Comparison of Double-Lumen Tube and EZ-Blocker for Lung Separation in Thoracic Surgery - A Randomised Controlled Clinical Trial

A randomised, controlled trial was conducted in 80 patients undergoing elective thoracic surgery using DLT or SLT plus EZB for lung separation (German Clinical Trial Register DRKS00014816). The objective of the study was to compare the clinical performance of EZB with DLT. Primary endpoint was total time to successful lung separation. Secondary endpoints were time subsections, quality of lung collapse, diculty of intubation, any complications during the procedure, incidence of objective trauma of the oropharynx and supraglottic space and intubation-related subjective symptoms.

There are many different airway devices on the market to establish lung separation for thoracic surgery (e.g. double-lumen intubation, bronchus blocker) (1). The worldwide most used procedure is the doublelumen tube (DLT) technique. DLT intubation has certain disadvantages, including an increased risk ofairway trauma (2)(3)(4), improper sizing and requirement for replacing it with a single-lumen tube (SLT) if postoperative ventilation is needed in the ICU. DLT intubation is more challenging compared to SLT intubation (2,5,6). These disadvantages have resulted in the development of bronchus blockers (BB). BB such as the Univent torque control blocker, the wire-guided endobronchial Arndt Blocker and the Cohen Flex-tip Blocker represent alternatives to DLT intubation (7)(8)(9). In addition to these established BB devices, the EZ-Blocker™ endobronchial blocker (EZB) (AnaesthetIQ BV, Rotterdam, The Netherlands), was introduced in 2010 in clinical practice (10). Contrary to the classic shape of 'single-ended' BBs, the 'double-ended'EZB has a Y-shaped distal end that mirrors the bifurcation of the trachea and has cuffs on both ends. Lung separation is achieved by in ating or de ating the bifurcated cuffs of the left or right side at the relevant main bronchus. The EZB presumably is easy to handle, with a low rate of malposition and fewer dislocations during repositioning and surgical manipulation. Safe and easy use of EZB has been described by researchers before (11,12). Previous studies have shown that severe trauma and major complications like bronchial rupture were rare complications when using EZB (13).
To our knowledge, only a few trials have assessed the performance of EZB in comparison with DLT or other BB (14)(15)(16)(17). Recent studies demonstrated longer times for placement of EZB in spite of shorter intubation times with SLT and equal e ciency for SLT plus EZB compared to DLT (16,17). Presumably, this new EZB device needs longer process times for lung separation. In terms ofairway trauma and patient-centred outcome parameters, e.g. the incidence of hoarseness, the literature shows con icting results (16,17).
We investigated the impact of using SLT plus EZB instead of DLT for lung separation. We focused our investigation on the time needed for correct placement and successful lung separation. In contrast to other studies, in addition to questionnaires; we performed a exible endoscopic investigation before and 24 hours after extubation for greater objectivity.

Methods
This study was approved by the University's Institutional Review Board (Ethikkommission Marburg, AZ17/18, 16.05.2018) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrolment at the German Clinical Trials registry DRKS (DRKS00014816, Principal investigator: Dr. Joachim Risse, Date of registration: 07.06.2018). This randomised controlled and patient-blinded trial adhered to the CONSORT guidelines. This study was performed in compliance with recognised international standards, including the principles of the Declaration of Helsinki. This study uses established methodology from a previously published work of our Airway Research Group with the focus on thoracic anesthesia; therefore there are similarities and overlaps in the methodology (18). After providing written informed consent, adult patients scheduled for elective thoracic surgery requiring general anesthesia with the need for lung separation with American Society of Anaesthesiologists physical status I-IV were enrolled from 11.06.2018 until 14.02.2020.
Exclusion criteria were patient age < 18 years, non-elective surgery, pregnancy, scheduled rapid sequence induction (RSI), contraindication for DLT insertion or lung separation as well as abnormal physical status of the cervical spine.

Primary endpoint
Primary endpoint is the duration for correct placement of the different devices to separate the lungs for thoracic surgery (s). The total time measured for lung separation (s) consists of the following three time segments: preparation time (s), time to successful intubation (DLT or SLT) (s), time for placement of EZB and lung separation (time for bronchoscopic position check (s) plus the time required for correct placement (s)).
Preparation time (s) consisted of the measured time segments: time for device preparation (s) and time for bronchoscope preparation (s).
The time for successful intubation was de ned as: blade passes mouth opening until positive capnography (visualisation of three expirations by capnography).
The time for bronchoscopic position check (s) was de ned as: insertion of the bronchoscope until the current position is recognised. In the event of incorrect position of the device for lung separation, the additional time required for correction was measured. The time for correct placement (s) was de ned as: start correction of current position until end of bronchoscopy and approval by the responsible performing anaesthesiologist. All time spans were measured and recorded by an independent investigator.

