Introduction
Ventilator-associated pneumonia (VAP) is a hospital-acquired infection that occurs in invasively mechanically ventilated patients as a result of aspiration of secretions contaminated with microbial pathogens, or colonisation of the endotracheal tube (ETT) with pathogens following intubation.1 VAP causes significant morbidity, mortality and increased healthcare costs among critically ill patients.2 It has been shown to increase the duration of mechanical ventilation by approximately 7 days, intensive care unit (ICU) stay by 8 days, hospitalisation by 11 days and is estimated to cost $C11 000 per occurrence.3 4 VAP-attributable mortality is estimated to be between 6% and 13%, which increases if it occurs in high-risk populations, or if therapy is inadequate or delayed.4 5 VAP incidence is approximately 10–20 cases/1000 ventilator days6 and can afflict approximately 50% of mechanically ventilated COVID-19 patients.7 The continued frequent occurrence of VAP was demonstrated in a recent large multicentre study that found a VAP incidence of 21%, or 23 cases/1000 ventilator days.8 Despite efforts made to reduce the incidence of VAP, it remains a prominent risk to patient health and incurs significant costs to healthcare systems.
Efforts to prevent VAP have focused on reducing the occurrence of aspiration, such as through head-of-the-bed elevation, decontamination of the oral cavity with chlorhexidine9 10 or modifications of the ETT.11 Strategies to modify the ETT, such as adding an extra port to suction accumulating secretions above the cuff, have been shown to reduce the incidence of VAP but have not been consistently shown to have a significant impact on mortality, patient-centred outcomes, cost-effectiveness or antibiotic utilisation.12–14 Further, concerns regarding the extra suction port and associated risk of tracheal injury have also been raised.15 An additional area of focus for VAP prevention is the reduction of biofilm formation on ETTs. After intubation, biofilm rapidly accumulates on ETTs from the colonisation of bacterial and fungal pathogens.16 Both interior and exterior biofilm formation has been found to occur on all ETTs removed from patients.17 18 Micro-organisms colonising ETTs can precipitate the production of cytokines, act as a reservoir for infection, are difficult to eradicate and may promote multidrug resistant strains through gene transfer among bacterial species.19 The pathogens reported from ETT biofilms include Pseudomonas, Staphylococcus aureus, Streptococcus species and other pathogenic Gram negatives, including antibiotic-resistant organisms.20
It is known there is a correlation between biofilm formation, colonisation of ETT with pathogens and VAP.16–18 21 However, there is limited evidence for strategies that reduce biofilm and colonisation to reduce the incidence of VAP. A randomised controlled trial (RCT) found reduced biofilm formation and endotracheal colonisation with the use of silver-coated ETTs.22 Another larger multicentre RCT found silver-coated ETTs reduced VAP rates by 36% overall and by 48% in patients intubated for 10 days or less.23 However, this ETT was not widely adopted due to cost and has since been discontinued. These studies have highlighted that the relationships between ETT biofilms, VAP and novel preventative approaches warrant further investigation.
A new approach for the reduction of ETT biofilms is coating ETTs with ceragenins (CSAs), which are synthetic cationic cholic acid-based mimics of antimicrobial peptides resembling components of the human immune system.24 25 CSAs have potent antimicrobial properties and are rapidly bactericidal, fungicidal and virucidal against a wide array of clinically relevant pathogens, including Pseudomonas, Acinetobacter and MRSA.25 They have also demonstrated the ability to prevent bacterial and fungal biofilms, which are nearly impossible to eradicate using conventional antibiotics and antifungals.26 Early preclinical testing has demonstrated that CSAs protect microbial colonisation of ETTs.27 A Health Canada regulated pilot feasibility and safety study of a novel CSA ETT (CeraShield ETT—N8 Pharma, NCT03716713)) found very low rates of microbial colonisation on the ETT. There were no observed device failures, malfunctions, safety concerns or device-related adverse events. This ETT is currently licensed for use by Health Canada, however, larger controlled studies are required to determine whether the low colonisation and bacterial burden observed in this preliminary study are superior to those seen with standard ETTs currently in use, and whether this CSA ETT reduces the incidence of VAP.
The present study will investigate the ability of CSA-coated ETTs to reduce the incidence of VAP through a prospective, longitudinal, cross-over, interrupted time, implementation study design. The primary outcome will be the occurrence of VAP. Secondary outcomes include antibiotic utilisation, healthcare utilisation, airway outcomes (incidence of postextubation stridor, lack of ETT cuff leak and reintubation) and feasibility outcomes (including acceptability among staff and patients, resource utilisation, safety events and the availability and suitability of data generated from routine care). It is hypothesised that CSA ETTs will reduce the incidence of VAP and improve clinical outcomes, including antibiotic utilisation, when compared with ETTs currently in use.
