A Randomized Controlled Study Comparing Dexmedetomidine-Midazolam with Fentanyl-Midazolam for Sedation during awake Fiberoptic Intubation in Anticipated Difficult Airway.

BACKGROUND: Awake fibreoptic nasotracheal intubation is an effective technique for the management of patients with difficult airways. Adequate sedation with effective topicalization of the airway is important to overcome discomfort and achieve intubation successfully. AIM AND
OBJECTIVES: Our aim was to compare the effectiveness of dexmedetomidine-midazolam with fentanyl-midazolam infusion for providing conscious sedation during fibreoptic intubation in patients with anticipated difficult airway under topical anaesthesia.
MATERIALS AND METHODS: Thirty adult patients of ASA physical status classification I and II with anticipated difficult airway and planned for elective awake nasal fibreoptic intubation under conscious sedation were randomly allocated into two groups. Dexmedetomidine 1 μg.kg-1 diluted in 50 ml saline was infused in Group DM over 10 min and Fentanyl 2 μg.kg-1 diluted in 50 ml saline was infused in Group FM over 10 min. Topicalization of the airway was done in all patients. All patients were assessed for sedation score, ease of endotracheal tube placement, patient comfort and cooperation, tolerance to endotracheal tube, any adverse events and recall of procedure.
RESULTS: The score of the modified OAA/S was comparable between the groups (P > 0.05). Quality of AFOI was comparable in both groups (P > 0.05). The intubation time and first EtCO2 were significantly lower in dexmedetomidine group (P <0.05). Group DM also showed better hemodynamics and less episodes of desaturation than Group FM.
CONCLUSION: Fentanyl-midazolam and dexmedetomidine-midazolam are both effective for awake fiberoptic intubation under topical anesthesia. Dexmedetomidine allows better endurance and more stable hemodynamics. Copyright:

INTRODUCTION

Awake fiberoptic intubation (AFOI) is an effective technique for the management of difficult airways, but it is associated with an increased sympathetic response if sedation is inadequate. It is challenging to provide adequate sedation and maintain patent airway and ventilation.[1] An ideal sedation regimen should provide patient comfort and contribution, blunting of airway reflexes, hemodynamic stability, amnesia, and the maintenance of a patent airway with spontaneous ventilation.[2] Many agents and their combinations have been reported to achieve conscious sedation for intubation. Dexmedetomidine, an α2 adrenoceptor agonist, is a valuable drug for use during fiberoptic intubation as it induces sedation and analgesia without depressing respiratory function.[3] Fentanyl and its congeners have been widely used to reduce the hemodynamic stress response to endotracheal intubation and AFOI in various clinical studies.[1] It is difficult to meet all the requirements for AFOI using a single drug or procedure. There are limited studies comparing the effectiveness of dexmedetomidine with other sedatives and sedation techniques. Hence, this study was undertaken to compare the sedation score and ease of intubation with dexmedetomidine-midazolam (DM) and fentanyl-midazolam (FM) during awake nasal fiberoptic intubation under topical anesthesia.

SUBJECTS AND METHODS

This prospective randomized study was conducted after Institutional Ethical Committee approval (Ethical Committee No: 2019-16 dated July 26, 2019). We recruited 30 adult patients of the American Society of Anesthesiologists (ASA) physical status Class I and II with anticipated difficult airway and planned for elective awake nasal fiberoptic intubation under conscious sedation. Patients with reaction to study drugs, bradycardia or atrioventricular block, history of reactive airway disease, gastrooesophageal reflux disease, morbid obesity (body mass index ≥40 kg.m−2), pregnancy, and coagulopathy were excluded from the study. All the patients were randomly assigned with a computer-generated randomization schedule into either DM group or FM group. Two experienced consultant anesthetists clinically managed the trial: one mainly responsible for performing the procedure of AFOI and the other mainly for observation and data collection. Both consultant anesthetists and the patients were blinded to group assignment.

