Dezocine prevents sufentanil-induced respiratory depression during awake intubation: a multicenter, randomized, controlled study

Sufentanil has sedative and inhibitory effects on the intubation response, but high doses of sufentanil can cause coughing and respiratory depression. Dezocine has been documented effectively suppressing sufentanil-induced cough. Whether dezocine can inhibit the respiratory depression caused by sufentanil is unknown. This study aims to observe the ecacy of dezocine combined with sufentanil in awake intubation. Four hundred and three patients of American Society of Anesthesiologists physical status Classes I and II, aged 18–65 years, were randomly allocated into four groups: Group saline (saline + 0.4 ug/kg sufentanil), Group D0.05 (dezocine 0.05 mg/kg + 0.4 ug/kg sufentanil), Group D0.10 (dezocine 0.10 mg/kg + 0.4 ug/kg sufentanil), and Group D0.15 (dezocine 0.15 mg/kg + 0.4 ug/kg sufentanil). The primary outcome of our study was to observe the incidence of respiratory depression. Secondary outcomes included the success rate of intubation, ease of intubation, intubation comfort score, sore throat, hoarseness, lethargy, limb movement, glottis exposing and the satisfaction of patients during intubation. Hemodynamic changes were recorded after sufentanil injection and awake intubation. 0.05). Our study indicated that 0.10 mg/kg and 0.15 mg/kg dezocine might prevent the occurrence of cough and respiratory depression induced by sufentanil during awake intubation and improve patient satisfaction. physical status classication of I-II. Exclusion criteria included: severe bradycardia or any type of electrocardiogram conduction block, use of an α agonist or antagonist within two weeks; opioid use within 24 hours; serious liver, kidney, or cerebrovascular disease; allergy the study; predictably dicult three instances of intubation unable to bear intubation; any respiratory illness; obstacles in language communication; or a person of unsound mind. dezocine and a saline group. Dezocine dosed in of specic method follows: each order statistical Randomization results opaque blind to the assigned group.

Dezocine prevents sufentanil-induced respiratory depression during awake intubation: a multicenter, randomized, controlled study Introduction Anesthesia safety has greatly improved in the last half century. However, the incidence of di cult airway in patients undergoing endotracheal intubation is still between 1% and 18% [1], and the mortality rate associated with di cult airway is sometimes as high as 30% [2]. Retaining spontaneous breathing and awake intubation are effective methods to manage patients with suspected di cult airway [3], but awake intubation can lead to intense stress and cardiovascular response. There are many methods of awake intubation. Reasonable sedation and analgesia are the keys to this procedure's success [4]. Sufentanil is a synthetic opioid drug mainly used to activate µ receptors. It has a strong analgesic effect, little effect on hemodynamics, and can effectively inhibit endotracheal intubation response. At present, sufentanil is the most commonly used analgesic drug in general anesthesia induction and maintenance [5]. However, while sufentanil inhibits analgesia and endotracheal intubation, central respiratory inhibition is also common [6]. Balancing sufentanil analgesia with respiratory depression is a challenge for anesthesiologists.
Sufentanil is associated with an increased risk of hypoxemia and apnea [7], which is particularly undesirable for patients and anesthesiologists. This may due to the µ-selective opioid sufentanil showing high a nity for its binding sites which close vicinity to the respiratory regulating centers in the brainstem. Dezocine is a synthetic compound that functions as an µ receptor agonistantagonist. Our previous studies have shown that pre-injection of dezocine can effectively inhibit the coughing response to sufentanil during induction [8], which may be related to the antagonism of µ receptors. Whether dezocine can inhibit the respiratory depression caused by sufentanil by partially antagonizes µ receptors has not been clinically reported. Dezocine has a strong analgesic effect and can effectively suppress the stress response caused by endotracheal intubation [9]. Therefore, this study aimed to explore the rate of respiratory depression and patient satisfaction. Patients were randomly divided into a dezocine group and a saline group. Dezocine was dosed in kilograms of body weight. The speci c method of random grouping is as follows: the patients in each center entered the test groups according to the order of enrollment and the random number (scratch card) generated by the statistical software. Randomization results were concealed in opaque envelopes until informed consent had been given. Patients and perioperative period observers were blind to the patient's assigned group.

