Comparison of Intranasal Versus Intravenous Dexmedetomidine to Attenuate Haemodynamic Response of Laryngoscopy and Endotracheal Intubation in Elective Lumbar Spine Surgery: A Randomized Controlled Study

Introduction

The augmented cardiovascular responses in the form of tachycar-dia, hypertension, and even myocar-dial infraction brought about by the noxious stimulus of laryngoscopy and intubation may be detrimental for patients with cardiovascular and cerebrovascular diseases.¹

Adequate premedication is neces-sary for stable haemodynamics during laryngoscopy and intubation, which is an integral component of general anaesthesia.

A perfect premedication should be anxiolytic, sedative, analgesic, and antisialagogue. It should have a brief duration of action, a rapid onset, be administered non-parenterally, and have no adverse hemodynamic or respiratory effects²

Dexmedetomidine (DEX) is a highly selective, short-acting, alpha 2-adrenoreceptor agonist used for conscious sedation, and analgesia perioperatively. The intranasal mode of administration of dexmedetomidine has advantage over the intravenous mode in respect to ease of administration.

There needs to be more literature regarding compari-son of the efficacy between intranasal (IN) and intravenous (IV) DEX as a premedication to attenuate haemodynamic response during laryngoscopy and endotracheal intubation in lumbar spine surgery.

So, this study intends to compare the efficacy of IN dexmedetomidine and IV dexmedetomidine for the prevention of haemodynamic surges during laryngoscopy and endotracheal intubation in patient undergoing lumbar spine surgery.

Materials and Methods

A double-blind, randomised control study was con-ducted in a teaching institution of tertiary care after approval of the Institutional Ethical Committee (RmC/IHEC/2021/93) and the informed consent of the participants.

Seventy adults, 18 to 60 years of age, ASA (American Society of Anaesthesiologists physical status) I and II, undergoing elective lumbar spine surgery under general anaesthesia with endotracheal intubation, were included in this study.

Excluded from this study were patients who refused to participate, had a known allergy or hypersensitivity to dexmedetomidine, had severe cardiac and respiratory disease, and were predicted to have a difficult airway. All patients were assessed for intranasal pathology during the preoperative visit. Patients with nasal ulcers, nasal polyps, or nasal septum deviation were pre-cluded from the study. Individual patients underwent a comprehensive pre-operative evaluation and any necessary investigations. Both groups of patients fasted for six hours and received ranitidine (150 mg) and alprazolam (0.5 mg) the night before surgery as premedication.

The randomization was based on a computer-generated random number table. This randomisation schedule allowed for the assignment of patients in two equal groups (Group -D_IV and Group DJ. The list was concealed in opaque, sealed envelopes that were numbered and unsealed sequentially after obtaining patient consent.

On the day of the operation, all participants were moved to the preparatory area two hours beforehand. In the preoperative room, all standard monitors, including pulse oximetry, noninvasive blood pressure (NIBP), and electrocardiogram (ECG), were affixed, and baseline haemodynamic parameters were recorded. An 18G peripheral venous cannula administered 80ml/h of Ringer's lactate solution as maintenance fluid.

Group D_IV received intravenous DEX (0.50 μg /kg) over the course of 40 minutes before induction. The equiva-lent volume of NS was intravenously administered to the Din group.

Patients in Group -D_IN- received IN DEX (1 μg /kg) in its undiluted, parenteral formulation (100 g/ml) form. Intranasal medication was administered into both nostrils using a 1 ml syringe in the supine, head-down position approximately 40 minutes prior to induction. The equivalent volume of NS was intranasally adminis-tered to the D_IV group. All patients were instructed to avoid sucking and sneezing following intranasal drug administration. Neither the person administering the medication nor the patients were informed of their group assignment during the course of the study.

Heart rate (HR), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and SpO2 were measured in the preoperative room at 10-minute intervals until induction of anaesthesia.

In the operating room, hemodynamic parameters were recorded during intubation, then every minute for the next five minutes, at seven minutes, and ten minutes after intubation. Using the Ramsay sedation scale (RSS), an observer evaluated the sedation status of both groups at baseline and 40 minutes after drug administration.

After transferring the patient to the operating room, general anaesthesia techniques were standardised for both groups. In the operating room, additional monitors, such as a neuromuscular monitor and an ETCO₂ monitor, were affixed, and monitoring continued until the end of the procedure. The monitoring of hemodynamics was maintained throughout the perioperative period. After 3 minutes of preoxygenation with 100% oxygen, all patients were induced with propofol (2 mg/kg) and fentanyl (1 μg /kg) administered intravenously. The administration of intravenous rocuronium bromide (1 mg/kg) facilitated tracheal intubation. When the train of four (tOF) count was zero, an experienced anesthesiologist performed laryngoscopy with a Macintosh laryngoscope blade and endotracheal (ET) intubation with an appropriate size cuffed-disposable armoured ET tube. The laryngoscopy & intubation time limit was 15-20 sec-onds. If laryngoscopy & intubation were not completed within 15 to 20 seconds, the data were excluded from the study analysis. No surgical procedure was permit-ted until 10 minutes after intubation. Anaesthesia was maintained with (40% O₂ and N₂O with sevoflurane) and repeated intermittent bolus doses of rocuronium in both groups. All patients were ventilated utilising volume-controlled ventilation with a closed circuit to maintain an EtCO₂ level between 35 and 40 mm Hg. The timing of extubation was determined by neuromuscular surveil-lance (TOF watch).

