Safety and efficacy of remimazolam combined with alfentanil in flexible fiberoptic bronchoscopy: A randomized controlled trial

Abstract

Objective

The sedation protocol for flexible fiberoptic bronchoscopy has long been a matter of inconclusiveness. The aim of this study was to evaluate the safety and efficacy of remimazolam combined with alfentanil in flexible fiberoptic bronchoscopy and provide insights for optimizing clinical anesthesia strategies.

Methods

This study was a randomized, single-blind controlled trial. A total of 118 patients who underwent flexible fiberoptic bronchoscopy were randomized into two groups (59 patients per group). Both groups received intravenous alfentanil 10 µg/kg 2 min before sedation treatment, followed by either 0.2 mg/kg remimazolam (Group R) or 2 mg/kg propofol (Group P). During the flexible fiberoptic bronchoscopy, the experimental drugs were administered in patients in each group as needed to maintain the depth of sedation (modified observer’s assessment of alertness/sedation score ≤ 3). The primary outcome was the incidence of hypoxemia. The secondary outcomes included other safety outcomes and effectiveness outcomes.

Results

A total of 115 participants completed the study. Compared with Group P, the incidence of severe hypoxemia in Group R was lower (3.4% vs. 15.8%, P = 0.029); the incidences of injection pain and hypotension in Group R were lower (10.3% vs. 33.3%, P = 0.003); and the incidences of hypotension, dizziness, and grade of cough in Group R were lower (P < 0.05). The sedation success rate and sedation success rate at an induced dose were similar between Groups R and P (P > 0.05). Compared with Group P, sedation recovery time in Group R was shorter, and the operator comfort scores and patient comfort scores in Group R were higher (P < 0.05).

Conclusions

Remimazolam, when combined with alfentanil, has shown excellent clinical potential in flexible fiberoptic bronchoscopy. Compared with propofol, it significantly reduced the incidence of severe hypoxemia, injection pain, hypotension, dizziness, and intraoperative coughing while maintaining comparable sedation success rates. It also shortened recovery time and improved both operator and patient comfort scores. These results support remimazolam plus alfentanil as a safe, effective, and well-tolerated alternative sedation regimen in this setting.

Introduction

Flexible fiberoptic bronchoscopy (FFB) is a commonly used invasive examination for diagnosing lung diseases. FFB is important for diagnosing conditions, such as hemoptysis, chest infections, parenchymal lung disease, pulmonary nodules or masses, persistent pulmonary infiltrates, and enlarged mediastinal lymph nodes. Furthermore, it can be used to treat foreign body aspiration as well as ablate or reduce endobronchial masses, relieve airway stenosis, and perform lung lavage. The procedure typically takes a relatively short time, usually ranging from a few minutes to 10 min. However, this operation strongly stimulates the airway, which can tend to cause severe coughing, fear, and anxiety in patients, and may even lead to serious adverse reactions, such as hypoxemia and malignant arrhythmia. ¹ During the operation, if only local surface anesthesia is used, 40% to 60% of patients report an unpleasant and unbearable examination experience.^2,3 To enhance patient comfort and ensure a smooth procedure, the British Thoracic Society recommends that all patients undergoing FFB should receive sedation and anesthesia, provided there are no contraindications. ⁴ However, during the FFB procedure, sedation and anesthesia can significantly impact a patient’s respiratory and cardiovascular functions. Providing effective sedation while ensuring safety is a major challenge in clinical practice. Propofol combined with opioid drugs is a common anesthesia regimen for FFB, but it has significant disadvantages, including dose-dependent respiratory depression and a high incidence of hypoxemia.^5,6 Remimazolam is a novel, short-acting benzodiazepine drug that has shown safety and effectiveness in gastrointestinal endoscopy; however, there is relatively little research on its application in FFB.^7,8

The purpose of this study was to investigate the effectiveness and safety of remimazolam combined with alfentanil for FFB using a randomized controlled trial design. The study evaluated their performance based on operator satisfaction and patient comfort, aiming to provide a scientific foundation for optimizing anesthesia strategies during FFB.

