Sedative and analgesic validity and administration routes of dexmedetomidine and fentanyl combined with ketamine in awake fiberoptic intubation: An exploratory randomized controlled trial

Background: Awake fiberoptic bronchoscope intubation (AFOBI) is the gold standard technique for the management of patients with difficult airways. Adequate sedation and analgesia are essential for successful AFOBI. The aim of this study was to evaluate the sedative and analgesic validity and administration routes of dexmedetomidine and fentanyl combined with ketamine in awake fiberoptic intubation. Methods: Patients undergoing head and neck surgery under general anesthesia with predicted difficult airways were included. Participants were randomly assigned to 6 different groups (n=6): groups 1-3 were intravenous (IV), while groups 4-6 were intranasal(IN) (group 1: dexmedetomidine (DEX) 1 μg/kg + fentanyl (FEN) 1 μg/kg; groups 2-3: DEX 1 μg/kg+ FEN 0.7 μg/kg + ketamine (KTM) 0.1/0.2 mg/kg; group 4: DEX 1.5 μg/kg + FEN 1.4 μg/kg; and groups 5-6: DEX 1 μg/kg + FEN 1 μg/kg + KTM 0.4/0.6 mg/kg). The visual analog scale (VAS) score during intubation, time required for the modified observer’s assessment of alertness/sedation scale (OAA/S) score to reach above 2 and for the bispectral index (BIS) to decrease to 60-80, motor activity assessment scale (MAAS) score, changes in vital signs and adverse effects were recorded. Results: Among the IV groups, the VAS score of group 1 (5.65±2.11) was higher than those of group 2 (1.89±2.16, P =0.012) and group 3 (1.15±0.98, P =0.001). Among the IN groups, the VAS score was lower in group 6 (0.86±1.27) than in group 4 (7.20±2.70, P <0.001) and group 5 (3.93±2.73, P =0.031). Participants in group 5 and group 6 were less

consumption used in AFOBI and provide better sedative and analgesic effects.
Severe events may occur, such as respiratory depression, hypoventilation, hypoxemia, brain damage or even death if the patient's airway is not secured [3]. Although local anesthesia and many types of medicines are used to mitigate anxiety and pain, awake intubation can be an extremely unpleasant experience. The sedative and analgesic effect of a low dose of a single agent is poor, resulting in obvious pain and an inability to cooperate well with the tracheal intubation. However, high doses may cause adverse effects, such as different degrees of inhibition of the respiratory and circulatory systems, that threaten the lives and safety of patients [4,5].
Dexmedetomidine (DEX) is a selective α-2-adrenoceptor agonist that has the ability to sedate, functions as an anxiolysis, is analgesic sparing, and reduces salivary secretion [6].
It can induce a 'wakable' state that is similar to normal sleep. There are many studies on the use of dexmedetomidine in awake fiberoptic bronchoscopy intubation (AFOBI) [7]. A recent review reported that dexmedetomidine can cause fewer desaturation episodes than propofol and opioids when used in AFOBI [8]. As a classic opioid analgesic, fentanyl (FEN) can pass through the blood-brain barrier and takes effect quickly due to its high lipid solubility. When used in large doses, fentanyl can cause respiratory depression, asphyxia, muscle stiffness and bradycardia. However, it cannot provide adequate analgesia at low doses. Thus, it is always combined with other anesthetics in the clinic to achieve sufficient analgesia and avoid adverse effects.
Ketamine (KTM) is an N-methyl-D-aspartate (NMDA) receptor antagonist and is used for sedation and analgesia in children and adults. As a strong analgesic agent, it provides an adequate analgesic effect at subanesthetic doses (< 1 mg/kg) and has a fast onset [9]. In addition to inhibiting respiration slightly, it has a sympathetic effect that can increase heart rate, blood pressure and bronchiectasis. It is suitable for patients with circulatory instability or asthma [10,11]. Higher doses can achieve satisfactory analgesic effects clinically. However, the adverse reactions caused by larger doses of ketamine, including increased sputum production, brain metabolism and cerebral blood flow, can be alleviated by combining it with other intravenous anesthetics with complementary pharmacological properties [12]. Low-dose ketamine can reduce the target concentration of dexmedetomidine required for the loss of consciousness, enhance the sedative effect of the dexmedetomidine, and ensure more stable hemodynamics [13]. Furthermore, low-dose ketamine combined with dexmedetomidine significantly reduces the necessary dosage of fentanyl, providing a better sedative effect [14].
In addition to intravenous application, intranasal application is another common route of drug administration. The bioavailability of intranasal dexmedetomidine can reach 82% of that of intravenous administration. Regarding fentanyl, the efficacy of intranasal fentanyl spray has been reported in several studies; these studies showed a rapid time to analgesic effect and indicated that the bioavailability of intranasal fentanyl was 89% of the intravenous bioavailability [15,16]. A more recent study indicated that pain could be significantly alleviated in 5 min in cancer patients with the intranasal administration of fentanyl; it is as effective as intravenous morphine in adults, and its bioavailability is 70% [17]. The intranasal bioavailability of ketamine can reach 50% and 45% of the intravenous bioavailability in children and adults, respectively [18]. To date, there have been few reports about the combined use of ketamine, dexmedetomidine and fentanyl in AFOBI, either intravenously or intranasally.
The aim of this study was to evaluate the sedative and analgesic validity and the different administration routes of dexmedetomidine and fentanyl combined with ketamine in awake fiberoptic intubation.