Methods
This study is ongoing and the protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (see attached SPIRIT checklist).28
Study design and implementation
This is a prospective, single-centre, longitudinal, cross-over, interrupted time, implementation study aiming to evaluate the efficacy of the CSA ETT compared with the standard-of-care ETT currently in use (Covidien ETT with subglottic secretion drainage) in critically ill mechanically ventilated patients. This study takes place at Kingston Health Sciences Centre, a tertiary university affiliated (Queen’s University) teaching hospital in Kingston, Canada. Completion of this study will provide feasibility data and preliminary evidence of efficacy, allowing for the conduct of a definitive multicentre cluster randomised trial.
The design of the study is outlined in figure 1 with four study periods of 11–12 weeks each separated by a washout period in which routine practice is resumed with the standard ETT in use. For the first study period, one type of ETT will be used followed by a washout period of 2 weeks. In the subsequent study time period, the second type of ETT will be used followed by a washout period. In the third study time period, we will revert back to the first ETT followed by the fourth time period in which the second type of ETT will be used. The washout period will ensure that only one type of ETT is in use during each study period (figure 1).
Study implementation design highlighting discrete periods with either conventional endotracheal tubes or CeraShield endotracheal tubes followed by 2-week washout periods. CSA, ceragenins; ETT, endotracheal tube; SSD, subglottic secretion drainage.
For study implementation, all ETTs in the emergency department, critical care units, intubation kits and on resuscitation carts will be replaced at the start of each intervention period. Since intubations occurring in the operating room (OR) are usually short term and use standard ETTs without subglottic secretion drainage, they will not be included in the present study. If a patient is anticipated to require mechanical ventilation and ICU care after the OR, the study ETTs will be available to OR staff and they will be encouraged to use the ICU ETT in use during the applicable study period. The CSA ETTs are operationally identical to currently used ETTs, minimising the education required for staff. In our previous feasibility study, there were no operational issues noted. Clinicians will select the size of the ETT clinically indicated as per usual. All care, including antibiotic prescribing, will be at the discretion of the treating clinician. All relevant departments including anaesthesia, emergency medicine and critical care medicine have provided approval for this study.
To minimise bias, the order of the ETT implementation (ie, whether the first time period will be standard ETT or CSA ETT) was determined randomly using a random number generator. With this, the first study period was selected to be done with the CSA ETT. To reduce the impact of seasonal variation in the types of critical illness admitted to the ICU, a study time period of 11–12 weeks has been selected to allow utilisation of both types of ETTs within broad seasons. Study recruitment and implementation began in February 2023.
Data collection and outcomes
Data will be collected on all patients who receive the study ETT within the study period. No study-specific procedures will be completed, and only data generated from routine clinical care will be collected. All microbial cultures and antibiotic prescriptions will be at the discretion of the treating clinician. We will collect data on all positive cultures including respiratory and blood cultures during the patients and data on all antibiotic utilisation. Data will be collected and securely stored in a Research Electronic Database Capture database hosted at the Queen’s University Center for Advanced Computing.29 30
The primary outcome will be the occurrence of VAP defined as new, progressive or persistent radiographic infiltrate on chest radiograph plus any 2 of the following: (1) hyperthermia (temperature >38°C) or hypothermia (temperature <36°C); (2) white cell count less than 3.0×109/L or exceeding 10×109/L and (3) purulent sputum.31 32 Other data will also be collected to permit the measure of VAP using other definitions, specifically bacterial culture quantification and speciation.33 34
Since clinicians and study personnel cannot be blinded to the intervention and VAP may be partially subjective, all cases of VAP (the primary outcome) will be adjudicated by an adjudication committee blinded to the type of ETT analogous to a Prospective, Randomized Open, Blinded End-point (PROBE) trial.35 The adjudication committee will be composed of two ICU clinicians who will be given patient data including clinical notes, microbiology, antibiotic and radiological data blinded to the type of ETT used.8 36 Disagreement will be resolved by consensus between the two reviewers and through a third reviewer if agreement cannot be reached.
The following clinical secondary outcomes will be evaluated to assess the morbidity associated with VAP: (1) antibiotic utilisation, measured as antibiotic-free days defined as the number days alive and not receiving antibiotics in the 28 days after intubation37; (2) healthcare utilisation outcomes including duration of mechanical ventilation and ventilator-free days defined as the number of days live and free of invasive mechanical ventilation in the 28 days after intubation,38 duration of ICU stay, duration of hospital stay and hospital mortality and (3) airway outcomes including incidence of postextubation stridor, lack of ETT cuff leak (standard evaluation on all intubated patients) and rate of reintubation within 48 hours of extubation.39
Feasibility outcomes will be collected to inform the design of a multicentre cluster randomised trial. Data will be collected on the acceptability of the intervention (survey of staff including physicians, respiratory therapists and nurses) using the Acceptability of Intervention Measure,40 resources required for implementation (from ICU management), preliminary evidence of efficacy to inform sample size for the future study (from the primary and secondary clinical outcomes), adverse events directly attributed to the ETTs and the availability of data generated from routine care. For the future conduct of large cluster randomised trial, acceptable availability of routinely collected data is defined as less than 10% missing data.
