A double blind randomised study to determine the efficacy of dexmedetomidine nebulisation in attenuating the stress response to laryngoscopy and intubation

INTRODUCTION

Laryngoscopy followed by intubation is a common procedure done in patients undergoing surgical procedures under general anaesthesia. This often leads to intense sympathetic stimulation and haemodynamic stress response, manifesting as hypertension and tachycardia. This stress response is due to an increased release of catecholamines into the plasma in response to the stimulation of laryngoscopy and intubation.^[1-3]

Blunting this haemodynamic stress response is important, particularly in high-risk patients such as those with ischaemic heart disease, hypertension, diabetes, etc.^[4] as it may result in rhythm disturbances, myocardial infarction, stroke, pulmonary oedema, and elevated intracranial pressure.^[1]

Dexmedetomidine, a specific agonist of the α-2 adrenergic receptors, stimulates the α-2 adrenoceptors in the pontine locus coeruleus (LC). This results in their hyperpolarisation, followed by a reduction in the firing of LC neurons and the initiation of anaesthesia. The effect of dexmedetomidine on ventilation is so minimal that even high infusion rates of the drug do not produce respiratory depression. Intracranial pressure is not much affected by the drug. However, during intravenous (IV) administration, it may cause significant hypotension, bradycardia, atrial fibrillation, etc. These adverse effects can be overcome by administering it as nebulisation with better haemodynamic stability.^[5,6]

The primary objective of this study was to determine if pre-operative nebulisation with dexmedetomidine can attenuate haemodynamic stress response to laryngoscopy and intubation in patients undergoing surgical procedures under general anaesthesia. We also intended to know if dexmedetomidine, when administered by the nebulisation route, can reduce the induction dose of propofol, produce significant sedation, or be associated with adverse effects such as cough, bradycardia, hypotension, etc.

MATERIAL AND METHODS

This was a randomised controlled study conducted in a tertiary healthcare institute over a period of one year from 22^nd Jan 2021 to 18^th Jan 2022, including 90 patients in the age group of 18-60 years. After receiving approval from the institutional ethics committee (IEC approval number ECR/486/Inst/KA/2013/RR-16 dated 22nd January 2021) and registering with the Clinical Trials Registry-India (CTRI/2021/09/036244), the study subjects were recruited. Informed, valid, written consent was taken from the patients. Subjects of either gender, in the age group of 18 to 60 years, belonging to American Society of Anesthesiologists (ASA) physical status grade I and II having a body mass index (BMI) within the range of 18.5 - 29.9 kg/m² and undergoing surgery under general anaesthesia with intubation were included in the study. Patients with anticipated difficult airways, seizure disorders, pregnant patients, and those on antidepressants or antipsychotic medications were excluded from the study. The study followed all the principles of the Declaration of Helsinki (2013) and good clinical practice guidelines.

Sample size estimation was done based on a study conducted by Kumar et al, where the authors used dexmedetomidine nebulisation to attenuate the stress response to laryngoscopy and intubation.^[1] Considering 80% statistical power, 5% alpha error, and 10% drop rate, a sample size of 90 was deemed adequate.

Simple randomisation was done by computer-generated random numbers in closed envelopes. The subjects were randomised into two groups, group D (n = 45) and group N (n = 45). Patients in group D received 1 µg/kg of dexmedetomidine diluted to 5ml with normal saline as nebulisation 10 minutes prior to induction. Patients in Group N (n = 45) received 5 mL of normal saline (NS) nebulisation as a placebo 10 minutes before induction.

All the patients underwent standard preanaesthetic evaluation and were adequately fasted as per standard guidelines prior to surgery. Monitoring included electrocardiogram, oxygen saturation, non-invasive blood pressure, and end-tidal carbon dioxide.

