Randomized Intubation with Polyurethane or Conical Cuffs to Prevent Pneumonia in Ventilated Patients

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Randomized intubation with polyurethane or conical cuffs to

prevent pneumonia in ventilated patients

François Philippart, MD, PhD 1, Stéphane Gaudry, MD, PhD 2,13, Laurent Quinquis,

MSc3, Nicolas Lau, MD 1,5, Islem Ouanes, MD 4, Samia Touati, MD 1,5, Jean Claude

Nguyen, Pharm D 6, Catherine Branger, Pharm D 7,10, Frédéric Faibis, Pharm D 8,

Maha Mastouri, Pharm D 9, Xavier Forceville, MD, PhD 5, Fekri Abroug, MD 4, Jean

Damien Ricard, MD PhD 2, 10, Sophie Grabar, MD, PhD 11, 12 and Benoît Misset, MD 1,

12, * for the TOP-cuff study group

1: Intensive Care Unit, Saint Joseph Hospital network, Paris, France

2: Intensive Care Unit, Louis Mourier Hospital, Assistance Publique-Hôpitaux de

Paris, F-92700, Colombes, France

3: Biostatistics and Epidemiology Unit, GH Cochin Hôtel Dieu, Assistance Publique-

Hôpitaux de Paris, Paris, France

4: Intensive Care Unit, Fattouma Bourguiba University Hospital, Monastir, Tunisia

5: Intensive Care Unit, General hospital, Meaux, France

6: Microbiology Unit, Saint Joseph Hospital network, Paris, France

7: Microbiology Unit, Louis Mourier Hospital, Assistance Publique-Hôpitaux de Paris,

Colombes, France

8: Microbiology Unit, General hospital, Meaux, France

9: Microbiology Unit, Fattouma Bourguiba University Hospital, Monastir, Tunisia

10: Université Paris Diderot, IAME, 1137, Sorbonne Paris Cité, F-75018, Paris,

France

of 37 AJRCCM Articles in Press. Published on 13-January-2015 as 10.1164/rccm.201408-1398OC

Copyright © 2015 by the American Thoracic Society

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11: Biostatistics and Epidemiology Unit, GH Cochin Hôtel Dieu, Assistance Publique-

Hôpitaux de Paris, Paris, France

12: Université Paris Descartes, Paris Sorbonne Cité, Paris, France

13 : Université Paris Diderot, ECEVE, 1123, Sorbonne Paris Cité, F-75010, Paris,

France

Corresponding author : Benoît Misset, MD, Intensive Care Unit, Saint Joseph hospital

network, 185 rue Raymond Losserand, 75014 Paris, France

Phone : + 33 1 44 12 34 15

Fax : + 33 1 44 12 73 51

Authors’ contributions:

Drs Grabar and Misset had full access to all of the data in the study and take

responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Philippart, Nguyen, Grabar, Ricard, Misset

Acquisition of data:

Philippart, Gaudry, Lau, Ouanes, Touati, Nguyen, Branger, Faibis, Mastouri,

Forceville, Abroug, Ricard, Misset

Acces to data, analysis and interpretation:

Philippart, Gaudry, Quinquis, Forceville, Ricard, Grabar, Misset

Drafting of the manuscript:

Philippart, Ricard, Grabar, Misset

Critical revision of the manuscript for important intellectual content:

Philippart, Gaudry, Ouanes, Nguyen, Forceville, Ricard, Grabar, Misset



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Statistical analysis:

Quinquis, Grabar

Obtained funding:

Misset

Administrative, technical, or material support:

Philippart, Gaudry, Quinquis, Lau, Ouanes, Touati, Nguyen, Branger, Faibis,

Mastouri, Forceville, Abroug, Ricard, Grabar, Misset

Collaborators:

Members of the TOP-cuff study group

The TOP-cuff study group is made of the authors of the article and the following

investigators: Laurence Lecomte, Elsa Bournaud, Zineb Kacher, Pascale

Gendron, Radhia Cheurfi, Hélène Lozano, Sophie Pfister and Jean-Marc Treluyer

(Clinical Research Unit, Necker hospital, Assistance Publique-Hôpitaux de Paris,

Paris, France), Julien Fournier (Clinical Research Center, Saint Joseph hospital

network, Paris, France), Cindy Mathis, and Vincent Gobert (Clinical Research Center,

General hospital, Meaux, France), Guilène Barnaud and Typhaine Billard-Pomares

(Microbiology laboratory, Louis Mourier Hospital, Assistance Publique – Hôpitaux de

Paris, Colombes, France)

for data collection, data quality control and data management.

Vivian Viallon and Myriam Ben Boutieb (Biostatistics and Epidemiology Unit, Cochin

hospital, Assistance Publique-Hôpitaux de Paris, Paris, France), for data analysis



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Members of the independent committee of surveillance

Emilie Moreau, Pharm D (Pharmacy, Saint Joseph hospital network, Paris, France).

