European Journal of Cardiovascular Medicine

Intubation and direct laryngoscopy both involve instrumenting the upper airway, which might cause a hemodynamic stress response. Intubation and laryngoscopy both trigger reactions that control hemodynamics: the sympathetic Adreno-medullary response and the hypothalamo-pituitary-adrenocortical response.1 These reactions won't last forever. 3,4 The hemodynamic response to intubation and laryngoscopy reaches its peak 30–45 seconds after intubation and usually subsides within 10 minutes, after a 15-second lag. Various pharmacological agents, such as local anaesthetics (applied topically or administered intravenously with lidocaine), beta-adrenergic blockers, calcium channel blockers, opioids, vasodilators, and alpha 2 agonists, have been used to modify the hemodynamic response during laryngoscopy while under general anesthesia.4 – 6

Dexmedetomidine is one such suitable anaesthetic agent. It shows little changes in respiratory variables and is a “strong α2-adrenoreceptor agonist with sedative, hypnotic, analgesic, and sympatholytic effects”.7 It exerts its vasoconstrictor effect by its receptors located in blood vessels and inhibits norepinephrine release by its receptors located in sympathetic terminals leading to a fall in BP and HR.8

Lacuna in Knowledge

Intravenous infusion of Injection Dexmedetomidine is routinely used in anaesthesia for achieving a deeper plane of anaesthesia but there have not been many studies regarding the administration of Dexmedetomidine in nebulized form for faster onset of action.

Objectives

To compare the effect of intranasal dexmedetomidine and intravenous dexmedetomidine on HR and MAP to laryngoscopy for endotracheal intubation.

Study Design: The anaesthesiology department of Sri Devraj Urs Medical College in Kolar, Karnataka, India, undertook this comparative observational research between October 2022 and July 2023. The research was approved by the Institutional Ethical Committee [EC NO. SDUMC/KLR/IEC/272/2022-23], and patients gave their permission before they were enrolled. Sample Size: The sample size was calculated according to the following formula. N = 4 Pq d2 N = Sample Size P = 57.1% – Prevalence [Niyogi S et al 19] q = 1 – P – 42.9% d = 10 - precision N = 98 (round of 49 participants/group) The sample size of 49 participants per group (a total sample of 98 participants) was calculated based on expected prevalence of 57.1% with 80% power of the study. The sample frame consisted of all patients having surgery while under general anesthesia. Subject to inclusion and exclusion criteria, these patients were enrolled as research participants after being informed of the study's purpose and obtaining their consent: Inclusion Criteria • Adults aged 18 to 60 years. • Patients with ASA – PS I and II • Patients undergoing surgeries under general anaesthesia. Exclusion Criteria • Not willing to participate in the study • ASA-PS III and above • Patients with predicted difficult airway • Patients requiring emergency surgeries • Pregnant patients SAMPLING PROCEDURE: All patients (henceforth study participants) who provided informed consent were assessed pre-operatively. Furthermore, in accordance with the protocol, a thorough examination and investigation were conducted prior to the anesthesia in order to prepare for the operation. The night before surgery, all subjects were given 150 mg of ranitidine and 0.25 mg of alprazolam in tablet form. On the day of the surgery, Electrocardiogram, pulse-oximeter, and non-invasive BP were connected in the preoperative area. Furthermore, a suitable intravenous cannula was obtained for the delivery of fluids and medications. Fifteen minutes before to induction, the subjects were given the research medication. Using a computer-generated sequence of random numbers, the research participants were divided into two groups. The subjects were split into two categories: Group A: Received dexmedetomidine nebulization (0.7 mcg/kg) diluted to 4 ml with 0.9% normal saline and 10 ml of 0.9% normal saline intravenous infusion. Group B: Received Dexmedetomidine infusion (0.7 mcg/kg) diluted to 10 ml of 0.9% normal saline over ten minutes and 4 ml of 0.9% normal saline as nebulization. On the way to the operating room, patients' pre-operative baseline vitals were obtained using a multi-parameter monitor. These included HR, BP, respiratory rate, oxygen saturation, and MAP. They were first pre-oxygenated with 100% oxygen for three minutes. Then, they were given an intravenous bolus of ten milligrams of propofol and one milligram of fentanyl per kilogram of body weight until they stopped responding to vocal commands. The patient was intubated via the trachea after receiving 0.08 mg/kg of intravenous Vecuronium. After three minutes of 100% oxygen ventilation, participants underwent laryngoscopy using a Macintosh laryngoscopy blade of the proper size, and endotracheal intubation was conducted. We documented how long it took to intubate the patient. An expert anesthesiology resident performed the intubation process. Hemodynamic parameters [HR, SBP, DBP, and MAP] were assessed regularly and recorded at 1st, 3rd, 5th, 7th, and 10th minute after intubation. The neuromuscular blockade was restored by “intravenous neostigmine and glycopyrrolate at doses of 0.05 mg/kg and 0.01 mg/kg”, respectively, after surgery. We followed the conventional method for extubation and noted the time of extubation. The protocol for rescue treatment in the event of hemodynamic instability included: · Hypotension – 30% reduction in baseline SBP of < 50mmHg: will be treated by reducing the infusion of Dexmedetomidine or 0.1mg/kg of ephedrine intravenous bolus. · Bradycardia – Less than or equal to (</=) 50 beats/min: will be treated with 0.02mg/kg intravenous bolus of Atropine, repeated in one minute until HR is more than 50 beats/min or overall amount of 2mg Atropine is reached. · Tachycardia – More than or equal to (>/=110) beats/min will be treated with 2mcg/kg of injection Fentanyl. · Parameters Assessed · Participants SBP, DBP, HR, and MAP were monitored by the investigator and recorded at baseline, before induction, during intubation, after 1st , 3rd, 5th , 7th , and 10th minute respectively. · STATISTICAL ANALYSIS Data analysis was conducted using Microsoft Windows and SPSS for Windows (SPSS ver. 22.0, Armonk, NY). To check whether the data followed a normal distribution, Shapiro-Wilk test is used. Data that followed a normal distribution was examined using parametric testing. We used the unpaired t-test to compare continuous data from the nebulizer group with those from the intravenous group. Tables and graphs were used in order to present the information. A significance criterion of P < 0.05 was established.

