Clinical trial NCT03521505
Conditions: Bronchoscopy
Keywords: Sedation dexmedetomidine brain perfusion bronchoscopy
Sponsor: Chang Gung Memorial Hospital
Start date: 2018-05-11; Completion date: 2020-01-22
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Preventing hypoxemia is one of the major goal of studies for bronchoscopic sedation. Dexmedetomidine is a sedative agents via α2 adrenergic agonist, with little respiratory suppression. In the preset study, we evaluate the safety and feasibility of the Dexmedetomidine in the specific bronchoscopic procedure, endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration.

Detailed description:
Patients undergoing flexible bronchoscopy (FB) experience procedure-related symptoms. Current guidelines of FB recommend sedation to all patients undergoing FB, except when there are contraindications. Propofol plus an opioid is the common combination used to improve patient tolerance and satisfaction during FB. However, controversy about combining propofol and opioids persists because of the risk of over-sedation and cardiopulmonary depression, especially for the time-consuming endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA). Similar with other published data, around 40% of hypoxemia event was observed during FB sedation in the investigators' hospital. Dexmedetomidine, is a sedative agents via α2 adrenergic agonist, with little respiratory suppression. It has been applied in patients with mechanical ventilation, undergoing gastroendoscopy and extracorporal shockwave lithotripsy. Little evidences are available for Dexmedetomidine in sedation for EBUS-TBNA.

In this study, the investigators will evaluate the safety and feasibility of Dexmedetomidine for sedation of EBUS-TBNA comparing to Propofol for sedation of EBUS-TBNA. Generally, the FB sedation can divided into three parts: the induction (from starting sedative administration to insertion of bronchoscope); the maintenance ( from insertion of bronchoscope to its removal) and the recovery (from bronchoscope removal to patients gain consciousness). The primary endpoint is the proportion of patients with hypoxemia during maintenance of sedation. the investigators will also observe the other sedative outcomes, e.g. blood pressure, sedative drug dosing and patient tolerance and cooperation. The present study will also observe the association between brain perfusion and sedative outcomes via non-invasive monitor. Based on the unique pharmacokinetic property of Dexmedetomidine and the real-time brain perfusion monitor, Dexmedetomidine-based sedation may provide better safety profile for EBUS-TBNA than propofol and discover novel connection between sedative outcomes and brain perfusion.

Arms: arm 1: Dexmedetomidine will be administrated for sedation of EBUS-TBNA arm 2: Propofol will be administrated for sedation of EBUS-TBNA
Interventions: intervention 1: Dexmedetomidine arm intervention 2: Propofol arm
Intervention descriptions: intervention 1: Induction: Dexmedetomidine 1ug/kg infusion for 10 minutes. 5 mg/kg alfentanil (1:10 dilution) slow injection 2 min before complete Dexmedetomidine induction Maintenance: Dexmedetomidine 0.5\~1.4ug/kg/hour infusion±0.2ug/kg/hour to maintain stable vital signs and The Observer Assessment of Alertness and Sedation scale (OAA/S) 3\~2. the infusion rate was increased by 0.2ug/kg/hour if the patient persistently had eye opening, talked, or became irritable and interfered with the procedure. The infusion rate was reduced by 0.2ug/kg/hour, if the following adverse events occurred: hypoxemia (SpO2 \< 90%) or hypotension (mean arterial pressure (MAP) \< 65 mmHg, or systolic blood pressure (SBP) \< 90 mmHg) in any duration intervention 2: 5 mg/kg alfentanil (1:10 dilution) slow injection 2 min before induction Induction: The initial effect-site concentration (Ce) of propofol was targeted to 2.0 μg/ml for induction (Schneider model of target-controlled infusion (TCI), Injectomat total intravenous anaesthesia (TIVA) Agilia, Fresenius Kabi, France). If OAA/S did not reach 3 while Ce achieved 2.0 μg/ml, Ce was increased by 0.2 μg/ml every 90 seconds until OAA/S 3\~2.