Jean-Ralph Zahar, MD, PhD (Infectious diseases consultant, Necker hospital,

Assistance Publique-Hôpitaux de Paris, Paris, France). Laurent Dupic, MD (Pediatric

Intensive Care Unit, Necker hospital, Assistance Publique-Hôpitaux de Paris, Paris,

France)

Sources of funding:

Grant from the European Critical Care Research Network (ECCRN) of the European

Society of Intensive Care Medicine (ESICM). Grant from Assistance Publique –

Hôpitaux de Paris (AP-HP) Network (# 2008-A00712-53). Grant from Covidien TM.

The tracheal tubes were provided by Covidien TM and by Kimberley-Clark TM. None of

the supporting companies took part in the data analysis or the manuscript redaction.

Conflicts of interest:

Drs Ricard and Misset were invited at meetings organized by Covidien TM and by

Kimberley-Clark TM.

The authors declare no other potential conflicts of interest in relation with the subject

of the present manuscript.

Subject category of the manuscript

# 4.4 Clinical Trials in Critical Care Medicine

Word count of the body text: 3467



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Running title

Polyurethane or conical cuffs in ventilated patients



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At a Glance Commentary

Scientific Knowledge on the Subject

ICU patients with acute respiratory failure who require tracheal intubation and

mechanical ventilation are at risk of acquiring ventilator-associated pneumonia. The

material and the shape of the cuff surrounding the tracheal tube may influence the

occurrence of aspiration and subsequent ventilator-associated pneumonia. Prior

studies suggest a reduction in VAP when these cuffs are used in combination with

subglottic secretions drainage or in selected populations.

What This Study Adds to the Field

Our results do not confirm a better efficacy of polyurethane made or conically shaped

cuffs by comparison to conventional polyvinyl chloride and cylindrical cuffs in a

multicenter general intensive care unit population. Additional studies are mandatory

to address the potential benefit of these new cuffs in combination with subglottic

secretion drainage and/or continuous monitoring of the cuff pressure.



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ABSTRACT

Rationale

The occurrence of ventilator-associated pneumonia is linked to the aspiration of

contaminated pharyngeal secretions around the endotracheal tube. Tubes with cuffs

made of polyurethane - rather than polyvinyl chloride - or with a conical - rather than

a cylindrical - shape increase the tracheal sealing.

Objective

To test whether using polyurethane and/or conical cuffs reduces tracheal colonization

and VAP in patients with acute respiratory failure.

Methods

Multicenter prospective open-label randomized study in 4 parallel groups in 4

intensive care units between 2010 and 2012. A cohort of 621 patients with expected

ventilation longer than two days were included at intubation with either a (A)

cylindrical polyvinyl chloride (n = 148), (B) cylindrical polyurethane (n = 143), (C)

conical polyvinyl chloride (n = 150) or (D) conical polyurethane (n = 162) cuff. We

used Kaplan-Meier estimates and logrank tests to compare times to events.

Measurements and main results

After excluding 17 patients who secondarily refused participation or had a non

inclusion criterion, 604 were analyzed in intention to treat. Cumulative tracheal

colonization over 103 cfu/mL at day 2 was: (A) 0.66 [0.58-0.74], (B) 0.61 [0.53-0.70],

(C) 0.67 [0.60-0.76], (D) 0.62 [0.55-0.70], (p = 0.55). Ventilator-associated

pneumonia developed in 77 (14.4%) and post-extubational stridor in 28 (6.4 %)

patients (p = 0.20 and 0.28 between groups).



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Conclusion

Among mechanically ventilated patients, polyurethane and/or conically shaped cuffs

were not superior to conventional cuffs to prevent tracheal colonization and

ventilator-associated pneumonia.

Clinical trial registered at clinicaltrials.gov # NCT01114022

Word count of the abstract: 248

Keywords

Intensive care, ventilator associated pneumonia, prevention, cuff, polyurethane,

bacterial colonization



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INTRODUCTION:

Almost 800,000 patients require mechanical ventilation (MV) each year in the United

States as a consequence of acute respiratory failure (1). These patients are at risk of

ventilator-associated pneumonia (VAP). Although recent studies have down toned

attributable mortality of VAP between 5-10% (2, 3) it remains a considerable burden

to patients and institutions. The mechanisms leading to VAP include oropharyngeal

colonization with oral or gastric pathogens and repetitive microaspirations of

secretions around the endotracheal tube’s cuff. Studies to prevent VAP have focused

on reducing oropharyngeal bacterial colonization (4), removing excessive secretions

using sub-glottic secretion drainage (SSD) (5, 6) and improving tracheal sealing. This

can be achieved by controlling cuff pressure (7) or modifying the cuff design.

Conventional cuffs are made of polyvinylchloride (PVC) and have a cylindrical shape.

They are designed with a high internal volume enabling the use of low pressure to

prevent mucosal ischemia and tracheal lesions (8). This results however in an

incomplete inflation of the cuff and CT-scan studies have shown that folds of the cuff

create channels through with secretions may leak (9).

