A Comparative Study of Intravenous Esmolol, Labetalol and Lignocaine in Low Doses for Attenuation of Sympathomimetic Responses to Laryngoscopy and Endotracheal Intubation.

BACKGROUND: Direct layngoscopy and endotracheal intubation is a noxious stimuli and induces sympathomimetic responses. Although well tolerated in healthy subjects, it may impose life threatening arrhythmias, left ventricular failure or rupture of cerebral aneurysm in susceptible patients. Esmolol, Labetalol and Lignocaine attenuate these responses but are associated with side effects of bradycardia, hypotension etc. In lower doses, chances of these side effects are comparatively low. So we designed this prospective clinical trial to assess the efficacy of intravenous esmolol, labetalol and lignocaine in low doses for attenuation of sympathomimetic responses to endotracheal intubation.
MATERIALS AND METHODS: Seventy-five consenting patients of ASA physical status I or II of age range 20 to 60 years, scheduled for different general surgical procedures were randomly assigned to one of the three groups; group ES, group LB and group LG. Participants of group ES, group LB and group LG was given esmolol HCL 0.5 mg/Kg, labetalol HCL 0.25 mg/kg and lignocaine HCL 1 mg/Kg body weight respectively. Outcome variables were HR, SBP, DBP, MAP and RPP. These variables were recorded just after intubation and thereafter at 1,3,5, 7 and 10 minutes of intubation.
RESULTS: There was no statistically significant difference regarding the demographic characteristics of the groups. Heart rate and systolic blood pressure was lower throughout the study period in labetalol group. But the values of study parameters were always higher than the baseline in esmolol and lignocaine group. Values of mean arterial pressure was slightly higher in labetalol group but it was much higher in two other groups throughout the study period. Diastolic blood pressure was higher in all the groups. Values of rate pressure product was higher during intubation and at 1minute after intubation in labetalol group but thereafter it was always lower than baseline values.
CONCLUSION: Labetalol 0.25 mg Kg-1 is an effective and safe drug to be used for attenuation of sympathomimetic responses to endotracheal intubation. Esmolol 0.5 mg Kg-1 and lignocaine 1 mg Kg-1 are also effective to some extent and are safe.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Direct laryngoscopy and endotracheal intubation frequently induces a cardiovascular stress response manifesting as hypertension, tachycardia, and increase in serum catecholamine.[1] This reflex hemodynamic changes are better tolerated in health, but they are greatly exaggerated and detrimental in patients with comorbidities.[234] In susceptible individuals, these hemodynamic stress responses can evoke life-threatening conditions such as left ventricular failure, myocardial ischemia, cerebral hemorrhage, and ruptured cerebral aneurysm etc.[5]

Intravenous (IV) lignocaine[678] has showed a promising result. The mechanism of IV local anesthetics appears to result from an increased threshold for airway stimulation and central inhibition of sympathetic transmission. Although increasing dose of lignocaine may lead to hypotension, bradycardia, and hypoxia. Esmolol is a cardio selective b1-blocker having rapid onset and short duration of action. It causes depressor effect on myocardium; therefore, its place still remains to be defined especially in cardiac risk patients. Labetalol, an α and β blocker, has also been found to be useful in preventing perioperative undesirable cardiovascular events,[9101112] but in higher doses, it may cause hypotension and bradycardia.

Here, originates in the rationale to continue the quest for an ideal anesthetic technique which is effective as well as safe to attenuate undesirable cardiovascular effects. Numerous efforts have been made to obtund these untoward reflexes by the use of various measures and drugs. Selection of a pharmacological adjunct is tricky because efficacy has to be weighed against its safety. All the three study drugs have shown their efficacy but in higher doses and only limited studies are available with low doses. Hence, this clinical study was carried out to evaluate the effects of IV esmolol HCl, lignocaine HCl, and labetalol HCl in low doses for attenuation of hemodynamic response to laryngoscopy and intubation.

Aim and objectives

The primary objectives of this study are:

To assess the hemodynamic changes during laryngoscopy (DL) and endotracheal intubation

To evaluate the efficacy of esmolol HCl, labetalol HCl, and lignocaine HCl in attenuating sympathomimetic response to laryngoscopy and endotracheal intubation

To compare and select best among the drugs in prevention of sympathomimetic response DL and endotracheal intubation

To observe any untoward, adverse, and beneficial effects.

MATERIALS AND METHODS

After approval of the institute ethical committee, this study was conducted by the Department of Anaesthesiology in G R Medical College and J A Group of Hospitals, Gwalior. Seventy-five consenting patients of age group 20–60 years of either sex and American Society of Anesthesiologists (ASA) Grade I or II scheduled for various general surgical procedures under endotracheal anesthesia were included in this study. Patients of ASA Grade III or more, pregnant and lactating women, morbid obesity, hypertension, and anticipated difficult intubation were excluded from the study.