After obtaining informed written consent, patients were kept fasting for 6 h. In the preoperative room, patients were asked to breathe through each nostril to assess patency. The nostril with the greatest patency was prepared with xylometazoline nasal drops, 4% lidocaine packs, and lidocaine jelly. Airway topical anesthesia was performed with 10% lignocaine spray over the tongue and hypopharynx and transtracheal injection of 4 ml of 2% lignocaine was given. In the operation theater, standard monitoring was applied including noninvasive blood pressure, pulse oximetry (oxygen saturation [SpO2]), and electrocardiography. After insertion of an intravenous cannula, injection midazolam 0.02 mg.kg−1 body weight, injection glycopyrrolate 0.2 mg, and injection ondansetron 4 mg were given intravenously (i.v.) as premedication and the infusion of the study drug was started. Oxygen was delivered at 4 L.min-1 via a nasal sponge placed in the nostril other than used for AFOI. All patients received the same drug in delivery mode, with which their respective drug was infused via a pressure-driven syringe pump. Group DM received an infusion of 1 μg.kg−1 body weight dexmedetomidine diluted in 50 ml saline over 10 min and Group FM received an infusion of 2 μg.kg−1 body weight fentanyl diluted in 50 ml saline over 10 min. Crystalloid fluid (5–10 ml. kg−1.h−1) was administered simultaneously during the infusion of the study drug.

The level of sedation was assessed by the anesthetist doing AFOI using modified Observer's Assessment of Alertness/Sedation scale (OAA/S),[4] 1 = appropriate verbal response to patient's name, 2 = lethargic response, 3 = reacts only after the name is spoken loudly and/or repeatedly, 4 = reaction after mild prodding or shaking, and 5 = reaction after painful stimuli. At the end of sedative infusion, any patient with a modified OAA/S = 1 was given an additional 0.5 mg midazolam at 2 min intervals until a modified OAA/S of 2–3 was reached. After adequate sedation achieved, a fiberoptic scope (Pentax FI 13 RBS, 4.2 mm; Tokyo, Japan) loaded with an appropriate size endotracheal tube for patients was inserted through the prepared nostril into the hypopharynx. Once the position of the fiberscope in the trachea was confirmed, the tracheal tube was railroad and positioned approximately 3 cm above the carina and secured. After confirmation of endotracheal tube position by end-tidal capnography (EtCO2) and auscultation, general anesthesia was administered. Heart rate (HR), blood pressure, and SpO2 were recorded every 3 min from starting the infusion of the study drug until the fiberoptic scope was introduced through the nose. Thereafter, vital parameters were recorded every minute until the completion of the AFOI. Hypotension was defined as systolic blood pressure (SBP) <80 mmHg, diastolic blood pressure (DBP) <50 mmHg, or an SBP decrease to ≥30% below the baseline. Hypertension was defined as SBP >180 mmHg, DBP >100 mmHg, or a SBP increase to ≥30% above the baseline. Bradycardia was defined as HR <50 beats/min or a decrease to ≥30% below the baseline. Tachycardia was defined as HR >120 beats/min or an increase to ≥30% above the baseline. Respiratory depression has been characterized as respiratory rate <8 breaths/min or a fall to ≥25% below the baseline. Hypoxia was characterized as pulse SpO2 <94% or 10% below the baseline. If any hypoxic episode occurred without an improvement via instructing to make deep breathes, infusion of the study drug was discontinued and naloxone 50 μg was planned to be administered i.v. The patients receiving naloxone were excluded from the study.

