Introduction
Direct laryngoscopy is a procedure used to visualize the larynx. It serves two primary purposes: facilitating endotracheal intubation, typically performed by anaesthesiologists, and diagnostic evaluation, mainly conducted by otorhinolaryngologists. The diagnostic applications include examining cases of stridor, cysts or masses causing airway obstruction, vocal cord palsy, and papillomas.
In this article, we will focus on diagnostic direct laryngoscopy performed by otorhinolaryngologists using a rigid laryngoscope. Specifically, we will discuss the intermittent apnoea technique, which provides excellent visibility for the surgeon and ensures safety when using laser technology.
The key anaesthetic consideration for this procedure is maintaining adequate depth of anaesthesia for hemodynamic stability. The procedure triggers a polysynaptic response where impulses travel via cranial nerves IX and X to the brainstem and spinal cord. This results in sympathetic activation, causing norepinephrine release from adrenergic terminals, epinephrine release from adrenal glands, and renin-angiotensin system activation, ultimately leading to tachycardia and hypertension. These cardiovascular responses can lead to cardiovascular collapse secondary to myocardial ischaemia and airway manipulation can trigger three key respiratory responses: laryngospasm, coughing, and bronchospasm.1 Maximum hemodynamic changes occur immediately after laryngoscopy begins, lasting 5-10 minutes.2 The magnitude of this response is greater with increasing force and duration of laryngoscopy.
Premedications are typically administered via various routes to reduce this response without compromising the patient’s ability to maintain spontaneous ventilation.3 Intranasal administration offers improved patient compliance and decreased preoperative anxiety due to its non-invasive nature, overcoming challenges associated with parenteral drug therapy.4 The nasal route is preferred for systemic medication delivery due to the greater vascularization and permeability of nasal mucosa, which lacks the highly keratinized stratum corneum found in skin. Instead, it forms numerous microvilli with rich underlying vascularity. Another advantage of the intranasal route is the avoidance of the hepatic first-pass effect, allowing atomized drugs to enter the central nervous system through the olfactory epithelium. The mucosal atomization device (MAD) creates 30-100 µm particles, providing higher bioavailability.5
Α-2 agonists like Clonidine and Dexmedetomidine have emerged as premedication alternatives to reduce laryngoscopy stress responses. They decrease sympathoadrenal responses by inhibiting noradrenaline release and suppressing neuronal firing in the locus ceruleus, improving hemodynamic stability during direct laryngoscopy with minimal respiratory depression.6
Clonidine, an α-adrenergic and imidazoline receptor agonist, affects the posterior hypothalamus and medulla, enhancing cardiac baroreceptor reflex responsiveness and causing sudden blood pressure rises. It also has sedative and anaesthetic-sparing effects.
Dexmedetomidine, a newer, more potent α2 agonist approved by the FDA in 1999, has eight times higher affinity for α-2 receptors than clonidine.7 It inhibits sympathetic activity, decreasing heart rate and blood pressure. Its’ anaesthetic and sedative properties can be attributed to G-protein activation by the presence of α 2a receptors in the brainstem which inhibits norepinephrine release, with a short half-life and having a bioavailability of around (72.6–92.1%) when administered via the intranasal route.8
This observational study compared administration of dexmedetomidine and clonidine as premedication in adult patients undergoing direct laryngoscopy via intranasal mucosal atomization device.
Materials and Methods
This observational study was conducted in the operation theatre of a tertiary health care center under the department of Anaesthesiology after getting permission from the Institutional Ethical Committee (SVIEC/ON/MEDI/BNPG21/SEP/2218). 80 patients of either sex, aged 18 to 65 years & belonging to ASA 1 & 2, undergoing diagnostic Direct Laryngoscopy procedure were included in this study. All participants were subjected to a pre-anaesthetic evaluation, during which history was taken, a clinical examination in the Pre-Anaesthetic Checkup OPD was conducted and investigations were evaluated. Patients who were morbidly obese, had concomitant cardiovascular or any other systemic conditions, diabetes, or who were taking any medications not permitted in the study or with known allergies to study medications were excluded.
The sample size was calculated based on the expected minimum detectable difference in mean heart rate (HR) between the two groups. Utilizing an α error of 0.05 and a power of 80%, the required sample size was determined to be 37 subjects for each group, as indicated in the study by Usha Bafna et al. 9 To account for potential non-compliance with the inclusion criteria, a total of 80 patients were recruited and divided into two groups of 40 each. The patients were randomly allocated to one of two groups, using Random Allocation Software version 1.0.0. Privacy of allotted groups was ensured with sealed non-transparent envelopes. Coded syringes ensured that the study was conducted in a double-blind fashion.