Intervention plan and group allocation

Patients were blinded by sealed envelope technique and observer anesthesiologist was kept unaware of which drug was injected to which patient thus avoiding observer bias. The anesthesiologist who injected the study drugs took no further part in the study. Selected 75 patients were randomly divided into three groups depending on the study drug to be given:

Group ES: Injection esmolol HCl 0.5 mg/kg body weight diluted to 10 ml with 0.9% saline was given IV 5 min before intubation over 60 s

Group LB: Injection labetalol HCl 0.25 mg/kg body weight diluted to 10 ml with 0.9% saline was given IV 5 min before intubation over 60 s

Group LG: Injection lignocaine HCl 1 mg/kg body weight diluted to 10 ml with 0.9% saline was given IV 5 min before intubation over 60 s.

Preanesthetic assessment

All the selected patients were carried out with complete history, general examination, airway assessment, systemic examination along with routine blood investigations, chest X-ray, and electrocardiogram (ECG).

Premedication

All the patients were kept nil orally for at least 8 h before procedure. Tablet lorazepam 1 mg and tablet ranitidine 150 mg were given night before surgery. All the patients were uniformly premedicated with injection glycopyrrolate 0.2 mg intramuscular, 30 min before shifting to operation theater.

Anesthesia management

On arrival of patient in the operation theater, IV access with 18 gauge cannula was established and ringer lactate (RL) infusion was started. All patients were preloaded with 500 ml RL before starting induction. Noninvasive monitoring such as noninvasvie blood pressure, pulse oxymeter, 5 leads ECG were connected and basal pulse rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) were measured and recorded.

Study drug was given 5 min before intubation over 60 s. Thereafter, preoxygenation with 100% oxygen was started and general anesthesia was induced with injection fentanyl 2 μg/kg, injection thiopentone sodium up to 5 mg/kg body weight. After securing mask ventilation injection vecuronium bromide 0.1 mg/kg body weight administered IV to facilitate endotracheal intubation. Mask ventilation with 100% oxygen was continued for 3 or more min in order to time endotracheal intubation after 5 min of administration of study drugs. Laryngoscopy was done with Macintosh laryngoscope blade and trachea was intubated with appropriate sized endotracheal tube. Tube was secured after confirming bilateral equal air entry on auscultation. Intermittent positive pressure ventilation was started with tidal volume 8 ml/kg body weight and frequency suitable to maintain end-tidal carbon-di-oxide within normal range.

Anesthesia was maintained with 50% oxygen in air and isoflurane up to 1 minimum alveolar concentration with intermittent doses of fentanyl and vecuronium. After intubation (AI) till conclusion of surgery and reversal of anesthesia, both continual and continuous monitoring of vital parameters were done. Any bradycardia, that is, heart rate (HR) below 50 beats/min was treated with small aliquots of 0.3 mg of IV atropine. Fall in MBP below 60 mm of Hg was treated with small boluses of mephentermine 6 mg. The incidence of bradycardia and hypotension was noted. At the conclusion of surgery, residual effect of muscle relaxant was reversed with combination of glycopyrrolate 0.01 mg/kg body weight and Neostigmine 0.05 mg/kg body weight. Any complications which occurred perioperatively were noted.

Total duration of laryngoscopy was noted. Those cases where duration of laryngoscopy and endotracheal intubation was more than 20 s were excluded from the study and equal number of new cases were added to complete the study.

Outcome variables

HR, SBP, DBP, MAP and rate pressure product (RPP).

Frequency of data recordings

Readings of hemodynamic parameters were taken before starting study drug and was taken as basal value (BV) and then during laryngoscopy & endotracheal intubation (DL). Five more readings were recorded at 1(AI 1), 3(AI 3), 5(AI 5), 7(AI 7) and 10 (AI 10) minute after endotracheal intubation.

Statistical analysis

Sample size was calculated on assumption of 30% reduction in HR with study drugs and with power of 80% and 95% confidence level. The sample size came to be 22 in each group. Although there was no chance of the loss of follow up of cases, however 10% more subjects were added in each group. Hence, finally, there were 25 cases in each group. Statistical analysis was carried out using SPSS version 19 (SPSS, IBM, Chicago, IL, USA). The study data were presented as mean + standard deviation. Demographic data were analyzed with Chi-square test and independent t-test. For comparison of means between groups ANOVA statistical tool was used.

RESULTS

In the present study, all three study groups were comparable on demographic pattern such as age, weight, and sex [Table 1]. Basal hemodynamic variables such as mean HR, SBP, DBP, MAP and RPP [Tables 1–5] were also comparable between the groups (P > 0.05 insignificant).

Table 1

Demographic pattern of the study population

Table 5

Comparison of mean arterial pressure among different groups

The increase in mean HR was observed in all three groups but least in labetalol group [Table 2]. There was increase in SBP in group lignocaine and esmolol but not in labetalol group [Table 3]. DBP increased in all three groups almost similarly [Table 4]. Increase in MBP was similar in group ES and group LG and was higher than that in group LB [Table 5]. RPP in peri-intubation period was most stable in group LB [Table 6].