Measuring variables

The primary outcome measures were the scores observed during fiberoptic endoscopy, intubation, and postintubation. These include intubation score, recall, and discomfort score. The intubation score was measured by addition of three variables:

Ease of placement of the fiberoptic scope and endotracheal tube on a scale of 1–3 (1 = easy, 2 = moderate, and 3 = difficult)[5]

Patients' reaction to placement of the fiberoptic scope and the tracheal tube on a 5-point scale (1 = no reaction; 2 = slight grimacing; 3 = severe grimacing; 4 = verbal objection; and 5 = defensive movement of the head, hands, or feet)[6]

Patients' tolerance after intubation was assessed as: 1 – cooperative, 2 – restless/minimal resistance, and 3 – severe resistance/general anesthesia required immediately).[5]

Every patient was asked to grade his/her recall of the procedure (1 = none, 2 = partial, and 3 = full) and satisfaction score of the procedure (1 = none, 2 = mild, 3 = moderate, and 4 = severe) assessed 24 h after surgery.[7]

The intubation time (from inserting the fiberoptic scope into the nostril to the confirmation of tracheal intubation with capnography) and first EtCO2 after intubation were recorded.

The secondary outcome includes changes in HR, SBP and DBP, SpO2 during the procedure, and adverse effects if any.

Statistical analysis

Power calculation identified a minimum requirement of 10 patients to be randomized to each group to demonstrate a 20% difference in intubation scores with a power of 0.9 and a Type-1 error of 0.05. To allow for study error and attrition, we recruited 30 adult patients. Data were expressed as mean ± standard deviation, number (proportion), or median (interquartile range [range]). Statistical analyses were done using Student's t-tests, Tukey–Kramer multiple comparisons tests, repeated-measures analysis of variance for numerical data, Mann–Whitney U-tests for ordinal data, and Chi-square test and Fisher's exact test for categorical data, as appropriate. The data analysis was performed using SPSS version 20 (IBM, Armonk, NY, USA) and P < 0.05 was taken as statistically significant.

RESULTS

No patients were excluded from our study [Figure 1]. The demographic characteristics (age, gender, height, weight, and ASA physical status classification) were comparable between both the groups (P > 0.05) [Table 1]. The score of the modified OAA/S was similar at the end of infusion of the loading dose, before intubation, and 2 min after the intubation between the groups (P > 0.05) [Table 2].

Figure 1

Consort flow diagram

Table 1

Demographic data

Variables	Mean±SD		t or χ2/df/P
	Group DM (n=15)	Group FM (n=15)
Age (years)	45.02±12.8	46.50±13.2	t=0.31/28/0.75
Height (cm)	156.3±8.20	158.13±6.	t=0.46/28/0.651
Weight (kg)	68.2±10.08	69.43±8.16	t=0.37/28/0.716
Sex (males/females)	14/1	13/2	χ2=0.37/1/0.542
ASA I/II	7/8	8/7	χ2=0.13/1/0.715

P<0.05 (significant), SD=Standard deviation, ASA=American Society of Anesthesiologists, DM=Dexmedetomidine-midazolam, FM=Fentanylmidazolam

Table 2

Observers’ assessment of alertness/sedation scale score in the study groups

	Group DM (n=15)	Group FM (n=15)	χ2, df, P
Modified OAA/S (1/2/3/4/5)
At the end of infusion of loading dose	6/5/4/0/0	7/5/3/0/0	0.22, 2. 0.89
Before intubation	0/9/5/1/0	0/10/5/0/0	1.05, 2, 0.59
Post intubation	0/9/4/1/1	0/9/5/1/0	1.11, 2, 0.77

OAA/S=Observers’ assessment of alertness/sedation scale (1=Appropriate verbal response to patient’s name, 2=Lethargic response, 3=Reacts only after name is spoken loudly and/or repeatedly, 4=Rection after mild prodding or shaking, 5=Reaction after painful stimuli). P<0.05 (significant), df= degree of freedom. DM=Dexmedetomidine-midazolam, FM=Fentanyl-midazolam

Quality of awake fiberoptic intubation procedure

The scores of ease of AFOI, patients' reaction to the AFOI procedure, and patients' tolerance after intubation were comparable in both the groups (P > 0.05). No statistically difference was found in recall/awareness of the AFOI procedure and patients' satisfaction score between the groups (P > 0.05). The intubation time and first EtCO2 were found to be significantly lower in the dexmedetomidine group (P < 0.05) [Table 3].

