Effectiveness of nebulized dexmedetomidine as a premedication in flexible bronchoscopy in Indian patients -a prospective, randomized, double-blinded study

1. Introduction

Flexible bronchoscopy (FB) is being increasingly performed in clinical practice to visualize the airway for diagnostic and therapeutic purposes. Although considered safe, the procedure can cause pain, discomfort, cough, breathing difficulty, trauma, and irritation to the nose and throat. Most patients experience stress, anxiety, and fear before the bronchoscopy procedure. Hence the use of sedation is recommended as per new guidelines for improved patient comfort, tolerance, and ease of bronchoscopy [1]. Moreover, sedation is becoming a routine part of any procedure. Physicians and patients prefer it for a simple, safe, comfortable, and complete procedure which could significantly increase the yield. Multiple studies have proven the efficacy of intravenous dexmedetomidine in patient comfort during flexible bronchoscopy. The advantage of using dexmedetomidine over conventional sedative drugs is the absence of respiratory depression [2,3]. However, intravenous dexmedetomidine, though considered safe, may sometimes be associated with adverse events such as bradycardia and hypotension. Hence an anesthetist is ideally required when intravenous dexmedetomidine is administered, which adds to the procedure cost. Therefore, the continued search for a comparable drug with equal or superior efficacy with minimal side effects is on. Nebulized dexmedetomidine is an easy, non-invasive method of administering sedation in situations where manpower is not trained in intravenous sedation. It alleviates the need for an anesthetist during the procedure and thus reduces the overall procedural cost. Studies have already proven that using the nebulized form of dexmedetomidine in FB is more effective in patient comfort and tolerance, with a shorter recovery time compared to the existing methods used for premedication, while being safer than intravenous dexmedetomidine [4,5]. Dexmedetomidine can relieve bronchospasm in its nebulized form [6]. However, the studies involved a smaller sample size. To the best of our knowledge, there are no Indian studies that use nebulized dexmedetomidine as a premedication in flexible bronchoscopy. The efficacy and effectiveness of nebulized dexmedetomidine need to be studied in a larger population. Hence we plan to do a current study comparing two effective methods of premedication in FB to add to the existing data pool for better clarity regarding the patient comfort, tolerance, and side effect profile. Moreover, if found effective, it could revolutionize the practice of sedation in any procedure with superior efficacy and fewer or negligible side effects and thus move more into daycare procedures.

2. Materials and equipment

The study requires dexmedetomidine drug and normal saline, which will be administered in the nebulized form to patients requiring bronchoscopy in our department.

The study was conducted after obtaining clearance from the institutional ethics committee (IEC KMC MLR 10/2021/310) and is registered with the Central Trial Registry-India (CTRI/2022/03/040799)

3. Methods

Study Design: Randomized, double-blinded single-center study.

Departments involved: Respiratory Medicine department in a tertiary care center in South India.

Study period: 12 months.

Sample size: Anticipating a SD of 3.39 and a minimum clinically significant difference of 3 in the composite score for a power of 90% at 95% confidence level, using the formula,

n = 2[(Z_1-α/2 + Z_1-β)]²σ2]/d², a minimum of 27 in each group need to be recruited.

Z_1-α/2=1.96 is a standard value at a 5% level of significance (95% confidence interval)

Z_1-β=1.28 is a standard value at 90% power, σ = Combined SD = 3.39 [3]

d = Clinically significant difference = 3.

Inclusion criteria: All patients aged 18 to 65 undergoing flexible bronchoscopy in the Department of Respiratory Medicine.

Exclusion criteria.

• a.Patients with known or suspected allergy to Dexmedetomidine
• b.Patients with nasal infection or complete obstruction
• c.Patients with thrombocytopenia/bleeding diathesis
• d.Patients requiring additional interventional procedures such as biopsy
• e.Patients with renal or hepatic insufficiency
• f.Patients with a seizure disorder
• g.COPD patients with FEV1 <50%
• h.Patients with psychiatric disorders
• i.Hemodynamically unstable patients, including cardiac failure
• j.Heart rate <50 beats per min or second or third-degree heart block
• k.Patients with a body weight of more than 70 kg.
• l.Pregnancy and lactation
• m.Patients were posted for bronchoscopy but did not consent to be study participants.

3.1. A detailed description of procedure/processes

Written informed consent will be taken from all study participants. Demographic details like age, gender, height, weight, BMI, history of prior bronchoscopy procedures, current indication for bronchoscopy, and the procedures done during bronchoscopy will be recorded from patients who meet the inclusion criteria.