At Baseline Pre-induction

Table 1.1: Comparison of baseline SBP, DBP, MAP and HR between intravenous and nebulizer groups (pre-induction)

SD-standard deviation; **Statistically significant using unpaired t-test

SBP: It was found that the mean SBP of participants in the intravenous group was higher than the SBP of participants in the Nebulizer group. Notable statistical significance was found in the mean variance among the two groups (P = 0.001).

DBP: It was found that the mean DBP of participants in the intravenous group was higher than the DBP of participants in the Nebulizer group. Notable statistical significance was found in the mean variance among the two groups (P = 0.004).

MAP: It was found that the mean MAP of participants in the intravenous group was higher than the MAP of participants in the Nebulizer group. Notable statistical significance was found in the mean variance among the two groups (P = 0.001).

HR: It was found that the mean HR of participants in the intravenous group was higher than the HR of participants in the Nebulizer group. Notable statistical significance was found in the mean variance among the two groups (P = 0.012).

After 10 minutes – Pre-induction

Table 1.2: Comparison of Mean SBP and DBP, MAP, and HR after 10 minutes between intravenous and nebulizer groups (Pre-induction)

“SD-standard deviation; NS-not significant using unpaired t-test”

SBP: The results showed that the mean SBP did not vary significantly among the two groups (P = 0.55).

DBP: The mean DBP did not vary significantly among the two groups (P = 0.82).

MAP: Mean MAP values were not significantly different among the two groups (P = 0.56).

HR: The mean MAP did not vary significantly among the two groups (P = 0.73).

Baseline – post-inductionTable 2: Comparison of Mean SBP and DBP, MAP, and HR between intravenous and nebulizer groups at baseline (post-induction)

“SD-standard deviation; NS-not significant using unpaired t-test”

SBP

The mean SBP at baseline post-induction was not suggestively different between the intravenous and nebulizer groups (P = 0.88).