The patient was made to relax in a quiet, undisturbed area. Drugs were given according to allotted groups. Patients receiving intranasal dexmedetomidine 1.5µg/kg were considered as Group D and patients receiving intranasal clonidine 3µg/kg were considered as Group C. The half dose was injected in each nostril 30 minutes before surgery using the MAD.
All patients were premedicated with Inj. Glycopyrrolate 0.004mg/kg IM, Inj. Ondansetron 0.1 mg/kg IV and Inj diclofenac 1.5mg/kg IM 20 minutes before procedure began.
Baseline vital parameters (HR, SBP, DBP, MAP, SpO2, RR) were recorded and Level of sedation and vitals was checked 30 minutes after administering the study drugs.
Level of sedation was graded using Four point sedation score (Filos et al)10 described as given below:10
Table 0
|
Sedation score |
Level of sedation |
|
1 |
Awake and alert |
|
2 |
Drowsy, responsive to verbal stimuli |
|
3 |
Drowsy, arousable to physical stimuli |
|
4 |
Unarousable |
Patient was preoxygenated by administering 100% oxygen for 5 minutes via face mask. After confirming that the patient can be ventilated by bag and2 supply was maintained via high flow nasal oxygenation at 15 L/min. Inj propofol 0.5mg/kg and Inj succinylcholine 0.5mg/kg were given intermittently as and when required till Direct Laryngoscopy procedure was completed. Primary outcomes were monitoring for HR, SBP, DBP, MAP, SpO2 at baseline, before induction, before Laryngoscopy, and then immediately after Laryngoscopy started at 0 min, 2 min, 4 min, 6 min, 8 min,10 min, 15 min and 20 min till surgery ended.
Patient was then shifted to post operative recovery room and monitored every hour for the next 6 hours to assess for hemodynamic changes and any complications or side effects such as bradycardia, hypotension, respiratory depression, nausea, vomiting, etc. that may be recorded as the secondary outcomes during the study.
Statistical analysis
Epi-Info version 7.0 was used to collect data and clean-up was made to check accuracy, consistency, and errors. Identified errors were corrected and consequently, the data was transported to SPSS Version 20 for analysis and presented in a tabulated form. Numerical variables were represented as mean and standard deviations (SD) & categorical variables were presented as frequency and percentage. For comparison between both the groups of numerical variables, the unpaired student-t test was used; while the chi-square test was used for categorical variables. The difference was considered statistically significant when p<0.05.
Results
Eighty patients were divided into two groups: one receiving intranasal clonidine i.e. Group C and the other receiving intranasal dexmedetomidine i.e. Group D. Both groups showed comparable demographic data in terms of age, gender, weight, and ASA grading. (Table 2)
Table 1
Comparison of demographic data
Table 2
Comparison of level of sedation
|
|
Categories |
Group C |
Group D |
Chi Square |
P-value |
|
N (%) |
N (%) |
||||
|
Level of Sedation |
1 |
36 (90%) |
22 (55%) |
10.596 |
0.0011 (HS) |
|
|
2 |
4 (10%) |
18 (45%) |
|
|
Sedation levels were assessed using the four-point Filos et al. sedation scale (Table 3). Patients who received dexmedetomidine injection (Group D) showed significantly better sedation compared to those who received clonidine injection (Group C), with p < 0.001. Notably, no patients reached grade 3 or 4 sedation levels.
Based on the results of Figure 1, heart rates were comparable between the clonidine injection group (Group C) and dexmedetomidine injection group (Group D) prior to direct laryngoscopy (p > 0.05). However, after laryngoscopy began, dexmedetomidine was significantly more effective than clonidine in reducing heart rate. This difference was observed at 0, 2, 4, 6, 8, 10, 15, and 20 minutes during the procedure (p < 0.0001).
Systolic blood pressure measurements compared between the two groups (Figure 2) revealed that intranasal dexmedetomidine (Group D) provided better blood pressure control than intranasal clonidine (Group C). This superior control was evident throughout the Direct Laryngoscopy procedure, specifically at 0, 2, 4, 6, 8, 10, 15, and 20 minutes from the start until completion.
Both groups exhibited comparable diastolic blood pressure from baseline until Direct Laryngoscopy began (p > 0.05). Following laryngoscopy initiation, intranasal dexmedetomidine (Group D) demonstrated significantly better control of diastolic blood pressure compared to intranasal clonidine (Group C). This difference was observed at 0, 2, 4, 6, 8, 10, 15, and 20 minutes during the procedure (p < 0.001). Figure 3 illustrates these findings.
