for patients and their families who agreed in participating in this study
and to all site members for their support.

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Figure Legends
Figure 1: Study Flowchart
Figure 2: (A) Cumulative mortality for both groups over time; (B) Cumulative mortality and
occurrence of sepsis for both groups.

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Table 1: Overall patient characteristics
Coated Devices Control (n=55) Total (n=103)

(n=48)
Age, years, mean ± SD 55.3 ± 15.7 (n=48)58.6 ± 15.8 (n=55) 57.1 ± 15.7 (n=103)
Female sex, n (%) 24/48 (50%) 23/55 (41.8%) 47/103 (45.6%)
Type of admission
Medical 34/48 (70.8%) 41/55 (74.5%) 75/103 (72.8%)
Urgent Surgery 14/48 (29.2%) 14/55 (25.5%) 28/103 (27.2%)
SOFA score, mean ± SD 6.1 ± 3.3 6.5 ± 3.1 6.3 ± 3.2
SAPS3 score, mean ± SD 55.3 ± 16.7 65.3 ± 22.3 60.6 ± 20.4
Infection on admission, n (%)
Any infection 23/48 (47.9%) 28/55 (50.9%) 51/103 (49.5%)
Respiratory 17/48 (35.4%) 17/55 (30.9%) 34/103 (33%)
Blood stream 0/48 (0%) 1/55 (1.8%) 1/103 (1%)
Urinary Tract Infection 1/48 (2.1%) 3/55 (5.5%) 4/103 (3.9%)
Soft tissue 0/48 (0%) 0/55 (0%) 0/103 (0%)
Central Nervous System 0/48 (0%) 1/55 (1.8%) 1/103 (1%)
Others 2/48 (4.2%) 4/55 (7.3%) 6/103 (5.8%)
Undefined 3/48 (6.2%) 2/55 (3.6%) 5/103 (4.9%)
Suspected sepsis at admission, 39/48 (81.2%) 43/55 (78.2%) 82/103 (79.6%)
n (%)*
Antibiotic use, n (%) 32/48 (66.7%) 40/55 (72.7%) 72/103 (69.9%)
Comorbidities, n (%)
Diabetes 8/48 (16.7%) 13/55 (23.6%) 21/103 (20.4%)
Chronic Renal Failure 7/48 (14.6%) 10/55 (18.2%) 17/103 (16.5%)
Heart failure 2/48 (4.2%) 4/55 (7.3%) 6/103 (5.8%)
AIDS 1/48 (2.1%) 6/55 (10.9%) 7/103 (6.8%)
Solid organ transplantation 1/3 (33.3%) 3/4 (75%) 4/7 (57.1%)
Hematologic stem cell 2/3 (66.7%) 1/4 (25%) 3/7 (42.9%)
Rheumatological disease 2/48 (4.2%) 0/55 (0%) 2/103 (1.9%)
Prior corticosteroids use, n(%) 7/48 (14.6%) 6/55 (10.9%) 13/103 (12.6%)
* defined as suspected infection (which could or could not be confirmed later) plus a SOFA
score of at least two. This was the stratification variable.

Page 21 of 47
Table 2: Follow-up information, density of device use and raw secondary outcomes
Coated devices (n=48) Uncoated devices (n=55)
Hospital-Days Follow-up 700 758

Mean (Standard Deviation) 14.58 (10.43) 13.8 (9.08)
Median [Quartiles] 13 [5 - 28] 13 [8 - 20]
ICU days follow-up 468 517
Mean (Standard Deviation) 9.75 (8.09) 9.4 (6.34)
Median [Quartiles] 6 [4 - 15] 9 [5 - 11]
Days in the ICU in use of:
Urinary tract catheter 326 (69.6%) 425 (82.2%)
Mechanical Ventilation 296 (63.2%) 339 (65.6%)
Central Venous Catheter 400 (85.5%) 462 (89.4%)
Number of changes in antimicrobial 113 116
treatment
Patient with at least one episode*, n
(%)
CAUTI or VAP or CRBSI 8 (16.7%) 9 (16.4%)
CAUTI 2 (4.2%) 3 (5.5%)
VAP 6 (12.5%) 4 (7.3%)
CRBSI 2 (4.2%) 5 (9.1%)
Sepsis, n (%) 13 (27.1%) 13 (23.6%)
Vital status
ICU Mortality 17 (35.4%) 22 (40.0%)
Hospital mortality 20 (41.7%) 27 (49.1%)
28-day mortality 18 (37.5%) 24 (43.6%)
28-day sepsis or death 25 (52.1%) 31 (56.4%)
* episodes confirmed after adjudication

Page 22 of 47
Table 3: Secondary endpoints
Absolute difference Adjusted* relative

Endpoints Coated devices Uncoated devices (95% CrI) Crude relative risk risk
(n=48) (n=55) (95% CrI) (95% CrI)
Days alive at the ICU free of
29.0 [24.5 - 34.1] 19.6 [16.2 - 23.6] 9.4 [3.6 – 15.4] 1.48 [1.16 - 1.89] 1.41 [1.09 - 1.81]
antibiotics (per 100 patients-day)
Infection rates (per 1,000 patients-
day)
20.5 [10.5 –
CRUTI or VAP or CRBSI‡ 22.6 [11.7-38.5] -2.0 [-19.9 – 17.7] 0.92 [0.39 – 3.85] 0.92 [0.38 - 2.17]
35.7]
CRUTI† 5.6 [1.0 – 16.9] 6.6 [1.7 – 16.9] -1.2 [-13.1 – 11.5] 0.87 [1.2 – 48.0] 0.88 [0.11 - 5.47]
19.1 [7.50 –
VAP† 10.9 [3.70 – 25.8] 8.4 [-9.9 – 29.8] 1.78 [0.46 – 6.59] 1.50 [0.39 - 6.00]
38.8]
CRBSI† 4.5 [0.8 – 15.2] 10.3 [3.5 – 22.4] -5.8 [-18.8 – 6.5] 0.45 [0.7 – 20.9] 0.44 [0.06 - 2.17]
37.8 [22.7 –
Sepsis rate (per 100 patients-day) 26.9 [15.4 – 43.0] 10.5 [-11.5 – 34.6] 14.1 [7.0 – 27.9] 1.30 [0.63 - 2.68]
56.8]
Patient with at least one episode,
proportion
CRUTI or VAP or CRBSI 16% [8% - 28%] 16% [8% - 27%] 0% [-14% – 16%] 1.02 [0.42 – 2.70] 1.00 [0.38 – 2.50]
CRUTI 4% [1% – 11%] 5% [1% - 12%] -1% [-9% – 7%] 0.74 [0.09 - 4.57] 0.71 [0.01 - 4.50]
VAP 12% [5% - 23%] 7% [2% - 15%] 5% [-6% – 17%] 1.77 [0.51 - 7.32] 1.75 [0.50 – 7.01]
CRBSI 3% [1% – 11%] 9% [3% - 18%] -5% [-20% – 11%] 0.42 [0.06 - 2.06] 0.40 [0.02 – 1.80]
Sepsis, n (%) 27% [16% - 40%] 23% [13% - 35%] 4% [-13% – 20%] 1.15 [0.57 - 2.26] 1.29 [0.61 - 2.87]
Vital status
ICU Mortality 35% [23% - 49%] 40% [28% - 53%] -4% [-22% - 14%] 0.89 [0.53 - 1.44] 0.86 [0.48 - 1.55]
Hospital mortality 42% [29% - 55%] 49% [36% - 62%] -7% [-26% - 11%] 0.85 [0.54 - 1.31] 0.73 [0.41 - 1.25]
28 day mortality 37% [25% - 52%] 43% [31% - 57%] -6% [-25% - 13%] 0.85 [0.52 - 1.36] 0.85 [0.48 - 1.41]
(*) Model adjusted for baseline SOFA score; † only days in use of the device were considered when calculating infection rate; ‡ number of days in the
ICU were considered for this estimate

