
==== Front
J Res Pharm Pract
J Res Pharm Pract
JRPP
J Res Pharm Pract
Journal of Research in Pharmacy Practice
2319-9644
2279-042X
Wolters Kluwer - Medknow India

JRPP-12-123
10.4103/jrpp.jrpp_12_24
Original Article
Effect of Preoperative Intravenous and Inhalational Dexmedetomidine on the Hemodynamic Response of Laryngoscopy: A Prospective Double-blinded Randomized Study
Singh Shivanya 1
Gupta Priyanka 2
Dhar Mridul 2
Pasha Arhan 2
1 Department of Anesthesia and Critical Care, AIIMS, New Delhi, India
2 Department of Anesthesia and Critical Care, AIIMS, Rishikesh, Uttarakhand, India
Address for correspondence: Dr. Priyanka Gupta, E-mail: drpriyankagupta84@gmail.com
Oct-Dec 2023
08 8 2024
12 4 123129
01 4 2024
11 5 2024
25 5 2024
Copyright: © 2024 Journal of Research in Pharmacy Practice
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
ABSTRACT

Objective:

Laryngoscopy induces potent noxious stimuli causing reflex autonomic activation manifested by an increase in blood pressure and heart rate (HR). Various drugs with different routes have been tried to prevent this response. The literature comparing inhalational dexmedetomidine with intravenous (IV) dexmedetomidine to prevent laryngoscopy response is limited.

Methods:

A total of 150 American Society of Anesthesiologists Physical Status Class I/II, undergoing elective surgery requiring laryngoscopy and intubation, were included and randomized into two groups. Patients in Group DINH received nebulized dexmedetomidine (1 μg/kg) and in Group DIV received IV dexmedetomidine (0.5 μg/kg), 15 min before anesthesia induction. For blinding, nebulized or IV saline was used simultaneously. The primary outcome was to compare the mean arterial pressure (MAP) and HR at laryngoscopy, intubation, and 1, 5, and 10 min after intubation. The secondary outcome was to compare sedation, following the administration of dexmedetomidine, propofol consumption during induction, and any side effects.

Findings:

There was no significant difference in MAP (mmHg) postlaryngoscopy and intubation (immediate after intubation 78.5 ± 11.3 vs. 82.3 ± 16.0, P = 0.093). The mean HR was clinically similar in both groups postlaryngoscopy and intubation (immediate after intubation, 80.9 ± 12.5 vs. 76.3 ± 10.9). Patients in the DIV group were more sedated than the DINH (Ramsay Sedation Scale 3–4 vs. 1–2, P < 0.001). Bradycardia was seen in eight patients of the DIV group only.

Conclusion:

Preoperative nebulized dexmedetomidine is as effective as and safer than IV dexmedetomidine in preventing laryngoscopic response among adults.

KEYWORDS:

Dexmedetomidine
hemodynamics
inhalational
intravenous
laryngoscopic response
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pmcINTRODUCTION

Laryngoscopy and endotracheal intubation are done to secure the airway of a patient under general anesthesia. However, it induces a potent noxious stimulus through vagal and glossopharyngeal afferents, which in turn causes reflex autonomic activation manifested by an increase in blood pressure and heart rate (HR). Other consequences of laryngoscopy may include laryngospasm, bronchospasm, rise in intracranial pressure, and intraocular pressure. In healthy individuals, these brief transient reactions usually do not cause much detrimental effects; however, patients who suffer from reactive airways, hypertension, coronary artery disease, myocardial insufficiency, cerebrovascular diseases, and raised intracranial pressure may be adversely affected.[12] Many drugs and methods have been explored to reduce this stress response, with varied degrees of efficacy and associated side effects.[134]

Dexmedetomidine is a potent and selective α2 adrenoreceptor agonist with anxiolytic, sedative, analgesic, anti-sialagogue, and sympatholytic properties, rendering it suitable as a premedication agent.[5] Dexmedetomidine administered intravenously before laryngoscopy can successfully reduce the laryngoscopic stress response but may cause side effects such as hypotension, bradycardia, and delayed recovery.[6] The intranasal route stands out as a frequently employed alternative for administering dexmedetomidine. This route allows the systemic absorption of drugs by bypassing the first-pass metabolism in the liver. Intranasal dexmedetomidine has been explored for preoperative sedation in children.[7] Nebulizing dexmedetomidine offers rapid absorption through the nasal, respiratory, and buccal mucosa, with a 65% bioavailability through the nasal mucosa and 82% through the buccal mucosa.[89]