DBP

Statistical analysis revealed no significant change in mean DBP between the intravenous and nebulizer groups at baseline after induction (P = 0.27).

MAP

After induction, the mean MAPs of the intravenous and nebulizer groups were not significantly different at baseline (P = 0.99).

Heart rate (HR)

When comparing the intravenous and nebulizer groups at baseline post-induction, no statistically noteworthy change in mean MAP was monitored (P = 0.79).

After 1 minute – post-induction

Table 3: Comparison of mean SBP, DBP, MAP and HR between intravenous and nebulizer groups after 1 minute (post-induction)

“SD-standard deviation; NS-not significant using unpaired t-test”

SBP

Despite the fact that the individuals in the nebulizer group had somewhat higher SBP than those in the intravenous group, there was not a statistically significant difference in the mean SBP between the two groups after one minute of post-induction (P = 0.6).

DBP A minute after induction, there was no statistically significant change in mean diastolic blood pressure (DBP) between the nebulizer and intravenous groups, even though the nebulizer group's DBP was somewhat higher (P = 0.14).

MAP The nebulizer group had slightly higher mean arterial pressure (MAP) than the intravenous group at one minute post-induction, but this difference was not statistically significant (P = 0.39).

HR The nebulizer group did have a slightly higher heart rate (HR) than the intravenous group, but after one minute after induction, there was no statistically significant difference (P = 0.27).

After 3 minutes – post-induction

Table 4: Comparison of Mean SBP and DBP, MAP, and HR between intravenous and nebulizer groups after 3 minutes (post-induction)

“SD-standard deviation; NS-not significant using unpaired t-test”

SBP: The nebulizer group had slightly higher systolic blood pressure (SBP) than the intravenous group three minutes after induction, although this difference was not statistically significant (P = 0.53).

DBP: Three minutes after induction, there was no statistically significant change in mean diastolic blood pressure (DBP) between the nebulizer and intravenous groups, even though the nebulizer group's DBP was somewhat higher (P = 0.12).

MAP: There was no statistically significant difference in mean artery pressure (MAP) between the intravenous and nebulizer groups three minutes post-induction, however the nebulizer group did have modestly higher MAP (P = 0.31).

HR: Three minutes after induction, there was no statistically significant difference in mean HR between the intravenous and nebulizer groups, despite the fact that the nebulizer group had a slightly higher HR (P = 0.06).

After 5 minutes – post-induction

“SD-standard deviation; *Statistically significant and NS-not significant using unpaired t-test”

SBP

It was found that though SBP was slightly higher among members in the nebulizer group, there was no statistically noteworthy difference in mean SBP between intravenous and Nebulizer groups after 5 minutes post-induction (P = 0.45).

DBP

It was found that participants in the Nebulizer group had higher DBP when compared to members in the intravenous group. This difference in mean DBP after 5 minutes post-induction was statistically significant (P = 0.05).

MAP

It was found that though MAP was slightly higher among members in the nebulizer group, there was no statistically noteworthy difference in mean MAP between intravenous and Nebulizer groups after 5 minutes post-induction (P = 0.12).

HR

It was found that participants in the Nebulizer group had higher HR when compared to members in the intravenous group. This difference in mean HR after 5 minutes post-induction was statistically noteworthy (P = 0.013).

Table 5: Comparison of Mean SBP and DBP, MAP, and HR between intravenous and nebulizer groups after 5 minutes (post-induction)

After 7 minutes – post-induction

Table 6: Comparison of Mean SBP and DBP, MAP, and HR between intravenous and nebulizer groups after 7 minutes (post-induction)

 “SD-standard deviation; *Statistically significant and NS-not significant using unpaired t-test”

SBP

It was found that though SBP was slightly higher among members in the nebulizer group, there was no statistically noteworthy difference in mean SBP between intravenous and Nebulizer groups after 7 minutes post-induction (P = 0.09).

DBP

It was found that participants in the Nebulizer group had higher DBP when compared to members in the intravenous group. This difference in mean DBP after 7 minutes post-induction was statistically noteworthy (P = 0.006).

