Remifentanil Target Controlled Infusion Versus Standard of Care for Conscious Sedation During EBUS-TBNA
Condition: Lung Cancer; Lung; Node; Sedation Complication; Endoscopy
MeSH terms: Lung Neoplasms
Study type: Interventional

Summary: 
      Background: endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a
      minimally invasive procedure for diagnosing and staging mediastinal lymph node lesions in
      lung cancer. Adequate sedation is crucial for patient comfort and diagnostic accuracy.
      Different sedation modalities, including moderate sedation/conscious sedation, deep sedation,
      and general anesthesia, are utilized. This study aims to evaluate patient comfort and
      satisfaction levels of healthcare providers (bronchoscopists and anesthesiologists) when
      administering remifentanil through Target Controlled Infusion (TCI) for conscious sedation
      during EBUS-TBNA. A prospective randomized study design compares this approach to the
      standard sedation protocol involving midazolam, fentanyl, and/or propofol.

      Methods: this study will enroll 30 eligible patients randomly divided into two groups. Group
      1, "REMIFENTANIL TCI", underwent EBUS-TBNA under conscious sedation with remifentanil TCI
      infusion targeting a concentration of 3-6 ng/ml. Group 2, "STANDARD", received conscious
      sedation with a combination of midazolam, fentanyl, and/or propofol administered in boluses
      based on clinical requirements. Complications, safety, and satisfaction levels of the
      operator, anesthesiologist, and patients will be evaluated.
    

Detailed description: 
      BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a
      minimally invasive procedure that has gained major relevance in diagnosis lung cancer and
      staging of mediastinal lymph nodes (LN). Adequate sedation is an important part of the
      procedure since it improves patient's comfort and tolerance potentially positively affecting
      the diagnostic yield. It is also considered a standard of care for patients undergoing
      fiberoptic bronchoscopy unless specifically contraindicated.

      The choice of the different level of sedation (from conscious to moderate to deep sedation)
      has always been challenging and, to date, no standardized practice exists. Deep sedation may
      be preferred in those cases where additional procedures such as placement of endobronchial
      stents, are required, or in order to make the procedure more suitable by limiting the
      patients motion. In remaining cases, conscious sedation allows to complain with the clinical
      demand without affecting respiratory and cardiovascular function, decreasing the cough reflex
      and maintaining sufficient swallowing capacity.

      Not appropriate sedation can have serious complications, including respiratory depression or
      even arrest, hypoxia and/or hypercapnia, and cardiovascular and neurological side effects.

      Commonly used drugs for sedation include propofol and a combination of benzodiazepines and
      opioids. However, achieving the ideal level of sedation can be challenging, since it may
      occasionally lead to over sedation, with detrimental effects. These risks are even greater if
      the patients present with lung disease, obesity, or heart disease. Conversely, under sedation
      can result in discomfort for the patient and challenging procedure it for the healthcare
      provider. Furthermore, benzodiazepines and medium-long-acting opioids continue their effect
      even after the procedure is finished, thus lasting the negative effects of these drugs over
      the time of the procedure.

      In a recent case series, Scarlata and colleagues have provided a preliminary evidence of a
      TCI remifentanil protocol safety and effectiveness, providing an ideal and performant
      condition for bronchoscopists and a satisfactory comfort for patients.

      Using a TCI continuous infusion protocol of Remifentanil can exploit the sedative, analgesic
      and antitussive capabilities of this short-acting opioid, achieving a level of conscious
      sedation that ensures an adequate level of comfort for the patient while at the same time
      decreases the incidence of side effects typical of deep sedation. The patient remains
      contactable and can respond and execute commands, such as breathing, swallowing, etc.

      TCI is a method of continuous drug administration where the infusion of the drug is remotely
      controlled. There are different administration algorithms and there is the possibility to
      titrate the target concentration both at the effect site (CNS) and in the plasma.

      There are numerous studies confirming the efficacy of remifentanil administered by TCI during
      intubation with an awake patient, and the advantages of the latter compared to other
      techniques, such as propofol infusion. One study determined the efficacy of infused
      remifentanil and propofol for bronchial endoscopy procedures, but did not use the TCI
      technique for infusion. There are no clinical studies assessing endoscopic transbronchial
      needle biopsy procedures with remifentanil infusion in TCI mode.

      The aim of this study is therefore to conduct a prospective, randomized, controlled trial to
      evaluate the administration of remifentanil in TCI for conscious sedation during EBUS-TBNA
      procedures, the degree of patient and operator satisfaction and the relative advantages and
      disadvantages versus the of standard sedation protocol with midazolam and/or fentanyl and/or
      propofol.

      METHODS This is a single center, randomized, investigator initiated clinical trial of 30
      patients undergoing EBUS-TBNA for mediastinal staging of lung cancer. Patients were randomly
      assigned to one of two groups: Group 1 "REMIFENTANIL TCI" (Experimental Group): the patients
      performed the EBUS-TBNA procedure under conscious sedation with infusion of Remifentanil TCI
      with a target between 3 and 6 ng/ml; Group 2 "STANDARD" (Control Group): the patients
      performed the EBUS-TBNA procedure in conscious sedation with the association of midazolam
      and/or fentanyl and/or propofol in refracted boluses based on clinical needs (agitation,
      unsatisfactory level of sedation or not collaborative patient) and according to the
      anesthesiologist's clinical judgement.