Secondary endpoints
In addition to total time for lung separation (primary endpoint) we analysed all the different time subsections as secondary endpoints. Further secondary endpoints of this study were quality of lung collapse, number of intubation attempts, assessment of di culty, any complications and incidence of intubation-related injuries in both groups.
Quality of lung collapse was assessed by the surgeon (blinded to the randomisation result) under direct (thoracotomy) or indirect view (thoracoscopy). Classi cation of lung collapse was made on a three-point-Likert scale as previously described: 1. excellent (complete collapse with perfect surgical exposure); 2. moderate (total collapse, but still some air in the lungs); 3. insu cient (no collapse or partial collapse with interference in surgical procedure) (17,19).
Intubation-related injuries were investigated by two consecutive exible endoscopic examinations (at the end of surgery and on postoperative day one (POD1)). We examined the oral cavity, the oropharynx, the supraglottic space, the vocal cords and the trachea. A follow-up survey by questionnaire according to an established protocol (18) was performed on POD1.

Sample size calculation
The sample size calculation was based on a previous study (17), which reported a mean placement time of 85 ± 55 seconds in the DLT group and 192 ± 90 seconds in the EZB group. Based on these results, an a priori power analysis was performed for the primary endpoint given a beta value of 0.80 and a signi cance level alpha of 0.05. We calculated a minimum required sample size of 37 patients per group to detect a 15% difference in the time taken for placement of DLT or SLT plus EZB. Because of assumed drop-outs, we added a surcharge of three patients per group to achieve a study sample size of at least 80 patients. Power analysis was performed using G*Power3.1.9.6 for Mac OS X (20,21).

Randomisation and allocation concealment
Allocation concealment was achieved using sealed opaque envelopes. Performance blinding was not possible due to study design. Patients and study investigators assessing postoperative outcome parameters were both unaware of the randomisation result. Statistical analysis was performed blinded to study allocation.

Preoperative assessment
Patients were pre-medicated with 3.75-7.5 mg oral midazolam 45 minutes before surgery. In the induction area, patients were positioned supine, standard monitoring was applied according to current national guidelines and peripheral intravenous access was established. Patients received pre-oxygenation with 100% oxygen through a mask over ve minutes. After pre-oxygenation, anesthesia was induced with 0.3 µg kg − 1 sufentanil and 2 mg kg − 1 propofol intravenously. Thereafter, 0.6 mg kg − 1 rocuronium bromide was applied. Neuromuscular monitoring was performed by relaxometry train of four (TOF). Intubation was performed when full relaxation status (TOF 0/4) was reached. Maintenance of general anaesthesia was performed as total intravenous anaesthesia (TIVA) according to the local standards using propofol (4-6 mg kg − 1 h − 1 ) and remifentanil (15-25 µg kg − 1 h − 1 ) adjusted according to the measured anaesthetic depth using bispectral index monitoring (BIS) at a target of 40-60.
The size of the DLT (RüschBronchopart; Tele ex Medical GmbH, Dublin, Ireland, 35-41 FR) used was determined for each patient according to Slinger et al. (22). Only left-sided DLTs were used in this trial. Intubation was performed using a conventional MacIntosh blade (size 3 or 4) as the rst line in both groups. In case of di culties, an intubation attempt with videolaryngoscopy (GVL) was allowed (GlideScope® size 3 or 4). All intubations were performed by the same four experienced anaesthesiologists with extensive training in all types of lung separation techniques including a training course explaining the standardised handling of EZB before starting the study. All bronchoscopies were performed with the Ambu® Broncho aScope 4 slim3.8/1.2 with the associated Ambu® aViewTM monitor ( Fig. 1). A bronchoscopic check of the position of DLT or EZB and the time measurement were performed rst directly after successful intubation. Correct placement of the respective device was rechecked again after patient positioning before starting the surgical procedure.

Postoperative assessment
The rst endoscopic examination was performed at the end of surgery before extubation orally under general anaesthesia, while the follow-up endoscopic examination was performed transnasal on POD1 under topical anaesthesia. Stored endoscopic video clips were postprocessed for anonymisation and blinding. Thereafter, they were evaluated by three independent investigators (investigator-blinded). The hypopharynx, the vocal cords and the arytenoid cartilage were evaluated on the basis of various criteria.
The different criteria were scored from according to the degree of injury (0 = not assessable, 1 = without pathological ndings, 2 = minor injuries, 3 = severe injuries). The results were averaged for further analysis. Second, the patients rst completed a questionnaire (Validated H&N35 Quality of Life Questionnaire Head and Neck Module and NRS) to express their subjective symptoms (hoarseness, etc.). NRS scores 1-3 correspond to mild, scores 4-6 to moderate and scores ≥ 7 to severe symptoms. H&N Score ranged from 0-100. A high score correlated with a high degree of complaints and symptoms (23).