Mean arterial pressure was monitored throughout Direct Laryngoscopy, from initiation through 0, 2, 4, 6, 8, 10, 15, and 20 minutes until completion. Figure 4 demonstrates that dexmedetomidine (Group D) provided more effective suppression of the pressor response than clonidine administered via MAD (Group C), resulting in better control of mean arterial pressure (p < 0.001).
Postoperative vitals measured every hour for the first 6 hours after Direct Laryngoscopy procedure were comparable in both groups (p>0.05) and none of the participants experienced any postoperative complications.
Discussion
Direct laryngoscopy, whether performed for diagnostic purposes by otorhinolaryngologists or for intubation by anesthesiologists, elicits similar sympathetic stress responses. However, diagnostic laryngoscopy poses unique challenges for anesthesia management. The primary challenge lies in maintaining stable hemodynamics during extended periods of noxious stimulation while ensuring minimal respiratory compromise.
The sympathetic stress response begins within 5 seconds of initiating laryngoscopy, reaches its peak at 1-2 minutes, and typically persists throughout the procedure.11, 12
Both clonidine and dexmedetomidine activate presynaptic α2 adrenergic neurons in the medulla's vasomotor centers, producing a sympatholytic effect. Reduced central sympathetic outflow leads to peripheral vasodilation, decreasing systolic blood pressure, heart rate, and cardiac output.13, 14, 15, 16, 17, 18, 19
Intranasal pre-anaesthetic drug administration is preferred as it eliminates the need for patient cooperation and is well-tolerated due to its non-invasive nature. The Mucosal Atomization Device, a harmless and simple metered-dose delivery appliance, painlessly administers medication intranasally. This atomizer reduces medications to an appropriate size for enhanced absorption across mucosal membranes, bypassing first-pass metabolism.11, 20
This study evaluated the comparative efficacy (primary objective) and adverse effects (secondary objective) of intranasal medications administered via mucosal atomizer device: dexmedetomidine (1.5µg) versus clonidine (3µg). Previous research by Larsson P et al. demonstrated that intranasal clonidine (3-4 μg/kg) achieved adequate sedation at 30 minutes post-administration,21 while Yuen VM et al. found that intranasal dexmedetomidine (1-1.5 μg/kg) induced sedation at 45 minutes post-administration.22 Based on these findings, we administered premedication 30 minutes before Direct Laryngoscopy to ensure adequate onset time for both drugs.
When comparing sedation levels using the Four-point Filos et al. sedation score 30 minutes after premedication, dexmedetomidine produced significantly deeper sedation than clonidine. This superior sedative effect of dexmedetomidine over clonidine was statistically significant (p = 0.001). While both drugs provided sedation, the dexmedetomidine group consistently achieved higher sedation scores on the Filos scale. This effect may be attributed to dexmedetomidine's selective α2 agonist properties. It acts on the locus coeruleus and attenuates the presynaptic release of norepinephrine, leading to greater sedative and hypnotic action. Stimulation of α2-adrenoreceptors in the descending medulla-spinal noradrenergic pathway provides increased analgesic effects. The superior sedative and analgesic properties of dexmedetomidine compared to clonidine are attributed to its greater affinity for the α2 A adrenoreceptor subtype.13, 14, 15, 16, 17, 18
Average time from drug administration to laryngoscopy in our study group was 45 minutes. This is similar to the study performed by Devshri Raval et al and Usha Bafna et al comparing the action of intranasal clonidine 3µg/kg with dexmedetomidine (1µg/kg & 2µg/kg respectively) as a premedicant. Sedative effect of both drugs was analyzed and maximum sedation was noted in both studies after 45 minutes and sedation with dexmedetomidine was observed to have significantly better sedation than clonidine (p<0.05).13, 9
A number of studies have compared the sedative action of intranasal clonidine with dexmedetomidine. Although we did not assess the anxiolytic effect of these drugs, a study conducted in 2016 by Gurkaran Kaur Sidhu et al evaluated changes in anxiety level and differentiated the sedative effect from the anxiolytic effect using intranasal dexmedetomidine 2µg/kg with intranasal clonidine 3µg/kg as premedication in pediatric surgery. In their study, anxiolysis as well as sedation were in higher proportion with dexmedetomidine in comparison to clonidine with p < 0.05.23
In our study, intraoperative vitals including HR, SBP, DBP, MAP and oxygen saturation were monitored and recorded at baseline, 30 minutes after premedication, before induction, before Direct Laryngoscopy, and at 0 minutes, 2 minutes, 4 minutes, 6 minutes, 8 minutes, 10 minutes, 15 minutes and 20 minutes once laryngoscopy commenced as the primary outcome. It was observed that intraoperative vitals till before laryngoscopy began were statistically not significant (p<0.05),
but once laryngoscopy commenced, the difference in HR, SBP, DBP and MAP were highly significant with p <0.001 although no difference in oxygen saturation was noted (p<0.05).