MAP

It was found that participants in the Nebulizer group had higher MAP when compared to members in the intravenous group. This difference in mean MAP after 7 minutes post-induction was statistically noteworthy (P = 0.018).

HR

It was found that participants in the Nebulizer group had higher HR when compared to members in the intravenous set. This difference in mean HR after 7 minutes post-induction was statistically noteworthy (P = 0.007).

After 10 minutes – post-induction

Table 7: Comparison of Mean SBP and DBP, MAP, and HR between intravenous and nebulizer groups after 10 minutes (post-induction)

“SD-standard deviation; *Statistically significant and NS-not significant using unpaired t-test”

SBP

It was found that though SBP was slightly higher among participants in the nebulizer cluster, there was no statistically noteworthy difference in mean SBP between intravenous and Nebulizer groups after 10 minutes post-induction (P = 0.33).

DBP

It was found that participants in the Nebulizer group had higher DBP when compared to participants in the intravenous group. This difference in mean DBP after 10 minutes post-induction was statistically noteworthy (P = 0.022).

MAP

It was found that participants in the Nebulizer group had higher MAP when compared to participants in the intravenous group. This difference in mean MAP after 10 minutes post-induction was not statistically noteworthy (P = 0.059).

HR

It was found that participants in the Nebulizer group had higher HR when compared to participants in the intravenous group. This difference in mean HR after 10 minutes post-induction was statistically noteworthy (P = 0.002).

Laryngoscopy and intubation may be performed with less pressor reaction using a variety of anesthetic procedures and pharmaceutical substances. Dexmedetomidine has been the agent of choice due to its hypotensive effect, sedative effect, anaesthetic sparing properties, analgesic effect, and more importantly its ability of hemodynamic stability.9 Nebulization is another viable option having the added benefit of systemic absorption, ease of administration, and high bio-availability due to high vascularization of the nasal and buccal mucosa. 10,11 This research aimed to evaluate the intubation response to nebulized dexmedetomidine (0.7 mcg/kg) and dexmedetomidine infusion (0.7 mcg/kg) in terms of hemodynamic stability.

 While both groups' hemodynamic parameters were comparable after 10 minutes, we discovered that the IV groups were significantly higher at baseline (before induction) than the nebulized group's (before induction).  Our study did not show any noteworthy changes in hemodynamic parameters from baseline (on induction) till 3rd minute. Only on the 5th minute, we observed a significant increase in DBP and HR among participants in the nebulized group which remained till the 7th minute with an additional increase in MAP in the nebulizer group. The increase in DBP and HR remained elevated till the 10th minute with no significant change in the SBP and the MAP. Therefore, nebulized dexmedetomidine was able to attenuate all the hemodynamic parameters only till 3rd minute and failed to alternate. DBP and HR from 3rd minute till the 10th minute respectively. Our finding was in contrast to the findings of Misra et al who stated that “nebulized dexmedetomidine controlled the ascent of HR but failed to arrest MAP rise” whereas in our study, nebulized dexmedetomidine was able to control a rise in MAP but could not attenuate HR.11

In addition, our study was partly in line with studies conducted by Paul et al in 2023,12 and Shrivastav et al in 2022.75 Paul et al shown a randomized double-blind study among 100 participants (50 in each group) to observe hemodynamic changes occurring as a response to the administration of nebulized dexmedetomidine of 1 µg/kg in 4 ml of 0.9% saline 30 minutes before the induction when compared to saline. Paul et al found a significant attenuation of SBP, DBP, and MAP at 1st, 5th, and 10th min following intubation in the group receiving nebulized dexmedetomidine. In addition, an intra-group assessment revealed no significant attenuation of HR among participants with nebulized dexmedetomidine between different time intervals. Shrivastav et al also observed a noteworthy reduction of hemodynamic parameters by nebulized dexmedetomidine before laryngoscopy, after intubation, at 1st, 5th, and 10th min respectively following intubation. Kumar et al. 13 found similar things in their 2020 investigation. A randomized controlled trial involving 120 people who all had the same goal was carried out by Kumar et al. The experimental group was given 1 µg/kg of dexmedetomidine in 3–4 ml of 0.9% saline by the authors, whereas the control group received saline. HR in the study's experimental group were meaningfully lower than those in the control group. But after laryngoscopy, the authors failed to detect a statistically noteworthy difference in SBP) between the two sets of patients. The reason for this is because dexmedetomidine is bio-available when administered via the buccal and nasal mucosa, which is comparable to the impact of intravenous dexmedetomidine at 0.5 µg/kg, which is not very significant in addressing hemodynamic alterations after laryngoscopy and intubation. 14, 10, 15