Statistical analysis
Statistical analysis was performed using SPSS (IBM Corp. Released 2016, IBM SPSS Statistics for Windows, Version 25.0, Armonk, NY: IBM Corp.). The normality of the distribution was assessed using the Shapiro-Wilk test. All values for descriptive statistics and outcome parameters were non-normally distributed. All non-normally distributed data are presented as median and interquartile range (IQR).
Dichotomous outcome parameters are expressed as events (percentages). Non-parametric data were analysed using the Mann-Whitney U-test. P < 0.05 was considered statistically signi cant.

Results
For the study 123 patients were assessed for eligibility, in the period from 11.06.2018 until 14.02. 2020. Out of these patients 43 were excluded (Not met inclusion criteria n = 5, declined to participate n = 16, other reasons n = 22). After the exclusion 80 patients were randomised for our study. Finally 74 completed the study and were included in the nal analysis (Fig. 2). Two patients in the DLT group and four patients in the EZB group were excluded from the nal analysis. Two participants randomised to the DLT group and two in the EZB group refused postoperative nasal endoscopic examination. In the EZB group, one participant needed rapid sequence induction and one participant needed long-term postoperative ventilation and was lost to follow-up. All six participants were excluded from the nal analysis due to relevant study protocol violation, as prede ned (Fig. 2).The groups showed no signi cant differences in demographics, preoperative airway assessments and descriptive intubation data (Table 1).  First-attempt success did not differ signi cantly between the DLT group (76%) and the EZB group (89%) (P > 0.05) ( Table 2). There was no statistically signi cant difference between groups regarding the frequency of intubation attempts (P > 0.05).
During bronchoscopic control, correct positioning of the DLT or SLT plus EZB for selective lung ventilation was reported in 71% in the DLT group directly after successful endobronchial intubation, whereas only 44% of the devices in the EZB group were adequately positioned (P = 0.021) ( Table 2).
The quality of lung collapse was equal in both groups (DLT group 89.5% were excellent vs. 83.3% EZB Group (P = 0.444)) (Fig. 4). Inadequate lung collapse in ve patients of the EZB group resulted in unsuccessful repositioning attempts and secondary DLT placement. These ve crossover cases showed adequate lung separation after DLT placement.
There were signi cantly more carina traumas in the DLT group (P = 0.047) ( Table 3). There was no other signi cant difference in terms of direct complications after intubation between the two groups. When analysing the postoperative questionnaires (H&N35 and NRS scores) to record the subjective symptoms after intubation, signi cant more incidence of sore throat, hoarseness and speech problems were found in the DLT group. With the NRS score, the items sore throat (P = 0.009) and hoarseness (P = 0.02) were signi cantly lower in the EZB group (Table 4). With the H&N35 score the two items sore throat (P = 0.015) and speech problems (P = 0.047) were signi cantly lower in the EZB group (Table 5). However, there was no difference in the valid total H&N35 score between the two groups (P = 0.064).  In contrast to the subjective symptoms, postoperative endoscopic examinations revealed signi cant differences in the EZB group compared to the DLT group in terms of objective trauma, i.e. subglottic haemorrhage (P = 0.047) ( Table 6).

Discussion
Our study showed a signi cantly prolonged time required for successful lung separation using EZB. In addition, there was a signi cantly higher incidence of malpositioned devices in the EZB group, but on the other hand we found a signi cantly higher rate of airway trauma as well as subjective complaints in the DLT group.

Process times
Prolonged intubation times for EZB were shown in previous studies and have a greater risk of hypoxia (16,17). However, the combination of EZB with SLT guarantees a secured airway and oxygenation while the EZB is positioned.
The prolonged total time for successful lung separation was notably in uenced by the prolonged preparation time. A shorter intubation time for SLT seems to be relativised based on the total time for a successful lung separation. This seems logical, because SLT plus EZB is a two-step procedure. A shorter intubation time is certainly relevant in patients with a higher risk of aspiration and desaturation.
In our opinion, the marginal difference in the process times is in the end not clinically relevant. In the case of emergency intubation due to pulmonary bleeding, rapid intubation with SLT plus EZB may offer advantages, because DLT intubation requires more expertise. Therefore, when using EZB, there should also be a focus on non-elective use in the intensive care units and emergency rooms.