Table 3

Comparison of quality of awake fiberoptic intubation

	Group DM	Group FM	χ2, df, P
Ease of AFOI (1/2/3)α	13/2/0	10/4/1	2.06, 2, 0.35
Patients reaction to AFOI (1/2/3/4/5)β	10/4/1/0/0	6/5/3/1/0	3.11, 3, 0.37
Patients tolerance after intubation (1/2/3)γ	12/2/1	10/3/2	0.73, 2, 0.69,
Satisfaction score (1/2/3/4)>	13/2/0/0	12/2/1/0	1.04, 2, 0.59
Recall of procedure (1/2/3)δ	14/1/0	12/3/0	1.15, 1, 0.28
Time for intubation	2.35±0.26	3.12±0.12	t=10.41, df=28, P<0.0001*
First EtCO2 after intubation (mean±SD)	40.22±4.6	44.60± 3	t=3.09, df=28, P=0.005*

*Significant, SD=Standard deviation, αEase of awake fibroptic intubation (1=Easy, 2=Moderate, 3=Difficult), βPatients reaction to placement of the fiberoptic scope and the tracheal tube (1=No reaction, 2=Slight grimacing, 3=Severe grimacing, 4=Verbal objection, 5=Defensive movement of head, hands, or feet), γPatients tolerance (1=Cooperative, 2=Restless/minimal resistance, 3=Severe resistance/general anaesthesia required immediately), ΣSatisfaction score (1=None, 2=Slight, 3=Moderate, 4=Severe), δRecall of procedure (1=None, 2=Partial, 3=Full). DM=Dexmedetomidine-midazolam, FM=Fentanyl-midazolam, AFOI=Awake fibreoptic intubation, EtCO2=End-tidal carbon dioxide

Hemodynamic parameters

Tables 4-7 show comparison of changes in mean HR, SBP, DBP, and SpO2 at baseline, before intubation, and after completion of tracheal intubation. During intragroup comparisons, we observed a statistically significant difference from the baseline in HR, DBP, and SpO2 in both the groups. During intergroup comparisons, we did not observe significant change except changes in DBP in postintubation period which was observed lower in group DM (P < 0.05).

Table 4

Heart rate in the studied groups

Heart rate (beats/min)	Mean±SD		t, df, P
	Group DM (n=15)	Group FM (n=15)
Baseline (at the start of infusion)	84.23±9.90	83.6±8.13	0.19, 28, 0.85
Before intubation	72.42±7.78	76.68±9.90	1.31, 1, 0.200
After intubation	80.62±8.07	86.10±7.76	1.90, 28, 0.068
P	0.0023	0.013

P<0.05 (significant). SD=Standard deviation, DM=Dexmedetomidine-midazolam, FM=Fentanyl-midazolam

Table 7

Oxygen saturation in the studied groups

SpO2	Mean±SD		t, df, P
	Group DM (n=15)	Group FM (n=15)
Baseline (at the start of infusion)	99.35±0.88	99.12±0.74	0.77, 28, 0.44
Before intubation	95.98±4.56	93.34±5.89	1.37, 28, 0.18
After intubation	96.78±3.24	95.01±0.88	2.04, 28, 0.05
P	0.019	0.0001

P<0.05 (significant). SD=Standard deviation, SpO2=Oxygen saturation, DM=Dexmedetomidine-midazolam, FM=Fentanyl-midazolam

Adverse events

The incidence of adverse events such as hypertension, hypotension, tachycardia, bradycardia, and hypoxia was comparable between the groups [Figure 2].