New cuffs were recently developed to improve tracheal sealing in which the

cylindrical shape was changed for a conical one and polyurethane (PU) replaced

PVC. Bench studies (10) suggest that both these features may influence leakage

across the cuff. In ICU patients, a randomized study documented a reduction in VAP

using a combination of PU and continuous aspiration of the subglottic secretions (6).

As both innovations were combined in this study, the net effect of each is

indecipherable. The potential benefit of PU cuffed tubes was also shown in cardiac

surgery patients in whom a reduction in early postoperative pneumonia was observed



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with PU cuffs (11). However, the mechanisms of postoperative pneumonia and VAP

may differ in part, these results may thus not be applicable to the mixed ICU setting.

Our aim was to test whether the new PU and/or conically-shaped cuffs were able to

reduce bacterial colonization of the trachea and the occurrence of VAP in patients

with acute respiratory failure intended to receive MV for more than two days, as

compared to a PVC and cylindrical cuff. Results of this study have been presented in

part under abstract form (12, 13).

MATERIAL AND METHODS:

- Study design

We conducted a prospective cluster randomized open label study testing tracheal

tubes with different cuffs in 4 parallel groups. The study was registered #

NCT01114022 on clinicaltrials.gov.

- Study participants

Eligible patients were adults hospitalized in 4 medical-surgical ICUs, 3 in France and

one in Tunisia, requiring emergency tracheal intubation with a 7.5 or 8.0 mm

diameter tube – because we previously observed that over 95 % of the patients in

each center were intubated with these diameters - for acute respiratory failure, and

anticipated to be mechanically ventilated for at least 48 hours. Non-inclusion criteria

were intubation before admission in the ICU, MV for more than 24h within the 7

previous days, lung surgery in the previous month and documented bronchectasis or

cystic fibrosis.

- Randomization procedure

Individual randomization was considered too complex because tracheal intubation of

ICU patients with acute respiratory failure is often urgent. Therefore, to prevent



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selection bias, we pre-determined clusters of 9 or 10 consecutive patients, stratified

by centers, using permutation blocks, each cluster being assigned to one of the study

groups. Inclusions in a single cluster were anticipated to cover 4 to 6 weeks in each

center. At each cluster change, the appropriate endotracheal tubes were made

available for all the future patients of the center. Each patient was included in the

study at the time of intubation.

- Patient’s information

Because all the tubes tested were already approved and available on the market, the

trial was considered “minimal risk”. When the patient was not able to consent, and in

the absence of a proxy at the time of inclusion, French and Tunisian regulations

authorized inclusion of the patient as long as patient’s consent to pursue was

collected as soon as he/she was able to. In case of refusal, patient’s data was not

used in the analysis. The study was approved by the ethical committee Ile de France

III, # ID-RCB-2008-A00712-53.

- Intervention

Each group was assigned a different combination of cuff shape and material in a 2x2

design: 1) PVC, cylindrical (Hi-LoTM, Covidien, Dublin, Ireland), 2) PU, cylindrical

(MicrocuffTM, Kimberly-Clark, Irving, Texas), 3) PU, conical (SealGuardTM, Covidien,

Dublin, Ireland) and 4) PVC, conical (TaperGuardTM, Covidien, Dublin, Ireland). The

tracheal tubes corresponding to the allocated cluster were stored and available in the

intubation equipment of each ICU. The insertion of the tracheal tube was made

according to professional guidelines (14) and the cuff was inflated to a pressure of 25

to 30 cmH2O.

Airway management and VAP prevention were protocolized in all centers (8). These

measures included: oro-pharyngeal disinfection with 0.12% chlorhexidin every 6



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hours (15), use of a positive end expiratory pressure (PEEP) ≥ 5 cmH2O (16), use of

a heat and moisture exchanger except for patients with permissive hypercapnia and

consequent respiratory acidosis for whom a heated humidifier was used (17), no

selective digestive decontamination with antibiotics (18), semi-recumbent position

(19) except for patients requiring prone positioning for ARDS, stress ulcer prophylaxis

with proton pump inhibitors in cases of hypo-coagulability state (20), and low-dose

erythromycin (200 mg/12h) in case of gastric residual over 250 mL/6h (21).

Compliance with these measures was assessed on days 1, 2, 3 and 7 for each

parameter. SSD (5) was not performed. The cuff pressure was checked with a

manual manometer every 6 hours (8, 22) to minimize micro-aspiration and tracheal

lesions.

- Study outcomes

The primary endpoint was the occurrence of a bacterial colonization in the trachea

greater than 103 cfu/mL over time. Colonization, rather than VAP, was chosen as the

primary endpoint, because its definition is more reproducible than that of VAP (23).

Secondary endpoints were the incidence of a first episode of VAP, of post-

extubational stridor, and percentages of patients with colonization greater than 104,

105, and 106 cfu/mL.

- Data collection and definitions

Demographics, medical diagnoses, vital signs, treatments and study outcomes were

collected prospectively for each patient. Tracheal colonization was assessed at

intubation and on days 1, 2, 3, and 7 through suctioning with a sterile catheter

without a closed circuit suction system.

