Inhibition of Stress and Spontaneous Respiration: Ecacy and Safety of Monitored Anaesthesia Care by Remifentanil in Fibreoptic Bronchoscopy for Patients with Severe Tracheal Stenosis

Objective To determine the effective concentration of target-controlled infusion (TCI) of remifentanil used to inhibit stress during the treatment of severe tracheal stenosis with breoptic bronchoscopy and to evaluate the safety of the monitored anaesthesia care (MAC) by remifentanil. Methods A study of 60 patients with severe tracheal stenosis who underwent diagnostic and therapeutic breoptic bronchoscopy at Shanghai Pulmonary Hospital aliated with Tongji University was performed. Dexmedetomidine was initially administered at a bolus dose (0.8 mcg/kg), followed by a 0.5 mcg/(kg·h) continuous infusion. Remifentanil was administered by TCI. When the target concentration was reached, the nasopharyngeal airway was inserted, and then oxygen was supplied by a connected anaesthesia machine. The effective concentration of remifentanil was titrated by the improved sequential method, and 30 patients were included. The EC95 of remifentanil was set as the plasma target concentration to evaluate the safety of the MAC, and another 30 patients were included. Remedy measures: Propofol (10-20 mg) was injected intravenously. The primary outcome measures were the cough score and the incidence and severity of hypoxemia. The tolerance score for nasopharyngeal airway placement, Ramsay sedation score, haemodynamic changes, satisfaction score, patients’ 24 h recall score, patients’ willingness to re-receive the procedure, and related adverse events were recorded.


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Background With the development of endoscopic technology, interventional treatment via breoptic bronchoscopy has become one of the main methods of diagnosis and treatment for patients with benign and malignant tracheal stenosis, and the demand for breoptic bronchoscopic interventional treatment for patients with severe tracheal stenosis continues to increase [1][2][3]. Compared with ordinary patients, severe patients tend to be anxious and exhibit obvious di culty breathing, tachycardia, hypersecretion or expectoration of sputum, and lung infections, and they must often be placed in unnatural postures to maintain airway patency. Even if apnoea occurs, most conscious patients cannot tolerate the diagnosis and treatment of breoptic bronchoscopy, which could improve airway obstruction [4].
Effective and safe anaesthesia management technology can inhibit the stress response to breoptic bronchoscopy in severe patients, reduce the occurrence of choking cough and laryngeal spasm, and reduce serious complications that may be life-threatening, such as asphyxia, massive bleeding and malignant arrhythmia [5,6]. MAC with spontaneous respiration has signi cant advantages over local anaesthesia and laryngeal mask general anaesthesia [7][8][9][10][11]. However, there are few studies on anaesthesia management techniques for such severe patients, there is no precise standard scheme, and there is a lack of evidence-based medicine at home and abroad. In our study, on the basis of sedation with dexmedetomidine, the effective concentration of remifentanil for inhibiting the stress response was titrated through a modi ed sequential method during breoptic bronchoscopy of patients with severe tracheal stenosis, and the safety of the MAC regimen with remifentanil was evaluated.

Study design and population
This prospective interventional study was conducted at the respiratory endoscopy centre of Shanghai and registered in the Chinese Trial Registry (12/02/2021,ChiCTR2100043380). All patients enrolled in this study received informed consent.
Sixty patients who received breoptic bronchoscopy treatment were included, all of whom were diagnosed with severe tracheal stenosis for the rst time. The effective concentration of remifentanil was titrated by the improved sequential method in 30 patients, the safety of the MAC protocol was evaluated using EC95 as the plasma target concentration in 30 patients, and the inclusion of patients was completed by LJM. The inclusion criteria included patients with severe tracheal stenosis (the reduced area of the tracheal cavity was more than 50%) who wanted to be treated by breoptic bronchoscopy, were aged 18 ~ 65 years, and had ASA I -III status. The exclusion criteria were as follows: abnormal nasal anatomy, severe coagulation dysfunction, severe hepatic and renal dysfunction, history of abnormal recovery from surgical anaesthesia, chronic opioid treatment, substance abuse or drug use, pregnancy, history of allergy to related drugs, and no informed consent. Included patients were later excluded if general anaesthesia by laryngeal-mask or endotracheal intubation was required for the operation or the operation was over 60 min in duration.