Alpha-2 adrenoreceptor is also found peripherally, including respiratory mucosa.[10] Thus, inhaled dexmedetomidine exerts its analgesic, sympatholytic, and anti-inflammatory effect locally on respiratory mucosa.[11] Nebulized dexmedetomidine also has been found to be effective in preventing postoperative sore throat.[12]

The literature comparing inhalational dexmedetomidine with intravenous (IV) dexmedetomidine to prevent laryngoscopy response is limited. With this background, the current study was planned to evaluate whether preoperative use of inhalational dexmedetomidine would be as effective as IV dexmedetomidine in minimizing the hemodynamic response following laryngoscopy in patients undergoing elective surgical procedures under general anesthesia requiring endotracheal intubation.

METHODS

A prospective, randomized, double-blinded study was conducted in a tertiary care hospital in India. The study protocol was approved by the Institutional Ethical Committee (AIIMS/IEC/21/206) and registered with the Clinical Trials Registry of India, (www.ctri.nic.in) (CTRI/2021/11/038005, date: November 12, 2021) before patient enrolment.

All American Society of Anesthesiology Physical Status Class I-II patients, aged 18–60 years of either gender, undergoing elective surgery that required endotracheal intubation were included in the study. Patients with anticipated difficult laryngoscopy and intubation, requiring more than one attempt for intubation, having significant cardiovascular, hepatic, or renal dysfunction, pregnant patients, known allergies to the study drug, and patients with raised intracranial pressure were excluded. Before enrolment, all patients were provided with a patient information sheet, and written informed consent was taken.

Patients were randomized and allocated into two parallel groups (allocation ratio 1:1) by computer-generated random table (http://www.randomizer.org). Allocation concealment was done by the sealed opaque envelope technique which was opened once patients were received in the preoperative area on the day of surgery. The studied groups were: Group DINH: received IV normal saline infusion over 15 min and dexmedetomidine nebulization (1 μg/kg) over 5 min. Group DIV: received dexmedetomidine IV infusion (0.5 μg/kg) over 15 min and nebulization of normal saline over 5 min.

In the IV dexmedetomidine group, the dose of 0.5 μ/kg was chosen as the lowest effective dose with minimal side effects such as bradycardia and hypotension.[13] Since the bioavailability of topical dexmedetomidine is lower through the nasal and buccal mucosa as compared to intravenous administration. That is why a comparatively higher dose (1 μ/kg) was used for inhaled dexmedetomidine.

The anesthesiologist (not participating in clinical management or data recording of the patient) opened the sealed envelope allocated to the patient in the preoperative area and prepared the IV and nebulization drug. All IV solutions were prepared in a 50-ml syringe using dexmedetomidine or normal saline diluted to 50 ml. All nebulization drug solutions were prepared in identical syringes with a final volume diluted to 5 ml by adding normal saline as required. The drugs were handed over to a nurse (blinded to the group allocation) who executed the interventions on the patient. Nebulization was administered with a nebulization mask and oxygen at a rate of 6 L/min for 5–10 min (till the drug solution disappeared). Outcome parameters were recorded by another anesthesiologist blinded to group allocation.

On the day of surgery, patients were shifted to the preoperative area 1 h before surgery. On arrival at the preoperative area, HR and mean arterial pressure (MAP) were recorded, and appropriate IV access was obtained.

IV infusion of study drug or normal saline according to group allocation was started 30 min before shifting the patient to the operating room (OR), administered with a 50-ml syringe using an infusion pump at a rate of 200 ml/h over 15 min. This was followed by nebulization of the study drug or normal saline with a nebulization mask with 100% O2 at a rate of 6 L/min by blinded nursing staff for 5–10 min. The patient was shifted to the OR after 10 min of completion of nebulization.

After shifting to the OR, the level of sedation was assessed with the Ramsay Sedation Scale (RSS). Standard multipara monitoring including HR, pulse oximetry, noninvasive blood pressure, electrocardiogram, and bi-spectral index (BIS) were attached, and baseline parameters were noted. Then, the patient was preoxygenated with 100% oxygen using an appropriately sized anatomical face mask. Anesthesia was induced with an injection of fentanyl 2 μg/kg, propofol 1.5–2.5 mg/kg (targeted to BIS of 40–60) through an infusion pump, and vecuronium 0.10 mg/kg. Train of four (TOF) monitoring was then initiated, and once the TOF count was 0 with BIS of 40–60, laryngoscopy was performed with a Macintosh blade 3 or 4 in sniffing position by an anesthesiologist with a minimum of 3 years of experience.