Page 23 of 47
127 Screened
Not randomized (9)
7 patients more than 48 hours in ICU

or more than 7 days in hospital
1 patient had anticipated issues for

catheter insertion
1 patient missed (electronic CRF

offline)
118 Randomized
Allocated to intervention (n=59) Allocated to control (n=59)
Received intervention (n=48) Received intervention (n=55)
Did not receive intervention (n=11): Did not receive intervention (n=04):
 4 denied consent to participate  2 denied consent to participate
 7 did not use trial devices:  2 did not use trial devices:
o 2 urgent surgery cancelled ◦ 1 already using habitual device
o 2 clinical improvement ◦ 1 transitioned to comfort care only and was

not intubated
o 1 already using habitual device
o 1 conventional CVC was inserted
o 1 died before device insertion
Lost to follow up (n=0) Lost to follow up (n=0)
Analyzed (n=48) Analyzed (n=55)
 Excluded from analysis (n=11) because did not use trial devices  Excluded from analysis (n=04) because did not use trial devices
Page 24 of 47

Page 25 of 47
Online Data Supplement
Bundle of Coated Devices to Reduce Nosocomial Infections in the Intensive Care Unit: CRITIC Pilot
Randomized Controlled Trial
Fernando G Zampieri, Neymar Elias de Oliveira, Antonio Paulo Nassar Jr, Airton Leonardo de Oliveira Manoel,
Cintia Grion, Fábio H Lacerda, Israel Maia, Marlus Thompson, Thiago Simões Giancursi, Priscilla de Aquino
Martins, Thiago Lisboa, Tamiris Abait, Lucas P Damiani, Flávia R Machado, Alexandre B Cavalcanti for the
BRICNet
CRITIC
Coated devices to decRease InfecTion in the ICu
Pilot Randomized controlled trial assessing the efficacy of a bundle of coated devices to reduce nosocomial
infections in the ICU
Electronic Supplementary File

Page 26 of 47
Appendix 1 – Study Protocol
PROTOCOL FOR CRITIC TRIAL
Coated devices to decRease InfecTion in the ICu
Randomized controlled trial assessing the efficacy of a bundle of coated devices to reduce nosocomial infections in
the ICU
PILOT STUDY
v 2.1
Fernando G Zampieri, MD, PhD

Alexandre B Cavalcanti, MD, PhD
Research Institute, HCor-Hospital do Coração, São Paulo, Brazil
Sponsor:
Bactiguard AB, Tullinge, Sweden
Sponsor representative:
Dorota Johansson, MSc, PhD

Page 27 of 47
Principal Investigator Endorsement Page
I, the undersigned, am responsible for the conduct of the study: “CRITIC: Coated devices to decRease InfecTion in the
ICu Randomized controlled trial assessing the efficacy of a bundle of coated devices to reduce nosocomial infections in
the ICU”, Clinical Investigational Plan/Protocol (CIP), and agree to the following:
 I understand and will conduct the clinical trial according to the CIP, any approved amendment to CIP, the ISO
14155:2011, the Declaration of Helsinki and all applicable national laws.
 I will not deviate from the CIP without prior written permission from the Sponsor and prior review and written
approval from the Ethical Committee, except where necessary to prevent any immediate danger to patients.
 I have sufficient time to properly conduct and complete the trial within reasonable time, and I have an adequate
number of qualified staff available and adequate facilities for the foreseen duration of the trial in order to
conduct the trial safely and properly.
 I will ensure that any persons at my site who are involved in the study are adequately trained regarding to their
responsibilities toward Bactiguard AB and the CIP. In the case that I delegate any of my study responsibilities, I
will notify Sponsor immediately.
Principal Investigators Signature Date
______________________________ ____________________
Alexandre Biasi Cavalcanti Date
Director
HCor-Research Institute
______________________________ ____________________
Fernando G Zampieri Date
Research Physician
HCor-Research Institute
Sponsors Signature
__________________________________ ____________________
Dorota Johansson, MSc, PhD Date
Clinical and Research Director
Bactiguard
Statistician Signature
__________________________________ ____________________
Lucas Petri Damiani Date
Statistical Department; HCor-Research Institute

Page 28 of 47
Synopsis
Title A pilot study to assess the use of Coated devices to decRease InfecTion in the ICu (CRITIC Study)
Design Pilot explanatory, randomized, open label, controlled trial. Critically ill patients which will demand
placement of invasive devices for organ support (endotracheal tube - ETT, central venous catheter -
CVC and urinary Foley catheter – UC) will be randomized 1:1 to receive coated (Bactiguard®) or
habitual (non-coated) devices.
Bias control Allocation concealment with web-based randomization stratified by center and by presence of
sepsis at admission. Intention-to-treat analysis.
Primary objectives To assess feasibility and potential recruitment rate for a larger trial using coated (Bactiguard®)
devices in critically ill patients. Additionally, to establish the incidence of ICU-acquired sepsis in
the most severe critically ill patients in Brazil.
Inclusion Criteria All patients admitted to the ICU which will require simultaneous insertion of all three devices
(ETT, CVC and UC) due to illness severity as defined by the attending physician
Exclusion criteria Any of the criteria bellow:
1. Patients admitted to the ICU for more than 48 hours or admitted in the hospital for more than
seven days
2. Presence of any of the invasive devices (ETT, CVC or UC) before randomization and absence
of the intention to exchange the devices. For example, patients with previous CVC may be
included if they will require device exchange.
3. Age < 18 years
4. Known pregnancy
5. Known allergy to gold, silver and palladium
6. Suspected or confirmed infection or sepsis related to the device

7. Severe chronic obstructive pulmonary disease or previous inflammatory occurrence/thrombosis
in the insert site of the device
8. Suspected or confirmed brain death

9. Previously enrolled in the study
Study treatments Patients which will require invasive devices (ETT, CVC and UC) due to illness severity will be
randomized to receive coated (Bactiguard®) or non-coated devices. These devices will be used
until they are no longer necessary; in case of need of device exchange due to malfunctioning or
other complications, the same type of device will be used until ICU discharge or 28 days after
randomization
Objectives Primary objectives:
1. To assess feasibility of the simultaneous insertion of coated and uncoated ETT, CVC and UC
in recently admitted critically ill patients without previous invasive devices in a randomized
controlled trial.
2. To determine how many patients admitted to the ICU will require CVC, ET and UC insertion
and, of those, how many will develop sepsis from 48 hours after randomization until day 28
after randomization or until ICU discharge.
Secondary objectives (clinical outcomes):
1. Occurrence of nosocomial sepsis up to 28 days after randomization in control (uncoated
devices) versus intervention (coated devices) groups
2. Combined endpoint of any of the following infections occurring during ICU stay: Ventilator
associated pneumonia (VAP), Catheter related bloodstream infection (CRBSI) and Catheter
associated urinary tract infection (CAUTI)
3. Occurrence of each nosocomial infection individually (VAP, CRBSI, CAUTI) in both groups
and rates of positives cultures at each site