An interesting study conducted by Singh et al. in 2022 16 reported similar findings. The authors conducted a randomized controlled trial among 120 participants who were to receive dexmedetomidine (similar concentrations – 1 µg/kg) in form nebulized and via the intravenous route. The authors found no significant difference in hemodynamic parameters up to 3 minutes following which there was a noteworthy decrease in the intravenous group.  The authors conclude that the intravenous route had produced better results, however, nebulized dexmedetomidine had better haemodynamic intra-operatively and during evaluation of post-operative outcomes. The results from the present study are in line with the findings of Singh et al.  Hussain et al 17 reported complete attenuation of hemodynamic parameters until the 3rd minute, similar to our study. The findings of our study do not align with a meta-analysis conducted by Gupta et al in 2023 who reported that premedication with nebulized dexmedetomidine was associated with a reduction in HR and BP. 73 Our study also covers an important lacuna in that it compares the nebulized route with an intravenous route that is routinely followed. Interestingly, we observed that our study was in line with, or partly in line with most studies that have used 1 µg/kg dexmedetomidine in 3 – 4 ml of 0.9% saline. In our study, we report almost similar findings with a lesser concentration of dexmedetomidine (0.7 µg/kg). A difference of 0.3µg/kg dexmedetomidine can bring about significant changes in hemodynamic parameters after intubation against the findings of our study where we found a significant difference only after 3rd minute. Perhaps this is a landmark finding that nebulized dexmedetomidine 0.7µg/kg and 1 µg/kg elicit the same response.

Additionally, we found that the duration of intubation was almost same across the two groups. Although it has been shown that blood pressure increases fifteen seconds after intubation, we discovered that intubation took around eighteen to nineteen seconds per group. Nebulized dexmedetomidine considerably improved intubation circumstances and demonstrated a statistically significant improvement when contrasted with saline nebulization, according to a randomized, double-blind clinical study by Paul et al. 71 The use of Nebulized dexmedetomidine has been alluring owing to its bioavailability and faster absorption. In addition, the adverse effects of dexmedetomidine are dose-dependent, we did not find any perioperative adverse effects in the present study.

It is very evident that α2 adrenoreceptor agonists are a special class of agents that seems to provide favorable results when used in conjunction with anaesthesia. The use of nebulization in administering dexmedetomidine is a potential response to drawbacks that arise as a result of intranasal and intravenous routes.

Our study has some limitations:

·             To start, we only looked at one dosage of dexmedetomidine in the nebulized form, so we don't know how the body reacts to pressor response after laryngoscopy and intubation at other doses.

·             Second, we did not assess the level of sedation that patients achieved.

·             Third, in the present study, we did not record any adverse events either perioperatively or post-operatively and hence we are not able to provide a comprehensive picture regarding the novel route.

·             In this investigation, we did not evaluate the effectiveness of nebulized dexmedetomidine in decreasing post-operative nausea and vomiting, even though dexmedetomidine inhibits early postoperative nausea and vomiting (PONV).

·             Fifth, we did not assess if the newer route had any effect on the consumption of Propofol, any intra-anesthetic usage and analgesic consumption.

Within the parameters of the study, it can be concluded that nebulized dexmedetomidine (0.7 µg/kg) administered 15 minutes before the induction of anaesthesia meaningfully attenuated the effects of laryngoscopy and intubation till 3 minutes for all hemodynamic parameters. However, post 3 minutes, nebulized dexmedetomidine could successfully attenuate only SBP and MAP and failed to attenuate DBP and HR.