Ethical considerations
The trial protocol was approved by the Clinical Research Ethics Committee of Shanghai Ninth People's Hospital affiliated with Shanghai Jiaotong University, School of Medicine (approval number, SH9H-2018-T38-3). It was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn; ChiCTR1900021185). Written informed consent was obtained from all participants or their legal representatives the day before surgery. This study adhered to CONSORT guidelines.

Participants and groups
We screened the patients the day before surgery and recruited those who met all the following criteria: (1) undergoing elective head and neck surgery with a predictive difficult airway and with BMI>26 kg/m 2 , toothless, obstructive sleep apnea hypopnea syndrome (OSAHS)/snoring, Mallampati grade III/IV, limited mandibular protrusion, short hyperthyroidism (<6 cm) and mass that may influence intubation; (2) age ≥16 and <60 years old; and (3) ASA physical status I or II. Patients who met any of the following criteria were excluded: (1) had chronic systemic diseases, such as high blood pressure, coronary disease, asthma, or thyroid disease (hyperthyroidism); (2) had cardiac electrophysiological disease, such as sinus bradycardia and atrioventricular heart blockage; (3) had intracranial hypertension or mental illness; and (4) special situations that needed to be determined by the chief surgeon.
A total of 36 patients in Shanghai Ninth People's Hospital were randomly assigned to 6 different groups (n=6): groups 1-3 received intravenous medication, while groups 4-6 received intranasal medication (group 1 DEX 1 μg/kg + FEN 1 μg/kg; groups 2-3: DEX 1 μg/kg + FEN 0.7 μg/kg + KTM 0.1/0.2 mg/kg; group 4: DEX 1.5 μg/kg + FEN 1.4 μg/kg; groups 5-6: DEX 1 μg/kg + FEN 1 μg/kg + KTM 0.4/0.6 mg/kg). Random numbers were generated by professionals in the department of statistics and placed in random envelopes that were opened on the day of operation. Anesthesiologists administered drugs according to the patient's assigned subgroup. Patients and the personnel who collected and analyzed the data were blinded to the specific grouping.
Anesthesia procedure and data collection Standard fasting guidelines were followed. No preoperative medication was administered.
Patients lay in the supine position, and a peripheral vein in the dorsal venous hand or a cephalic vein was established. At the same time, the patient inhaled oxygen (2 L/min), and the electrocardiogram (ECG), noninvasive blood pressure (NIBP), pulse oxygen saturation (SpO 2 ), respiration rate (RR), and bispectral index (BIS) were recorded.
For the intravenous (IV) route (Fig. 1A), each group was given dexmedetomidine (Guorui Medical, Inc., Sichuan, China; 0.1 mg/ml) at a total dose of 1 μg/kg of body weight, which was diluted with sterile saline solution (Chimin Pharmaceutical Co., Ltd., Zhejiang, China) to a final concentration of 4 μg/ml and intravenously pumped for 10 min. Fentanyl (Humanwell Pharmaceutical Co., Ltd., Yichang, China; 0.05 mg/ml) was given intravenously 6 min after dexmedetomidine administration. The dose given to group 1 was 1 μg/kg, and that given to groups 2 and 3 was 0.7 μg/kg. Nine minutes later, groups 2 and 3 were intravenously injected with ketamine (Gutian Medical, Inc., Fujian, China; 50 mg/ml) at doses of 0.1 mg/kg or 0.2 mg/kg of body weight, respectively. After 10 min, the patients underwent thyrocricocentesis with 2% lidocaine hydrochloride (Hualu Pharmaceutical Co., Ltd., Shandong, China; 0.02 g/ml) for local anesthesia. Lidocaine aerosol (Xiangxue Pharmaceutical Co., Ltd., Guangzhou, China; 50 g:1.2 g) was sprayed into nose in preparation for intubation, and then the nasal cavity was contracted with ephedrine hydrochloride and nitrofurazone nasal drops (Winguide Huangpu, Shanghai, China; 10 ml:2 mg). Then, the patients were intubated intranasally with a fiberoptic bronchoscope. At the same time, the motor activity assessment scale (MAAS) score was determined. All patients breathed spontaneously during the procedure.
For the intranasal (IN) groups (Fig. 1B), monitoring was the same as for the intravenous groups, and anesthetics were administered intranasally using a mucosal atomizer device (MAD, Wolfe Troy Medical Inc., Utah, USA). An independent investigator prepared and administered the anesthetics or placebo (0.9% saline) with a 2.5-ml syringe that was attached to an MAD via a lure lock connector. All the anesthetics used were diluted with 0.9% saline to a final volume of 1.5 ml. The unilateral nasal cavity administration volume was no more than 0.3 ml each time, and administration intervals of 1 min were observed to ensure that the drug was completely absorbed through the nasal mucosa.
Dexmedetomidine was given to group 4 or groups 5-6 at a dose of 1.5 μg/kg or 1 μg/kg of body weight, respectively. Ten minutes later, ketamine at 0.4 mg/kg or 0.6 mg/kg was given to group 5 or group 6, respectively. Then, 20 min later, fentanyl at 1.4 μg/kg or 1 μg/kg was given to group 4 or groups 5-6, respectively. Thirty minutes later, local anesthesia was administered as described above, and nasal tracheal intubation was performed using fiberoptic bronchoscopy.
Vital signs such as RR, HR, NIBP, and SpO 2 were recorded before drug administration as the baseline and were collected every 5 min during the procedure. The modified observer's assessment of alertness/sedation Scale (OAA/S) score was assessed every 3 min three times and each minute after 9 min. The MAAS score and the time required for the BIS to reach 60-80 were recorded. Atropine (0.5 mg) was given when HR was lower than 45 beats per minute, and 6 mg ephedrine was given when systolic blood pressure (SBP) was lower than 90 mmHg or diastolic blood pressure (DBP) was lower than 60 mmHg or either dropped below 70% of the baseline value. The visual analog scale (VAS) score during intubation was noted. All intubations were performed by the same senior anesthesiologist.
The primary endpoint was the VAS score. Secondary endpoints included the time required for the modified OAA/S score to reach above 2 and for the BIS value to decrease to 60-80; the MAAS score; changes in HR, RR, NIBP, and SpO 2 ; and the incidence of adverse reactions such as nausea, vomiting, coughing, sinus bradycardia and low blood pressure (a decrease in SBP/DBP of more than 30% compared to the baseline value).