Maintenance: the Ce was increased by 2.0 μg/mL every 90 seconds if the patient persistently had eye opening, talked, or became irritable and interfered with the procedure. The Ce was reduced by 0.2 μg/ml every 90 seconds, if the following adverse events occurred: hypoxemia (SpO2 \< 90%) or hypotension (mean arterial pressure (MAP) \< 65 mmHg, or systolic blood pressure (SBP) \< 90 mmHg) in any duration.

Protocol documents:
Prot_SAP_001.pdf: 
Study title: Dexmedetomidine and Brain Perfusion Monitor for Sedation 
of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration 
 
NCT number: NCT03521505 
 
Date of the documentation: 2017/01/23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study protocol 
This prospective, open-labelled, randomized study was conducted in a medical center 
(Chang-Gung Memorial Hospital, Linkou, Taiwan). The study protocol was approved 
by the Chang Gung Medical Foundation Institutional Review Board (No.201601093A3). 
The trial was registered at clinicaltrials.gov (NCT03521505). Patients who required 
EBUS-TBNA and agreed to undergoing the procedure under sedation were screened 
for enrolment. The exclusion criteria included age <20 years, American Society of 
Anaesthesiologists (ASA) physical status classification 4 or 5, a Mallampati score of 4, 
severe sleep apnoea syndrome (apnoea-hypopnea index >40), second or third degree 
atrioventricular blockage, heart rate <50 beats per minute, systolic blood pressure 
<90mmHg, neurologic disorders or other conditions contributing to difficulty in 
assessing response, body mass index >42 in males or >35 in females, and pregnancy. 
Patients with a known history of allergy to the study drugs, or to eggs, soybeans, or 
sulfite products, were also excluded. All enrolled patients provided written informed 
consent. Enrolled patients were randomised using a predetermined random computer 
code into the study group or the control group at a ratio of 1:1. 
Patient preparation 
Blood pressure was monitored using an automated pressure cuff, and heart rate (HR) 
was monitored using a three-lead electrocardiograph (ECG). A peripheral pulse 
oximeter was used to monitor oxyhemoglobin saturation (SpO2), while a nasal cannula 


delivered oxygens at rate of 2 L/min. A disposable BIS Quatro Sensor (Aspect Medical 
System Inc, Newton, MA, USA) was applied to the forehead of patients. Smoothening 
time was set at 15 s. The BIS level was covered (i.e., blinded to the investigator in 
charge of sedation). A patient monitor (Philips MP60) was used to continuously record 
all parameters except for the blood pressure, which was recorded every 2.5 minutes. 
The monitoring software was developed in Microsoft Visual Basic 6.0 (Windows XP) 
based on the Philip Patient Monitor communication protocol. An intravenous catheter 
was placed in the forearm for drug administration. An oral bite block was placed prior 
to sedation. Pre-medication was achieved using nebulized 2% xylocaine inhalation. 
The investigators in charge of sedation were specifically trained in the administration 
of sedatives and monitoring sedative depth. They were responsible for monitoring 
patients for cardiopulmonary depression and determining the need for interventions. 
The interventions are detailed in the supplemental materials. EBUS-TBNA operations 
were performed by experienced bronchoscopists (Kuo C-H and Chung F-T) using a 
convex probe endobronchial ultrasound (BF-UC260FW, Olympus, Tokyo, Japan). via 
the oral route, with assistance from a well-trained technician. 
Sedation protocol 
Study group: Alfentanil (5 μg/kg) was administered in a 1:10 dilution with normal 
saline under slow injection for 2 min prior to full induction using an infusion of 