Methods

Ethics and trial registration

We conducted this study in accordance with the Helsinki Declaration of 1975, as revised in 2024. This study was approved by the local institutional review board (Lishui People’s Hospital Ethics Committee, location: No. 1188, Liyang Street, Lishui, Zhejiang, China, approval number: LLW-FO-403, and date of approval: 27 March 2023). The trial was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2500095562). Written informed consent was obtained from all participants or from authorized family members. The reporting of this study conforms to the Consolidated Standards of Reporting Trials (CONSORT) 2025 statements. ⁹ There was no patient or public involvement in the design, conduct, or reporting of this trial.

Inclusion and exclusion criteria

This study involved 115 patients who underwent FFB in Lishui People’s Hospital from April 2023 to March 2024. The procedural characteristics of FFB included bronchoalveolar lavage for the diagnostic evaluation of pulmonary infection and interstitial lung disease, bronchial biopsy for suspected tumors or inflammatory lesions, and bronchial treatment for therapeutic purposes such as secretion clearance, hemostasis, or airway dilation.

The inclusion criteria were as follows: (a) patients aged 18–75 years with a body mass index of 18.5–23.9 kg/m²; (b) patients with an American Society of Anesthesiologists (ASA) grade of I–II; (c) patients scheduled to undergo FFB and requiring anesthesia and sedation; and (d) patients who have voluntarily provided written informed consent after being informed about the anesthetic used in this study.

The exclusion criteria were as follows: (a) patients with contraindications to conventional bronchoscopy, including severe hepatic and renal dysfunction, coagulation disorders, as well as a full stomach or gastrointestinal obstruction with gastric content retention; (b) patients with potentially life-threatening circulatory and respiratory diseases that are not adequately controlled, such as acute coronary syndrome, uncontrolled severe hypertension, severe arrhythmias, severe heart failure, recent acute myocardial infarction, and acute asthma attacks; (c) patients with a history of long-term use of antipsychotics or antidepressants; (d) patients without an accompanying person or legal guardian; (e) patients with a sedation/anesthesia drug allergy or other extremely high risk of anesthesia; (f) patients who are allergic or contraindicated to the study drug; and (g) patients with anticipated difficult airways requiring advanced airway management.

Randomization and masking

This was a randomized, single-blind controlled trial. Participants were randomly assigned into two groups, Group R and Group P, in a 1:1 ratio using a computer-generated randomization process. Participants were not informed about the sedative drug that they received; however, because of the clear differences in the appearance and injection characteristics of propofol (milky emulsion) and remimazolam (clear solution), complete blinding of patients could not be ensured, and the anesthesiologists administering the drugs were also not blinded. To minimize potential bias, clinical outcomes were assessed by a blinded evaluator who was not involved in the drug administration and remained unaware of the group assignments throughout the study. Data analysis was conducted by independent statisticians who were also blinded, ensuring unbiased interpretation.