The baseline blood pressure – systolic blood pressure(SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and baseline sedation score based on Ramsay sedation scale were recorded. This was followed by nebulisation with dexmedetomidine or placebo according to the group the patients were allocated to, with a nebuliser mask and a continuous oxygen flow at 6 L/min, 10 minutes before induction. The test drug was prepared and administered by an anaesthesiologist not involved in the study, ensuring blinding of both the observer and the patient. Vital parameters like HR, MAP, peripheral oxygen saturation (SPO₂), and sedation score were noted after nebulisation. Preoxygenation was done for 3 minutes with 100% oxygen. Glycopyrrolate 0.2mg IV, midazolam 0.05 mg/kg IV, and fentanyl 2 µg/kg IV were administered as premedication to all the patients. Induction was done with the injection of propofol 1-2 mg/kg, whose dose was titrated to loss of verbal contact with the patient, and the quantity of drug required to attain this effect was noted. Succinylcholine in the dose of 2 mg/kg was administered as a muscle relaxant. Laryngoscopy was performed using a correct-size Macintosh blade, and intubation was carried out with an appropriately sized endotracheal tube by an experienced consultant anaesthesiologist. Following intubation, the patient was connected to the ventilator and vital parameters, including HR, blood pressure [SBP, DBP, MAP, and SpO₂ were noted at 1, 5, 10 and 30 minutes (T1, T5, T10, T30). Patients with an unanticipated difficult airway who required more than one laryngoscopy and intubation attempt were excluded from the study. The sedation score before and after nebulisation, the total dose of propofol used for induction, and the presence of any adverse effects such as hypotension, bradycardia, or arrhythmia were noted.

Data was entered in a Microsoft Excel data sheet and analysed using Statistical Package for the Social Sciences (SPSS) 22 version software. The results are expressed as mean ± standard deviation or percentage. An independent sample t-test was the test of significance applied for quantitative data. The Chi-square test was used for analysing the significance of qualitative data. A p-value of less than 0.05 was considered statistically significant.

RESULTS

A total of 90 patients were included in this study [Figure 1]. Both groups were similar with respect to their demographic data. The baseline vital parameters were similar in the two groups [Table 1].

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Figure 1:

CONSORT (Consolidated Standards of Reporting Trials) flow diagram. n: Number of patients; group C: Control group; group D: Dexmedetomidine group; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MAP: Mean arterial pressure; HR: Heart rate

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During the pre-induction period, after the administration of nebulisation, it was observed that SBP, DBP, MAP, and HR decreased from baseline values in the dexmedetomidine group compared to the control group.

The intubation response was maximal 1 minute after intubation in the control group, whereas in the dexmedetomidine group, SBP, DBP, and MAP were maintained around the baseline and started to gradually decrease for the next 30 minutes. The maximal decrease was noted 10 minutes after intubation.

The HR was maintained around baseline after 1min of intubation, which gradually started to decrease over the next 30 minutes, but it increased after 1 min of intubation in the control group.

There was a significant reduction in HR in group D from a baseline of 88.2/min to mean values of 86/min at 1 minute with p value 0.002, 85.4 at 5 minutes with p value of 0.02, 81/min at 10 minutes (p value 0.024) compared to NS group which had mean values of 88.3/minutes, at baseline, 90.8/min at 1min, 89.3/min at 5 min, 86/min at 10 minutes [Figure 2].

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Figure 2

Comparison of heart rate between the two study groups. HR: Heart rate; bpm: Beats per minute

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Following laryngoscopy and intubation, SBP, DBP and MAP were significantly increased in the group N from an average baseline of 123.2 mm Hg (SBP) and 90.6 mm Hg (MAP) to SBP of 135.8 mm Hg at 1 minute, 118.3 mm Hg at 5 minutes, 113.7 mm Hg at 10 minutes, and MAP of 100.1 mm Hg at 1 minute, 89.5 mm Hg at 5 minutes, 85.3 mm Hg at 10 minutes after intubation, whereas in group D there was a fall in SBP from the baseline of 123.5 mm Hg to 116.7 ± 8.2 at 1 minute after intubation, 5 minutes-104.7 ± 6.5, 10 minutes-101.5 ± 6.5, and fall in MAP from 91.8 mm Hg 85.9 ± 5.8 at 1 minutes, 5 min-78.4 ± 6.3 and 10 minutes- 75.7 ± 6.4 [Figures 3 and 4].

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Figure 3

Comparison of mean arterial pressure between the two study groups. MAP: Mean arterial pressure

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Figure 4:

Comparison of systolic blood pressure between the two groups. BP: Blood pressure

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It was observed in Group D patients that a lesser dose of propofol was sufficient for induction with test drug usage. The mean dose of propofol used for induction was significantly lower in group D compared to group N, with a mean value of 98.4 ± 7.1 in group D and 108 ± 11.8 in the NS group, with a p-value < 0.001 [Table 2].

The sedation score of 2 was observed throughout the study period before induction in both groups, indicating that nebulised dexmedetomidine did not cause sedation.

No adverse effects or complications were seen in either group.

DISCUSSION

It was observed in the present study that dexmedetomidine nebulisation given as premedication significantly attenuates the pressor response to laryngoscopy and intubation.