Monitoring of HR and MAP was done at the time of laryngoscopy, just after intubation, 1, 5, and 10 min after intubation. The amount of propofol consumed during induction of anesthesia was recorded. Perioperative hypotension or hypertension was defined as MAP less than or more than 20% of baseline, respectively.[14] Bradycardia or tachycardia was defined as HR less than or more than 20% of baseline, respectively.[15] Injection atropine 20 μg/kg and injection mephentermine 3–6 mg aliquots were used to treat bradycardia and hypotension, respectively. Bolus injection of esmolol 1–2 mg/kg was given to treat hypertension and tachycardia.

Following laryngoscopy, the patient was left undisturbed without any stimulus for 10 min. Painting and draping were then initiated, followed by the surgical incision. All patients were continuously monitored for any intraoperative hemodynamic changes throughout the surgery. At the end of the surgery, the patient was reversed with injection neostigmine (0.05 mg/kg) + injection glycopyrrolate (0.01 mg/kg), extubated, and shifted to postanesthesia care unit.

The primary outcome of the study was the MAP and HR immediately after laryngoscopy and intubation following laryngoscopy. The secondary outcomes were sedation levels following the administration of dexmedetomidine (RSS), propofol consumption during induction, and any associated side effects.

Decoding was done once the data analysis was complete. In case of any significant adverse events, decoding of that case was done immediately and recorded.

The sample size for the study was based on a study by Niyogi et al.[6] this study compared intravenous and intranasal administration of dexmedetomidine for attenuation of hemodynamic responses of laryngoscopy and intubation. Taking the mean HR value of the IV group at laryngoscopy to be 80.54 ± 6.48, and assuming a medium effect size of 0.46, the sample size was estimated to be 130 with 65 patients in each group, including 5% dropouts with a power of 85% and confidence interval of 95% using formula sample size N = 2 (zα + z1−β)2 σ2/δ2.

Data were coded and recorded in MS Excel spreadsheet program. Statistical analysis was performed using SPSS 23.0 (IBM Corp., Armonk, NY, US). The results were presented as descriptive statistics, and summarized as mean (standard deviation), the median (interquartile range), or number (percentage). The numerical variables were analyzed by the Mann–Whitney U-test/unpaired t-test. The categorical variables were analyzed by the Chi-square test/Fisher’s exact test. P < 0.05 was considered significant.

RESULTS

A total of 150 patients were considered for eligibility, out of which 130 (65 in each group) were randomized to receive dexmedetomidine nebulization (1 μg/kg) (Group DINH) or dexmedetomidine IV infusion (0.5 μg/kg) (Group DIV) [Figure 1]. The two groups were comparable with respect to demographic data, including age, height, weight, BMI, and gender [Table 1].

Figure 1 CONSORT flow diagram

Table 1 Patient demographics among groups

Parameters	GroupDINH	GroupDIV	P	
Age (years)	40.00 9±9.94	37.78±11.06	0.232	
Height (cm)	158.77±9.50	159.28±7.82	0.253	
Weight (kg)	63.23±11.49	61.62±9.56	0.444	
BMI (kg/m2)	24.96±3.22	24.23±2.84	0.171	
Male, n (%)	22 (33.8)	22 (33.8)	1.0	
Female, n (%)	43 (66.2)	43 (66.2)	1.0	
Data are presented as mean±SD. Parametric tests (t-tests) were used to make group comparisons. DINH=Inhalational group, DIV=Intravenous group, SD=Standard deviation, BMI=Body mass index

The preinduction MAP was comparable in both groups; there was no significant difference in MAP between the two groups at all time points [Table 2]. The preinduction mean HR was comparable between the two groups. The mean HR in Group DIV was clinically similar to Group DINH at all time points; the mean HR was lower than the preinduction mean HR in both groups at all time points [Table 3].

Table 2 Comparison of the two groups in terms of the mean MAP (mmHg) over time

MAP (mmHg)	Group	P value	
	
Inhalational	IV	
Baseline	92.46±9.05	89.85±8.98	0.114	
At laryngoscopy	71.52±13.30	71.45±12.24	0.963	
Just after intubation	82.31±16.03	78.49±11.39	0.093	
1 min after intubation	83.26±14.20	90.46±75.74	0.336	
5 min after intubation	77.83±12.56	76.02±11.68	0.410	
10 min after intubation	73.03±12.08	70.38±10.49	0.128	
Data are presented as mean±SD. Nonparametric tests (Wilcoxon–Mann–Whitney U-test) were used to make group comparisons. SD=Standard deviation, IV=Intravenous, MAP=Mean arterial pressure