MAC protocol
All patients fasted for 8 h, and water was forbidden for 4 h preoperatively. In the anaesthesia preparation area, 0.03 mg/kg midazolam (Midazolam®, Nhwa, China) was given intravenously to relieve preprocedural anxiety. ECG, HR, SpO 2 and MAP and Rf were monitored regularly after patient entry into the operating room. Oxygen inhalation through a nasal catheter (2 L/min) was performed. A simple mask breathing apparatus and anaesthesia machine were used as a standby. Dexmedetomidine (0.8 mcg/kg, Dexmedetomidine®, Yangtze River, China) was administered within 10 min using a Fresenius DPS workstation, and plasma target-controlled infusion (TCI) of remifentanil (Remifentanil®, Yichang Humanwell, China) was completed within 5 min. When the effector chamber concentration reached the target concentration, a nasopharyngeal airway (No. 6/7, Medis, UK) was placed, and oxygen was given by an anaesthesia machine (6 L/min) with an adjustable pressure-limiting (APL) valve setting of 30 cmH 2 O.
Four millilitres of 1% lidocaine (Lidocaine®, CSPC, China) was injected through the nasopharyngeal airway for topical anaesthesia, and then breoptic bronchoscopy was started. When the breoptic bronchoscope (BF-1T260/6C260, Olympus, Japan) was placed, 4 ml of 1% lidocaine was injected through the bronchoscopic tube into the acoustic gateway and subglottis for topical anaesthesia.
Intraoperative dexmedetomidine was pumped continuously at 0.5 mcg/(kg·h). The effective concentration of remifentanil was titrated by a modi ed sequential method. The plasma target concentration of remifentanil in the rst patient was 2.5 ng/ml, and the difference between adjacent targets was 0.5 ng/ml. After 3 cycles of negative and positive reactions, the difference in adjacent target concentrations was changed to 0.2 ng/ml. The stress response was de ned as positive if the change in HR or MAP exceeded 15% of the baseline or a choking cough affected the operation. Intravenous injection of 10-20 mg propofol was used as a remedy and was used repeatedly if necessary. After obtaining the EC95 of remifentanil, the plasma target concentration was set to EC95 to evaluate the perioperative safety of the MAC during the operation.
Related events and their management: de nition of hypoxemia: SpO 2 < 90% at any time. The severity of hypoxemia was classi ed as follows: subclinical hypoxemia (SPO 2 of 90-95%), moderate hypoxemia (SPO 2 of 75-89%, ≤ 60 s), and severe hypoxemia (SpO 2 < 90% for > 60 s or SpO 2 < 75% at any time). The treatment process for hypoxemia was as follows: stimulation and awakening, increasing the oxygen ow (10 L/min), supporting the lower jaw, mask-assisted ventilation, and mechanical ventilation with a laryngeal mask. hypotension: for MAP < 80% of baseline or 60 mmHg, if necessary, an intravenous injection of norepinephrine (25 ~ 100 µg/time) was used to maintain the blood pressure and was repeated when needed. bradycardia: HR < 50 bmp, with administration of atropine as appropriate; if arrhythmia occurred, vasoactive drugs were administered by the anaesthesiologist based on his or her clinical judgement.

Outcome measures
The primary outcome measures were the cough score and the incidence and severity of hypoxemia. The secondary outcomes included recovery time; dosage of propofol; Ramsay score; arterial blood gas analysis before and after the operation; haemodynamic changes; the tolerance score for nasopharyngeal airway placement; satisfaction scores of the operator, anaesthesiologist and patient; throat pain and epistaxis at 30 min after the end of the operation; throat pain; patients' scores on operation recall and willingness to receive treatment again at 24 h; and related adverse events such as postoperative pruritus, nausea and vomiting, bleeding, haemoptysis requiring invasive re-treatment, pneumothorax, etc.

Statistical analysis
All statistical analyses were performed using SPSS 26.0. Continuous variables are presented as the mean Continuous variables were compared using the Mann-Whitney U test or T-test. EC95, EC50, the standard error and the logarithm value of the 95% con dence interval (CI) of remifentanil were calculated by the formula of the sequential method [12]. The sample size of the effective concentration titrated by the improved sequential method is not clearly de ned. A sample size of 20-40 has been used in general studies [12]. In the present study, the sample size of the effective concentration titrated by remifentanil was 30. The safety of 30 patients was also observed. Two-sided p values < 0.05 were considered signi cant.

