This was a single-centre, randomised, single-blinded, and controlled, first in man, post Conformity Euro-permit (EC) certification and CE marking study. Patients undergoing elective surgery of the upper gastrointestinal tract with an expected duration of at least 3 h were asked to participate. The study was conducted at a Karolinska University Hospital in Sweden and approved by the Ethical Review Board in Stockholm (Dnr 20121205–31, protocol number 1842-2026-CDOC). Written informed consent from each patient was obtained before entry into the study. All patients signed a written informed consent before participating in the study. The study is outlined in clinicaltrials.gov database with the identifier: NCT01682486.
Investigational device BIP ETT
BIP ETT is an endotracheal tube designed for insertion through the mouth or nose. The, in- and outside surfaces are coated with the Bactiguard® coating (Sweden) which consists of a noble metal alloy of silver, palladium and gold, which reduces bacterial adhesion in-vitro. The latter phenomenon is a contributing factor to microbial colonisation and biofilm formation, which in turn increases the risk for VAP. The BIP ETT is made from medical grade polyvinyl chloride (PVC). It is a sterile single use 100 % latex free, two-lumen tube (one lumen connected to a high volume low pressure cuff with a standard connector), has a Magill curve and rounded tip with a Murphy eye.
Standard uncoated ETTs made of PVC, normally used for intubation at the investigators site (Mallinckrodt™ ETT) with standard labelling, were used as reference devices. They were sterile single use 100 % latex free, two-lumen tubes (one lumen connected to a high volume low pressure cuff with a standard connector), had a Magill curve and rounded tip with a Murphy eye.
Inclusion criteria were adults ≥18 years of age, requiring endotracheal intubation ≥3 h needing an endotracheal tube sized 7 or 8 mm. Exclusion criteria were cognitive dysfunction (i.e., inability to understand and fill out the study questionnaires), transmissible blood disease, multi-resistant bacterial colonization, current or continuous treatment with immune modulating therapies, e.g., systemic (or inhalation) use of cortisone or non-steroid anti-inflammatory drugs (NSAID), on-going respiratory infection, as well as deficient poor skills in writing and or speaking Swedish.
Screening and randomization
The list of scheduled major surgery eligible patients were identified and scanned and thereafter screened by reading the patients’ journal. Eligible patients were later approached for information and consent. In total, 30 patients were screened and 30 patients were enrolled in the study. The enrolled patients were randomised to airway management during anaesthesia and surgery with either the BIP ETT (n = 20) or standard ETT (n = 10). The randomisation was designed to distribute the patients in a ratio of 2:1 in favour of the BIP ETT group. One patient in the BIP ETT group was prematurely withdrawn from the study due to vomiting during induction of anaesthesia. The patient then needed a rapid sequence induction and therefore, pre-intubation bronchoscopy could not be carried out. Therefore, the patient was withdrawn from the study.
The difference between the treatments (BIP ETT versus standard ETT) for each of the 8 questions in the modified European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Head & Neck with 35 questions (QLQ H&N35) , on the day after tracheal intubation.
The difference between treatments (BIP ETT versus standard ETT) in photo assessment (blinded assessment), and direct assessment (unblinded assessment) of the surface tracheal lining, before intubation and after extubation.
Safety assessed based on adverse events (AE) and serious AEs (SAEs) and on any problems occurring during the post-operative course (Yes/No).
Performance assessed by bacterial colonization of BIP ETT versus standard ETT, microbiological testing of bacteria from a defined area of the ETT surface ex vivo (quantification and typing).
Demographics, smoking habits, medical history of significance, and concomitant medication were assessed prior to surgery. The study comprised of four visits; a telephone contact by a study nurse to inform the patient about the study and send the written patient information to the patient up to 28 days prior to screening (Visit 1); a screening visit 1 to 14 days prior to surgery when also the informed consent form was signed and demographic data, medical history gathered and physical examination was performed (Visit 2); the actual day of surgery/intubation (Visit 3), and a follow-up on the day after surgery (Visit 4).
The study intervention was carried out at Visit 3. As the patient arrived in the operating theatre, local routines were followed. No lidocaine or lubricating jellies were used in conjunction with the ETT. Prior to intubation of the ETT, the endotracheal cuff was inflated as a test. The intubation was carried out after a bronchoscopy where the ETT was pulled over the fiberscope, and the cuff pressure was kept below 20 cmH2O if possible. Endotracheal cuff pressures were recorded using an intra-cuff monitor, and the pressure was recorded during the anaesthesia. After induction of anaesthesia, the number of intubation attempts and the need for other intubation devices were recorded, as well as any injuries to lip, tongue or teeth. The ETT was not to be repositioned unless necessary. During extubation, a bronchoscope was again placed in the trachea through the ETT. The ETT was then removed and the trachea inspected. The time for intubation and extubation, as well as the type of fibre-optic bronchoscope were noted. The medical techniques and aseptic procedures used were according to currently accepted practice.