Statistical analysis
Continuous variables were analyzed with one-way ANOVA or paired t-test. Categorical variables were analyzed with Chi-square test or Fisher's exact test. A P-value <0.05 was considered statistically significant. SPSS 24.0 for Windows (SPSS, Inc., Chicago, IL, USA) software was used for all statistical analyses.

Participant characteristics
Between February 1, 2019, and March 25, 2019, 36 patients were enrolled and randomized; all participants completed the study, with 6 in each final group (Fig. 2). All patients could be woken up during the intubation procedure. There was no significant difference in age, sex, or BMI (Table 1). Data are presented as the mean (SD), median (interquartile range) or percentage (%) of patients.

Secondary outcomes
The time required for the OAA/S score to reach above 2 was not significantly different among IV groups or IN groups (Fig. 3C, D). There was no obvious difference in the time needed for the BIS to decrease to 60-80 (Fig. 3E, F) or in the MAAS score (Fig. 3G, H). The same results were obtained for HR, NIBP, and SpO 2 (Fig. 4). In addition, we found that the respiration rates of group 1 and group 2 differed at the 10-, 15-, and 20-min time points, with a P value < 0.05. Considering that they were also different at 0 min, it was difficult to determine whether the differences between the two groups were caused by different drug administrations.
We found that the participants in group 5 and group 6 were less likely to cough when intubated than those in group 4 (both were 16.67% vs. 100.00%, P = 0.002), while no difference was found among IV groups. The differences in the incidences of other adverse effects (nausea, vomiting, sinus bradycardia and low blood pressure) were not significant among the groups.