Perioperative management and interventions

All participants were fasted for 8 h prior to inspection and received atomized inhalation of 4 mL of a 2% lidocaine solution (atomization took approximately 10 min) to minimize airway irritation. Upon the patient’s arrival in the bronchoscopy room, an intravenous line was established for infusion purposes. The Carestation 620 A2 monitor (GE Healthcare, Chicago, Illinois, USA) was connected to record blood pressure, heart rate (HR), respiratory rate, and pulse oxygen saturation. The participants then received nasal tube oxygen inhalation for 3 min at a flow rate of 5 L/min before sedation treatment was administered. Subsequently, participants were given intravenous alfentanil at a dose of 10 µg/kg (Hubei, Yichang Humanwell Pharmaceutical Co., Ltd), with the sedative drugs being administered over more than 30 s in each group: 1. Group R: 0.2 mg/kg remimazolam (Hubei, Yichang Humanwell Pharmaceutical Co., Ltd); 2. Group P: 2.0 mg/kg propofol (Beijing Fresenius Kabi Pharmaceutical Co., Ltd, Beijing, China). Three minutes after administering intravenous sedative drugs, the depth of sedation was evaluated using the modified observer’s assessment of alertness/sedation scale (MOAA/S). The MOAA/S scale is defined as follows: 5 = readily responds to name spoken in a normal tone; 4 = lethargic but responds to name spoken in a normal tone; 3 = responds only after name is called loudly, repeatedly, or both; 2 = responds only after mild prodding or shaking; 1 = responds only after a painful trapezius squeeze; and 0 = does not respond to a painful trapezius squeeze. ¹⁰ Sedation success was defined as a MOAA/S score of ≤3, at which point the respiratory physician initiated the FFB. If the MOAA/S score increased to >3, an additional dose of 0.05 mg/kg remimazolam was given to patients in Group R, and 0.5 mg/kg propofol to patients in Group P. If sedation was not successful after administration of three additional doses, it would be regarded as sedation failure, and 1 mg/kg propofol would be administered to rescue sedation. If the MOAA/S score was greater than 3 during the FFB, additional sedative drugs were added until the inspection was completed. During the examination, all patients received continuous oxygen inhalation through a nasal cannula (flow rate of 5 L/min). If SpO₂ was less than 90%, the patient’s jaw was immediately raised; if SpO₂ was less than 80%, the jaw was raised, and mask ventilation was implemented; mechanical ventilation support was provided when necessary. During the observation, if hypotension, bradycardia, hypertension, or tachycardia occurred and lasted for more than 30 s, patients were treated with the following vasoactive drugs: ephedrine, atropine, urapidil, and esmolol.

Outcomes

Primary outcome

The primary outcome was the incidence of hypoxemia during the FFB. Hypoxemia was defined as SpO₂ between 75% and less than 90%, lasting less than 60 s. Severe hypoxemia was defined as SpO₂ less than 75% at any time or less than 90% lasting more than 60 s. ¹¹

Secondary outcomes

The sedation success rate was defined as the percentage of successful sedation cases within each group. The success rate at a single induced dose was defined as the percentage of successful sedation cases after the induced dose within each group. Other effectiveness outcomes included the number of additional sedations required, the grade of cough (0 = severe, ≥5 coughs; 1 = moderate, 3–4 coughs; 2 = minimal, 1–2 coughs; and 3 = no coughing), the time to loss of consciousness, and sedation recovery time. The operator comfort score was defined as the level of comfort operators experienced while performing the procedure, rated on a numeric scale from 0 (“very uncomfortable conditions”) to 5 (“maximal comfort”), which was assessed after the FFB. The patient comfort score was defined as the level of comfort patients experienced while undergoing the procedure, rated on a numeric scale from 0 (“very uncomfortable conditions”) to 5 (“maximal comfort”), which was evaluated 24 h after FFB. Adverse events included injection pain, dizziness, intraoperative awareness, postoperative nausea and vomiting, postoperative sore throat, severe hypoxemia, hypotension (mean arterial pressure (MAP) ≤70% of baseline and/or <65 mmHg), hypertension (MAP > 120% of baseline), bradycardia (HR < 45 bpm), and tachycardia (HR ≥ 120% of baseline). Among these, the assessment time for dizziness, postoperative nausea and vomiting, and postoperative sore throat was 2 h after the patient woke up.

Sample size and statistical analysis

Before the experiment it was observed that the incidence of hypoxemia was 10.5% in Group R and 36% in Group P. The sample size was estimated using PASS 15.0 software (PASS, Kaysville, Utah, USA), with α = 0.05, two-tailed, and a power of 90%. Our study required 106 participants. Considering a 10% dropout rate, a total of 118 participants were needed (59 participants in each group).