Table 3 Comparison of the two groups in terms of the mean heart rate (bpm) over time

HR (bpm)	Group	P value	
	
Inhalational	IV	
Baseline	86.22±10.64	82.71±10.45	0.060	
At laryngoscopy	72.46±11.05	67.48±11.35	0.005	
Just after intubation	80.98±12.57	76.34±10.91	0.013	
1 min after intubation	78.60±13.35	72.85±12.53	0.0070	
5 min after intubation	75.92±12.43	69.74±11.66	0.007	
10 min after intubation	72.26±11.64	68.03±10.80	0.027	
Data are presented as mean±SD. Nonparametric tests (Wilcoxon– Mann–Whitney U-test) were used to make group comparisons. SD=Standard deviation, IV=Intravenous, HR=Heart rate

The level of sedation was compared between the two groups based on the RSS. There was a significant difference (P < 0.001) in terms of the degree of sedation between the two groups. A larger proportion of patients were cooperative (RSS score 1–2) in Group DINH, while a larger proportion of patients were responsive to commands only (RSS Score 3–4) in Group DIV [Table 4].

Table 4 Association between group and degree of sedation preoperatively after intervention (Ramsay Sedation Scale)

Degree of sedation (RSS)	Group	Fisher’s exact test	
	
Inhalational	IV	Total	χ 2	P	
Cooperative	53 (81.5)	21 (32.3)	74 (56.9)	34.638	<0.001	
Response to verbal commands	11 (16.9)	44 (67.7)	55 (42.3)			
Anxious	1 (1.5)	0	1 (0.8)			
The data are presented as a n (%). RSS: Ramsay Sedation Scale, IV: Intravenous

There was a significant difference between the two groups (P = 0.003) in terms of propofol consumption (mg), with the median propofol consumption being the highest in Group DINH (110 mg) compared to Group DIV (100 mg) [Table 5]. In our study, bradycardia (maximum fall in HR >20% of baseline) was observed in eight patients of Group DIV only.

Table 5 Comparison of the two subgroups in terms of propofol consumption

Propofol consumption (mg)	Group	Wilcoxon–Mann–Whitney U-test	
	
Inhalational	IV	W	P	
Mean±SD	115.38±21.15	105.08±18.15	2723.000	0.003	
Median (IQR)	110 (100–130)	100 (100–110)			
Minimum–maximum	50–180	60–150			
Nonparametric tests (Wilcoxon–Mann–Whitney U-test) were used to make group comparisons. SD=Standard deviation, IQR=Interquartile range, IV=Intravenous

DISCUSSION

In this study, there was no significant difference in MAP, and it remained lower than the baseline values in both groups following laryngoscopy and intubation. We also observed that HR was also clinically similar to patients who received IV dexmedetomidine (Group DIV) compared to patients who received inhalational dexmedetomidine (Group DINH) at all time points following laryngoscopy and intubation. However, following induction, the mean HR was never higher than the baseline HR, in both groups. We compared the lower dose of IV dexmedetomidine (0.5 μg/kg) to match the lower bioavailability of inhaled dexmedetomidine compared to previously done studies.

Inhalational dexmedetomidine has lower bioavailability compared to IV. The serum concentration of intranasal dexmedetomidine has been found much less than the IV infusion of it. Intranasal/inhalational dexmedetomidine has a slower and more gradual onset than the IV dexmedetomidine. A more gradual onset may actually be desirable in avoiding the ᾳ-1 agonist effects seen with rapid IV administration (hypertension and bradycardia).

Niyogi et al. compared IV dexmedetomidine (0.5 μg/kg) with the intranasal route (1 μg/kg) on the hemodynamic response following laryngoscopy. They observed no significant difference in MAP between the two groups; however, the HR increased at laryngoscopy, and it was significantly higher in the intranasal group.[6] A relatively earlier medication delivery (40 min before induction), may be the cause of this difference in HR. Shrivastava et al. administered dexmedetomidine nebulization (1 μg/kg) 30 min before induction and observed a significant reduction in MAP and HR at laryngoscopy, just after intubation and 1, 5, and 10 min after intubation compared to placebo.[16] Misra et al. (120 adult patients) compared nebulized dexmedetomidine (1 μg/kg) with placebo and concluded that nebulization of dexmedetomidine, 30 min before induction, significantly attenuated the increase in HR, but there was no difference in systolic blood pressure compared to placebo. This difference can be attributed to the fact that all patients received midazolam as premedication just before induction; however, in our study, no such premedication was used.[17] A very recent study by Shankar et al. (90 adult patients) compared IV dexmedetomidine (1 μg/kg) and with nebulized (1 μg/kg) dexmedetomidine and IV fentanyl (2 μg/kg) administered 15 min before induction. They observed suppression of hemodynamic response (MAP and HR) by nebulized dexmedetomidine, and it was comparable to IV fentanyl or IV dexmedetomidine. However, there was a significant fall in MAP and HR following the administration of IV dexmedetomidine.[18] In contrast to them, we used a lower dose of dexmedetomidine (0.5 μg/kg) intravenously to minimize adverse effects. These studies correlate with our findings, and thus, nebulization of the drug 15 min before shifting the patient to the OR can be considered as an adequate period for optimal action of dexmedetomidine through the nebulization route.

