Through the improved sequential method, we concluded that the EC95 for remifentanil inhibition of the stress response in fibreoptic bronchoscopy for patients with severe tracheal stenosis was 2.710 ng/ml (95% CI, 2.471–4.473 ng/ml) based on dexmedetomidine sedation and that the EC50 was 2.243 ng/mL (95% CI, 2.061–2.446 ng/mL). For all 30 patients, spontaneous breathing was retained during the diagnosis and treatment period, which improved the perioperative safety of severe patients and provided an effective and accurate MAC program for patients with severe tracheal stenosis who were undergoing fibreoptic bronchoscopy.
With the development of fibreoptic 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 . A large number of clinical studies have confirmed 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 PaO2, 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 fibreoptic bronchoscopy [14–16]. The application of sedative medicine during fibreoptic 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 significantly increasing the related complications [15, 17, 18]. Compared with general patients, patients with severe stenosis are less tolerant to fibreoptic 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 fibreoptic 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 fibreoptic 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 . However, the depth of anaesthesia tolerated with the laryngeal mask is often deeper than that required for fibreoptic bronchoscopy, resulting in significant circulation inhibition, longer recovery time and difficulty in meeting the needs of efficient operation. The fibreoptic 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 difficulties 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 fire during laser cauterization. Compared with local and general anaesthesia, the MAC with autonomous breathing provided by the nasopharyngeal airway for oxygen has obvious advantages .
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 reflecting changes in the drug concentration and effect. EC95 refers to the effective concentration for 95% of subjects with a specific 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 SpO2 was 85%, and SpO2 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 SpO2 % median (IQR) before and after the operation was [96 (95–97) & 99 (95–100), P < 0.05], PaO2 (mmHg) median (IQR) values were [82.0 (77.0-86.5) & 99.6 (85.0-145.2), P < 0.05]. The increase in SpO2 and PaO2 during the operation may have been related to the use of the nasopharyngeal airway  (No. 6/7, Medis, UK); oxygen was delivered by the anaesthesia machine (6 L/min), and the APL valve was set to 30 cmHO2. This special nasopharyngeal airway can be connected with an anaesthesia machine to supply oxygen, providing a higher concentration and more effective oxygen therapy than nasal catheters. At the same time, changes in end-expiratory carbon dioxide and respiratory rate can be continuously monitored to detect respiratory depression as early as possible and even provide an early warning before the occurrence of decreased SpO2 to reduce the risk of clinical hypoxemic events. In the future, relevant randomized controlled studies can be designed to obtain evidence-based medicine evidence. The PaCO2 (mmHg) median (IQR) before and after the operation was 41.5 (40.3–43.7) and 58.3 (50.7–63.0), respectively (P < 0.05)], the pH median (IQR) values were [7.41 (7.39–7.43) & 7.33 (7.28–7.36), P < 0.05], and the Lac (mmol/L) median (IQR) values were [1.50 (1.20–1.80) & 1.20 (1.00-1.80), P > 0.05.]. Respiratory depression that occurred during the operation led to an increase in PaCO2, 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; 30 mg of propofol was injected twice intravenously in order to complete the operation. The haemodynamics of all patients were stable at all time points during the operation, and no vasoactive drugs were used, indicating that this MAC can effectively inhibit such stress without affecting circulatory stability. The median tolerance score for nasopharyngeal airway placement was 2, the median Ramsay sedation score was 3, the median cough score was 1, the median operator-physician satisfaction score was 9, the median anaesthesiologist satisfaction score was 8, the median patient satisfaction score was 10, the median patient recall score for 24 h was 1, and the willingness of patients to accept the procedure again was 93.3%. The results show that the MAC scheme of this study provides a comfortable process of diagnosis and treatment for patients and makes the operator more comfortable completing the operation. However, the satisfaction of anaesthesiologists is not as high as that of operators and patients, which may be related to the continual focus of anaesthesiologists on the patients’ breathing status. Anaesthesiologists have to spend more effort completing anaesthesia-related tasks. Other sedation-related adverse effects included an increasing heart rate and blood pressure, none of which exceeded 20% of baseline. Thirty minutes after the operation, 5 patients (16.7%) had laryngopharyngeal pain, with VAS < 3. The MAC technique of fibreoptic 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 [25–27]. 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 [28–30]. 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 efficiently 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  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 fibreoptic bronchoscope operators.