Discussion
Our study found that the VAS score was inversely proportional to the dose of ketamine, meaning that the more ketamine the patients in our study received, the less pain they felt during the AFOBI procedure. The MAAS score of all groups reached below 4, which meant that the degree of analgesia and sedation was adequate for AFOBI.
The main purpose of medication during AFOBI is to keep patients responsive and cooperative without respiratory and cardiovascular function depression [6,19]. To achieve these effects, the agent used must have an immediate onset of action, be easily titratable, and produce adequate sedation [20].
The three anesthetics used in our study all act quickly when administered intravenously and have strong sedation and analgesia effects. Dexmedetomidine is usually used at 1 µg/kg over 10 min as a loading dose with or without a maintenance dose of 0.3 µg/kg/h to 0.7 µg/kg/h [9,[21][22][23][24][25][26].
Considering that we combined dexmedetomidine with other anesthetics, we finally chose a loading dose of 1 µg/kg infused intravenously over 10 min with no continuous infusion. Fentanyl takes 1 min to take effect when injected intravenously and 4 min to reach a peak, and the analgesia effect is maintained for 30 to 60 min. The induction dosages of fentanyl in general anesthesia differ with the type of surgery, ranging from 1 µg/kg to 4 µg/kg. The final intravenous injection dosage of fentanyl was set at 1 µg/kg, consistent with the current literature [2]. A previous study reported that low doses of ketamine could produce analgesia and modulate opioid tolerance, which is consistent with our study [9]. Ketamine is typically administered intravenously and has a relatively short half-life (2-3 h). However, it is inconvenient for use in ambulatory settings [27]. There have been few studies on the use of ketamine in awake intubation. Considering that dexmedetomidine and fentanyl were combined, we finally set a dosage gradient of 0.1 mg/kg and 0.2 mg/kg for IV, which is lower than the dosage used to treat cancer pain intravenously [28].
In our study, the incidences of coughing were lower in group 5 and group 6 than in group 4 (P = 0.002), indicating that ketamine could suppress coughing. A previous study reported that a mixture of ketamine and dexmedetomidine could suppress coughing induced by fentanyl, consistent with our study's findings [29]. However, no difference was found among the IV groups. The results of our study suggest that the addition of ketamine could reduce coughing, especially when administered intranasally. This outcome may result from the local anesthetic effect of ketamine [30].
In this study, we calculated the dosages of intranasally administered drugs according to their bioavailability. Considering that the dosage of ketamine was 0.75 mg/kg in the study of Andolfatto G. et al. [31], we chose lower doses of 0.4 and 0.6 mg/kg. To achieve the maximum analgesic effect of drugs at the same time, we set the dosing interval by referring to the pharmacokinetic data reported in other studies. Intubation was performed when the blood concentrations of the three anesthetics were at their highest -that is, when sedation and analgesia were at their best -to minimize patients' pain and anxiety.
There were a few limitations in our study. On one hand, the sample size was not large enough because this was an exploratory study, and more samples will be recruited in the future. On the other hand, the pharmaceutical concentration of dexmedetomidine was not high enough, so a small dose was given repeatedly.
We also noted a few tips that might ensure the effectiveness of intranasal administration. First, we examined the patients' nasal structure and mucosa, cleaned the nasal cavities and minimized the barriers to drug absorption. Second, we tried to increase the concentration of the drugs by not diluting them. Third, we used a special nasal spray device to distribute the drug evenly onto the nasal mucosa to reduce drug loss. Fourth, we performed nasal administration in both nasal cavities to increase the nasal mucosal surface area that could absorb the drugs. Fifth, an administration method that repeatedly provided a small amount of the drug was used, and the amount delivered to a single nasal cavity was controlled to be no more than 0.3 ml at a time. Finally, the participants were asked to lean their heads back during spraying and to breathe with their mouths temporarily.

Conclusions
Our study indicated that the addition of subanesthetic doses of ketamine could reduce the dosages of fentanyl and dexmedetomidine used in AFOBI and provide better sedative and analgesic effects both intravenously and intranasally. Furthermore, the addition of intranasal ketamine could suppress coughing, while no difference was found for the groups that received intravenous ketamine. electrocardiogram; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; NIBP, noninvasive blood pressure; SpO2, pulse oxygen saturation; RR, respiration rate.

Declarations
Foundation of Shanghai (17DZ1205403). The funding agents play no role in the study design, data collection, analysis, interpretation of data or in writing the manuscript.

Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.

Ethics approval and consent to participate
The trial protocol was approved by the Clinical Research Ethics Committee of Shanghai Ninth People's Hospital affiliated with Shanghai Jiaotong University, School of Medicine (approval number, SH9H-2018-T38-3). Written informed consent was obtained from all participants or their legal representatives the day before surgery.

Consent for publication
Participants have expressed their consent for anonymized data publication in written or verbal form.

Supplementary Files
This is a list of supplementary files associated with the primary manuscript. Click to download. CONSORT_Checklist.doc