Page 29 of 47
4. Antibiotic-free days until 28 days

5. ICU and Hospital mortality in both groups
Data monitoring On-site monitoring
Central statistical monitoring and quality assurance
Safety Safety and tolerability will be assessed by monitoring serious adverse events
Sample Size A total of 100 patients from 10 ICUs in Brazil
Statistical Analysis All analyses will be based on the intention-to-treat principle. A secondary per protocol analysis is
planned. Primary endpoints will be assessed using descriptive statistics. Binary secondary outcomes
will be compared through relative risks, 95% CIs, and chi-square tests.
A priori defined Subgroup analysis according to presence or absence of sepsis at admission
subgroups

Page 30 of 47
Introduction
Critically ill patients frequently require invasive devices to receive appropriate monitoring and/or support to
organ failure (Polderman, Intensive Care Med 2002). Endotracheal tubes (ETT), urinary Foley catheters (UC) and central
venous catheters (CVC) are among the most used devices in intensive care medicine (Polderman, Intensive Care Med
2002; Nicolle, Antimicrob Resist Infect Control 2014). Despite lifesaving, invasive devices represent a rupture of the
natural protections of the human body to microorganisms and are an important risk factor for infection (Salomao, Rev
Panam Salud Publica 2008). In fact, infection related to the extensive use of invasive devices represents an important
public health issue since it increases costs, increases antibiotic use (contributing to the emergence of multidrug resistant
pathogens) and may be related to higher mortality (Apostolopoulou, Am J Crit Care 2013). While the most obvious way
to decrease infection related to invasive devices is through avoiding their use, invasive device may be necessary in the
most severe patients. Therefore, strategies that could reduce infection related to invasive devices must be sought
(Apostolopoulou, Am J Crit Care 2013; Hu, Am J Infect Control 2013).
Infection related to invasive devices may be related to a sequential process that involves bacteria adhering to the
surface of the devices, proliferation (colonization and biofilm formation) and sequential infection (Gil-Perotin, Crit Care
2012; Yousif, Adv Exp Med Biol 2015; Delcaru, Pathogens 2016). In the lungs, for example, biofilm formed on the ETT
surface may detach and migrate to the lungs, representing an important pathogenic source of infection (Gil-Perotin, Crit
Care 2012). While this mechanism may not be the only responsible for infection in patients with invasive devices, it has
been implicated in the pathogenesis of infections related to ETT (both ventilator-associated tracheobronchitis – VAT -
and ventilator-associated pneumonia – VAP), CVC (catheter related bloodstream infection - CRBSI) and urinary tract
(catheter associated urinary tract infection - CAUTI) (Gil-Perotin, Crit Care 2012; Yousif, Adv Exp Med Biol 2015;
Delcaru, Pathogens 2016). The development of coated devices that can inhibit bacterial adhesion to the invasive device
has been suggested to reduce biofilm formation and the development of infection (Kollef, JAMA, 2008; Lederer, J
Wound Ostomy Continence Nurs 2014). There are many types of coated devices available. Some use antibiotics or a
mixture of chlorhexidine and silver-sulfadiazine while others use a mixture of gold, silver and palladium. These latter
devices employ a thin layer of noble metals that is able to create a “galvanic” effect that prevents bacterial adhesion to
the device and minimizes biofilm formation. These devices do not depend on the “release” of active components (such as
chlorhexidine or silver ions) in order to kill bacteria, relying solely on their anti-adhesion properties to reduce biofilm
formation. An example of such devices includes the Bactiguard® products. Some studies using this technology show a
positive effect in reducing device-related infection (Lederer, J Wound Ostomy Continence Nurs 2014), while other
reported null results for short term catheterization (Pickard, Lancet 2012).
Invasive devices are frequently used together in intensive care. For example, the most severe critically ill
patients demand mechanical ventilation (and therefore placement of an ETT), require a reliable venous access (preferably
a CVC) that is capable of delivering vasopressors, fluids and antibiotics and need urinary output monitoring (which is
only capable when a UC is in place). This creates a cycle where the most severe patients are exposed to a greater risk of
further infection due to the presence of the multiple invasive devices. Additionally, occurrence of one infection is a risk
factor for a following episode due to antibiotic use, host immune modulation and due to the need to prolong invasive
device use (Ward, Clin Chest Med 2008). For example, occurrence of VAP may prolong mechanical ventilation (Kollef,
Infect Control Hosp Epidemiol 2012), which will demand a longer use of CVC and UP, which in turn increase the risk
for infection. Therefore, it is expected that the prevention of the occurrence of one infection may further reduce the
others.

Page 31 of 47
While the isolated impact of device-associated infection such VAT, VAP and CAUTI on mortality may be
questionable (Bekaert, Am J Respir Crit Care Med 2011; Laupland, Crit Care 2005), the presence of sepsis, regardless its
source, is associated with worse short and long term outcomes, as well as higher costs (Ramanathan, Surg Infect 2015;
Moerer, Intensive Care Med 2002). The attributable mortality of sepsis may be over 20% for patients admitted without
infection (van Vught, JAMA 2016). The hallmark of sepsis is the development of organ failure (Singer, JAMA 2016).
Approximately half of all critically ill patients with nosocomial infections will develop sepsis (Alberti, Intensive Care
Med, 2002), which is associated with a mortality of over 30% that may peak at over 50% in some scenarios.
From the before mentioned, it seems reasonable affirm that: (1) If coated devices are effective in reducing
device-associated infection this will be specially relevant to patients that need several invasive devices and thus are at
higher risk; (2) The use of a bundle of coated devices may be more effective in reducing infection than the isolated use of
each device alone and (3) In order to be considered effective for critically ill patients, coated devices should preferably be
associated with a lower incidence of nosocomial sepsis and not only with a reduction in specific infections (such as VAP
or CAUTI). In this sense, we plan to conduct a randomized controlled trial to assess the impact of the simultaneous
insertion of coated ETT, CVC and UC in the ICU on the development of nosocomial sepsis in Brazil.
There are, however, two major issues to be solved before the execution of definitive study on this subject: (1)
There is no reliable data on the incidence of nosocomial sepsis in Brazilian ICUs and (2) The feasibility of the
implementation of the intervention (that is, the simultaneous insertion of coated ETT, CVC and UC at ICU admission) is
unknown.
Despite a recent advance in sepsis epidemiology in the past years, it is still uncertain which is the incidence of
nosocomial infection in the strata of the most severely ill patients. In a previous prevalence study of critically ill patients
in Europe, approximately 20.4% of all patients had ICU-acquired infection (Vincent, JAMA 1995) and 9% had ICU
acquired sepsis (Vincent, Crit Care Med 2006). There are no clear data for developing countries and no direct data
available in Brazil. An indirect estimate may be done considering several assumptions that may not still hold true.
Considering that (1) The incidence of ICU acquired infection in developing countries has been estimated to be close to
47.9 episodes for each 1,000 patients/day (Allegranzi, Lancet 2011) and (2) The typical ICU length-of-stay in Brazil is
about 10.5 days (Cavalcanti, JAMA 2016), we can conjecture that approximately 50% of all admissions in Brazil will
develop ICU-acquired infection. Considering that 53.8% of all nosocomial infections will evolve to sepsis (Alberti,
Intensive Care Med 2002), an approximation of 26.9% of all ICU admissions in Brazil may develop sepsis. These figures
are, however, largely speculative, making any sample size calculation for a clinical trial unreliable.
Additionally, the simultaneous insertion of ETT, CVC and UP devices may be challenging. Many patients
receive one or more of these devices outside the ICU setting. For example, intubation may be performed in the
emergency room but CVC placement may be delayed until ICU admission. The insertion of devices in different places
and under different circumstances may be an important source of bias. For example, emergency department length-of-
stay before ICU admission is associated with development of pneumonia regardless of severity (Carr, J Trauma 2007).
While the inclusion of patients that are admitted without the devices in the ICU may limit external validity, it is essential
to evaluate the independent role of coated devices in the context of a reasonable sample size.
In order to cope with those two limitations, we propose a pilot randomized controlled trial involving coated
devices to obtain a reliable estimate of nosocomial sepsis in ICUs in Brazil and to confirm the feasibility of the
intervention. Clinical outcomes such as occurrence of nosocomial sepsis and of device-related infection will be assessed
between groups as secondary outcomes.
Objectives

