Prospective Randomized Study Comparing the Usefulness of Dexmedetomidine versus Esmolol in Blunting Hemodynamic Responses to Intubation in Surgical Patients.

Background: Sympathetic response due to laryngoscopy and endotracheal intubation though transient, could be life-threatening in patients with underlying cardiovascular diseases. Aim of the Study: The aim of this study is to assess the effects of dexmedetomidine and esmolol on the hemodynamic response to laryngoscopy and endotracheal intubation in patients undergoing general anesthesia for elective surgery. Settings and Design: Prospective, randomized study conducted in a tertiary care center. Materials and
Methods: Sixty patients were recruited and randomly divided into two groups. Group A received 0.5 mcg.kg-1 dexmedetomidine and Group B 0.5 mg.kg-1 esmolol infusions over 10 min. All patients were induced with propofol 2 mg.kg-1 followed by succinylcholine 2 mg.kg-1 and intubated. The heart rate (HR) and mean arterial pressure (MAP) were recorded at different time points. Statistical Analysis Used: Chi-square test, independent sample t-test, and paired t-test.
Results: Baseline HR was statistically different in both groups. There was significant decrease in percentage change in baseline HR in Group A compared to Group B at preinduction (20.44% ± 10.82%, 13.63% ± 11.84%), before intubation (23.49 ± 12.62, 13.95 ± 14.86), and 7 min after intubation (14.65 ± 12.62, 6.80 ± 16.11). Percentage change in HR remained comparable in all other time points. Baseline MAP was comparable between the groups. Percentage change from baseline of MAP was significantly higher in Group B before intubation. All other time points MAP were comparable. The incidence of hypotension was comparable in both groups. Conclusions: Both dexmedetomidine and esmolol suppressed the hemodynamic response to laryngoscopy and intubation, but dexmedetomidine was more effective than esmolol in maintaining hemodynamic stability. Copyright:

INTRODUCTION

The hemodynamic responses to laryngoscopy and intubation are attributed to the sympathetic stimulation and subsequent catecholamine release. The resultant tachycardia and hypertension are transient in nature, reach peak values at 1–2 min, and return to baseline in 5–10 min of intubation. This may not be clinically significant in healthy individuals, but in patients with underlying cardiovascular disease, it may develop life-threatening complications.[1]

A variety of nonpharmacological and pharmacological strategies have been investigated to reduce the stress response by acting at various levels of the autonomic reflex system that modifies the hemodynamic responses.[2] Attenuation of the sympathetic response has been achieved using alpha agonists such as dexmedetomidine, which is a highly selective and specific α2 agonist.[34] Esmolol is a fast-acting, short-acting, water-soluble, and cardioselective beta-blocker used to blunt sympathetic activation during procedures such as laryngoscopy and endotracheal intubation. None of the strategies or agents has proven to be ideal. As a result, the search for an ideal agent, optimal dose, and administration method to decrease hemodynamic responses is still ongoing.

The primary objective of the present study was to compare the percentage change in heart rate (HR) from baseline following premedication with dexmedetomidine versus esmolol after intubation in patients undergoing surgical procedures. The secondary objectives included the comparison of changes in mean arterial pressure (MAP), incidence of hypotension, and interventions required to correct hypotension or bradycardia.

MATERIALS AND METHODS

The present study was an open-labeled randomized control trial conducted after obtaining approval from the Institutional Ethics Committee (IEC-AIMS-2020-ANES-048 dated May 11, 2020) and was registered in the Clinical Trials Registry India (CTRI/2020/06/025700). Informed consent was obtained from all patients for participation and the use of patient data for educational and research purposes. The study was designed in accordance with the ethical standards of the Declaration of Helsinki.