Patients
All 63 patients enrolled in the study; 3 patients were excluded because the operation time was more than 60 min, 60 patients were eligible for the data analysis, and none were discontinued due to safety concerns. The ow chart is shown in Fig. 1. Demographic and operation-related data for all 60 patients are shown in Table 1. Height,mean ± SD, m 1.7 ± 0.1 Weight,mean ± SD, kg 64.8 ± 9.3 BMI, mean ± SD, kg/m 2 23.8 ± 2.6  Effective concentration of remifentanil Figure 2 shows that the stress response of 30 patients with severe tracheal stenosis during breoptic bronchoscopy treatment was treated with remifentanil at different blood concentrations using the modi ed sequential method. The half effective effect-chamber concentration of remifentanil (EC50) was 2.243 ng/ml (95% CI, 2.061-2.446 ng/ml), and the EC95 was 2.710 ng/ml (95% CI, 2.471-4.473 ng/ml), as shown in Table 2.  Table 3. One case with remedy by 30 mg propofol was completed. The tolerance score for nasopharyngeal airway placement, Ramsay sedation score, cough score and satisfaction score are shown in Table 4. The incidence of respiratory depression was 50%, the incidence of subclinical respiratory depression was 30%, the incidence of moderate hypoxemia was 20%, and the incidence of severe hypoxemia was 0%. Among all patients with respiratory depression, 86.7% were restored to normal by awakening, 1 was restored to normal by mask-assisted ventilation, and another was restored to normal by laryngeal-mask mechanical ventilation ( Table 5). The analysis of arterial blood gas before and after the operation is shown in Fig. 3. Other sedation-related adverse reactions are shown in Table 6. There were cases of increased heart rate and blood pressure, none of which exceeded 20% of the baseline value. Adverse reactions related to oxygen delivery, including throat pain 30 min and 24 h after the operation, are shown in Table 7. T 0 : before procedure,T 1 procedure T 2 5min after procedure T 3 10min after procedure T 4 15min after procedure T 5 end of procedure    With the development of breoptic bronchoscopy technology, it has been widely used in clinical practice, and more than 500,000 bronchoscopy procedures are performed in the United States every year [13]. A large number of clinical studies have con rmed that the stress response cannot be effectively suppressed under only local anaesthesia, which may lead to choking cough or laryngeal spasm resulting in a decrease in PaO 2 , aggravating the patient's dyspnoea, interrupting the operation, and even causing serious life-threatening complications such as asphyxia, massive bleeding, malignant arrhythmia and so on. Except for patients with obvious contraindications, the guidelines recommend routine sedation for all patients undergoing breoptic bronchoscopy [14][15][16]. The application of sedative medicine during breoptic bronchoscopy can effectively improve the patient's tolerance, reduce the choking cough during the operation and increase the patient's willingness to revisit the diagnosis and treatment without signi cantly increasing the related complications [15,17,18]. Compared with general patients, patients with severe stenosis are less tolerant to breoptic bronchoscopic intervention, which may improve airway obstruction. Therefore, it is a great challenge for anaesthesiologists to provide anaesthesia management for patients with severe tracheal stenosis through breoptic bronchoscopy, and there is currently no recognized standardized anaesthesia management plan here or abroad [15,19]. The level of nociceptive irritation that results from airway insertion or breoptic bronchoscopic procedures is similar to that of surgical incisions, and there are unique challenges to anaesthesiologists sharing the airway with the operator. The implementation of sedation and anaesthesia reduces risk, improves the comfort of patients and operators and increases the continuity and success of the procedure. In 2009, a study in China showed that 2 out of 58 hospitals routinely used general anaesthesia-assisted or controlled ventilation through laryngeal masks to complete such endoscopic diagnosis and treatment [20]. However, the depth of anaesthesia tolerated with the laryngeal mask is often deeper than that required for breoptic bronchoscopy, resulting in signi cant circulation inhibition, longer recovery time and di culty in meeting the needs of e cient operation. The breoptic bronchoscope must enter the airway through the outer laryngeal mask in the mouth, which can lead to high airway pressure, air leakage and even obstruction of ventilation. There are many di culties with respiratory management in clinical practice. Moreover, the concentration of oxygen in the airway is often too high when the laryngeal mask is ventilated, and this easily causes airway re during laser cauterization. Compared with local and general anaesthesia, the MAC with autonomous breathing provided by the nasopharyngeal airway for oxygen has obvious advantages [21].
Sequential methods, also known as up-down methods or step-down methods, are simpler and more effective methods to study the effective concentration of drugs. The advantage of the sequential method is that it can make full use of the data provided by fewer cases and obtain results quickly and accurately, which can reduce the number of trial cases by 30% ~ 40%. Remifentanil has a quick onset and rapid elimination, TCI makes its dose accurate and easy to adjust, and the inhibition of cardiovascular responses caused by stress can be quickly determined, which is suitable for sequential study [22,23].
EC50 refers to half of the subjects at a particular reaction dose and can be sensitive in re ecting changes in the drug concentration and effect. EC95 refers to the effective concentration for 95% of subjects with a speci c reaction. The EC50 study concentration-response relationship of a drug is more sensitive and accurate than the EC95; however, the effectiveness of the EC95 is higher, and drug-related adverse reactions may be increased because of the higher drug concentration. In the second part of this study, the EC95 of remifentanil was used to evaluate patients' hypoxemia and other related adverse reactions, and its safety could be investigated better.