Page 32 of 47
Primary objectives:
1. To assess feasibility of the simultaneous insertion of coated and non-coated ETT, CVC and UC in recently
admitted critically ill patients without previous invasive devices in a randomized controlled trial.
2. To determine how many patients admitted to the ICU will require CVC, ETT and UC insertion and, of those,
how many will develop sepsis during the first 28 days after ICU admission.
Secondary objectives (clinical outcomes):
1. Occurrence of nosocomial sepsis up to 28 days after randomization in control (uncoated devices) versus
intervention (coated devices) groups
2. Combined endpoint of any of the following infections occurring during ICU stay: Ventilator associated
pneumonia (VAP), Catheter related bloodstream infection (CRBSI) and Catheter related urinary infection
(CAUTI)
3. Occurrence of each nosocomial infection individually (VAP, CRBI, CRUI) in both groups
4. Antibiotics free days up to 28 days after randomization in both groups
5. ICU and Hospital mortality in both groups
Methods
Design
Pilot open label randomized controlled trial assessing the feasibility and clinical outcomes of coated (intervention
group - Bactiguard® coated ETT, CVC and UC) versus uncoated (control group) in critically ill patients admitted to the
ICU. The study aims to include 100 patients (50 in each arm) in ten (10) intensive care units in Brazil.
Eligibility
Inclusion criteria: All patients admitted to the ICU which will require simultaneous insertion of all three devices (ETT,
CVC and UC) due to illness severity as defined by the attending physician.
Exclusion criteria: Any of the criteria below:
− Patients admitted to the ICU for more than 48 hours or admitted in the hospital for more than seven days
− Presence of any of the invasive devices (ETT, CVC or UC) before randomization and absence of the intention to
exchange the devices. For example, patients with previous CVC may be included if they will require device
exchange
− Age < 18 years
− Known pregnancy
− Known allergy to gold, silver, and palladium
− Suspected or confirmed infection or sepsis related to the device
− Severe chronic obstructive pulmonary disease and/or previous inflammatory/thrombosis occurrence in potential
insertion sites for the CVC that may limit catheter insertion
− Suspected or confirmed brain death
− Previously enrolled in the study
Interventions
Patients which will require invasive devices (ETT, CVC and UC) due to illness severity will be randomized to
receive coated (Bactiguard®) or the habitual non-coated devices in an open label fashion. The uncoated control group

Page 33 of 47
will consist on the habitual uncoated ETT, CVC or UC in use in the ICU. All devices will be used within their approved
intended use. BIP CVC is not yet approved in Brazil and will be used according to its approved and certified intended use
in outside Brazil). For the CVC, we recommend jugular or subclavian vein sites over femoral site and the use of catheters
with three lumens. The ETT in both groups will be without subglottic suctioning port.
All other treatments will follow local clinical practice guidelines. The devices will be used until they are no
longer necessary, and patients will be followed up to 28 days after randomization. In case of need of device exchange due
to malfunctioning or other complications, the same type of device will be used until ICU discharge or 28 days after
randomization. The decision to exchange a device is left to the attending physician. Use of other intravascular devices,
such as larger bore catheters for dialysis, will be left at discretion of the attending physician and local practices, but will
be noted in the CRF.
Outcomes
The analysis of the two main outcomes involves both the feasibility of the study and the need to obtain
epidemiological data on the occurrence of nosocomial sepsis after ICU admission. The feasibility will be assessed by
study recruitment rate and by local input on the challenges of the randomization process. We expect a recruitment rate of
approximately 1.3 patients a month per center.
Sepsis will be defined as the occurrence of infection plus presence of organ failure, assessed by the Sequential
Organ Failure Assessment (SOFA) score (Singer, JAMA 2016; Vincent, Intensive Care Med 1996). The presence of
infection with an increase in SOFA score in at least two points will be considered as sepsis (Singer, JAMA 2016). Sepsis
will be further classified as probably related to devices or non-related to the devices. Sepsis non-related to the devices
will be those where an obvious source of infection that is not related to the devices and is present at device insertion or
when the time between device insertion and sepsis diagnosis is less than 48 hours. Obvious sepsis sources unrelated to
the devices include: Meningitis, soft tissue infections away from the puncture site (i.e., necrotizing fasciitis),
intrabdominal infection and surgical wound infection.
VAP will be defined considering the classic diagnostic criteria (Kalanuria, Crit Care 2014):
1. New or progressive radiographic consolidation or infiltrate. In addition, at least 2 of the following:
a. Temperature > 38 °C
b. Leukocytosis (white blood cell count ≥ 12,000 cells/ mm3) or leukopenia (white blood cell
count < 4,000 cells/mm3)
c. Presence of purulent secretions
CRBSI will be defined if one of the following is present plus criteria for identifying the catheter as the source
(ECDC, 2013):
1. Patient has a recognized pathogen cultured from one or more blood cultures, and the pathogen is not
related to an infection at another site. OR
2. Patient has at least one of the following signs or symptoms: fever (>38.0°C), chills, or hypotension, and
the pathogen is not related to an infection at another site or, if the organism is a common commensal, it
must be present from two or more blood cultures drawn on separate occasions. AND
3. Culture of the same organism from both the catheter tip and at least one percutaneous blood culture
4. Culture of the same organism from at least two blood samples (one from a catheter hub and the other
from a peripheral vein or second lumen) meeting criteria for quantitative blood cultures (at least 5

Page 34 of 47
times greater in catheter blood) or differential time to positivity (at least 2 hours earlier in catheter
blood).
Therefore, for CRBSI to be diagnosed, patient must have criteria 1 OR 2 plus 3 OR 4.
Finally, CAUTI will be defined if all the following are present (Nicolle, Antimicrob Resist Infect Control 2014):
1. One or more organisms are present at quantitative counts ≥10⁵ colony-forming units/mL from an
appropriately collected urine specimen
2. The attending physician believes there is an acute infection and prescribes antibiotics
3. There is no other plausible source of infection at the time the diagnosis of CAUTI is made
The number of antibiotic free days at 28 days will be defined as 28 less the number of days the patient received
antibiotics.
All events will be adjudicated by the coordinating center.
Temporal Sequence
Data will be collected at randomization (day 0), whenever the current antibiotic scheme is changed (that is,
whenever a new antibiotic is added or a new antibiotic scheme is started due to suspected infection and at ICU and
hospital discharge). This event-driven data collection reduces burden on participating centers and allow us to obtain
detailed information on how the suspicious of infection was made.
Additionally, data will be collected when there is need to exchange the device for any reason. In this situation,
the following information will be collected:
 Device that will be exchanged (ETT, CVC, UC)
 Reason for exchanging
 In the case of CVC, site of new CVC
Study visits and variables to be collected will be as follow:
Randomization (Day 0):
− Confirmation of inclusion and exclusion criteria
− Obtainment of informed consent form (ICF)
− Randomization and device placement (including site of puncture for the CVC)
− Demographic information: Age, gender, major comorbidities (diabetes, chronic kidney disease, heart
failure, acquired immunodeficiency syndrome, rheumatological disease, previous corticosteroid use and
dose)
− Illness severity (SAPS 3 score)
− Admission type (medical, elective surgery, emergency surgery)
− Active source of infection (if any): Respiratory, Blood Stream, Urinary, Soft Tissues, Central Nervous
System, Other, Unknown.
− Active of use of antibiotics (if any, type and number of previous days of use)
− Sequential Organ Failure Assessment (SOFA) score and its components (neurological, hematological,
respiratory, hemodynamic, renal and hepatic)
− Leukogram (if available)
− C-Reactive Protein (CRP) levels (if available)
Event days:

Page 35 of 47
− Active of use of antibiotics (if any)

− Newly added antibiotics (if any)
− Active suspected source of infection (if any)
− Fulfillment of diagnostic criteria for VAP, CRBI or CAUTI. In the case where infection is suspected but the
source is still unclear, the investigator will be prompted to fill data in 48 hours after the suspicion is made to
confirm or refute the diagnosis.
− Chest X-ray (if the diagnosis of VAP is made)
− Data from cultures (blood, respiratory tract, urine or other sources)
− Sequential Organ Failure Assessment (SOFA) score and its components (neurological, hematological,
respiratory, hemodynamic, renal and hepatic)
− Leukogram (if available)
− C-Reactive Protein (CRP) levels (if available)
Daily follow up (up to 28 days or ICU discharge):
− Use of urinary catheter (yes/no)
− Use of mechanical ventilation (yes/no)
− Use of CVC (yes/no)
− Use of antibiotics (yes/no)
− SOFA score
ICU discharge:
− Vital status; if dead occurred in the ICU, the main cause of death (sepsis versus non-sepsis)
Hospital discharge
− Vital status
Randomization, Data Collection and Data Management

Randomization list will be electronic generated using appropriate software and will be done in blocks stratified
by centre and by the presence of sepsis at randomization. Allocation group will only be informed after patient register in
the electronic database, thereby preventing the investigator of anticipating for which group the patient will be
randomized. Due to technical reasons, there will be no blinding.
Randomization and data collection will be done using a web-based solution which will be specifically developed
for the study. In order to guarantee data quality, several procedures will be applied:
1. All investigators will receive proper training at site or using web conference tools before the initiation
of the trial
2. There will be an available telephone dedicated to answer questions on the case report form in real time
during weekdays
3. Database cleaning and check for inconsistencies will be done at every 15 days. Centers will be
contacted if any data inconsistency is found.
4. The coordinating center (HCor) will monthly review data on triage of eligible patients, inclusion,
follow-up and completeness.
5. On-site monitoring will be done in selected centers in selected cases when issues with recruitment or
adhesion to the protocol arise.

Page 36 of 47
No interim analyses are planned. Data will be monitored locally at the coordinating centre.
Safety and Adverse Events Report

Severe unexpected adverse events directly related to the study should be reported to the coordinating center
(which will also forward it to the sponsor) and to local ethics committee whiting 24 hours after its occurrence. Severe
unexpected adverse events are defined if both criteria are present:
1. The event if fatal, threatens life (immediate risk of death), leaves temporary or permanent harm or
prolongs hospital stay AND;
2. The attending physician believes the event is related to the inclusion of the patient in the CRITIC
study; for example, the physician believes the event is related to the use of study devices
Additionally, other adverse events and data on malfunction of the devices (both coated and uncoated) will be
collected in dedicated forms.
Statistical Analysis
This is a pilot study including 100 unique patients. For the primary outcomes (feasibility and incidence of sepsis
in the selected population) only descriptive statistics will be used. The density of incidence of sepsis and other device-
related infection (VAP, CRBSI and CAUTI) will be calculated as the number of events over the total number of
patients/day at risk. We plan to elaborate an SAP in the near future that may change the analytical approach. At this time,
we plan to use, for the secondary binary outcomes, proportion tests (Chi² or Fisher’s exact test) and Student’s t test for
secondary continuous outcomes. We pretend to use an intention to treat approach; however, since the primary endpoint is
feasibility and presence of sepsis in patients that require the three devices, a per-protocol analysis may be considered. A
subgroup analysis according to presence/absence of sepsis at admission is planned.
Ethics and Study Dissemination

The investigator must send the study protocol, the informed consent form and other required documents to the
local ethics committee before starting the study. A letter stating that the protocol was locally accepted must be sent to the
coordinating center (HCor). All significant protocol amends must also be locally approved by the local ethics committee.
All patients or their legal representatives must sign the informed consent form. Some important aspects on the
procurement of the informed consent should be highlighted:
1. The study intervention is done during medical emergencies; that is, the insertion of ETT, CVC and UC
in the ICU are done in critically ill unstable patients and cannot be postponed; all devices (both coated
and uncoated) will be used within their approved intended use
2. Presence of family or legal representatives in the ICU is mostly limited in Brazil;
3. Coated devices are frequently used in clinical practice and have been available for more than thirty
years, with an excellent safety profile (see Appendix 1);
4. Brazil’s national resolution 466/2012, section III, subsection 2, item “g” foresees the procurement of
the informed consent form a posteriori in selected cases.
In view of the above, we reassure that the informed consent will be obtained for all patients without any
exceptions. We nevertheless understand that it is reasonable to postpone procurement of the informed consent until the
family/legal representative attends to the ICU or until the patient is able to do so by him/her. We acknowledge and
respect the autonomy of each local ethics committee to ask for changes in the informed consent form. It is responsibility
of the investigator or co-investigator to obtain proper informed consent, consisting of two identical forms per patient,

Page 37 of 47
both with date and signature of the investigator plus patient (or legal responsible). Participating in CRITIC is absolutely
voluntary and no form of compensation will be provided for enrolled patients.
No identified data will be sent to the coordinating center. All data collected by the investigators must be stored
under confidential terms.
The results of the CRITIC pilot study are planned to be submitted to publication (unless judged to be
biased/invalid due to any reasons) in name of the steering committee, which will have unrestricted access to the database
all are held responsible for the veracity of all information. The CRITIC pilot study maybe published on its own or
together with the main study, which will possibly be run after the pilot study.
Risks and Benefits

While CRITIC will include very severe patients requiring multiple invasive procedures, the intervention under
investigation is not associated with increased risks. All Bactiguard devices to be used in this study are already approved
in several countries with an excellent safety profile and will be used within their approved intended use. Patients will not
receive different interventions due to their enrollment in the trial; procedures, including insertion technique, criteria for
device removal, etc, will be exactly the same except for the presence or absence of coating on the invasive devices. There
is no direct benefit for patients included in the CRITIC pilot study. Patients will not receive any financial compensation
for their enrollment in the trial. There are indirect benefits, such as the epidemiological data obtained and, if the trial
proves itself feasible, the benefit to future patients with similar conditions.
Funding and Coordination

This study in founded by Bactiguard Sweden through an unrestricted research grant obtained at HCor (Hospital
do Coração). Bactiguard has no role in data collection or data analysis. In no hypothesis Bactiguard will have access to
individual non de-identified patient information.
The study is coordinated at HCor-Hospital do Coração by Fernando Godinho Zampieri, and Alexandre Biasi
Cavalcanti.
References
Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an
international multicentre cohort study. Intensive Care Med. 2002 Feb;28(2):108-21
Allegranzi B, Bagheri Nejad S, Combescure C, et al. Burden of endemic health-care-associated infection in developing
countries: systematic review and meta-analysis. Lancet. 2011 Jan 15;377(9761):228-41
Apostolopoulou E, Raftopoulos V, Filntisis G, et al. Surveillance of device-associated infection rates and mortality in 3
Greek intensive care units. Am J Crit Care. 2013 May;22(3):e12-20
Carr BG, Kaye AJ, Wiebe DJ, Gracias VH, Schwab CW, Reilly PM. Emergency department length of stay: a major risk
factor for pneumonia in intubated blunt trauma patients. J Trauma. 2007 Jul;63(1):9-12.
Cavalcanti AB, Bozza FA, Machado FR, et al. Effect of a Quality Improvement Intervention With Daily Round
Checklists, Goal Setting, and Clinician Prompting on Mortality of Critically Ill Patients: A Randomized Clinical Trial.
JAMA. 2016 Apr 12;315(14):1480-90
Delcaru C, Alexandru I, Podgoreanu P, et al. Microbial Biofilms in Urinary Tract Infections and Prostatitis: Etiology,
Pathogenicity, and Combating strategies. Pathogens. 2016 Nov 30;5(4)
European Centre for Disease Prevention and Control. Point prevalence survey of healthcare associated-infections and
antimicrobial use in European acute care hospitals. Stockholm: ECDC; 2013.