Patients undergoing FB will be randomized in a one is to one ratio using a computer-generated randomization table using Microsoft Excel software and will be allocated to any of the two groups (Group A or Group B).

Patients in group A (Study group) will receive a nebulized form of dexmedetomidine at one mcg/Kg, diluted with 0.9% saline to make it up to 5 ml, and administered via nebulizer 15 min before bronchoscopy. Patients in group B (control group) will receive 5 ml of 0.9% saline nebulization via nebulizer apparatus 15 min before bronchoscopy [4]. All the patients (both in groups A & B) will receive lignocaine installation for local anesthesia in addition to the study drug and placebo during FB.

Groups	A (Study Group)	B (Control Group)
Study Intervention	Nebulized Dexmedetomidine	0.9% Saline Nebulization (5 ml)
	One mcg/kg (diluted with NS to 5 ml)
	+	+
	Lignocaine local anesthesia	Lignocaine local anesthesia

The study will begin with the administration of either dexmedetomidine in the nebulized form (group A) or 0.9% saline nebulization (group B) 15 min before the procedure using a Philips compressor nebulizer (SN: 1021993545) after recording the baseline characteristics and hemodynamic parameters. Two ml of 2% lignocaine jelly will be instilled into the patient's nostril. Three sprays of 10% lignocaine are then administered at the oropharynx. Two ml of 1% lignocaine is instilled as a "spray-as-you-go" technique at the level of vocal cords, over the trachea, and each bronchus.

After the cough subsides, the bronchoscope will be advanced to examine the entire bronchial tree, and the planned sampling procedure will be completed. Additional 1 ml of 1% lignocaine aliquots will be sprayed if the patient develops a recurrent cough. A composite scoring technique, which is a validated scoring table used to assess patient comfort and tolerance, is used to assess the patient while undergoing the procedure both before and after crossing the vocal cords by observer C. Heart rate, cardiac rhythm, Non-invasive blood pressure (NIBP), respiratory rate, and pulse oximetry saturation will be recorded before the start of bronchoscopy, monitored continuously during the procedure till its completion and 10 min post-procedure. The patient is further assessed after 2 h and asked to give their opinion on the procedure, the quality of sedation, discomfort, any adjustment needed in the dose of sedation, and willingness for a repeat procedure if required and is documented [3]. The patient will be monitored by both Observer B and Observer C during the procedure and post-procedure by Observer C.

The study involves three different observers.

Observer A	- Junior Resident in the department.
	- Generates randomization table, prepares the study drug, and administers the medications ensuring blinding.
	- Observer A will not be involved in further study.
Observer B	- Senior Consultant pulmonologist in the department of Respiratory Medicine.
	- Observer B will be performing the bronchoscopy.
	- Observer B will not be aware of the administered medication.
Observer C	- Senior Resident in the Department of Respiratory Medicine
	- Observer C will assess the patients, explains the study methodology, takes consent, and records the study parameters.
	- Observer C will not be aware of the medications administered.

The patient, operator (Observer B), and outcome assessor (Observer C) will be blinded to the allocation.

The patient comfort with bronchoscopy will be assessed both subjectively and objectively.

The timeline, from enrolment to the completion of the study, is summarized in Fig. 1.

Fig. 1.

Timeline of events during the study.

6. Statistical methods: The independent t-test or Mann-Whitney U test will be used to compare the composite score between the two groups. Continuous variables like age, height, weight, etc., will be compared between the two groups using the independent t-test. Categorical variables like gender, Ramsay sedation score, etc., will be compared between the two groups using the chi-square test/Fisher's exact test.

7. Implications of the study.

• •
  Primary Objectives:

  • 1.
    To assess the patient comfort and tolerance during bronchoscopy using the composite score [3].
  • 2.
    To assess pain and intensity during the procedure using the Numerical Rating Scale (NRS) for pain intensity and distress [7].
  • 3.
    To evaluate the intensity of cough using the Visual Analogue Scale (VAS).
  • 4.
    To assess the degree of sedation using the Ramsay Sedation Score (RSS) [8].
  • 5.
    To determine the ease of the bronchoscopy procedure as assessed by Observer B.
• •
  Secondary Outcome measures:

  • 1.
    Willingness for repeatability of the procedure as felt by the patient using a proforma.
  • 2.
    Variations in heart rate (HR), blood pressure (BP), and oxygen saturation (SpO2).
  • 3.
    Duration of bronchoscopy procedure
  • 4.
    Procedures undergone during bronchoscopy (Bronchial washing, broncho-alveolar lavage (BAL), bronchial brushing, endobronchial biopsy, transbronchial needle aspiration (TBNA), or transbronchial lung biopsy (TBLB)

The study's major events are incorporated into a consort diagram, as shown in Fig. 2.