The tracheal colonization was assessed quantitatively - by repeated dilutions - on

aspirates sampled two hours after an oral disinfection with 0.12% chlorhexidin.



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Samples were cultured and bacteria were classified as: Streptococcus viridans,

Streptococcus pneumoniae, Haemophilus spp, Neisseria spp, Staphylococcus spp,

Pseudomonas aeruginosa and Enterobacteriacae.

The diagnosis of VAP was considered between 48 hours after intubation and 48

hours after extubation. VAP was suspected on the basis of clinical, biological and

radiological patterns. Bacterial samples were collected in all suspected cases, and

VAP was confirmed when the quantitative culture was at least 104 cfu/mL in a

bronchoalveolar lavage performed by fiberoptic bronscopy or 105 cfu/mL in a

quantitative tracheal aspirate (23).

A stridor was defined as the development of an audible high-pitched inspiratory

wheeze. It was systematically assessed during the 48 hours following extubation.

Sample size calculation:

We planned to compare the occurrence of tracheal colonization as a time dependent

variable. As the only data published in large series is not cumulative, we used the

percentage of anticipated colonization at day 2 to calculate the number of patients to

include (24, 25). We anticipated a tracheal colonization rate of 30% at day 2 with the

conventional (PVC cylindrical) cuff and a 10% lost of follow-up. Based on the 45%

(11) to 64 % (6) relative reduction in VAP in prior clinical studies we considered that a

50 % reduction in colonization was plausible. A sample size of 150 patients per arm

was needed to be able to detect a 15% absolute reduction between the groups with a

type-1 error of 5% and a type-2 error of 10%.

Statistical analyzes:



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Data are expressed as number (percentage) and median [IQ25-IQ75]. All the

analyses were based on the intention to treat principle. Patients who secondary

withdrew consent or had a non-inclusion criterion were excluded from the analyzed

population. As the clusters were less than 10 patients, we considered that intra-

cluster correlation was negligible (26), while this could not be a posteriori checked as

our study addressed time to event endpoints (27).

Times to colonization and to VAP elapsed from inclusion to the first event or to

extubation, whatever came first. They were estimated with Kaplan-Meier estimates

and compared with the log-rank test.

Risk factors for colonization were assessed through uni and multivariate analyzes

using a Cox model. The variables included in the multivariate analysis were those

with a p-value below 0.15 in univariate analyzes and the study group was forced to

stay into the model. As both pneumonia and antibiotic use at inclusion had a p-value

below 0.15 and were strongly correlated, only antibiotic use was kept in the final

model. The interaction between the material and the shape of the cuff was tested in

the Cox model. A p-value below 0.05 was considered significant. The statistical

analyses were conducted using the SAS 9.3 software (Cary, North Carolina).

RESULTS

A total of 621 patients were included between July 2010 and November 2012.

Among these patients, 10 refused subsequent participation and 7 were secondarily

found to have a non-inclusion criterion – 6 under curatorship and 1 not able to

understand French -, leading to a total of 604 patients included in the intention to

treat analysis (figure 1). Thirteen patients received a different cuff than allocated, in

all cases because the appropriate tubes had not been replaced in time when



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changing from a cluster to the following one. With respect to the intention to treat

principle, these patients were kept in their group of randomization. In the group “PVC

cylindrical”, 2 patients received a PVC conical and 1 a PU conical cuff. In the group

“PU cylindrical”, 1 patient received a PVC cylindrical, 1 a PVC conical and 1 a PU

conical cuff. In the group “PVC conical”, 4 patients received a PU cylindrical cuff. In

the group “PU conical”, 3 patients received a PVC cylindrical cuff.

Table 1 shows the characteristics of the patients at inclusion. Main comorbidities

were diabetes (24.0% of the patients), chronic respiratory insufficiency (21.2 %) and

malignancies (14.4 %). Reasons for ICU admission were mainly acute respiratory

failure (48.5 %), altered consciousness (18.4 %) and septic shock (13.6 %). SAPS II

score was 43 [33-58] points and SOFA score was 6 [4-8] points. Vaso-constrictive

drugs were used in 41.6%, proton pump inhibitors in 39.9 % and antibiotics (mostly

beta-lactams) in 48.5% of the patients. Antibiotics were administered for pneumonia,

urinary tract infection, meningitis, soft tissue infection and intra-abdominal infection in

33.8 %, 9.9 %, 5.1 %, 2.7 % and 2.0 % of the cases respectively, and in 45.7 %

without a documented infection.

Duration of tracheal intubation and length of stay in the ICU were 5.4 [2.3-10.4] and

10.5 [5 - 18] days respectively (Table 2). Tracheal intubation was performed by oral

route in 97.7% of the cases, with a 7.5 mm diameter tube for 56.7% and a 8.0 mm

one for 41.2 %. Gastric tubes were inserted in 63.9 % of the patients, by oral route in

46.1 % and by nasal route in 53.9 %. It was used for aspiration in 60.6 % and feeding

in 39.4 %.