Stress response to laryngoscopy and intubation is of significant concern in all patients undergoing procedures under general anaesthesia with intubation. Attenuation of this response is of primary importance, particularly in patients with comorbid conditions such as ischaemic heart disease, diabetes, hypertension, etc. The undesired haemodynamic responses are believed to be caused by the stimulation of mechanoreceptors in the pharyngeal wall, epiglottis, and vocal cords. These responses occur within 30 seconds after intubation and last for less than 10 minutes.^[7-10]

Previous studies show that laryngoscopy and intubation lead to an increase in HR by 26 to 66% and in blood pressure by 35 to 46%.^[11] Inhibition or attenuation of these responses is important to decrease morbidity and mortality, especially in patients with comorbid conditions.^[12]

Various drugs and techniques have been used to attenuate the stress response to laryngoscopy and intubation, such as β-blockers, lignocaine (used both intravenously and as local instillation over the vocal cords), opioids, magnesium sulphate, vasodilators (nitroglycerin), clonidine, etc.^[13-15] Dexmedetomidine, an α-2 agonist with anxiolytic, sedative, analgesic, and anaesthetic sparing effects, is also one such effective agent. It has been reported to reduce the serum concentration of norepinephrine, resulting in a reduction in blood pressure and HR without the adverse effects like postoperative nausea and vomiting, respiratory depression, etc. Its action on the LC induces sedation and alters nociceptive neurotransmission.^[16] It is quite commonly used as a premedicant by the IV route to reduce the stress response to the procedure of laryngoscopy followed by intubation. It has several other beneficial effects, such as sedation, anxiolysis, induction agent dose-reducing effect, etc.

Studies in children have shown that nebulised dexmedetomidine premedication is more effective compared to midazolam and ketamine with regard to sedation, parental separation, mask acceptance, and stable haemodynamics.^[17] There are not many studies evaluating the effect of dexmedetomidine for reducing the stress response to laryngoscopy and intubation when administered by nebulisation route in adults.^[2,18]

The present study shows that when dexmedetomidine is administered by nebulisation route 10 minutes prior to induction of general anaesthesia, it efficiently decreases the stress response occurring during laryngoscopy and intubation. It was noted that there was a significant reduction in pulse rate and blood pressure as compared to the values before laryngoscopy and intubation. The placebo group, i.e., saline group, in the study had a significant increase in all the parameters observed.

Niyogi et al. conducted a study comparing dexmedetomidine IV versus the intranasal route and observed that intranasal dexmedetomidine is as effective as IV dexmedetomidine in attenuating the pressor response to laryngoscopy and intubation.^[2] In a similar study, Kumar et al. used dexmedetomidine nebulisation in adult patients to attenuate the stress response to laryngoscopy and intubation. Their results revealed that dexmedetomidine nebulisation was most effective at 1 minute after intubation in attenuating the stress response, caused significant sedation, and reduced the mean induction dose of propofol by 20 mg.^[1] In the present study, too, it was observed that the decrease in blood pressure was most evident at 1 minute after intubation. However, dexmedetomidine nebulisation did not cause significant sedation in the patients, and the reduction of the mean induction dose of propofol was 10 mg.

In the present study, the attenuation effect of nebulised dexmedetomidine was most evident at 1 minute after laryngoscopy and intubation, as the difference in SBP, DBP, and MAP between the two groups was highest at this point after intubation. Hence, we can infer that the reduction in the pressor effects with dexmedetomidine nebulisation is most effective during the first few minutes after intubation. It decreased the mean induction dose of propofol by 10 mg. However, it did not cause significant sedation in the patients. It may be pertinent to mention here that the mean bioavailability of dexmedetomidine via the upper airway mucosa is quite high, i.e. 82%,^[17], its distribution half-life is 6 minutes, and its elimination half-life is 2 hours.^[1] This may account for its effectiveness by the nebulised route.

Dexmedetomidine, when administered by nebulisation route may overcome its adverse effects because of diffuse deposition over the nasal, oral and pharyngeal mucosa, and resultant better systemic absorption, crossing the blood brain barrier and reaching the central nervous system directly as opposed to other routes such as IV route (significant bradycardia, hypotension and delayed recovery), intranasal route (nasal irritation and bronchospasm), per oral route (decreased bioavailability) and intramuscular route (unpredictable effect).^[1] Nonetheless, nebulised dexmedetomidine was well tolerated by the subjects in the present study without any serious adverse effects.

CONCLUSION

Nebulised dexmedetomidine administered as premedication significantly reduces the haemodynamic stress response to laryngoscopy and intubation, and also reduces the dose of propofol required for induction without any adverse effects.