Since we are studying two operationally equivalent types of ETT that are both licensed for human use and will not be subject to different standards of care, this study does not have a data monitoring committee.
Sample size and statistical analysis
All critically ill adult patients with respiratory failure requiring intubation and who receive the assigned ETT during the respective study periods will be included. Patients admitted to the hospital or ICU with a non-study ETT already in place and those unable to be intubated with a study ETT will be excluded. We will also exclude patients with a tracheostomy on ICU admission and those who decline participation in research in general or data collection. There will be two a priori specified subgroups: (1) patients who are intubated for greater than 48 hours and (2) patients in whom a tracheotomy is performed according to clinical indications. The tracheostomy will be performed with a standard tracheotomy tube.
Each ETT will be used for two study periods of 11–12 weeks, with an anticipated enrollment rate of 100 mechanically ventilated patients during each study period based on current centre data.8 This yields an estimated 200 patients for each type of ETT or a total sample size of 400 patients overall. With a baseline VAP incidence of 20%, 200 patients per group and a type 1 error rate of 5%, there will be 80% power to detect a relative risk of 0.50 or a 50% reduction in VAP using a Z-test for two proportions. Although not powered to detect small differences between the ETTs, this study is not designed as definitive, and the data collected will be used to determine the acceptability and feasibility of a larger definitive study.
To account for potential clustering, a modified Poisson regression model with robust SEs controlling for intervention period, calendar season and admission diagnosis will be used to determine a relative risk of VAP using the CSA ETT versus the standard ETT.
For secondary outcomes, between-group differences in ventilator-free days and antibiotic-free days will be assessed via a Wilcoxon rank-sum test. Differences in incidence of postextubation stridor, lack of cuff leak and reintubation will be assessed via a χ2 test. Differences in duration of ICU stay and hospital stay will be assessed via the Fine and Gray subdistribution hazards model to account for death as a competing risk.41
A priori set targets will be used to determine feasibility. For acceptability of the intervention, 80% of surveyed staff and patients/substitute decision-makers will need to indicate acceptability to be deemed feasible. Resources required for study implementation will be recorded and will need to be similar between study periods. Sample size considerations supported by preliminary evidence of efficacy will determine the size and resources required for the definitive study and will also inform its feasibility. It will be important for the conduct of future studies that only data generated from routine care be used to ensure generalisability for wide-scale implementation; less than 10% missing data will be considered acceptable a priori. Adverse events directly attributed to the ETTs will be assessed via a χ2 test or Fisher’s exact test if expected cell counts are less than 10.
Timeline
Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (HSREB) approval was obtained in August 2022. Study recruitment for the first study period began in February 2023 and the study is currently underway. With four study periods of 11–12 weeks (23 weeks for each type of ETT) and three wash-out periods of 2 weeks, allowing for delays, total study duration will be approximately 12 months (figure 2).
Anticipated study timeline beginning with Queen’s University Health Sciences and Affiliated Teaching Hospital Research Ethics Board (HSREB) approval and finishing with dissemination of results. VAP, ventilator-associated pneumonia.
Patient and public involvement
Patient views and experiences were not accounted for in the design of this study since intubation is emergent or urgent (not an elective procedure) among patients with respiratory failure. Both types of ETT are licensed for clinical use and can be used to deliver mechanical ventilation, allowing for limited ability to guide study design. However, patient and public involvement will be conducted to guide interpretation of study results where there may be differences between the two types of ETTs in the number of adverse events, clinical outcomes and healthcare costs. At the end of the study, we will convene a panel of ICU survivors to assess the acceptability of the study interventions. Patient perspective data will help inform future implementation efforts.
Ethics and dissemination
This study comparing two Health Canada-approved devices has been approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (HSREB) and is currently ongoing. Only data generated from routine care will be collected. The decision to intubate patients, the size of the ETT, decisions regarding extubation and antibiotic prescribing will all be at the discretion of the clinicians caring for mechanically ventilated patients. Only data necessary for the determination of the primary and secondary study outcomes will be collected, with no additional biological sampling or data collection mandated in the study protocol. Protocol modifications, if any are needed, will be approved by the HSREB and the trial registry will be amended.
For these reasons, a deferred consent model will be used. Deferred consent is acceptable under conditions specified in the 2018 Tri-Council Policy Statement 2 (TCPS2).42 This study meets all stated requirements since two Health Canada-approved devices are being compared, the study is of minimal risk, it is impractical to get consent prior to intubation and the type of ETT used during each study period will be considered the standard of care. Additionally, to comply with Article 3.7A ‘e’ of TCPS2,42 an information sheet will be distributed to the participants or their substitute decision-makers (see online supplemental material). Although it will not be possible to change the ETT due to the hazards of changing the ETT, participants will be able to opt out of data collection.
Supplemental material
The trial results will be presented at conferences and published in peer-reviewed journals irrespective of results. Only the investigators and study coordinators will be eligible for authorship. Participant-level data will not be made available.
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