Assessments of tolerability
To assess the tolerability of the BIP ETT, a modified version of the head and neck module of the questionnaire developed for assessing quality of life was used (Quality of Life Head and Neck Module, QLQ-H&N35) . The questionnaire was originally developed by the European Organization for Research and Treatment of Cancer (EORTC) . In the present study, eight of the questions, which assessed symptoms that can occur after intubation, were used. Permission to use the adjusted version was obtained from EORTC. The selected questions were the following (the original question number in the EORTC QLQ H&N35 within parenthesis):
Have you had pain in your mouth? (31)
Have you had pain in your jaw? (32)
Have you had soreness in your mouth? (33)
Have you had a painful throat? (34)
Have you had problems swallowing liquids? (35)
Have you had a dry mouth? (41)
Have you coughed? (45)
Have you been hoarse? (46)
Each patient indicated the extent to which he/she had experienced these symptoms or problems as “Not at all”, “A little”, “Quite a bit” or “Very much”. The questionnaire was completed by the patients at 2 time points in time; prior to surgery (Visit 3, to cover the past 24 h) and in the morning of the first post-operative day (Visit 4, to cover the period post-surgery). The baseline was established before surgery in order to be able to distinguish between the intensity of symptoms in relation to the tube alone and not the patient’s condition prior to surgery.
In order to detect any changes in the tracheal mucosa correlated with the ETT, visual inspections were carried out by an anaesthesiologist/surgeon both before intubation and after extubation using a flexible fibre-optic bronchoscopy. The assessments were formulated using the following 4-graded scale:
No signs of irritation/inflammation of the mucosa in the trachea
Weak signs of irritation/inflammation of the mucosa in the trachea
Clear signs of irritation/inflammation of the mucosa in the trachea
Extensive signs of irritation or extreme discoloration/inflammation of the mucosa in the trachea
Assessments of performance and safety
Safety and Performance were assessed after surgery (Visit 3 and Visit 4) by noting Adverse Events, occurrence of complications during the post-operative course and any ETT handling problems experienced by the staff. It was the duty and right of the investigator to interrupt the patient’s participation if the patient’s health or well-being was threatened by continuation in the study. A patient could be discontinued if e.g., wrong ETT was placed by mistake. Further, concomitant medications could require a patient’s discontinuation. However, each case of withdrawal was to be discussed individually with the Sponsor prior to any decision of discontinuation, unless the decision was based on safety reasons. The pre-defined reasons for patient withdrawal were as follows:
Serious life threatening AE, related or unrelated to the treatment in test (i.e., the ETT). This could be events such as critical bleeding, myocardial infarct, urticaria, angioedema chock and asthma bronchiale.
Patient’s own request
Investigator’s opinion that it is in the patient’s best interest to discontinue. The reason, time and date of discontinuation had to be recorded in the eCRF.
Exploratory assessments of microbial adhesion to endotracheal tubes
Immediately after extubation, the distal piece of the ETT was cut with a sterile pair of scissors precisely above the cuff into a sterile tube containing PBS (Phosphate Buffered Saline) covering the tube to keep microorganisms alive. The container was immediately transported to the Department of Clinical Microbiology, to assess the quantity and type of pathogen and/or non-pathogen microbes. The antibiotic resistance of pathogen microbes (if those were found) was also to be determined.
At arrival in the lab, the tube was vortexed vigorously in order to remove mucus from the ETT piece. The ETT piece was then moved to a new tube containing 30 mL of PBS, washed by vortexing and if needed repeatedly washed until all visual mucus was removed. Thereafter it was put in another tube containing 10 mL PBS and 0.05 % Tween-20. In order to remove the adhered microorganisms from the surface it was vortexed for 1 min at maximum speed. The PBS-Tween solution with the removed microorganisms was diluted and plated out according to standard procedures for clinical airway sampling at the Dept. of Clinical Microbiology, and evaluated by viable count and microbiological typing the following day [20–22].
In this exploratory study, 30 patients (20 patients in the BIP ETT group and 10 in the uncoated, standard ETT group) were judged to be needed in order to reveal statistically significant differences in the primary analyses. With an estimated drop-out rate of 20 %, the expected number of evaluable patients was 24. At the end, 29 patients were evaluated (19 in the BIP ETT group and 10 in the standard ETT group).
For the 8 questions used from the EORTC QLQ H&N35, the difference between the treatment groups on the day after surgery were tested with Fisher’s Exact Test. Confidence intervals (95 %) of the proportion of patients for each treatment were calculated using the Clopper-Pearson method. The questions after surgery were analysed with a Proportional Odds Model, specifying a multinomial distribution and cumulative logit link. The model included the answer of the respective questions before surgery as a covariate, and tested the difference between the treatments using the likelihood ratio statistic. The proportional odds assumption was tested with the Score test. If more than 4 of the 8 score tests rejected the null hypothesis of proportional odds, then an extended Mantel-Haenzel analysis controlling for the EORTC QLQ H&N35 answer before surgery were to be applied for each of the questions.
Differences between the treatment groups of assessed changes in the tracheal mucosa, on the 4-graded scale, were analysed using Fisher’s Exact Test. Confidence intervals (95 %) of the proportion of patients for each treatment were calculated using the Clopper-Pearson method.
Direct assessment after extubation was also to be analysed using a Proportional Odds Model, including the evaluation/judgement prior to intubation as a covariate. However, since all patients in the standard ETT treatment group were in the same category at extubation, the Proportional Odds Model analysis was not applicable.
Adverse events (AEs) and adverse device related events (ADEs) were coded using MedDRA version 15.1. No statistical tests were carried out but an overall summary of the number and proportion of patients and the number of events in each AE category (AE, SAE (Serious AE), ADE, SADE (Serious ADE) was made. However, since only one AE was reported, no tabulation of AEs/ADEs was carried out. Problems during the post-operative course are presented with descriptive statistics by treatment group (number and proportion of patients). Problems related to the ETT handling were presented in descriptive statistics by treatment group as the number and proportion of patients in each category (Yes/No).