1.      Schommer NC, Helhammer DH, Kirschbaum C. Dissociation between reactivity of the hypothalamus-pituitary-adrenal axis and the sympathetic-adrenal-medullary system to repeated psychosocial stress. Psychosom Med 2003;65(3):450-460.

2.      Kovac AL. Controlling the hemodynamic response to laryngoscopy and endotracheal intubation. Journal of Clinical Anaesthesia 1996;8 (1):63-79.

3.      Vucevic M, Purdy GM, Ellis FR. Esmolol hydrochloride for management of the cardiovascular stress responses to laryngoscopy and tracheal intubation. Br J Anaesth. 1992; 68:529–530.

4.      Singh H, Vichitvejpaisal P, Gaines GY, White PF. Comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. J Clin Anesth 1995; 7: 5-8.

5.       Kauppila T, Kemppainen P, Tanila H, Pertovaara A. Effect of systemic medetomidine: An alpha-2 adrereceptor agonist, on experimental pain in humans. Anesthesiol 1990; 74:4-9.

6.      Jaakola ML, Ali-melkkila T, Kanto J et al. The effect of a single intravenous bolus dose of dexmedetomidine on intraocular pressure, hemodynamic & sympathoadrenal responses to laryngoscopy & tracheal intubation. Br J Anaesth 1992;68(6):570-575.

7.      Chorney SR, Gooch ME, Oberdier MT, Keating D, Stahl RF. The safety and efficacy of dexmedetomidine for postoperative sedation in the cardiac surgery intensive care unit. HSR Proc Intensive Care Cardiovasc Anesth. 2013;5(1):17–24.

8.      Naaz S, Ozalr E. Dexmedetomidine in current anesthesia practice: a review. J Clin Diagn Res 2014; 8(10): GE01–GE04.

9.      Scheinin H, Aantaa R, Anttila M, et al. Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2 adrenoceptor antagonist atipamezole. A pharmacodynamic and kinetic study in healthy volunteers. Anesthesiology. 1998; 89:574–584.

10.   Zanaty OM, ElMetainy SA. A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. Anesth Analg. 2015;12(1):167–71.

11.   Misra S, Behera BK, Mitra JK, Sahoo AK, Jena SS, Srinivasan A. Effect of preoperative dexmedetomidine nebulization on the hemodynamic response to laryngoscopy and intubation: a randomized control trial. Korean J Anesthesiol. 2021;74(2):150–7.

12.   Paul NS, Abraham V, Liddle D. A randomized double-blind study to evaluate the effect of nebulized dexmedetomidine on the hemodynamic response to laryngoscopy – Intubation and intubation conditions. Indian J Clin Anaesth 2023;10(4):358-364.

13.   Kumar NRR, Jonnavithula N, Padhy S, Sanapala V, Naik VV. Evaluation of nebulised dexmedetomidine in blunting haemodynamic response to intubation: A prospective randomised study. Indian J Anaesth. 2020 Oct;64(10):874-879.

14.   Niyogi S, Biswas A, Chakraborty I, Chakraborty S, Acharjee A. Attenuation of haemodynamic responses to laryngoscopy and endotracheal intubation with dexmedetomidine: a comparison between intravenous and intranasal route. Indian J Anaesth 2019; 63: 915-23

15.   Kumari K, Gombar S, Kapoor D, Sandhu HS. Clinical study to evaluate the role of preoperative dexmedetomidine in attenuation of hemodynamic response to direct laryngoscopy and tracheal intubation. Acta Anaesthesiol Taiwan. 2015;53(4):123-130. https://doi.org/10.1016/j.aat.2015.09.003

16.   Singh V, Pahade A, Mowar A. Comparison of Intravenous Versus Nebulized Dexmedetomidine for Laryngoscopy and Intubation-Induced Sympathoadrenal Stress Response Attenuation. Anesth Pain Med. 2022 October; 12(5): e132607 http://doi. doi.org/10.5812/aapm-132607.

Hussain M, Arun N, Kumar S, Kumar A, Kumar R, Shekhar S. Effect of dexmedetomidine nebulization on attenuation of hemodynamic responses to laryngoscopy: randomized controlled study. Indian Journal of anesthesia and analgesia.2019;6(4):1235- 40.