The primary outcome was to compare the mean arterial pressure (MAP) between the two groups starting 40 minutes before induction and continuing every 10 minutes until induction and at the time of intubation, and then every minute afterwards until 5 minutes, 7 minutes and 10 minutes following intubation. Comparisons of heart rate, systolic and diastolic blood pressure, sedation, and other adverse effects were the second-ary outcomes.

During the study period, episodes of hypotension (MAP 20% of baseline), bradycardia (HR 50/min), and hypoxia (SPO₂ 90%) were recorded and treated accordingly.

Infusions of neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg) were administered intravenously to reverse neuromuscular block after surgery. After extubation, the patient was transferred to the recovery area. When the patient's Aldrete score was > 9, he was transferred to the ward and his vital signs were monitored for 12 hours.

A pilot study was conducted to ascertain the sample size based on the 15-mmHg standard deviation difference between the two groups post-intubation MAP. It was determined that 35 subjects per group were required to detect a 10-mmHg difference in MAP with 80% power and 5% type-1 error probability. The sample size calculation was performed by the nMaster 2.0 programme. [Biostatistics Department, CMC Vellore].

Statistica version 6 [Tulsa, Oklahoma: StatSoft Inc., 2001] and GraphPad Prism version 5 [San Diego, California: GraphPad Software Inc., 2007] were utilised for statistical analysis. Except for the Ramsay Sedation Score and SpO2 values, all numerical variables in the descriptive statistics were normally distributed (Kolmogorov-Smirnov goodness-of-fit test). The RSS score of 2 (awake, oriented, and cooperative) was deemed adequate for statistical analysis. Student's unpaired t-test for normally distributed data and Mann-Whitney U test for skewed data were used to evaluate comparisons of numerical variables between two groups. If the data were normally distributed, repeated measures analysis of variance (ANOVA) was followed by Tukey's test as a post hoc test; if the data were skewed, Friedman's analysis of variance (ANOVA) was followed by Dunn's test as a post hoc test. A P value of 0.05 was deemed statistically significant.

Results

A total of 70 patients were analysed. Consort flow diagram is shown in (Figure 1). All the demographic data on patient's characteristics like age, height, weight, BMI and sex were comparable between the two groups (Table 1). In both the groups, the HR was decreased from the baseline value during the preoper-ative period, but in Group D the decrease in the HR was more (19.75% at 30 min and 23.50% at 40 min) than in Group D (15.16% at 30min and18.18% at 40 min). During intergroup comparison, a statistically significant difference in HR was shown at 30 and 40 minutes after the study drugs administration (p-value of 0.044 and 0.015 respectively). None of the patients in both groups has clinically significant bradycardia (Table 2). At 40 min intervals, 57.1% of patients in the DIN group remain in RSS stage II, whereas 77.14% of patients in the D_IV group remain in RSS stage III, 77.14%. The D_IV group's preoperative sedation score before induction was significantly higher than the D group's (P = 0.014). SBP, DBP and MAP were gradu-ally decreased from baseline values from 20 min onwards in both the groups, but it was more prominent in IV group than IN group. During intergroup compari-son, they found no statistically significant difference. (Maximum decrease of SBP at 40 min 11.45% in Group D_in and 11.9% in Group D_IV. Similarly maximum fall of dBp at 40 min 12.28% in Group D_IN and 15.20% in Group D Maximum fall of MAP at 40 min for Group D_in14.8% and Group D_IV13.20% (Table 3). It was found that the maximal increase in HR and BP occurred during laryngoscopy and endotracheal intubation, and then it gradually came down to normal limits within 10 min in both groups. The maximal increase in heart rate was 23.7% in Group D and 20.84% in D during laryngoscopy and endotracheal intubation. During intergroup comparison, there was no statistically significant difference in HR was found during and up to 10 mins after intubation. (Table 4). Similarly, maximal increase in MAP occurred during laryngoscopy and endotracheal intubation, then it gradually came down to the normal limit within 10 min in both the group. The increase in MAP was 19% in Group D_IN compared to 12.5% for MAP in Gr D_IV during laryngoscopy and

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Figure 1:

Consort Diagram

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Discussion

This study demonstrates that intranasal DEX adminis-tered 40 minutes before intubation is as efficacious as intravenous DEX in reducing laryngoscopic stress re-sponses. In both groups, all hemodynamic parameters (HR, SBP, DBP, MAP) remain within the permissible range during the preoperative and intraoperative phases. Preoperative sedation was substantially greater in the D_IV group than in the D_IN group. Laryngoscopy and endotracheal intubation are the two most consistent procedures leading to significant in-crease in heart rate and blood pressure. This has been attributed to a sympathetic response as evidenced by in-creased circulating catecholamine levels.³ These changes are found to be greatest 60 seconds after intubation and may even last for 5-10 min post-intubation. The haemodynamic changes brought about by laryngoscopy were first described by Reid and Brace Proper use of premedication may decrease this stress response.⁴ Numerous pharmacological agents such as opioids (fentanyl), adrenergic blocking agents (esmolol), vasodilating agents (sodium nitroprusside), and local anaesthetics drugs (intravenous lidocaine) have been attempted to attenuate these haemody-namic effects, but none have been able to attenuate these responses completely.⁵ Due to its unique sedative, hypnotic, anxiolytic, sympatholytic, antisecretory, and analgesic properties, DEX is widely utilised in in-tensive care units. The presynaptic activation of α-2 re-ceptors in locus caeruleus inhibits noradrenaline re-lease and causes sedation and hypnosis. Post-synaptic activation of α-2 receptors in central nervous system decreases sympathetic activity leading to bradycardia and hypotension.

Dexmedetomidine, a centrally acting α 2 agonists, of-fers a unique pharmacological profile with sedation, sympatholysis, analgesia, cardiovascular stability and with greater advantage in avoiding respiratory depression.

All this characteristics of DEX are highly attributable as an ideal premedication agent.^6,7

Lakshmi et al found that Intranasal dexmedetomidine is a better premedication agent in morbidly obese patients than oral alprazolam.⁸ DEX can be administered via intravenous,⁹ intramuscular,¹⁰ intranasal,¹¹ and intraoral¹² routes. Intranasal administration is more con-venient because it is innocuous, odourless, and re-quires no intravenous infusion. Intranasal administration of a substance allows it to cross the blood-brain bar-rier and reach the central nervous system directly ¹³. Be-cause of the increased vascularity of the nasal mucosa, medications can gain rapid access to the venous blood of the systemic circulation, thereby bypassing first-pass metabolism in the liver.¹⁴

Various clinical studies with intravenous DEX show that IV DEX can effectively attenuate the stress responses.

Till now intravenous DEX is most popularly used as premedication. However, it is documented that the sed-ative effect of IV DEX is more pronounced than the anal-gesic effect, accompanied by profound bradycardia and hypotension. Moreover, IV DEX may induce biphasic MAP oscillations, which are undesirable in an-aesthesia.

A study by Bloor BC et al on intravenous Dexmedeto-midine¹⁵ revealed that in spite of mild hypercapnia and hypoventilation intravenous dexmedetomidine was use-ful in providing perioperative sedation and analgesia without significant respiratory depression.

A clinical study by Sebastian B. et al documented that 0.75 μg/kg is the optimal IV dose for attenuation of stress response to laryngoscopy and endotracheal intubation without any haemodynamic disturbances.¹⁶

There is some clinical studies where intranasal DEX has been administered as a premedication especially in paediatric patients. In a study, Yuen VM, et al.¹⁷ did a randomised comparison of two intranasal dexmedeto-midine doses (1 μg /kg and 2 μg /kg) as premedication in children. They concluded that both doses produced a similar level of satisfactory sedation in children with no adverse haemodynamic effects in any of the groups. In this study, to avoid any untoward side effects, we used the lower safe dose of 1 μ/kg.

Nasal premedication with midazolam and Dexmedeto- midine has also been studied as alternative to oral premedication with comparable results¹⁸ Intranasal route has been successfully used as a sedative in chil-dren for magnetic resonance imaging, CT scan and for burn dressing.¹⁹ Noon et al found Intranasal administration of 1.5 μg/kg atomized dexmedetomidine is effective, convenient, and safe as a sedative for patients un-dergoing third molar extraction.²⁰

A recent study by Iriola T et al,²¹ documented that the peak concentration of intranasal DEX was achieved with a median time range 38-45 min later. So, in our study, we administered intranasal DEX 40 mins before induction.

In our study, preoperative HR was gradually decreased in both groups of patients and this decrease was more in the IV group than intranasal group. A similar finding was found in a study by Cheung et al.²² In our study, in both the group preoperative SBP, DBP and MAP, all gradually decreased from baseline value up to 40 min after study medication. However, these de-creases were more marked in intravenous group than the intranasal group which was statistically significant differences. None of these patients, however, devel-oped clinically significant decreases that required vasopressor or anticholinergics support.

In our study, the maximal increase in HR, SBP, DBP and MAP were occurred during laryngoscopy and endotracheal intubation; then it gradually came down to the normal limit within 10 min in both the group. Though the intranasal group had slightly higher values of SBP, DBP and MAP, they were not statistically significant during intergroup comparison.

Conclusion

This study demonstrates that, dexmedetomidine ad-ministered intravenously is equally efficient as intranasal dexmedetomidine in attenuating hemodynamic response during laryngoscopy and intubation. Additionally, during the preoperative phase, intravenous dexmedetomidine induces higher sedation than intranasal method. To control haemodynamic re-sponse during laryngoscopy and endotracheal intubation, intranasal dexmedetomidine can be utilised as a safer alternative premedication in patients under-going general anaesthesia for lumbar spine surgery.