Methods
Anesthesia and research procedure Baseline vital signs were recorded immediately before the procedure. All patients received supplemental oxygen intranasally (6L/min) and underwent continuous monitoring of heart rate (three-lead electrocardiography), oxygen saturation (pulse oximetry), blood pressure (automated blood pressure cuff, serial measurements every 3 minutes). The respiratory rate and end-tidal CO 2 were also recorded. Dezocine (5 mg/mL; Yangtze River Pharmaceutical, Co., Jiangsu, China) was diluted with normal saline to one mg/mL and was administered with one bolus of dezocine 0.05 mg/kg (D0.05 group), 0.10 mg/kg (D0.1 group), 0.15 mg/kg (D0.15 group), or an equal volume of 0.9% normal saline (saline group) intravenously three to ve seconds before anesthesia induction. Sufentanil (Yichang Humanwell Pharmaceutical Co., Hubei, China) was diluted with normal saline from its original concentration of 50 μg/mL to a concentration of 5 μg/mL. Two minutes later, all patients received 0.4 μg/kg sufentanil over three seconds. Five minutes after sufentanil injection, the anesthesiologist used a laryngoscope to expose the glottis, and topical anesthesia was performed with two mL 2% lignocaine via the larynx. Two minutes later, the anesthesiologist exposed the glottis for tracheal intubation.
Immediately after injection, an anesthetic registrar recorded the occurrence of cough as 'yes' or 'no'. Depending on the number of coughs observed, the cough severity was graded as mild (one to two), moderate (three to ve), or severe (> ve). Blood pressure and heart rate (HR) were recorded before sufentanil injection(T0-s), one minute (T1-s), three minutes (T3-s), and ve minutes (T5-s) after sufentanil injection. Blood pressure and HR were recorded during intubation (T1), and at one minute (T2) and three minutes (T3) after intubation, and the patient's intubation response were observed in terms of ve variables [10,11] a. Ease of intubation: 1 -very easy, 2 -easy, 3 -general, 4 -di cult, 5 -very di cult.
If patients experienced adverse reactions such as hypertension, hypotension, tachycardia, bradycardia, or respiratory depression during the experiment, we had corresponding uni ed treatment measures.
The primary outcome of our study was to observe the incidence of respiratory depression. Respiratory depression was considered to be signi cant when SpO 2 was 90%, end-tidal CO 2 was >50 mmHg at any time, respiratory rate was <6 breaths/minute, or when airway obstruction with the cessation of gas exchange was observed at any time (noted by an absent end-tidal CO 2 waveform). Secondary outcomes included the success rate of intubation, ease of intubation, intubation comfort score, sore throat, hoarseness, lethargy, limb movement, glottis exposing, and the satisfaction of patients during intubation. Hemodynamic changes were recorded after sufentanil injection and awake intubation. The patients' memories, throat pain, and hoarseness were followed up 24 hours after the operation.
Statistical analyses: According to the results of our preliminary experiment, this study required at least 88 patients per group to attain appropriate power (a = 0.05 [two-tailed]; β = 0.2). The sample size was increased to 120 patients per group to account for any dropouts. Data are expressed as mean ± standard deviation (SD) or as the number or percentage of patients. Patient characteristics and the hemodynamic variables between the groups were compared using unpaired two-tailed t-tests. The incidence and severity of cough, gender proportions, and ASA class were assessed using Chi-squared tests and Fisher's exact test with Bonferroni correction. P < 0.05 was de ned signi cance. A Bonferroni correction would be used if the difference between groups was P < 0.05. P < 0.0083 was used to de ne signi cance to reduce the risk of type I error due to multiple analyses or for subgroup interactions. All analyses were performed using SPSS 16.0.