Our study showed that the incidence of respiratory depression was 50% (15/30), that of subclinical hypoxemia was 30% (9/30), that of moderate hypoxemia was 20% (6/30), and that of severe hypoxemia was 0% (0/30) among 30 patients with TCI with EC95 of remifentanil. A total of 86.7% (13/15) of the patients with respiratory depression returned to normal by wakening, one patient returned to normal by face-mask-assisted ventilation, and another patient returned to normal by laryngeal-mask mechanical ventilation. The patient with laryngeal-mask mechanical ventilation was 65 years old, weighed 46 kg, and had a height of 175 cm, a BMI of 15, hypertension, diabetes, and 75% airway stenosis. The Ramsay sedation score was 5, the lowest SpO 2 was 85%, and SpO 2 became 100% by mask-assisted ventilation; however, breath was still not recovered. The operation was successfully completed through mechanical ventilation with the laryngeal mask, and the changes in MAP and HR did not exceed 10% of the baseline.
The patient awakened 8 min after the operation, and no adverse reactions were found during the 24 h follow-up. This patient was analysed as a frail patient with hypertension and diabetes accompanied by advanced age and low body weight. The EC95 was 2.710 ng/ml (95% CI, 2.471-4.473 ng/ml) for this patient, and the depth of anaesthesia may have been too deep, leading to moderate hypoxemia. According to the response of patients to narcotic drugs, the incidence of hypoxemia can be reduced by adjusting the dosage of narcotic drugs in a timely manner. The SpO 2 % median (IQR) before and after the during the operation led to an increase in PaCO 2 , but all of these values were < 70 mmHg, which was within the range of permissible hypercapnia. The changes in pH and Lac were clinically within acceptable ranges, and the patients' circulation was stable. There was no special treatment in clinical practice. One patient was treated with propofol because performance of the operation was affected by choking cough; 20% of baseline. Thirty minutes after the operation, 5 patients (16.7%) had laryngopharyngeal pain, with VAS < 3. The MAC technique of breoptic bronchoscopy is complicated, poses a high risk of respiratory depression and exacts a high demand from anaesthesiologists. Studies have shown that 50% of bronchoscope-related adverse events are related to sedation or (and) anaesthesia implementation, which is the main reason for the low rates of such surgical sedation and anaesthesia procedures in China [25][26][27]. In the process of MAC, sedation and inhibition of the airway response are mainly achieved by drugs. At present, there is no single drug that can perfectly achieve this purpose; consequently, the combined application of local anaesthesia, sedatives and opioids is clinically selected for MAC. In the UK, benzodiazepines are reported to be the most commonly used drugs (63%), followed by opioids (14%) and benzodiazepines combined with opioids (12%). The latest Australian and New Zealand censuses showed 53% use of midazolam and fentanyl. In China, benzodiazepines and/or opioids for sedation were found to be used in 44% of 58 hospitals [28][29][30]. Remifentanil can effectively inhibit choking cough, is also the mainstream clinical and ultra-short-acting opioid, is effectively and rapidly metabolized, and can better and more e ciently meet the demands of clinical operation. However, the literature has reported that chest wall rigidity and bradycardia often occur [31,32]. This study did not observe associated adverse events, which may have been related to the accurate quantitation of TCI. Minimal anaesthetic drugs were used to inhibit stress and to reduce adverse reactions, while 5 min was set to reach the plasma target concentration. Dexmedetomidine [33] is a new sedative and analgesic drug that does not easily cause respiratory depression and has obvious sedative effects. It can cause arousal sedation or cooperative sedation, is similar to normal sleep, and can reduce the dosage of opioid analgesics and adverse reactions. Therefore, in this study, the combination of remifentanil and dexmedetomidine reduced the incidence of respiratory depression and other drug-related adverse reactions.
The shortcomings of this study are as follows: it was a prospective interventional study, not a randomized controlled study, and it did not perform comparisons with other MAC regimens. However, we believe that safe, streamlined procedures and shorter induction and recovery times are better choices for patients, anaesthesiologists, and breoptic bronchoscope operators.

Conclusion
In summary, our study demonstrates that the MAC of remifentanil with spontaneous breathing provides a satisfactory sedative and analgesic effect for patients with severe tracheal stenosis during breoptic bronchoscopy. The EC95 of remifentanil for inhibiting the stress response of the operation was 2.710 ng/mL (95% CI, 2.471-4.473 ng/mL) and the EC50 was 2.243 ng/mL (95% CI, 2.061-2.446 ng/mL). Among the 30 patients with EC95 as the target concentration, 1 patient was treated with propofol to complete the operation. The stress of the remaining patients was effectively suppressed, and the satisfaction of both the operator and the patient was high. Comfortable medical treatment of the patients was realized under the MAC. The incidence of respiratory depression is 50%, and the incidence of hypoxemia is 20%; however, most of these cases can be improved by wakening, and the median SpO 2 during the operation is 99% [85-100]. MAC has high clinical safety. Nonetheless, the occurrence of respiratory depression should be further evaluated in the next randomized controlled trial to evaluate its safety more accurately. The response of patients to the stress of beroptic bronchoscopy