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Gil-Perotin S, Ramirez P, Marti V, et al. Implications of endotracheal tube biofilm in ventilator-associated pneumonia
response: a state of concept. Crit Care. 2012 May 23;16(3):R93
Hu B, Tao L, Rosenthal VD, et al. Device-associated infection rates, device use, length of stay, and mortality in intensive
care units of 4 Chinese hospitals: International Nosocomial Control Consortium findings. Am J Infect Control. 2013
Apr;41(4):301-6
Kalanuria AA, Ziai W, Mirski M. Ventilator-associated pneumonia in the ICU. Crit Care. 2014 Mar 18;18(2):208
Kollef MH, Afessa B, Anzueto A, et al. Silver-coated endotracheal tubes and incidence of ventilator-associated
pneumonia: the NASCENT randomized trial. JAMA. 2008 Aug 20;300(7):805-13
Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort.
Infect Control Hosp Epidemiol. 2012 Mar;33(3):250-6
Laupland KB, Bagshaw SM, Gregson DB, et al. Intensive care unit-acquired urinary tract infections in a regional critical
care system. Crit Care. 2005 Apr;9(2):R60-5
Lederer JW, Jarvis WR, Thomas L, et al. Multicenter cohort study to assess the impact of a silver-alloy and hydrogel-
coated urinary catheter on symptomatic catheter-associated urinary tract infections. J Wound Ostomy Continence Nurs.
2014 Sep-Oct;41(5):473-80.
Moerer O, Schmid A, Hofmann M, et al. Direct costs of severe sepsis in three German intensive care units based on
retrospective electronic patient record analysis of resource use. Intensive Care Med. 2002 Oct;28(10):1440-6.
Nicolle LE. Catheter associated urinary tract infections. Antimicrob Resist Infect Control. 2014 Jul 25;3:23
Polderman KH, Girbes AJ. Central venous catheter use.
Part 1: mechanical complications. Intensive Care Med. 2002 Jan;28(1):1-17
Pickard R, Lam T, MacLennan G, et al. Antimicrobial catheters for reduction of symptomatic urinary tract infection in
adults requiring short-term catheterisation in hospital: a multicentre randomised controlled trial. Lancet. 2012 Dec
1;380(9857):1927-35.
Ramanathan R, Leavell P, Mays C, et al. Impact of Sepsis on Surgical Outcomes. Surg Infect (Larchmt). 2015
Aug;16(4):405-9
Salomao R, Rosenthal VD, Grimberg G, et al. Device-associated infection rates in intensive care units of Brazilian
hospitals: findings of the International Nosocomial Infection Control Consortium. Rev Panam Salud Publica. 2008
Sep;24(3):195-202.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10
van Vught LA, Klein Klouwenberg PM, Spitoni C. Incidence, Risk Factors, and Attributable Mortality of Secondary
Infections in the Intensive Care Unit After Admission for Sepsis. JAMA. 2016 Apr 12;315(14):1469-79
Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results
of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee.
JAMA. 1995 Aug 23-30;274(8):639-44.
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ
dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive
Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10.
Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med.
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Page 40 of 47
Appendix 2 – Statistical analysis plan

Statistical Analysis Plan (SAP)
for the CRITIC Pilot Study (Coated devices to decRease InfecTion in the ICu).
ClinicalTrials.org Registration: NCT03868241
Protocol Version 2.0 – January, 2019.

SAP Revision:
SAP version Protocol Version Description and Reason for Change Date
1.0 2.1 Not Applicable 03/10/2019
Protocol Version 2.1– February, 2019.

SAP Revision:
SAP version Protocol Version Description and Reason for Change Date
Added prior for binary outcome which was 10/01/2020
1.1 2.1
unconsidered in previous version
NOTE: Version 1.0 is available at ClinicalTrials.gov. The new changes in version 1.1 are highlighted in red in this
manuscript and were not uploaded to ClinicalTrials.gov. The SAP published in ClinicalTrials.gov also describes the most
relevant information on the protocol which have been omitted in this appendix due to availability of the full protocol as
Appendix 1.
NOTE 2: Changes from the submitted SAP that were requested during peer review are in purple.
Sample size
This is a pilot study including 100 unique patients. The density of incidence of sepsis and other device-related infection
(VAP, CRBSI and CAUTI) will be calculated as the number of events over the total number of patients/day at risk. For
incidence of sepsis outcome, this sample size will be able to inform 95% credible intervals with approximately 3 events
per 100 patient-days overall (4 events per patient-day per group), and interval length based on Bayesian Poisson
regression model with intercept parameter assuming non-informative normal prior centered in 8 event per 100 patient-
days incidence rate. The prior has a large standard deviation, giving virtually no importance to its average choice, which
was established assuming a slightly worse scenario than was described for a European population of 5 events per 100
patient-days.
Analysis sets
Study protocol (v2.0) mentioned that analysis would be done considering the intention to treat principle. However,
during study conduction, some randomized patients did not require simultaneous insertion of all three devices (ETT,
CVC and UC) due to illness severity, or the attending physician decided not to insert the devices and did not obtain
consent. Those cases were excluded from the analyses. Consequently, main analysis will be carried out considering a per

Page 41 of 47
protocol set (PPS). Our expectations are that per protocol and full compliance sets will be the same. Nevertheless, if it
happens otherwise, full compliance set must be used to evaluate efficacy measures (infection incidences) and per
protocol set to evaluate security measures (adverse events).
 Per Protocol Set: All patients that were randomized, fulfilled all inclusion and exclusion criteria, and receive the
three devices (ETT, CVC and UC) from allocated arm (coated or habitual) at least one time.
 Full compliance set: All patients that were randomized, fulfilled all inclusion and exclusion criteria, and receive
the three devices (ETT, CVC and UC) from allocated arm (coated or habitual) all the times that were needed (no
full or partial crossover)
Statistical Analyses
Continuous data will be reported as mean (standard deviation) or median (quartiles) as appropriate. Categorical variables
will be described by absolute and relative frequencies. Patients’ baseline characteristics will be presented without any
hypothesis test comparing patients allocated to Coated versus Habitual devices.
Besides feasibility, the outcome of incidence (occurrence) of sepsis will be estimated via Bayesian Poisson regression
model with intercept parameter assuming non-informative normal prior centered in 8 event per 100 patient-day incidence
rate normal prior (N~(e0.08,5)). The same Bayesian Poisson regression model with intercept parameter assuming non-
informative normal prior centered in 8 event per 100 patient-day incidence rate will be done to estimate other infection
incidences (VAP, CRBSI, CAUTI). The same model will be used to compare patients that used coated devices versus
habitual devices. Results will be reported as Risk Ratios (RR) with 95% Credible Intervals. Although we initially
planned to adjust for admission type, baseline SOFA and the stratification variable (presence of suspected sepsis at
randomization), since most patients were admitted with sepsis and due to medical reasons (over 75%), we expected
difficulties in converging the models; therefore we decided to adjust models only for baseline SOFA. For the binary
endpoints, we plan to perform using logistic regression models and reporting results as odds ratios, adjusted by
intervention and baseline SOFA. We will use non-informative (flat) priors for intercept and intervention.
We also intended to evaluate SOFA during ICU stay using hierarchical Bayesian linear regression models assuming
intercept and slope hierarchical effects to patient to include individual time dependence, adjusted for baseline SOFA, and
interaction of time and allocated device (coated or habitual). This analysis, during peer review process, was considered
biases due to competing influence of mortality and was removed.
Safety and Adverse Events: All reported Safety and Adverse events as described in the protocol will be presented with
absolute and relative frequencies and tested with regular Fisher exact test between study groups (Coated vs. Habitual
devices).
Missing data and imputation: We expect minimal missing data; no data imputation is planned.:
Statistical software: R project version 3.6 with brms package.