Sixty patients aged 20–80 years of the American Society of Anesthesiologists Physical Status (ASA PS) Classes I and II were included in the study. Those with anticipated difficult airway, history of asthma or chronic obstructive pulmonary disease, pheochromocytoma, thyrotoxicosis, hypothyroidism, and those on rate-controlling drugs were excluded from the study. As there were no studies which compared similar doses of test drugs, a pilot study was initiated with 10 patients in each group. Based on the mean and standard deviation of percentage change of HR from baseline to 1 min after laryngoscopy and intubation between dexmedetomidine (12.35% ± 17.45%) and esmolol (−2.145% ± 18.74%), with 95% confidence interval and 80% power, the minimum sample size was calculated as 25. We recruited 30 cases in each group with a total of 60 cases during the 1-year study.

All patients had undergone a detailed preanesthesia checkup and were kept nil per oral night before surgery (6 h for solids and 2 h for clear fluids). They were orally premedicated with alprazolam 0.25 mg on the night before surgery along with pantoprazole 40 mg and metoclopramide 10 mg on the night before and on the morning of the day of surgery. Patients were randomly allotted to either Group A or B based on computer-generated random sequence of number. Allocation concealment was ensured by sequentially numbered opaque sealed envelopes.

Intravenous access was obtained after shifting to the operation theater, and they were hydrated with intravenous Ringer lactate (RL) 10 mL.kg− 1. Standard preinduction monitors including pulse oximeter, noninvasive blood pressure, and electrocardiography were attached and baseline values were recorded. Patients in Group A received dexmedetomidine 0.5 μg.kg− 1 body weight diluted in 20 mL saline as infusion over 10 min before induction. Patients in Group B received esmolol 0.5 mg.kg−1 body weight diluted in 20 mL saline as infusion over 10 min before induction.

During infusion midazolam (0.05 mg.kg−1) and as aliquots of fentanyl (2 μg.kg−1) were given. Following preoxygenation for 3 min, each patient was induced as per the standard protocol with propofol (2 mg.kg−1 body weight). Neuromuscular blockade to facilitate orotracheal intubation with the appropriate sized cuffed tube was achieved using succinylcholine 2 mg.kg−1. After 1 min, a quick and gentle laryngoscopy lasting <15 s was performed and intubation was done with endotracheal tube (ETT) of internal diameter 7.0 mm for females and 8.0 mm for males. After intubation, the appearance of end-tidal carbon dioxide waveforms and bilateral air entry were confirmed and ETT was fixed.

Patients were mechanically ventilated with a tidal volume of 8 mL.kg−1 and respiratory rate of 12–15 per min to maintain end-tidal carbon dioxide between 30 and 35 mmHg. Anesthesia was maintained with oxygen: air mixture (1:1) and 0.7%–1% end-tidal isoflurane and aliquots of cisatracurium (0.03 mg.kg−1) as and when required. HR and MAP were monitored and recorded at baseline, preinduction, and before intubation. Then the same parameters were noted at 1, 4, 7, and 10 min after intubation also.

HR <45 beats per min was considered bradycardia and was managed with atropine 0.6 mg intravenously. MAP <60 mmHg was considered hypotension and was initially managed with 250 mL RL fluid bolus followed by ephedrine (not exceeding 0.5 mg.kg−1) or phenylephrine (not exceeding 10 μg.kg−1). The incidence of hypotension/bradycardia, total number of fluid blouses and vasopressor used were also noted.

Statistical analysis

Categorical variables were expressed using frequency and percentage. Numerical variables were represented using mean and standard deviation. Statistical significance of the association of categorical variables was done using the Chi-square test. Using independent t-test, the continuous variables of both groups were compared. Paired t-test was used to test the statistical significance in the change in mean values from baseline within the group. Statistical analysis was performed using SPSS version 20.0 for windows (IBM Corporation Armonk, NY, USA).