Incidence of device malposition
Previous studies of Ruetzler et al. showed a lower incidence of malpositions with DLT (10%) for blind insertion without exible bre optic bronchoscopy (FOB) compared to EZB (79%) (17). In contrast, Mourisse and colleagues showed a very high incidence of initial malpositions and need for repositioning the device during FOB in both groups (85% DLT vs. 74% EZB) (16). With 29% initial malpositions, we had a signi cantly lower incidence for DLT, similar to the results by Ruetzler et al. With EZB the position during FOB had to be corrected in more than half of the cases (56%). Initial malpositions are caused by too-deep positioning of the SLT used for introducing the EZB (11). This was the most common cause for malposition in our study cohort as well. Because of the high incidence of malposition we underline the recommendation to use FOB for the placement of EZB (16). A correspondingly thin bronchoscope and an endotracheal tube as large as possible are obligate in order to t parallel with EZB.

Success and quality of lung collapse
Overall, we had good results for both techniques based on successful OLV. In all intubations with SLT, we did not have a single case of entrapment of an EZB in the Murphy eye (24).
OLV with EZB was described before as a safe and easy technique with good quality of lung collapse (11,12). We were able to con rm these ndings with our data. The only two randomised trials between DLT and EZB so far have shown no difference in quality of lung collapse assessed by the surgeon (16, 17).
Prima facie, our study results seem to con rm the previous ones. However, there was only a change in method to a left-sided DLT in ve of six cases in the EZB group, if the quality of collapse was not excellent. Conversely, in the DLT group with repositioning of the left-sided DLT, su cient surgery conditions intraoperatively could be achieved in all cases. In all ve cases, the reason was the inadequate closing of the aperture of the right upper lobe bronchus. Adequate OLV by EZB seems to cause di culties, especially for right-sided thoracotomies (12,25). The shorter distance between the main carina and the aperture of the right upper lobe can make the use of EZB di cult. Therefore, we recommend reconsidering the indication for EZB for a right open thoracotomy or video-assisted thoracoscopic surgery (VATS).

Incidence of airway trauma
With equal quality of lung collapse and less traumatic damage of the glottis and subglottic level, the extended time to separate the lungs with EZB takes a back seat. In our study, more carina trauma and subglottic haemorrhage in the endoscopic follow-up were the objective evidence for airway trauma.
Severe trauma such as bronchus perforation did not occur in our patients (13) and no patients required intervention to treat an airway damage.
Our ndings are in agreement with the ndings of Mourisse et al., who described placing EZB took more time and had a lower rate of airway injury (16). In contrast we found signi cantly more carina trauma by rst endoscopic follow-up in the DLT group. We expected more carina trauma with EZB, because of the initial blind insertion and the y-shaped distal end sticking xed on the carina. We conclude that pressure and forces during blind introduction and rotation manoeuvre of the left-sided DLT in the tracheal part might cause more airway trauma.
Regarding subjective symptoms, there are controversial results in the literature by Mourisse et al. and Ruetzler et al. (16,17). Our results show a signi cant trend to increased subjective complaints after DLT. We could show for individual items of H&N35 score and items of NRS score signi cantly more subjective symptoms 24 hours after extubation in the DLT group. But the recognised total score of H&N35 questionnaire showed no signi cant difference. The question remains as to whether the questionnaires used are sensitive enough to record differences in subjective symptoms.
We suggest from our results to waive blind insertion of EZB and to perform insertion under FOB control.
This might shorten the procedure and prevent even more airway trauma of the carina.

Limitations
Although time to intubation or time to lung separation is commonly used in airway studies, because they are methodologically easy to compare, the clinical relevance remains questionable. Operators were not blinded to the intubation device used. Nevertheless, the patient and follow-up endoscopic examinations were anonymised and blinded. Further limitation might be that the operators were not equally experienced with both devices. A small number of patients with an expected di cult airway (Mallampati 3 and 4) and the low incidence of predicted di cult airways (CL 3 and 4) is a further limitation of our study. EZB is an important technique for OLV in patients with an expected di cult airway. Furthermore, we cannot exclude injuries by the endoscopic exible bronchoscopies at the follow-up itself, although they were all done by experienced investigators. Lastly, we did not investigate a long-term outcome with our follow-up at 24 hours after surgery.

Conclusions
In summary, our randomised controlled trial showed that the total time for selective lung ventilation with SLT plus EZB is longer compared to DLT and the quality of lung collapse for the thoracic surgeon is prima facie equivalent. Five crossover cases in the EZB group resulted in unsuccessful repositioning attempts and secondary DLT placement to achieve adequate lung separation. In all ve cases the reason was inadequate closing of the aperture of the right upper lobe bronchus. Therefore, we recommend reconsidering the indication for EZB for a right open thoracotomy or right video-assisted thoracoscopic surgery (VATS). Despite some advantages due to less objective airway injuries, there was no subjective difference for the patient as a relevant patient-centred outcome parameter. Further studies are needed to underline the advantages of EZB for lung separation in thoracic surgery.      Bar chart and results of the quality of lung collapse.