Primary outcome
The intubation variables of 403 participants assigned to the dezocine or saline groups were shown in Table 2. Respiratory depression was statistically different between the four groups (P < 0.05). The incidence of respiratory depression in the saline group was 22.8%, while that in the D0.05 group was 19%, the D0.10 group was 3% and the D0.15 group was 2%. Fisher's exact test (2*C) showed that there was a statistically signi cant difference among the four groups (P < 0.001). Bonferroni correction was used to adjust the level of α for p2p comparison. There was no difference in the effect of normal saline and 0.05 mg/kg dezocine on respiratory depression (P = 0.603). The results showed that there were signi cant differences between 0.10 mg/kg dezocine and 0.15 mg/kg dezocine in respiratory inhibition compared with saline (all P < 0.0083).

Secondary outcomes
Intubation-related data, including sore throat, hoarseness, lethargy, and success awake intubation were similar across the four groups (all P > 0.05). The cough was statistically different between the four groups (P < 0.05). The incidence of cough was 37.6% in the saline group, 5% in the D0.05 group, and 0 in the D0.10, and D0.15 groups.
As shown in Table 3, there was no difference between the four groups except for patient satisfaction. In the saline group, ve (5%) patients were very dissatis ed during awake intubation, while there were no (0%) very dissatis ed patients in the D0.05 group, D0.1group, and D0.15 group. Notably, the ease of intubation was not signi cantly different between the four groups, and neither was tolerance to intubation, bodily-kinesthetic, or glottis exposure (P > 0.05).
The hemodynamic changes before and after sufentanil injection observed between the four groups were shown in Table 4. SBP was not signi cantly different between the four groups before or after sufentanil injection, nor was DBP (P > 0.05). Notably, there was a signi cant difference in HR (P < 0.05). The hemodynamic changes before and after intubation observed between the four groups were shown in Table 5. The SBP and DBP were also not signi cantly different between the four groups before or after intubation (P > 0.05), but there was a signi cant difference in HR (P < 0.05).