Figure 2

Adverse effects in the study groups

DISCUSSION

Anticipated difficult airway has always been a challenge for the anesthesiologist, and AFOI has been well recognized as one of the best techniques for the management of the anticipated or unanticipated difficult airway. Anesthesiologist usually encounters various difficult airway situations such as trauma, head-and-neck malignancies, and previous failed intubation attempts, and hence, adequate preparation for its management is required to prevent any airway compromise. In the present study, the sedation score of modified OAA/S was comparable at the end of infusion of the loading dose, before intubation, and 2 min after the intubation between the groups (P > 0.05). This was in contrary to the study done by Li et al.[8] who observed significantly lower OAA/S and BIS values in group DM compared to the sufentanil-midazolam group. The possible reason might be due to the use of sufentanil (5–10 times more potency than fentanyl) in combination with the midazolam group and use of spray as you go technique. In our study, there was no additional dosage of midazolam required to achieve sedation, and dosages of lidocaine required to perform topical anesthesia and nerve blocks were comparable in both the groups (P = 0.767). In the present study, there was no statistically significant difference in intubation conditions, tolerance, and comfort during AFOI between the groups (P > 0.05). Sayeed et al.[9] in their study compared the effectiveness of dexmedetomidine with a combination of midazolam and fentanyl in patients undergoing AFOI and observed better intubating conditions and patient cooperation and comfort scores in the dexmedetomidine group. The unique sedative characteristics of dexmedetomidine have prompted many studies to understand its important clinical role. Another study done by Bergese et al.,[4] comparing dexmedetomidine plus midazolam and midazolam alone, observed that patients remain calmer and more cooperative in DM group during elective awake fiberoptic nasotracheal intubation. In the present study, patient tolerance immediately after nasotracheal intubation shows statistically nonsignificant values among both the groups. This is in concordance to the study done by Chu et al.[7] who observed better tolerance to awake nasotracheal intubation without respiratory depression in patients with dexmedetomidine group compared to fentanyl group. Li et al.[8] compared DM with sufentanil-midazolam infusion for AFOI in a randomized double-blind study and observed comparable intubating conditions and patient tolerance to intubation. This also correlates with our study showing favorable results with dexmedetomidine. Ryu et al.[10] compared remifentanil with dexmedetomidine for conscious sedation during bronchoscopy and reported comparable satisfaction score(P > 0.05) between the groups. Similar satisfaction scores were also reported in our study; however, the results were statistically not significant between the groups. We had performed AFOI under sedation in addition to intratracheal instillation of lidocaine. In line with our study, Chatrath et al.[11] observed that 90% of the patients had good satisfaction score postoperatively under combined regional nerve blocks in awake orotracheal fiberoptic intubation. The recall affects the assessment of satisfaction of the patients to AFOI procedure and also puts them at a risk of the negative psychological state. The combination of midazolam and any other sedative agents may be an optimal sedation scheme for AFOI. In the present study, less incidences of recall have been observed in the DM group (7%) compared to the FM group (20%) which was not statistically significant. Shen et al.[12] also reported more incidences of recall in the sufentanil group (45%) compared to the dexmedetomidine group during awake fiberoptic nasotracheal intubation. Bergese et al.[4] described the incidence of recall as 60.8% in patients receiving midazolam in combination with dexmedetomidine. The findings of the above study reveal that midazolam causes antegrade amnesia and as premedication helps to decrease the ability to recall. In our study, the mean time to intubation was 2.35 ± 0.26 min in the DM group compared to 3.12 ± 0.12 min in the FM group. The values were found to be statistically significant in both the groups. However, the values were lower compared to the observation done by Shen et al.[12] and Li et al.[8] The reason may be due to the use of adequate topical anesthesia which facilitates AFOI. In the present study, HR, SBP, DBP, and oxygen saturation at baseline, before intubation, and after completion of tracheal intubation were recorded. Within the group, we observed a statistically significant difference from the baseline in HR, DBP, and SpO2 in both the groups. Group DM showed a fall in the HR contrary to the FM group compared to the baseline. SBP did not show a statistically significant increase in both the groups either during intragroup or intergroup comparison, while DBP had a statistically significant increase from the baseline within the groups in both the groups. However, DBP remained was significantly low in the group DM compared to the FM group, but later on, the blood pressure improved without any drug supplementation. Similar to our study, Mondal et al.[13] reported that patients of the dexmedetomidine group showed better hemodynamic stability compared to the fentanyl group. There was a statistically significant change of HR in the postintubation period in comparison to the baseline value in fentanyl group (P < 0.0001). However, within the group, there were no significant changes of HR in comparison to the baseline value in the dexmedetomidine group. Another similar study conducted by Rajan et al.[14] observed no significant hemodynamic changes or respiratory compromise during the study. Similarly, Bergese et al.[4] also reported that when dexmedetomidine used alone or in combination with midazolam, hemodynamic parameters such as SBP and DBP response were similar for both the groups. Sayeed et al.[9] also observed a statistically significant increase in HR from the baseline within the group in the FM group compared to dexmedetomidine group, similar to our study. Yavascaoglu et al.[15] in their study also reported that dexmedetomidine is effective in preventing the hemodynamic response to tracheal intubation more than esmolol. Awake nasotracheal fiberoptic intubation had been performed in both the groups of patients with limited complications reported in either of the patients' groups. Hypertension and desaturation occurred only in 1 (7%) patient in group DM and 2 (13%) patients in group FM. However, the difference between the groups was found to be statistically not significant. Similar to our study, Yousuf et al.[16] reported less episodes of desaturation in dexmedetomidine group (17%) compared to FM group where this was found to be around 40%. Another study done by Agrawal et al.[17] also found that respiratory rate and SpO2 were significantly low in FM group compared to the dexmedetomidine group before and during intubation. The same has also been observed by Mondal et al.[13] and Ryu et al.[10] who reported less incidence of desaturation in the dexmedetomidine group. In our study, EtCO2 values were significantly lower (40.22 ± 4.6) in group DM than the group FM (44.60 ± 3.2). This was in concordance to the study done by Li et al.[8] who observed higher EtCO2 values in the sufentanil-midazolam group compared to the DM group. Similar observations had also been reported by Shen et al.[12] with higher incidence (20%) of respiratory depression and higher PETCO2 (47 ± 4.3) in the group receiving sufentanil alone. Possible risk of respiratory depression can be minimized by maintaining cooperation and asking the patient for deep breathing during AFOI.