Airway management techniques at day 2 were used as follows (Table 3): oral

disinfection with chlorhexidin (94.8 % of the patients), use of a heat and moisture

exchanger (99.3 %), digestive decontamination with antibiotics (0.0 %), control of the



https://www.researchgate.net/publication/5970500_Influence_of_an_Endotracheal_Tube_with_Polyurethane_Cuff_and_Subglottic_Secretion_Drainage_on_Pneumonia?el=1_x_8&enrichId=rgreq-7cc11809-db3b-496a-8ceb-aa5fbfcf393c&enrichSource=Y292ZXJQYWdlOzI3MDk2NjQ4NDtBUzoyMDQwNTQ5NDU4OTg0OTZAMTQyNTY2MTg5ODI2OA==

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semi-recumbent bed positioning in the previous 6 hours (95.1 %), control of the cuff

pressure in the 6 previous hours (93.1 %), and use of a PEEP >= 5 cm H2O (72.7 %)

- 86.1 % of the patients were applied a PEEP >=3 cm H2O -. Steroids were used in

the 48 hours prior to extubation in 2.3 % of the patients.

Bacterial colonization of the trachea was greater than 103 cfu/mL on day 2 in 192

(31.8 %) patients and its incidence over time was similar in the 4 groups (figure 2a,

logrank test, p= 0.55), as well as for the 104,105 and 106 cfu/mL thresholds (table 4).

VAP occurred in 77 (14.4 %) patients (table 4) and its incidence over time was similar

in the 4 groups (figure 2b, logrank test, p = 0.28). The risk of VAP was similar in

patients with a feeding or a suctioning gastric tube (HR = 1.05 [0.87 ; 1.32], p =0.67).

At inclusion, the colonizing bacteria were mainly streptococci and staphylococci,

progressively replaced by Enterobacteriacae and P. aeruginosa over the first 7 days

of MV (figure 3). By comparison with French ones, the Tunisian patients were less

frequently colonized with streptococci, neisseria and staphylococci, and more

frequently with P aeruginosa (p = 0.02). Post-extubation stridor was experienced by

28 patients (6.4 %), similarly distributed among the 4 groups (p= 0.28). No interaction

was observed between the shape and the material of the cuff.

In univariate analyses, the factors associated with tracheal colonization over 103

cfu/mL at day 2 were pneumonia and use of antibiotic therapy at inclusion. In

multivariate analysis, the only factor associated with the occurrence of a tracheal

colonization at day 2 was antibiotic therapy (HR 0.76 [0.64-0.91], p = 0.002, table 5).

DISCUSSION

In this study, we observed that the use of cuffs made of PU and/or with a conical

shape, reduced neither bacterial colonization of the tracheal tree nor VAP over time



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in MV patients, by comparison with PVC cylindrical cuffs. The bacteria involved in

tracheal colonization were consistent with usual flora of ICU patients. The incidence

of post-extubational stridor was low in the four groups.

We designed this study because the cuff is the crucial interface between the tube

and the trachea that may be responsible for leakage of contaminated oropharyngeal

secretions leading to tracheal colonization and possibly to VAP. This leakage may be

the result of small channels formed by folds in the cuff (9, 10). While PVC and

cylindrical cuffs are the most routinely used devices, recent data suggests that PU

material and conical shape could better prevent VAP. PU allows for thinner and

stronger cuffs, leading to smaller folds (9). Because the trachea’s diameter varies

considerably throughout its length, a conical shape theoretically ensures that at some

point, cuff and trachea share the same diameter thereby preventing occurrence of

folds and improving tracheal sealing. These hypotheses were confirmed in a bench

(10) and a pilot study (16). Whether this improved sealing translates in to VAP

reduction remains unanswered, since studies have yielded conflicting results: (6, 11,

28, 29).

All these studies have limitations and we considered necessary to test the new cuffs

prospectively in a large unselected population. Tracheal colonization, assessed with

a quantitative technique, was chosen as our study’s principal endpoint because

colonization is an objective criterion and an essential step in the development of VAP

(23). We used a threshold of 103 cfu/mL (30) and performed additional analyses with

104, 105 and 106 thresholds. VAP was chosen as a secondary endpoint because,

while it is a major criterion of morbidity, its detection may be subjective (31). To

facilitate patient inclusion and group allocation and to prevent selection bias, the units

of randomization were pre-determined clusters of 9 or 10 consecutive patients.



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Neither colonization nor VAP was reduced by either of the devices. In terms of

comorbidities, reasons for ICU admission, and severity at inclusion, our population is

consistent with the usual ICU populations in the participating countries. The airway

management techniques we recommended (8, 22) were used with similar compliance

in the four study groups.