dexmedetomidine (1μg/kg) for 10 min [18, 22, 30]. Maintenance was conducted via 
dexmedetomidine infusion (0.5~1.4 μg/kg/hour) with the aim of maintaining stable 
vital signs and The Observer Assessment of Alertness and Sedation scale (OAA/S) of 
3~2. 
Control group: Patients were slowly administered alfentanil (5 μg/kg) in a 1:10 dilution 
with normal saline for 2 min prior to induction using a propofol infusion at an initial 
effect-site concentration (Ce) of 2.0μg/ml using a InjectomatR TIVA Agilia, (Fresenius 
Kabi, France)[11, 13]. OAA/S was evaluated every 30 s after the patients closed their 
eyes. In cases where OAA/S did not reach 3 when Ce reached 2.0 μg/ml, Ce was 
increased by 0.2μg/ml every 90 seconds until OAA/S reached 3~2. Maintenance of 
control group: Ce of propofol was titrated at a rate of 0.2μg/ml every 90 seconds to 
achieve stable vital signs and The Observer Assessment of Alertness and Sedation scale 
(OAA/S) 3~2. 
Following the procedure, the patients were monitored continuously in a recovery 
room until full recovery.  
Assessment 
SPO2, blood pressure, HR, and BIS were recorded immediately before induction (as a 
baseline), during induction, during the maintenance of sedation, and throughout the 
recovery period. The parameter levels and the difference from the baseline values 


were analysed. We recorded episodes of hypoxemia (SpO2<90%) and hypotension 
(mean arterial blood pressure (MAP) <65 mmHg or systolic blood pressure (SBP) <90 
mmHg) of any duration. Sedative drug doses were recorded at the infusion pump. 
Procedure time was recorded as the duration from the insertion of bronchoscope to 
its removal. Recovery time was recorded as the duration between the time at which 
bronchoscopy finished and the time when the patients spontaneously opened their 
eyes and were able to recall their date of birth and correctly perform the finger-to-
nose test. 
 After recovery, patients were asked to answer questionnaire about wakefulness, 
tolerance, and willingness to repeat the bronchoscopic procedure if clinically indicated. 
Wakefulness during the procedure was evaluated by asking patients if they heard or 
saw anything during the operation. The questionnaire used to assess patient tolerance 
to procedure-related symptoms included reactions to nebulized xylocaine inhalation, 
stimulation caused by insertion of the scope through the mouth, cough, dyspnea, pain, 
and global discomfort to the entire procedure. The questionnaire used a 100-mm 
visual analogue scale (VAS, 0: no bother, 100: intolerable). Patients were also asked 
about their willingness to undergo the bronchoscopic procedure again if clinically 
indicated (definitely not, possibly not, not sure, possibly yes and definitely yes). The 
bronchoscopist was questioned concerning the ease of scope insertion and biopsy, 


coughing by the patient, and global cooperation throughout the procedure using a 
100-mm VAS (0: most cooperative, 100: entirely uncooperative).  
The diagnostic yield of EBUS-TBNA was evaluated in terms of the pathology or cytology 
of mediastinal lymph nodes. Specimens without lymphocytes were defined as 
inadequate samples. There are two criteria by which to confirm a result as a true 
negative. The first is confirming a lack of malignancy in specimens obtained surgically. 
The second is a confirmation of stability or regression via computed tomography at 6 
months after the procedure. 
 
 
Statistical analysis plan 
Sample size 
Power calculations were based on the proportion of patients with at least one episode 
of hypoxemia during sedation of bronchoscopy. Among the patients who underwent 
bronchoscopy, 3% of those under dexmedetomidine sedation and 36.7% of those 
under propofol sedation experienced episodes of hypoxemia. Considering the 
complexity of EBUS-TBNA, a difference of 30% would be of clinical importance (α=0.05, 
power=0.8). Our analysis revealed that 25 subjects per group would be sufficient to 
detect a difference between the two groups.  
Statistical analysis 
Analysis was performed on the outcomes of all randomized subjects. The diagnostic 


yield among subjects who completed EBUS-TBNA was expressed as a number with a 
percentage or a mean with standard deviation. Ccontinuous variables were evaluated 
using the Mann-Whitney test. Patient characteristics and complications were analysed 
using the Chi-square test or Fisher’s exact test, in cases where the sample size was 
small. A p<0.05 was considered statistically significant. All the statistical analysis was 
performed using Prism 5 (GraphPad software Inc., San Diego, CA, USA).