Limitations

The sample size was small in our study, and the level of recall was not assessed for the evaluation of amnestic properties of the study drugs. The various scores used for assessment are based on the subjective responses of the individual which could be variable and cannot be standardized.

CONCLUSION

From the present study, we conclude that DM and FM provide good conscious sedative conditions for AFOI. The two regimens used in this study showed comparable intubating conditions, satisfaction scores, and recall for the procedure done. However, it is important to remain vigilant during the regimen used and keep the patients awake and cooperative, as the risk of desaturation is increased with a combination of drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 5

Systolic blood pressure in the studied groups

Systolic blood pressure (mmHg)	Mean±SD		P (t, df, P)
	Group DM (n=15)	Group FM (n=15)
Baseline (at the start of infusion)	124.10±16.90	128.40±14.03	0.76, 28, 0.45
Before intubation	110.32±10.98	116.75±67	0.37, 28, 0.71
After intubation	118.66±16.24	120.89±48	0.17, 28, 0.86
P	0.49	0.79

P<0.05 (significant). SD=Standard deviation, DM=Dexmedetomidinemidazolam, FM=Fentanyl-midazolam

Table 6

Diastolic blood pressure in the studied groups

Diastolic blood pressure (mmHg)	Mean±SD		t, df, P
	Group DM (n=15)	Group FM (n=15)
Baseline (at the start of infusion)	82.90±14.38	78.57±6.37	1.07, 28, 0.28
Before intubation	76.46±7.13	72.13±5.60	1.85, 28, 0.075
After intubation	86.71±4.26	90.64±2.29	2.15, 28, 0.003*
P	0.018	0.001

P<0.05 (significant), *Significant. SD=Standard deviation, DM=Dexmedetomidine-midazolam, FM=Fentanyl-midazolam