Fig. 2.

Consort diagram highlighting major events during the study period.

4. Advantages

• 1.The most crucial advantage of nebulized dexmedetomidine is that it is locally acting; hence the use of the drug does not require trained personnel.
• 2.The procedure cost is much less than other intravenous sedative agents, where an anesthetist backup is ideal.
• 3.Nebulized dexmedetomidine could attenuate the sympathetic response to the procedure; hence, the procedure could be completed without much hemodynamic issues.
• 4.Further, the property of dexmedetomidine to cause smooth muscle relaxation could positively benefit during bronchoscopy preventing bronchospasm and reducing cough response.
• 5.It can be safely given when a bronchoscopy is planned as a daycare procedure.

5. Limitations

The ease of bronchoscopy is observer B dependent and could vary with different observers. However, this could have been avoided if the same observer had done all the procedures.

6. Discussion

Flexible Bronchoscopy (FB) is an invasive procedure used to visualize the upper and lower respiratory tract for diagnosing and managing a spectrum of inflammatory, infectious, and malignant diseases of the airway and lungs.

Dexmedetomidine is a relatively newer drug currently being used as an ICU sedative [9]. It is an α_2-adrenoceptor agonist with sedative and analgesic action without causing any respiratory depression compared to the conventional agents used in sedation. Previous studies have used intravenous dexmedetomidine at various doses, an effective sedative agent. It is currently being used as one of the standard drugs for sedation in FB [3,10]. However, sometimes, intravenous dexmedetomidine, especially at higher doses, can cause a drop in blood pressure and heart rate. Studies have proved that nebulized dexmedetomidine is more effective in improving patient comfort, reducing cough, and shortened recovery time compared to the standard premedication agents used in FB, with a similar side effect profile [4,5]. Nebulized dexmedetomidine has the additional benefit of relaxing bronchial smooth muscle, hence is likely to prevent reflex bronchospasm while undergoing FB [6]. Indian studies which used 1mcg/Kg of dexmedetomidine as a premedication before laryngoscopy and intubation favorably attenuated hemodynamic response without any adverse events [11,[1], [2], [12]. The bio-availability of dexmedetomidine is 65% via inhalation through the nasal mucosa and 82% through buccal mucosa compared to the intravenous route. Hence adverse events such as hypotension, bradycardia, desaturation, and transient hypertension though possible, are expected to be rare [11,13]. Although multiple studies have previously used nebulized dexmedetomidine in various procedures like flexible bronchoscopy, endotracheal intubation, dental procedures, tonsillectomy, and peripheral intravenous access, additional data is required to explore the potential benefits and thus bring it to the routine clinical practice as a pre-medication in FB [[14], [15], [16]]. Hence our study compares the patient comfort, tolerance and safety of nebulized dexmedetomidine and lignocaine local anesthesia with conventional lignocaine administered as spray as you go technique. We propose that combining nebulized dexmedetomidine with lignocaine LA in bronchoscopy can cause an improved sedation, better patient comfort and tolerance, with similar or lesser adverse events compared to the standard agents used. Moreover, dexmedetomidine in a nebulized form could be used by the proceduralist himself which is an advantage when compared to intravenous sedatives.

The authors herby give an undertaking and certify that

• 1.The authors are the sole owners of the manuscript. The manuscript has not been submitted or considered for publication elsewhere in print or electronic.
• 2.All the listed authors have agreed to be as authors. All the authors have granted the corresponding author to enter into an agreement on their behalf. With the acceptance of the manuscript the authors shall undertake to transfer the full copyright of the manuscript.
• 3.The manuscript has no redundant data, plagiarism, data falsification or fabrication.
• 4.There is no conflict of interest in the paper.
• 5.Written informed consent has been obtained from patients attendant.

Contributions

Conceptualization: Preetam Acharya, Thomas Antony,

Methodology and validation: Preetam Acharya, Vishak Acharya Thomas Antony.

Writing: Thomas Antony.

Review, editing and approval of the final manuscript: All authors.

Data availability

No data was used for the research described in the article.