Discussion
Sufentanil intravenously increased opioid-induced cough and respiratory depression [8]. Our study found that dezocine combined with sufentanil for awake intubation completely suppressed the incidence of cough caused by sufentanil, This provided better awake intubation conditions, which was in agreement with the prior study [12]. Meanwhile, dezocine can inhibit the respiratory depression caused by sufentanil in awake intubation, The incidences of absent end-tidal CO 2 , SpO 2 < 90%, and RR < 6 breaths/min were signi cantly lower in Group D0.10 and Group D0.15 than in the saline group (p < 0.05). There was a dose-response relationship in terms of respiratory depression in the dezocine groups (p < 0.05). The incidence of respiratory depression was decreased when the dose of dezocine was increased. No statistically signi cant respiratory depression differences were noted between Group D0.10 and Group D0.15. Five patients developed respiratory depression in Group D0.10 and Group D0.15 (SPO 2 < 90%), but none of them required jaw support or emergency tracheal intubation. Five patients were still responsive to command and able to carry out instructions. The patient's hypoxemia was quickly relieved simply by giving the patient verbal encouragement to breathe.
Awake intubation is the standard of care for the management of the anticipated di cult airway in adult patients [13,14]. Awake intubation can improve the survival rate and reduce the death rate of patients with di cult airways. However, the disadvantages of awake intubation include poor patient tolerance, patient unwillingness to cooperate, and dramatic hemodynamic uctuations.
Optimal conditions for awake intubation include that a patient should be comfortable, cooperative, free of oropharyngeal blood and secretions, and able to maintain their airway with spontaneous ventilation [15]. An ideal drug should be short-acting, easily titratable, provide the required amount of sedation, and have little suppression of spontaneous ventilation are chosen [16]. In the last three decades, several drugs have been utilized such as midazolam, sufentanil, remifentanil, and dexmedetomidine [17][18][19]. When the sedative and analgesic drugs were selected for awake intubation, the adverse event most concerned by the anesthetists was respiratory depression. Opioids are strong analgesics with some hypnotic effect and can help attenuate the cough and hemodynamic changes during awake intubation. Opioids have been used as adjuncts to sedation for awake intubation [20]. Nevertheless, opioids with large doses for sedation can be associated with signi cant hypoxemia (SpO 2 < 90%), apnea, and hemodynamic uctuation [21].
Sufentanil is one of the strongest opioids to inhibition of tracheal intubation response. Studies have shown that an induced dose of 0.3 ug/kg causes hypotension [22]. In this study, we found that blood pressure and heart rate did not change more than 20% of the baseline value after sufentanil injection in the four groups (P > 0.05). It is suggested that 0.4ug/kg sufentanil is safe for awake intubation. Perfect tracheal epithelial anaesthesia is the key to inhibit awake tracheal intubation response, In our study,though it was found that the blood pressure and heart rate of patients after intubation were higher than before intubation, while the change value did not exceed 20% of the basic value.
Studies have shown that sufentanil is not an ideal drug for awake intubation alone [23]. In our study, the incidence of respiratory depression during awake intubation was 22.8% in the saline group, which was in agreement with previous studies [23,24]. While that in the D0.05 group was 19%, the D0.10 group was 3% and the D0.15 group was 2%. Our study found that dezocine can reduce the incidence of respiratory depression caused by sufentanil in awake intubation. Simultaneously, that dezocine combined with sufentanil could also provide a suitable depth of sedation and good depth of sedation during awake intubation increases patient satisfaction.
Opioids induce analgesia and respiratory depression via stimulation of µ-opioid receptors (MORs). MORs are found in abundance in respiratory control centers in pons and brainstem, such as the pre-Bötzinger complex, a respiratory rhythm generating area in the pons [25,26]. One approach to the development of opioid analgesic drugs with lower risk factors for respiratory depression has been the development of partial agonists at the MOR, such as dezocine [27]. Dezocine is a synthetic compound that functions as an µ receptor agonist-antagonist. Dezocine has a strong analgesic effect and can effectively inhibit the stress response caused by endotracheal intubation. The therapeutic dose of dezocine does not produce signi cant respiratory inhibition [28]. Does this separation of analgesia and respiratory depression mean that the subtype of MOR exists? The exact mechanism needs further study.
There were several limitations in this study. First, all patients in our study were not di cult airways, We did not explore the effect of dezocine in combination with sufentanil on awake intubation in patients with a di cult airway. Second, the satisfaction of patients in the saline group was lower than that in the dezocine group, which might be related to the sedative and analgesic effects of dezocine, which warrants further studies.

Conclusion
In conclusion, our results suggest that dezocine may effectively prevent the occurrence of sufentanil-induced irritating respiratory depression during awake intubation. Therefore, Sufentanil combined with dezocine could be a clinically effective method for awake intubation. The ndings of the study were reported according to the CONSORT guidelines.

Consent for publication
Not Applicable.

Availability of data and materials
The data that supports the ndings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Competing interests
The authors con rm that this article content has no con icts of interest.

Funding
This work was supported by grants from the National Natural Science Foundation of China (81870841, 81571039).
Authors' contributions X P and HY Z made substantive intellectual contributions to the interpretation of data and draft of the manuscript. R L, SJ X, X J, and Q Z assisted in data collection, analysis, and interpretation. GH X, XQ C, EW G, and XS L were involved in the design of this study, data collection, analysis, and interpretation of data, drafting and revising the manuscript.
The authors had read and approved the nal manuscript. Data are expressed as mean ± standard deviation (SD) or as the number or percentage of patients.
Patient characteristics between the groups were compared using unpaired two-tailed t tests.
Table2 Intra-operative variables for 403 participants allocated to intra-operative dezocine or saline. During the observation of respiratory depression, dezocine in different concentrations was compared with the saline group.
The incidence of intra-operative variables were assessed using Chi-squared tests and Fisher's exact test with Bonferroni correction. P < 0.05 de ned signi cance. The Intubation-related response were assessed using Chi-squared tests and Fisher's exact test with Bonferroni correction. P < 0.05 de ned signi cance.