Tracheal colonization was already present at the time of intubation in a number of

patients (as a result of aspiration or prior lung infection). Whether the cuff influenced

tracheal colonization in these patients is obviously difficult to decipher. However, not

including these patients, which represent a noticeable proportion of patients admitted

to the ICU that require intubation, would have considerably reduced the

generalization of our results and would not have reflected the “real life”. This is the

reason why we chose to assess colonization on day 2, so as to give time for the cuff

to have an impact (or not). Importantly, the proportion of patients with prior tracheal

colonization was equally distributed in the four groups.

The use of antibiotics in 48.5 % of the patients had a preventive impact on tracheal

colonization (HR = 0.76 [0.64-0.91], p = 0.002). As already shown in many studies, a

majority of ICU patients are admitted to the ICU with lower respiratory tract infections

and/or receiving antibiotics. This impacts occurrence and microbiology of subsequent

VAP (32) and may prevent early-onset VAP (27). Thus, it is not surprising that both

pneumonia and antibiotic administration at inclusion were protective of tracheal

colonization at day 2. Despite this, a significant number of patients were still

colonized after day 2, and no effect of the cuffs was found. Because patients were

evenly distributed among the four groups, we believe groups were similarly affected

by prior antibiotic treatment.



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The absence of benefit we observed is contrasting with prior studies (6, 10, 11, 16,

29, 33) and may have several explanations. The different bench models demonstrate

that a constant level of PEEP is mandatory (10), and while we decided to use a 5 cm

H2O PEEP for all patients, it may suffer variations over daytime due to mobilization of

the patient, aspiration of the tracheal secretions or disconnection of the tube from the

ventilator. Selected populations such as scheduled surgery (11) have specific risk

factors for pneumonia, and the risk of gross aspiration during surgery is higher than

during long-term MV. The combined use of SSD in one study (6) may have played a

more important role than the cuff itself (5). The criteria to diagnose VAP were

heterogeneous across studies and their reproducibility has been frequently

questioned (31). Finally, the type of cuff may be less important than keeping it

adequately inflated at a constant pressure (7).

As in any negative RCT, the power of our study must be addressed. Our calculation

was based on a potential crude 15% reduction (from 30% to 15 %) of colonization on

day 2 between an intervention and the control group. This potential reduction was

consistent with the effect size observed in two studies testing similar devices in a

cardiac surgery population (11) or in combination with SSD (6). However, we did not

observe such an effect. The largest reduction we observed was 6 % (from 32% to

26% with a PU cylindrical cuff). The a posteriori power of our study can therefore be

estimated to 22% and the number of patients to include in a future study to 793 per

group. Considering the 9% cumulative occurrence of VAP at day 21 in our patients,

the number of patients to include with a hypothesis of a 2 % crude reduction in VAP

would be 1735 per group. This information could not be determined from the existing

literature. However, a 2% crude reduction in VAP is certainly not clinically significant

enough to be tested in a trial on VAP prevention.



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Our study has several limitations. First, it was open label because blinding the

intensivists to the tubes was considered impossible using marketed devices.

However, because the principal endpoint, i.e. colonization, was an objective criterion,

assessed on day 2, independently of the patient’s status, by microbiologists unaware

of the patients’ allocation when examining the samples, we believe this bias had

negligible impact on the study. Secondly, we randomized clusters rather than

individuals. We chose this design because we anticipated that individual

randomization would have run the risk of delaying intubation which could have been

detrimental to patients who required emergent intubation or of missing a substantial

number of patients. Creating clusters allowed each center to prepare the same

intubation set for any future patient during a period of one to two months. The

clusters we defined were small, reducing the risk of correlation between data of the

patients inside a same cluster (34). Thirdly, the centers had several differences in

reasons for admission, compliance to airway management procedures, diagnostic

criteria of VAP, and mortality. These differences were however well distributed

among the study groups. Finally, it was not possible to test the effects of SSD and

continuous monitoring of cuff pressure. Although these measures have shown

promising results in VAP prevention, they are not widely used (35) and confirmatory

studies are needed.

CONCLUSION

In this multicenter randomized trial, we could not show that cuffs made of

polyurethane or conically shaped were superior to conventional PVC cylindrical cuffs

to prevent tracheal colonization and pneumonia in patients under mechanical

ventilation.



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26

Figure legends

Figure 1 :

No legend

Figure 2 a :

Legend : Y axis : cumulative risk of occurrence of tracheal colonization

Figure 2 b :

Legend : Y axis : cumulative risk of occurrence of tracheal colonization

Figure 3:

Legend : each patient may be colonized with more than one bacteria



27

Tables

Table 1: Characteristics of the patients at inclusion. n (%) or med [IQ25-IQ75]

Group PVC, cylindrical PU, cylindrical PVC, conical PU, conical

Number of patients 148 143 150 161

Age 65.6 [53.0-77.2] 65.3 [55.2-75.6] 63.2 [53.4-76.4] 64.7 [51.1-78.0]

Male sex 83 (56.1) 92 (63.9) 91 (60.7) 96 (59.3)

Comorbidities

Diabetes 25 (16.9) 42 (29.2) 30 (20.0) 48 (29.6)