In our study, there was a significantly higher level of sedation achieved in the IV group. A similar observation was made by Niyogi et al. with significantly higher preoperative sedation scores (RSS) in the IV dexmedetomidine group compared to the intranasal.[6] Shrivastava et al. found no difference in sedation between the nebulized dexmedetomidine group and placebo. However, they assessed sedation immediately after the completion of nebulization, which might be too early for the onset of action by the nebulization route.[16] Thus, dexmedetomidine through nebulization might be advantageous in neurosurgical patients, patients with neurological deficits, and patients with obstructive sleep apnea where minimal sedation is desirable.

We observed significantly higher propofol consumption in Group DINH compared to Group DIV. Shankar et al. showed significantly lower propofol requirement in both the nebulized and IV dexmedetomidine group when compared to the IV fentanyl group but without any significant difference between the nebulized and IV groups. This can be due to the administration of midazolam 0.02 mg/kg as premedication.[18] Singh et al. did not find any significant difference between the propofol requirement between the IV and nebulized dexmedetomidine groups. It might be due to the difference in endpoint for induction, we targeted BIS for induction and they targeted loss of response to verbal commands.[19]

In our study, we found a higher incidence of bradycardia in Group DIV despite using a lower dose (0.5 μg/kg), while no such incidence was reported in Group DINH. In studies by Shankar et al. and Mahajan et al., premedication with injection glycopyrrolate 0.2 mg was given preoperatively before the study drug administration in both groups; that is why no such adverse effects were noted. This finding suggests that nebulized dexmedetomidine may be safer than IV dexmedetomidine in patients receiving beta-blockers, with lower basal HRs, in valvular regurgitant lesions, and pediatric patients.[1820]

A combination of a calm sedated patient without bradycardia and respiratory depression along with remarkable blunting of hemodynamic response at intubation is a novel response seen with the administration of dexmedetomidine by the nebulized route which can be said to be comparable to IV administration of dexmedetomidine as premedication.

In comparison to IV administration, inhalational dexmedetomidine exhibits reduced bioavailability. Studies have revealed significantly lower serum concentrations of dexmedetomidine when administered intranasally compared to intravenously. In addition, the onset of action for intranasal or inhalational dexmedetomidine is slower and more gradual compared to IV administration. This gradual onset may be preferable for mitigating the α-1 agonist effects associated with rapid IV infusion, such as hypertension and bradycardia.[21]

This study had certain limitations. The present work was from a single-center study in healthy individuals, and difficult airway cases were excluded. Since only single-dose administration of IV and nebulized dexmedetomidine was studied, we cannot speculate about whether different doses will affect hemodynamics. The rate and amount of drug absorption cannot be controlled by nebulization; hence, quantification by blood serum values will be required to assess the ideal dose required for the desired action.

In conclusion, preoperative dexmedetomidine nebulization can be used effectively in patients undergoing surgery under general anesthesia requiring endotracheal intubation and is as effective as preoperative administration of IV dexmedetomidine in attenuation of hemodynamic response to laryngoscopy with a minimal level of sedation and stable hemodynamic. Hence, administration through nebulization may be advantageous in situations where profound sedation and bradycardia are undesirable.

AUTHORS’ CONTRIBUTION

S. Singh contributed to the acquisition, analysis, and interpretation of data and drafting the manuscript. P. Gupta contributed to the conception of the study design, interpretation of data, drafting the manuscript, critical analysis, and final approval of the manuscript. M. Dhar contributed to drafting and editing the manuscript and critical analysis of the manuscript. A. Pasha contributed during the conduct of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

The authors would like to acknowledge the support of the Department of Anesthesiology and Neurosurgery, AIIMS, Rishikesh, for the smooth conduct of the study.
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