      After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group
      "REMIFENTANIL TCI" or "STANDARD". A research randomizer software was used for randomization
      (iRANDOMIZER-SHMOOPI LLC-version 2.5). Both the bronchoscopist and the research assistant
      administrating the questionnaires were blinded to the assigned group. It was not possible to
      blind anesthesiologists involved in the patient's care.

      The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

      Study treatment The ASA scale, the Mallampati score, the presence of OSAS were recorded prior
      of the procedure. Also, data about the underlying oncological disease, whether chemotherapy
      and/or radiotherapy was performed, and the indication for the EBUS-TBNA test (diagnostic,
      staging, re-staging, or both diagnostic and staging at the same moment) were collected.

      The patient candidate for the endoscopic procedure underwent continuous monitoring of vital
      signs. ECG with precordial leads, continuous finger pulse oximetry, and noninvasive
      intermittent blood pressure measurements were monitored. Each patient was preoxygenated for
      about 5 minutes by administering O2 with nasal goggles at 3L/min or higher, if required.

      Lidocaine was topically nebulized at the level of the mucous membranes of the oropharynx.
      Oxybuprocaine 4mg/ml was also nebulized at the level of the vocal cords via the eco-endoscope
      before passing the glottic plane in all patients.

      Remifentanil group conscious sedation protocol (intra venous remifentanil in TCI). Drug
      administration begun 5 minutes before the procedure. The achievement of the ideal target
      occurs starting from an initial target at the effect site of 1 ng/ml and gradually increasing
      the desired target on the pump by 0.5 ng/ml at a time, until reaching a target between 3 and
      6 ng/ml and an adequate level of sedation (Ramsey Score between 2-3).

      Desired target was achieved by automatic infusion pumps (Infusomat® Space® Large Volume Pump,
      Braun medical inc) If, despite the maximum target, a satisfactory level of sedation was not
      reached, repeated boluses of propofol were given as clinically needed and the case considered
      as protocol failure.

      Patients in the STANDARD Group performed the EBUS-TBNA with bolus administration of midazolam
      and/or fentanyl and/or propofol. Shortly before the start of the procedure they received 1-2
      mg bolus midazolam and/or 50-100 range bolus fentanyl until they reach the level of sedation
      (Ramsey Score 2-3). In addition, repeated boluses of propofol could have been given according
      to clinical needs (state of agitation of the patient, requests from the operator due to
      difficulties in carrying out the procedure).

      Data were collected about the procedure performed, any changes in vital signs that occurred
      during the procedure and the depth of sedation.

      Anesthesiologist, bronchoscopist and patient's satisfaction tools At the end of the
      procedure, the patient was given a satisfaction questionnaire to evaluate the degree of
      satisfaction. The 0-5 Likert numerical scale was used to evaluate the symptoms onset of cough
      (0 none-5 very much), sore throat (0-5), chest pain (0-5), shortness of breath (0 eupnoea- 5
      worsening dyspnea), presence of memories (0 none - 5 vivid memories), and perioperative
      comfort (0 none - 5 excellent). The operator who performed the procedure and the sedation
      were also subjected to a satisfaction questionnaire which assessed the overall satisfaction
      (1 much worse than usual - 5 much better than usual).

      Statistical Analysis The analysis was performed on an intention to treat basis, regardless of
      actual compliance with the intended intervention.

      A two-tailed p value equal or less than 0.05 was considered as statistically significant. All
      tests, except for the primary outcome, were considered merely exploratory. When individual
      items were missing from a scale, the percent of missing values and, if more than 10% was
      calculated, the scale score was considered missing and therefore made unavailable for
      analysis. All the analyses were conducted using STATA (StataCorp. 2021. Stata Statistical
      Software: Release 17. College Station, TX: StataCorp LLC.).

      Outcome analysis Primary and secondary endpoints will be compared between the two groups of
      treatment by means of Student's t-test (or the Mann-Whitney U test, if necessary) for
      continuous quantitative variables and by means of the χ2 test (or Fisher's exact test ) for
      qualitative variables.

      Sample size determination Our previously published case series showed that the overall
      satisfaction rate for both the patient and the bronchoscopist were very high in the
      remifentanil TCI group (mean Likert score above 4/5 against a mean value ranging from 2 to 3
      in the standard group as available in the literature). Enrolling 30 patients (fifteen for
      each group) would have provided with 80% power at an alpha level of 0.05.
    

Intervention name(s): Remifentanil TCI; Midazolam injection; Fentanyl; Propofol
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): REMI-TCI administration begun 5 minutes before the procedure, starting from an initial target at the effect site of 1 ng/ml and gradually increasing by 0.5 ng/ml until reaching an adequate level of sedation (Ramsey score between 2-3).; Bolus administration of midazolam (1-2 mg)and/or until a Ramsey score 2-3 was reached; Bolus adminitration of fentanyl (50-100 mcg) until a Ramsey score 2-3 was reached; Bolus adminitration of propofol until a Ramsey score 2-3 was reached
Other intervention name(s): REMI - target control infusion; Bolus administration of midazolam; Bolus administration of Fentanyl; Bolus administration of Propofol
Intervention MeSH terms: Midazolam; Fentanyl; Remifentanil; Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Informed consent was obtained from each patient or legally authorized representative prior to enrollment in this study.
After obtaining a signed informed consent the patient was randomly allocated 1:1 to the group "REMIFENTANIL TCI" or "STANDARD". A research randomizer software was used for randomization (iRANDOMIZER-SHMOOPI LLC-version 2.5).
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: endobronchial ultrasound; mediastinal staging of lung cancer; sedation in endoscopic procedures