Cirrhosis 11 (7.4) 15 (10.4) 11 (7.3) 7 (4.3)

Chronic renal failure 12 (8.1) 16 (11.1) 13 (8.7) 15 (9.3)

Renal replacement 2 (1.4) 2 (1.4) 2 (1.3) 2 (1.2)

AIDS 3 (2.0) 2 (1.4) 4 (2.7) 4 (2.5)

Cancer / Hematologic malignancy 14 (9.5) 26 (18.1) 23 (15.3) 24 (14.8)

Organ transplant 2 (1.4) 1 (0.7) 0 (0.0) 2 (1.2)

Chronic respiratory failure, n(%) 33 (22.3) 33 (22.9) 24 (16.0) 38 (23.5)

Other 107 (72.3) 112 (77.8) 110 (73.3) 118 (72.8)

Reason for ICU admission

Acute respiratory failure 65 (43.9) 75 (52.1) 71 (47.3) 82 (50.6)

Coma, convulsive state 30 (20.3) 19 (13.2) 34 (22.7) 28 (17.3)

Septic shock 23 (15.5) 19 (13.2) 19 (12.7) 21 (13.0)

Other shock 5 (3.4) 5 (3.5) 3 (2.0) 8 (4.9)

Other 25 (16.2) 26 (18.1) 23 (15.3) 23 (14.2)

Severity at inclusion

SAPS II score 42 [33-58] 41 [33-58] 45 [33-58] 45 [33-57]

SOFA score 5 [4-8] 6 [4-8] 6 [4-8] 5 [4-8]

PaO2/FiO2 154 [95-239] 144 [89-227] 131 [92-230] 145 [93-251]

Chest X ray score >= 2 79 (53.4) 78 (54.2) 82 (54.7) 89 (54.9)

Blood platelets (G/L) 196 [138-278] 213 [136-284] 192 [137-272] 215 [158-285]

Serum creatinin (µmol/L) 94 [64-153] 100 [64-187] 94 [69-169] 93 [66-155]

Use of drugs at inclusion

Vaso constrictive drugs 25 (16.9) 36 (25.2) 33 (22.0) 42 (26.1)

Proton pump inhibitors 68 (45.9) 49 (34.0) 64 (42.7) 60 (37.0) Antibiotics 68 (45.9) 73 (50.7) 80 (53.3) 72 (44.4) Penicillin 11 (7.4) 15 (10.4) 17 (11.3) 10 (6.2) Penicillin + beta-lactamase inhibitor 20 (13.5) 21 (14.6) 20 (13.3) 17 (10.5) 1st or 2nd generation cephalosporin 3 (2.0) 0 (0.0) 3 (2.0) 0 (0.0) 3rd generation cephalosporin 31 (20.9) 33 (22.9) 38 (25.3) 34 (21.0) Carbapenem 3 (2.0) 4 (2.8) 1 (0.7) 5 (3.1) Aminoglycoside 4 (2.7) 9 (6.3) 6 (4.0) 5 (3.1) Fluoroquinolone 9 (6.1) 12 (8.3) 10 (6.7) 10 (6.2) Glycopeptide 2 (1.4) 2 (1.4) 5 (3.3) 2 (1.2) Other 25 (16.9) 21 (14.6) 27 (18.0) 39 (24.1)



28

Table 2: Length of stay in the ICU and exposure to tracheal and gastric tubes. n (%) or med

[IQ25-IQ75]

PVC,

cylindrical

PU,

cylindrical

PVC,

conical

PU,

conical

Number of patients 148 144 150 161

Length of stay in the ICU (days) 11.0 [5 – 18] 10.5 [5 – 18] 9.5 [5 – 17] 12.0 [6 – 19]

Tracheal intubation

Oral route (%) 145 (98.0) 140 (97.2) 147 (98.0) 158 (97.5)

Diameter = 7.5 mm (versus 8.0 mm) 82 (55.4) 79 (54.9) 86 (57.3) 94 (58.0)

Duration of tracheal intubation (days) 6.3 [2.1-11.6] 5.3 [2.2-9.1] 5.0 [2.1-9.0] 5.8 [2.5-11.3]

Gastric tube 100 (67.6) 94 (65.3) 87 (58.0) 105 (64.8)

Oral route (versus nasal) 52 (52.0) 40 (42.6) 42 (48.3) 44 (41.9)

Inserted for gastric aspiration 65 (65.0) 55 (58.5) 57 (65.5) 57 (54.3)

Inserted for gastric feeding 33 (33.0) 34 (41.5) 27 (34.5) 44 (45.7)



29

Table 3: Airway management and VAP prevention in patients present at day 2. n (%).