Page 42 of 47
Appendix 3 – CONSORT 2010 Checklist
Reported on page
Section/Topic Item No Checklist item No
Title and abstract
1a Identification as a randomised trial in the title 1
1b Structured summary of trial design, methods, results, and 3

conclusions (for specific guidance see CONSORT for abstracts)
Introduction
Background and objectives 2a Scientific background and explanation of rationale 4
2b Specific objectives or hypotheses 4
Methods
Trial design 3a Description of trial design (such as parallel, factorial) including 5
allocation ratio
3b Important changes to methods after trial commencement (such 5

as eligibility criteria), with reasons
Participants 4a Eligibility criteria for participants 5
4b Settings and locations where the data were collected 5
Interventions 5 The interventions for each group with sufficient details to allow 5-6
replication, including how and when they were actually
administered
Outcomes 6a Completely defined pre-specified primary and secondary 6

outcome measures, including how and when they were
assessed
6b Any changes to trial outcomes after the trial commenced, with 7

reasons
Sample size 7a How sample size was determined 7
7b When applicable, explanation of any interim analyses and NA

stopping guidelines
Randomisation:
Sequence generation 8a Method used to generate the random allocation sequence 5
8b Type of randomisation; details of any restriction (such as 5

blocking and block size)
Allocation concealment 9 Mechanism used to implement the random allocation sequence 5

mechanism (such as sequentially numbered containers), describing any
steps taken to conceal the sequence until interventions were
assigned
Implementation 10 Who generated the random allocation sequence, who enrolled 5

participants, and who assigned participants to interventions
Blinding 11a If done, who was blinded after assignment to interventions (for 5-7
example, participants, care providers, those assessing
outcomes) and how
11b If relevant, description of the similarity of interventions 6
Statistical methods 12a Statistical methods used to compare groups for primary and 5-6
secondary outcomes
12b Methods for additional analyses, such as subgroup analyses 7

and adjusted analyses
Results

Page 43 of 47
Participant flow (a diagram is 13a For each group, the numbers of participants who were randomly 7, 8, Flowchart 1
strongly recommended) assigned, received intended treatment, and were analysed for
the primary outcome
13b For each group, losses and exclusions after randomisation, Flowchart
together with reasons
Recruitment 14a Dates defining the periods of recruitment and follow-up 5
14b Why the trial ended or was stopped 7
Baseline data 15 A table showing baseline demographic and clinical Table 1

characteristics for each group
Numbers analysed 16 For each group, number of participants (denominator) included Table 1, 2
in each analysis and whether the analysis was by original
assigned groups
Outcomes and estimation 17a For each primary and secondary outcome, results for each Table 2
group, and the estimated effect size and its precision (such as
95% confidence interval)
17b For binary outcomes, presentation of both absolute and relative Table 2
effect sizes is recommended
Ancillary analyses 18 Results of any other analyses performed, including subgroup ESM
analyses and adjusted analyses, distinguishing pre-specified
from exploratory
Harms 19 All important harms or unintended effects in each group (for 8

specific guidance see CONSORT for harms)
Discussion
Limitations 20 Trial limitations, addressing sources of potential bias, 10
imprecision, and, if relevant, multiplicity of analyses
Generalisability 21 Generalisability (external validity, applicability) of the trial 10

findings
Interpretation 22 Interpretation consistent with results, balancing benefits and 9-10

harms, and considering other relevant evidence
Other information
Registration 23 Registration number and name of trial registry 2
Protocol 24 Where the full trial protocol can be accessed, if available ESM
Funding 25 Sources of funding and other support (such as supply of drugs), 1, 2

role of funders

Page 44 of 47
Appendix 4 – Supplementary Tables
Supplementary Table 1 – Inclusions per site
Center Principal Investigator N

Hospital de Base da Fundação Faculdade Regional de Medicina de
São José do Rio Preto Neymar Elias de Oliveira 22
Hospital do Câncer AC Camargo Antonio Paulo Nassar Junior 15
Hospital Estadual Jayme dos Santos Neves Priscilla de Aquino Martins 11
Hospital São Paulo - UNIFESP Flavia Ribeiro Machado 11
Hospital da Luz - Amico Saúde LTDA Fabio Holanda Lacerda 11
Hospital Universitário do Oeste do Paraná - UNIOESTE Thiago Simões Giancursi 10
Hospital Paulistano Airton Leonardo Manoel de Oliveira 9
Hospital Evangélico Cachoeiro do Itapemirim Marlus Muri Thompson 6
Hospital Nereu Ramos Israel Silva Maia 4
Hospital Evangélico de Londrina - Sociedade Evangélia
Beneficiente de Londrina Cintia Magalhães Carvalho Grion 3
Irmandade da Santa Casa de Misericórdia de Porto Alegre Thiago Costa Lisboa 1

Page 45 of 47
Supplementary Table 2 – Outcomes according to presence/absence of sepsis at admission after adjudication. All results are unadjusted.
Without sepsis (strata variable) $ With sepsis (strata variable)

Coated devices (n=9) Habitual devices (n=12) Coated devices (n=39) Habitual devices (n=43) Relative risk [95% CrI]
Days alive and free of antibiotics in the
ICU per 100 patients/day 27.16 27.17 29.30 [24.43 - 35.07] 18.07 [14.29 - 22.24] 1.63 [1.23 - 2.17]
Infection rates (per 1,000 patients-day)
CRUTI or VAP or CRBSI‡ 0 0 25.0 [12.4 – 46.7] 27.6 [14.8 – 46.6] 0.91 [0.37 – 2.16]
CRUTI† 0 0 6.5 [0.9 – 20.5] 7.7 [1.7 – 21.2] 0.85 [0.09 - 5.41]
VAP† 0 0 21.1 [8.1 – 46.2] 12.1 [3.7 – 27.1] 1.84 [0.47 – 7.20]
CRBSI† 0 0 5.0 [0.7 – 17.1] 12.1 [0.4 - 2.65] 0.42 [0.05 - 2.16]
Sepsis rate (per 100 patients-day) 12.3 10.9 42.9 [25.7 – 67.1] 29.7 [16.8 - 48.9] 1.45 [0.69 - 3.08]
Patient with at least one episode
CRUTI or VAP or CRBSI 0 (0%) 0 (0%) 20% [9% -34%] 20% [10% – 34%] 0.99 [0.39 - 2.34]
CRUTI 0 (0%) 0 (0%) 4% [1% – 14%] 6% [1 – 16%] 0.71 [0.07 - 4.58]
VAP 0 (0%) 0 (0%) 15% [6% – 28%] 9% [3 – 19%] 1.76 [0.52 – 6.75]
CRBSI 0 (0%) 0 (0%) 4% [1% – 14%] 11% [4 – 23%] 0.40 [0.04 – 1.79]
Sepsis, n(%) 1 (11.1%) 1 (8.3%) 30% [17% – 46%] 27% [15 – 42%] 1.09 [0.52 - 2.21]
Vital status
ICU Mortality 1 (11.1%) 1 (8.3%) 41% [26% - 56%] 49% [35% - 64%] 0.84 [0.50 - 1.35]
Hospital mortality 2 (22.2%) 1 (8.3%) 46% [31% - 61%] 60% [46% - 74%] 0.76 [0.49 - 1.15]
28-day mortality 1 (11.1%) 1 (8.3%) 44% [29% - 59%] 54% [40% - 68%] 0.81 [0.50 - 1.28]
$effect sizes and credible intervals are not reported due to absence of events; † only days in use of the device were considered when calculating infection rate; ‡ number of days in the ICU were
considered for this estimate.