SPSS 20.0 statistical software (IBM Corp., Armonk, New York, USA) was used for data processing and analysis, with statistical significance set at P < 0.05. The normality of the data distribution was assessed using the Shapiro–Wilk test. All data are presented as mean ± SD, number (percentage), or median (quartile (Q) 1, Q3), as appropriate. Normally distributed data were compared between the groups using an independent-samples t-test, whereas the nonnormally distributed data were compared using the Mann–Whitney U test. The chi-square test or Fisher exact test was used for the comparison of categorical data between groups. The significance level for the analysis was set at α = 0.05.

Results

A total of 130 participants were screened for this study; however, 10 participants declined to participate, and 2 were excluded based on the exclusion criteria. Consequently, 118 participants were included in the trial, with 59 participants in each group. Throughout the study, one participant from Group R and two from Group P withdrew due to unforeseen equipment failure. As a result, the analysis included 58 participants from Group R and 57 from Group P (Figure 1).

Figure 1.

Flow diagram of the study.

No significant differences were observed in baseline and procedural characteristics between the two groups (P > 0.05) (Table 1).

Table 1.

Patient baseline characteristics and procedural characteristics.

Characteristics	Group R (n = 58)	Group P (n = 57)	P
Age (years)	62.7 ± 8.3	63.7 ± 7.3	0.523
Body mass index (kg/m2)	21.2 ± 1.4	21.6 ± 1.4	0.224
Sex, n (%)			0.795
Male	38 (65.5)	36 (63.2)
Female	20 (34.5)	21 (36.8)
American Society of Anesthesiologists physical status, n (%)			0.645
I	15 (25.9)	17 (29.8)
II	43 (74.1)	40 (70.2)
Procedures, n (%)			0.783
Inspection only	3 (5.2)	5 (8.8)
Inspection + bronchoalveolar lavage	10 (17.2)	8 (14.0)
Inspection + bronchial biopsy	33 (56.9)	35 (61.4)
Inspection + bronchial treatment	12 (20.7)	9 (15.8)
Total inspection time (min)	16.4 ± 2.4	16.0 ± 2.3	0.334

Data are shown as mean ± SD or number (percentage).

As indicated in Table 2, Group R exhibited a lower incidence of hypoxemia than Group P (10.3% vs. 33.3%, P = 0.003). Additionally, the incidence of severe hypoxemia (3.4% vs. 15.8%, P = 0.029) and the occurrence of injection pain (1.7% vs. 14.0%, P = 0.016) were reduced in Group R. Conversely, a higher number of participants in Group P reported dizziness (3.4% vs. 15.8%, P = 0.029) and hypotension (1.7% vs. 15.8%, P = 0.008). The incidence of other adverse events was comparable between the two groups (P > 0.05).

Table 2.

Safety outcomes.

Adverse event	Group R (n = 58)	Group P (n = 57)	P
Severe hypoxemia, n (%)	2 (3.4) a	9 (15.8)	0.029
Hypoxemia, n (%)	6 (10.3) a	19 (33.3)	0.003
Injection pain, n (%)	1 (1.7) a	8 (14.0)	0.016
Hypertension, n (%)	3 (5.2)	4 (7.0)	0.720
Hypotension, n (%)	1 (1.7) a	9 (15.8)	0.008
Bradycardia, n (%)	1 (1.7)	1 (1.8)	>0.99
Tachycardia, n (%)	3 (5.3)	4 (7.0)	0.720
Dizziness, n (%)	2 (3.4) a	9 (15.8)	0.029
Postoperative nausea and vomiting, n (%)	3 (5.2)	4 (7.0)	0.720
Postoperative sore throat, n (%)	2 (3.4)	5 (8.8)	0.280
Intraoperative awareness, n (%)	0 (0)	0 (0)	>0.99

Data are shown as number (percentage).

^aP < 0.05, compared with Group P.