RESULTS

Data of 60 patients were analyzed [Figure 1]. The mean age, weight, distribution of gender, and ASA PS were comparable in both groups. The baseline HR was significantly different in both groups (79.53 ± 9.97, 88.03 ± 16.30, P = 0.018). Hence, the percentage changes from baseline were analyzed between the groups. The percentage change of HR from baseline when compared between the groups showed a statistically significant increase in percentage at preinduction (20.44% ± 10.82 vs. 13.63% ± 11.84%), before intubation (23.49% ± 12.62% vs. 13.95% ± 14.86%), and 7 min (14.65% ± 12.62% vs. 6.80% ± 16.11%) after intubation in Group A (P < 0.05), whereas the percentage change was comparable between both groups at 1, 4 and 10 min after intubation [Table 1].

Figure 1

CONSORT flow diagram

Table 1

Comparison of percentage change of heart rate from baseline

Time	Mean (%)±SD		P
	Group A	Group B
Preinduction	20.4±10.8	13.6±11.8	0.044
Before intubation	23.4±12.6	13.9±14.8	0.009
Maximum HR during intubation	9.2±13.2	2.1±16.2	0.066
1 min postintubation	13.6±14.0	5.6±15.9	0.053
4 min	13.5±15.4	7.7±16.8	0.132
7 min	14.6±12.6	6.8±16.1	0.044
10 min	15.6±12.4	6.4±18.0	0.066

SD: Standard deviation, HR: Heart rate

Intragroup analysis in both groups showed that there was a statistically significant reduction in mean HR from baseline at all-time points except the maximum HR at laryngoscopy which was not statistically significant in Group B [P < 0.05, Table 2]. Baseline mean MAP was comparable between the groups (101.5 ± 13.8 vs. 98.2 ± 12.7). The percentage change of MAP from baseline when compared between the groups, showed a statistically significant increase before intubation in Group B (P < 0.05), whereas the percentage change remained comparable in both groups at all other time points [Table 3]. Intragroup analysis in both groups showed that there was a statistically significant reduction in mean MAP from baseline at all-time points [P < 0.05, Table 4].

Table 2

Changes in heart rate from baseline in each group

Time	Mean±SD	P
Comparison of HR with baseline in Group A
Preinduction	16.8±9.9	<0.001
Before intubation	19.4±11.4	<0.001
Maximum HR during intubation	8.2±10.9	<0.001
1 min postintubation	11.8±12.2	<0.001
4 min	11.7±12.6	<0.001
7 min	12.4±10.9	<0.001
10 min	13.2±10.8	<0.001
Comparison of HR with baseline in Group B
Preinduction	12.7±11.3	<0.001
Before intubation	13.4±13.9	<0.001
Maximum HR during intubation	3.6±14.7	0.188
1 min postintubation	6.6±14.6	0.020
4 min	8.5±16.1	0.007
7 min	7.7±16.0	0.014
10 min	7.3±17.0	0.025

SD: Standard deviation, HR: Heart rate

Table 3

Comparison of percentage change of mean arterial pressure from baseline

Time	Mean (%)±SD		P
	Group A	Group B
Preinduction	11.6±11.0	16.8±12.5	0.107
Before intubation	17.2±9.9	26.1±11.7	0.002
1 min postintubation	10.8±11.4	9.9±18.7	0.859
4 min	16.2±11.0	17.4±12.7	0.416
7 min	15.3±10.8	18.8±16.1	0.064
10 min	18.2±9.9	17.3±15.0	0.912

SD: Standard deviation

Table 4

Changes in mean arterial pressure from baseline in each group

Time	Mean±SD	P
Comparison of MAP with baseline in Group A
Preinduction	11.3±10.4	<0.001
Before intubation	16.6±9.6	<0.001
1 min postintubation	10.4±10.9	<0.001
4 min	15.6±10.9	<0.001
7 min	14.5±10.6	<0.001
10 min	17.4±10.2	<0.001
Comparison of MAP with baseline in Group B
Preinduction	16.9±13.0	<0.001
Before intubation	25.7±13.3	<0.001
1 min postintubation	10.9±18.0	0.002
4 min	17.6±13.5	<0.001
7 min	18.9±16.2	<0.001
10 min	17.7±15.8	<0.001

SD: Standard deviation, MAP: Mean arterial pressure

No incidence of bradycardia and hypertension was noted in both groups. Two patients in Group A and three patients in Group B developed hypotension during the study [Table 5] which was managed with intravenous (IV) fluid bolus and phenylephrine. There was one case of bronchospasm in the esmolol group for an obese patient with no other comorbidities and no history of reactive airway.