Group PVC,

cylindrical

PU,

cylindrical

PVC,

conical

PU,

conical

Number of patients at day 2 129 123 129 153

Oral disinfection with chlorhexidin 120 (93.0) 116 (94.3) 123 (95.3) 147 (96.1)

PEEP >= 5 cm H2O 93 (72.1) 85 (69.1) 102 (79.1) 108 (70.6)

Use of a HME 129 (100.0) 122 (99.2) 128 (99.2) 151 (98.7)

SDD with antibiotics 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Bed positioning control every 6 hours 124 (96.1) 117 (95.1) 120 (93.0) 147 (96.1)

Cuff pressure control every 6 hours 121 (93.8) 113 (91.9) 118 (91.5) 145 (94.8)

PEEP : positive end expiratory pressure HME : heat and moisture exchanger SDD : selective decontamination of the digestive tract



30

Table 4: Tracheal colonization on day 2 and VAP occurrence during the ICU stay. n (%) or

med [IQ25-IQ75]

Group PVC,

cylindrical

PU,

cylindrical

PVC,

conical

PU,

conical p

Number of patients at day 2 129 123 129 153

Tracheal colonization at 48 hours

Over 103 cfu/mL 0.66 [0.58-0.74] 0.61 [0.53-0.70] 0.67 [0.60-0.76] 0.62 [0.55-0.70] 0.55

Over 10

4 cfu/mL 0.55 [0.47-0.63] 0.50 [0.42-0.58] 0.57 [0.48-0.65] 0.50 [0.42-0.58] 0.44

Over 105 cfu/mL 0.41 [0.33-0.50] 0.38 [0.31-0.47] 0.50 [0.42-0.58] 0.42 [0.34-0.50] 0.12

Over 106 cfu/mL 0.23 [0.17-0.31] 0.27 [0.20-0.35] 0.32 [0.25-0.41] 0.29 [0.22-0.37] 0.56

Cumulative VAP during the stay, n (%) 14 (10.8) 21 (17.1) 17 (13.2) 25 (16.3) 0.20



31

Table 5: Factors associated with tracheal colonization over 103 cfu/mL on day 2. Cox

proportional hazard univariate and multivariate analyzis.

Univariate analysis Multivariate analysis

HR [IC95%] p

Type of cuff (study group) PVC -

Cylindrical 1.0 0.64 1.0

0.60

PU - Cylindrical 0.99 [0.76 - 1.29] 0.99 [0.76-1.30]

PVC - Conical 1.14 [0.88 - 1.46] 1.15 [0.90-1.47]

PU - Conical 1.08 [0.84 - 1.39] 1.06 [0.82-1.40]

Age (years) <50 1.0 0.99

[50-65[ 0.98 [0.76 - 1.28]

[65-80[ 0.98 [0.75 - 1.27]

>=80 0.96 [0.75 - 1.27]

Gender Male 1.17 [0.98 - 1.41] 0.08 1.17 [0.98-1.40] 0.09

Center A 1.0 0.62

B 1.15 [0.91 - 1.45]

C 1.03 [0.79 - 1.34]

D 1.03 [0.77 - 1.37]

SAPS2 at inclusion <33 1.0 0.16

[33-43[ 1.15 [0.89 - 1.49]

[43-58[ 1.32 [1.04 - 1.68]

>=58 1.19 [0.93 - 1.53]

Pneumonia at inclusion present 0.60 [0.49 - 0.73] 0.0001

Antibiotic therapy at inclusion present 0.76 [0.64 - 0.91] 0.002 0.76 [0.64-0.91] 0.002

Chronic respiratory failure present 0.90 [0.73 - 1.12] 0.34

Route of gastric intubation Nasal 1.05 [0.83 - 1.33] 0.69

PEEP level (cm H2O) >= 5 1.08 [0.91 ; 1.28] 0.37

Shape of the cuff Conical 1.11 [0.93 - 1.33] 0.24

Material of the cuff Polyurethane 0.97 [0.82 - 1.16] 0.77



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Figure 1:

Title: Flow chart



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Figure 2 a :

Title: Kaplan-Meier estimates of the time to tracheal colonization with over 103 cfu/mL bacteria.



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Figure 2 b :

Title : Kaplan-Meier estimates of the time to ventilator associated pneumonia (VAP).



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Figure 3:

Title : Bacteria recovered from the tracheal aspirates



Randomized intubation with polyurethane or conical cuffs to prevent pneumonia in ventilated

patients

François Philippart et al.

Supplemental appendix

Figure:

Distributions of the antibiotic use durations in each study group

Legend: y axis: antibiotic use duration in days



Table :

Types of bacteria in French and Tunisian patients with VAP

Paris area, France

Monastir, Tunisia (Monastir)

p-value

Species 0.02

S viridans 3 (5.7) 0(0)

S pneumoniae 1 (1.9) 1 (4.2)

Haemophilus spp 0(0) 1 (4.2)

Neisseria spp 1 (1.9) 0(0)

Straphylococci 8 (15.1) 1 (4.2)

Enterobacteriacae 15 (28.3) 4 (16.7)

P aeruginosa 19 (35.8) 10 (41.7)

Acinetobacter spp 1 (1.9) 7 (29.2)

Enterococci 1 (1.9) 0(0)



Randomized Intubation with Polyurethane or Conical Cuffs to Prevent Pneumonia in Ventilated Patients

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