The operator comfort score was higher in Group R, with a score of 5 (4, 5), than in Group P, with a score of 4 (4, 5) (P = 0.011). The patient comfort score was higher in Group R, 4.5 (4, 5), than in Group P, 4 (3, 4) (P < 0.001). The sedation recovery time was shorter in Group R than in Group P (5.7 ± 1.3 min vs. 7.8 ± 1.6 min, P < 0.001). The grade of cough was lower in Group R, 2 (2, 3), than in Group P, 2 (1.5, 2) (P = 0.032). There was no significant difference in other effectiveness outcomes between the two groups, including the sedation success rate, the sedation success rate at an induced dose, and the number of additional sedations (P > 0.05) (Table 3).

Table 3.

Effectiveness outcomes.

Effectiveness outcomes	Group R (n = 58)	Group P (n = 57)	P
Successfully sedation, n (%)	58 (100)	57 (100)	>0.99
Successfully sedation at an induced dose, n (%)	53 (91.4)	51 (89.5)	0.730
Sedation recovery time (min)	5.7 ± 1.3 a	7.8 ± 1.6	<0.001
Number of additions sedation	1 (0–2)	0 (0–2)	0.390
Grade of cough	2 (2–3) a	2 (1.5–2)	0.032
Operator comfort score	5 (4–5) a	4 (4–5)	0.011
Patient comfort score	4.5 (4–5) a	4 (3–4)	<0.001

Data are shown as mean ± SD, median (Q1, Q3) or number (percentage).

Q: quartile.

^aP < 0.05, compared with Group P.

Discussion

The study results indicated no significant difference in sedative efficacy between remimazolam combined with alfentanil and propofol combined with alfentanil in FFB. Simultaneously, compared with propofol, remimazolam demonstrated a shorter sedation recovery time and a lower cough score. Furthermore, regarding safety, the incidence of hypoxemia, hypotension, injection pain, and postoperative dizziness resulting from remimazolam sedation was lower. These findings offer a new option for the selection of anesthesia regimens in FFB.

During FFB sedation, the primary safety concerns revolve around respiratory depression. Light anesthesia can lead to repeated insertion and aspiration with the bronchoscope, which may induce coughing in patients and potentially cause reflex bronchoconstriction. In cases of deep anesthesia, patients are at risk of experiencing respiratory depression. Remimazolam, with its rapid metabolic properties, not only reduces the risk of drug accumulation but also lessens the inhibition of respiratory function. In contrast, the dose-dependent respiratory depression associated with propofol increases the risk of respiratory-related complications during FFB. ¹² Alfentanil is a short-acting opioid with significant analgesic and antitussive properties, as well as mild respiratory depression. It has been proven safe and effective for use in FFB. ¹³ Therefore, the combination of remimazolam and alfentanil may provide appropriate sedation for FFB. The results of this study indicated that the incidence of hypoxemia was lower in Group R than in Group P (10.3% vs. 33.3%), and the incidence of severe hypoxemia was also lower in Group R than in Group P (3.4% vs. 15.8%). This is consistent with the findings reported by Zhou et al. ¹⁴ Previous results by our research team also showed that during the maintenance of elderly patients under deep sedation with FFB, remimazolam had a lower incidence of hypoxemia compared with propofol (9.1% vs. 45.5%). ¹⁵ The study shows that remimazolam was highly suitable for use in outpatient FFB requiring rapid discharge. Unfortunately, neither study analyzed postoperative delirium or cognitive function. However, the results of other studies have shown that in elderly patients who underwent colonoscopy, remimazolam demonstrated comparable cognitive recovery to that of propofol. ¹⁶

During the FFB, key factors influencing operator comfort are continuity of operations and patient cooperation. Common causes of operation interruption include intraoperative drug intervention and complications such as cough, hypoxemia, and hypotension. The results of this study indicated that the cough grade, incidence of hypoxemia, and incidence of hypotension were lower in Group R compared with Group P. Consequently, the operator comfort score was higher in Group R than in Group P. Patients’ comfort scores largely depend on postoperative feelings; the proportion of those experiencing injection pain and dizziness in Group R was smaller, and there was no intraoperative awareness. Consequently, the comfort level of patients in Group R was higher in our results. The research by Gao et al. ¹⁷ also demonstrated that the application of remimazolam in FFB could yield higher operator and patient comfort scores.