Table 5

Incidence of hypotension between the groups

	Yes, n (%)	No, n (%)	P
Group A (n=30)	28 (93.3)	2 (6.7)	0.589
Group B (n=30)	27 (89.7)	3 (10.1)

DISCUSSION

Multiple drugs such as opioids,[5] lignocaine,[6] α and β adrenergic blockers,[4] vasodilator agents,[7] and drugs inhibiting sympathoadrenal response have shown to blunt hemodynamic response due to tracheal manipulation.[8]

In this study, one of the most frequently used β-blocker, esmolol, was compared against a relatively newer drug, dexmedetomidine, an alpha-adrenergic agent to control stress response caused by hemodynamic reflex during laryngoscopy and intubation. Along with blunting the hemodynamic response to endotracheal intubation, dexmedetomidine also lessen myocardial ischemia during surgery. Esmolol has shown to attenuate the positive chronotropic and inotropic effects of increased sympathetic activity during laryngoscopy, thereby minimizing the increase in HR and myocardial contractility.

Hypotension and bradycardia during the loading period are the most prevalent dose-dependent adverse events of both esmolol and dexmedetomidine. Previous research had shown that lower loading dose along with slower infusion rate reduces inadvertent cardiovascular effects.[9101112] Because of these concerns, we used dexmedetomidine 0.5 μg.kg−1 and esmolol 0.5 mg.kg−1 as a slow infusion over 10 min and therefore observed consistent and reliable hemodynamic stability with no serious side effects. These observations were in agreement with the results of previous studies by Singh et al.[13] and Sulaiman et al.[910]

In our study, it was observed that baseline values of HR in both groups were significantly different (P < 0.05). Therefore, we found out the percentage difference of HR at various periods from baseline. We observed, dexmedetomidine produced more reduction in HR than esmolol in all-time points clinically, but statistically significant reduction was obtained only at preinduction, before intubation, and at 7 min. Similar result was seen in a study conducted by Varshney et al.[14] Group B showed a significant reduction in MAP before intubation than Group A which was not found in many earlier studies.[13] In both groups, the reduction in MAP was comparable at all-time points. However, the need for intervention for hemodynamic variations remained similar in both groups. The comparable requirement of vasopressors in both groups in our study could be due to the use of a lower dose and adequate hydration before test drug administration and slower administration of the drugs.

In our study, we observed that there was approximately 10%–25% reduction in blood pressure postintubation with dexmedetomidine and esmolol. Similar results were observed by Varshney et al.[14] However, while both drugs reduced HR, dexmedetomidine was able to attenuate the response to intubation more effectively and maintained the HR under control during the study, whereas esmolol had only modest control over the HR.

Although esmolol showed a moderate attenuation of the hemodynamic response in terms of blood pressure control, it failed to give good control over HR in the current study. One possible explanation for this is that we used a low dose of esmolol in our study. This could be explained by the delayed reduction in HR which was preceded by reduction in blood pressure by esmolol.[15] As the hemodynamic reflex to laryngoscopy and intubation is a transient response, it is important to use short-acting drugs which could control HR and blood pressure effectively.

The major limitations in our study were the trial was an open-label study. Among the hypertensives, only patients on beta-blockers and calcium channel blockers were excluded from the study. Although all intubations were done by experienced anesthesiologists, subjective variations were possible.

CONCLUSIONS

It is concluded that dexmedetomidine when administered before induction of general anesthesia is superior to esmolol in attenuating the hemodynamic responses to laryngoscopy and intubation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.