This effect may be explained by the fact that although both clonidine and dexmedetomidine initiate central sympatholysis by activating presynaptic autoreceptors, dexmedetomidine demonstrates 8-10 times greater selectivity for α2-adrenoreceptors compared to clonidine (1620:1 vs 220:1).23
Our findings were supported by the study published by Dharmendra Kumar Yadav et al, which compared the action of intranasal dexmedetomidine and clonidine on the hemodynamic response during laryngoscopy in hypertensive adult patients. They administered intranasal dexmedetomidine 1mcg/kg and intranasal clonidine 3mcg/kg in the form of nasal drops 45 min before surgery and found that hemodynamic response to tracheal intubation was significantly attenuated in the dexmedetomidine premedicated patients as compared to clonidine with the difference for HR p= 0.009, MAP p=0.0008.24 Similar findings were noted in the studies done by Devshri Raval et al and Usha Bafna et al with p<0.05.13, 9
The intranasal route of administration provides high bioavailability as mentioned earlier, but even using other routes of administration the hemodynamic attenuation of dexmedetomidine remains better than that of clonidine as demonstrated in the study done by Shirsendu Mondal et al.25 comparing the effect of pretreatment with intravenous dexmedetomidine 1µg/kg and clonidine 3µg/kg for attenuation of sympathoadrenal responses and anaesthetic requirements to laryngoscopy and endotracheal intubation. The study showed that the dexmedetomidine group had greater control of HR which was considered to be highly significant (p<0.001). The SBP and DBP increased after intubation compared to the baseline, but this inflection was significantly less with dexmedetomidine in comparison to clonidine with p<0.05 at all levels of assessment.
In our study, postoperative hemodynamics were comparable between the 2 groups and was statistically not significant (p>0.05). There were no postoperative side effects noted among the 2 groups. This finding was supported by the study done by Gurkaran Kaur Sidhu et al, which demonstrated that the time taken to achieve Aldrete score of 9 was similar between both groups receiving intranasal dexmedetomidine 2µg/kg vs intranasal clonidine 3µg/kg as premedication in pediatric surgery. They theorized that decreased requirement of IV induction agents caused by α2 agonists in the perioperative period counter balanced the sedative side effect of α2 agonists in the postoperative period therefore, there was no difference regarding time to achieve Aldrete score.
The limitations in the study included failure to correlate the effects of dexmedetomidine and clonidine premedication on the analgesic and anaesthetic requirements during diagnostic laryngoscopy. We also did not monitor the time to onset of sedation in our study nor did we include any hypertensive patients in whom control of stress response during laryngoscopy is of great importance. Finally, if plasma catecholamine level had been measured during laryngosopy, the hemodynamic stability offered by dexmedetomidine would have been established more firmly. The outcome of our study was also influenced by subjective changes in the assessment of level of sedation assessed that may vary with the understanding of the patients. This being a single-center hospital-based study, it lacks generalizability.
This study is the first to compare the use of premedication via a mucosal atomiser device specifically for diagnostic laryngoscopy. Our findings suggest that this method is effective for intranasal premedication in adults, expanding its use beyond pediatric populations. Our results align with earlier research by Yadav et al., Raval et al., and Bafna et al., which indicated that intranasal dexmedetomidine is more effective than clonidine in reducing hemodynamic stress during intubation.24, 14, 9 However, our research extends these findings by examining the drugs' effects under prolonged stress conditions such as which occur in diagnostic Direct Laryngoscopy procedures. While previous studies focused solely on the intubation period, our investigation provides insights into the sustained impact of these medications throughout extended periods of physiological stress. This enhances our comprehensive treatment strategies for patients undergoing procedures involving prolonged stress responses.
Conclusion
Both Dexmedetomidine and Clonidine effectively attenuate the sympathetic responses triggered by direct laryngoscopy; however, Clonidine provides significantly less attenuation compared to Dexmedetomidine. Therefore, it can be concluded that intranasal administration of Dexmedetomidine at a dose of 1.5 µg/kg via a mucosal atomizer device is a painless and effective method for reducing the sympathetic response during direct laryngoscopy, with no notable adverse effects or complications.