Page 46 of 47
Supplementary Table 3 – Reasons for device exchanges in both groups

Page 47 of 47
Supplementary Table 4 – Outcomes in the intention to treat population. This analysis includes 9 additional patients. Seven in the coated device groups did not receive trial
intervention. One died before device placement, two had their surgeries cancelled (hepatic transplant) and were discharged home; two had clinical improvement and only used
urinary catheter and did not have infection; one was already using conventional device and changing was not performed (this patient died on day 7 with a reported septic episode on
day 2, but no confirmed healthcare associated infection) and one received a conventional central venous catheter, a coated urinary catheter, was not intubated and was discharged
alive at day 10 with one documented sepsis episode. Two patients in the uncoated arm did not receive the intervention. One transitioned to comfort care and died less than 24h latter
and one other was discharged alive at day seven, however, details on antibiotic use and healthcare associated infections were not available for this patient. We considered that this
patient did not have sepsis neither other infections for the analysis. Events for these patients were not adjudicated.
Coated devices Uncoated devices Absolute difference Crude relative risk

Endpoints
(n=51) (n=56) (95% CrI) (95% CrI)
Days alive at the ICU free of antibiotics (per 100
31.1 [26.5 - 36.2] 19.8 [16.4 - 24.0] 11.3 [5.1 - 17.8] 1.58 [1.22 - 2.05]
patients-day)
Infection rates (per 1,000 patients-day)
CRUTI or VAP or CRBSI‡ 19.9 [9.8 - 34.4] 22.6 [11.9 - 37.8] -2.8 [-21.9 - 16.2] 0.88 [0.36 - 2.14]
CRUTI† 5.3 [0.8 - 17.5] 6.5 [1.5 - 17.1] -0.9 [-12.5 - 11.7] 0.85 [0.09 - 5.02]
VAP† 19.1 [7.3 - 38.7] 11.1 [3.2 - 26] 8.1 [-11.0 - 29.7] 1.75 [0.47 - 7.10]
CRBSI† 4.3 [0.5 - 13.4] 10.2 [3.4 - 22.3] -5.6 [-18.2 - 5.8] 0.42 [0.05 - 1.99]
Sepsis rate (per 100 patients-day) 38.4 [23.1 - 58] 26.7 [14.9 - 42.7] 11.2 [-10.7 - 33.6] 1.43 [0.72 - 2.98]
Patient with at least one episode, proportion
CRUTI or VAP or CRBSI 15% [7% - 27%] 16% [8% - 26%] -0.4 [-13.7 - 13.9] 0.97 [0.39 - 2.41]
CRUTI 3% [0% – 11%] 5% [1% - 12%] -1.3 [-9.4 - 6.6] 0.71 [0.08 - 4.88]
VAP 11% [5% - 22%] 7% [2% - 15%] 4.3 [-6.5 - 15.4] 1.64 [0.48 - 5.92]
CRBSI 3% [1% – 11%] 9% [3% - 18%] -5.1 [-14.7 - 4.2] 0.38 [0.05 - 1.77]
Sepsis, n (%) 27% [16% - 40%] 23% [13% - 35%] 4.3 [-12.6 - 20.6] 1.19 [0.61 - 2.31]
Vital status
ICU Mortality 35% [23% - 49%] 41% [29% - 53%] -5.9 [-23.2 - 12.1] 0.85 [0.53 - 1.38]
Hospital mortality 41% [28% - 55%] 50% [37% - 63%] -8.8 [-27.8 - 11] 0.82 [0.53 - 1.27]
28 day mortality 37% [25% - 51%] 45% [32% - 58%] -7.6 [-25.4 - 10.7] 0.83 [0.52 - 1.3]
† only days in use of the device were considered when calculating infection rate; ‡ number of days in the ICU were considered for combined infection rate estimates


Bundle of Coated Devices To Reduce Nosocomial Infections in The Intensive Care Unit: CRITIC Pilot Randomized Controlled TrialAnn Am Thorac Soc 2020

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1. Research Institute, HCor, São Paulo, Brazil

Running Title: CRITIC Pilot study

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

Keywords: coated devices; healthcare-associated infections; ventilator-associated pneumonia;

List of Participating (Collaborators at each site):

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

benefits of coated devices in most severe patients.

Objectives: To assess feasibility of a randomized controlled trial on simultaneous insertion of

incidence of sepsis and device-associated infections (ventilator associated pneumonia [VAP],

events were adjudicated.

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

patient-days, mean ratio of 1.48, 95% credible interval 1.16-1.89).

Clinical trial registered with ClinicalTrials.gov (NCT03868241)

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

infection related to invasive devices must be sought [7,9].

silver-palladium coated devices reported a positive effect in reducing device-related infection

feasibility of a strategy involving simultaneous insertion of coated-only devices in critically ill

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

We therefore performed a pilot feasibility randomized controlled trial involving coated

Pilot, single-blinded, randomized controlled trial on 12 ICUs in Brazil.

Inclusion and Exclusion Criteria

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

the attending physician.

Randomization and Trial Intervention

coated devices, Bactiguard ®) or shelf (uncoated) devices available at participating sites.

should use devices according to randomization arm up to 28 days, as needed. If device

exchange was needed, the same type of device should be used.

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

Study Endpoints and Outcome Measurements

the pilot nature of this study, including:

1. Incidence of sepsis between groups, following the same definition

2. Incidence of ventilator-associated pneumonia (VAP), central venous catheter-related

bloodstream infection (CRBSI) and urinary catheter-related infection (CRUTI, truncated

3. Rate of composite endpoint of ventilator-associated pneumonia and/or central venous

catheter-related bloodstream infection and/or urinary catheter-related infection

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

Secondary endpoints of occurrence of VAP, CRBSI and/or CRUTI were adjudicated by

indistinguishable to inspection on chest radiography. Only ETT without subglottic suctioning

port were used on both groups.

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

subgroup was presence/absence of sepsis at enrollment.

(supplied in the ESM Appendix 3).

Overall Results and Primary Endpoint

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ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

of sepsis and mortality over time is shown in Figure 2B.

the modified intention-to-treat.

without use of antibiotics.

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which potentiate occurrence of infectious complications.

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both mortality and antibiotic use in a single measurement.

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context of an unblinded trial, specially consent refusals. An additional important limitation is

and to all site members for their support.

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ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC

Figure 1: Study Flowchart

occurrence of sepsis for both groups.

ANNALSATS Articles in Press. Published June 11, 2020 as 10.1513/AnnalsATS.202003-206OC