Sedation is an important procedure for alleviating anxiety, pain, and discomfort in patients undergoing invasive surgical diagnosis and treatment. The sedation success rate of remimazolam is not inferior to that of propofol during upper gastrointestinal endoscopy. ¹⁸ This aligns with the findings of the present study, which once again showcased the sedative effect of remimazolam during invasive examinations. The sedation recovery time for patients in Group R was shorter compared with Group P (5.7 ± 1.3 min vs. 7.8 ± 1.6 min). Remimazolam induces sedative effects by selectively activating gamma-aminobutyric acid type A receptors, and its metabolism primarily involves hydrolysis by nonspecific esterases, resulting in the nonpharmacologically active metabolite zolam propionic acid. ¹⁹ Flumazenil is a specific antagonist of benzodiazepines, which can enable patients to recover rapidly from sedation. A study has shown that administering 0.5 mg of flumazenil intravenously following sedation treatment with remimazolam can significantly shorten the sedation recovery time to 67.1 (±9.6) minutes in endoscopic variceal ligation. ²⁰ Although flumazenil was not used in this study, patients in Group R still exhibited characteristics of rapid wakefulness. This outcome further highlights the benefits of remimazolam’s rapid metabolism and brief duration of action. ²¹ This study verified the clinical value of rapid wakefulness associated with remimazolam in FFB, further supporting its application in scenarios requiring short-term and efficient sedation.

Limitations

Although this study confirms several advantages of remimazolam in FFB, there are still some limitations that must be acknowledged. Remimazolam, a benzodiazepine drug, may pose a potential risk of postoperative delirium or cognitive impairment, particularly in elderly patients, which warrants further investigation. The follow-up period of this study was relatively brief, and no such issues were observed; however, future research should extend the follow-up to fully assess its safety profile. Additionally, remimazolam’s metabolism, which is independent of liver and kidney function, and its mild suppression of circulation and respiration indicate that it may have greater potential for use in high-risk patient groups. This study only included patients with ASA grades I or II and did not thoroughly assess the suitability of remimazolam for patients with higher ASA grades III or those with concurrent liver and kidney dysfunction. Lastly, because of the significant differences in appearance between remimazolam and propofol, this study was unable to achieve a strict double-blind design, which may have had a minor impact on the objectivity of the research outcomes.

Conclusions

In summary, this study indicates that the sedative effect of remimazolam combined with alfentanil in FFB is comparable with that of propofol combined with alfentanil. Moreover, it offers significant advantages in terms of respiratory protection, hemodynamic stability, postoperative recovery, and patient comfort. These results provide a new scientific basis for the application of remimazolam in FFB. Future studies should focus on further validating its applicability in high-risk patients and various clinical scenarios through multicenter and large-scale studies.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Data sharing statement

The original data analyzed in this study are included in the article; further inquiries can be directed to the corresponding author.

Ethics approval and consent to participate

This trial was conducted in accordance with the Declaration of Helsinki and the Chinese Clinical Trial Specifications. It was approved by the Medical Ethics Committee of Lishui People’s Hospital (No: LLW-FO-403). Written informed consent was obtained from all participants. This study adhered to the CONSORT guidelines.

Funding

This research was supported by the Horizontal project of Lishui People’s Hospital (NO: T2023-YW-076-MZK-002); Lishui Medical and Health System Key Supported Disciplines Construction Project (NO: 2023047885 and NO: 2023047901); and the Clinical Medicine Special Fund Project of Zhejiang Medical Association (NO: 2024ZYC-A604). The funder had no involvement in the study design, data collection, analysis, or interpretation, the writing of this article, or the decision to submit it for publication.