Table 2

Comparision of mean heart rate among different groups

Table 3

Comparison of mean systolic blood pressure among different groups

Table 4

Comparison of mean diastolic blood pressure among different groups

Table 6

Comparison of means rate pressure product among different groups

DISCUSSION

Our study showed a sudden increase in all the hemodynamic parameters up to variable extent DL and endotracheal intubation in different groups. Thereafter all hemodynamic variables started to fall throughout the study. These hemodynamic changes were reduced to varying degrees by all study drugs used but most effectively attenuated by labetalol. Esmolol does not effectively attenuate the hemodynamic response as compared to labetalol, but it is more effective than lignocaine in attenuating stress response to laryngoscopy and intubation.

The hemodynamic changes stemming from airway instrumentation are due to sympathoadrenal discharges caused by epipharyngeal and par pharyngeal stimulation.[13] This stimulation elicit physiological response in the form of sympatho-adrenal response seen in adults and vaso-vagal reflex predominantly seen in children.

Reid and Brace were the first to report the circulatory response to laryngeal and tracheal stimulation in anaesthetized man as tachycardia and increase in arterial blood pressure.[14] Takeshima et al. found rise in mean arterial pressure of 20 mmHg at the time of laryngoscopy and tracheal intubation and they concluded that laryngoscopy was a more potent stimulus to hypertension than intubation.[15]

In our study, we used 0.5 mg/kg of esmolol, given 5 min before intubation, which though attenuated the HR but showed significantly less effective attenuation as compared to labetalol group. The reason might be that both the drugs showed their maximum effect in 5 min and peak hemodynamic effects occurred within 6–10 min of administration[16] but esmolol had a shorter duration of action (elimination half-life of 9 min) as compared to labetalol (elimination half-life of 5–8 h). Even in study with esmolol 2 mg/kg as a bolus dose proved to be effective in attenuating increases in HR following laryngoscopy and intubation only and the rise in blood pressure was suppressed but not abolished.[17]

There was only slight and statistically insignificant increase in SBP in labetalol group at 1 min AI [Table 3]. Thereafter up to 10th min of intubation SBP was significantly lower than baseline values. Contrary to labetalol group in other two groups SBP was significantly higher at DL and intubation, and remained higher till 10th min of study period. Hence, comparison of labetalol with esmolol and lignocaine, labetolol was found to be more efficacious than esmolol and lignocaine in attenuating the SBP response to laryngoscopy and intubation.

Esmolol is a β1 (cardioselective) adrenergic receptor blocking agent with no action on peripheral vasculature whereas labetalol is selective α1 and nonselective β1 and β2 adrenergic receptor blocking agent, it lowers the systemic blood pressure by decreasing systemic vascular resistance (α1 action) and also controls reflex tachycardia triggered by vasodilatation by β blockade. It also has weak β2 agonistic activity therefore may cause vasodilatation. Cardiac output remains unchanged.[16] Lignocaine practically has minimal hypotensive and no vasodilating properties. Thus, the change in mean SBP was most effectively attenuated by labetalol followed by esmolol, whereas lignocaine showed least attenuation effect among the three study drugs.

In our study, the rise in DBP was not significantly attenuated (P < 0.05) by esmolol and lignocaine, whereas labetalol showed statistically significant attenuation at least up to 3 min [Table 4]. The reason might be that our study drugs esmolol, labetalol, and lignocaine are not very effective in controlling DBP rise. It is stated in the pharmacology of labetalol that “Increase in SBP rise during exercise are reduced by labetalol but corresponding changes in DBP are essentially normal. Esmolol also has more effect on SBP than on DBP.[1819]

Labetalol found to be more efficacious than esmolol in attenuating the mean arterial pressure response to laryngoscopy and intubation. However, this effect was not observed at DL and immediately thereafter. However, grossly the change in mean arterial pressure was most effectively attenuated by labetalol, followed by esmolol, while lignocaine showed least attenuation effect among the three study drugs.

Our results concurred with the study of Bensky et al.[20] they found that esmolol at dose of 0.2 mg/kg and 0.4 mg/kg resulted in 21.7% and 11.1% increase in mean arterial pressure immediately after laryngoscopy and endotracheal intubation. Whereas, the increase in mean arterial pressure was 27% in control group. Ergonenc et al. also showed that esmolol or lignocaine 1.5 mg/kg were not superior to each other in suppression of hemodynamic response to intubation.[21]

RPP is an index of myocardial oxygen consumption.[22] It is the product of SBP and HR. Values in excess of 15,000 are considered critical. Increase in RPP due to increase in HR is potentially more deleterious than that due to increase in blood pressure.[2324] In our study, in group LB RPP never exceeded critical 15,000 mark. Thus the change in mean RPP was most effectively attenuated by labetalol, followed by esmolol, whereas lignocaine showed least attenuation effect among the three study drugs.

In a recent study by Kewalramani et al., on comparison of labatelol with dexmedetomidine, dexmedetomidine better attenuated the sympathomimetic responses to endotracheal intubation. Although labetalol had maintained the stability of the blood pressure, HR response was not attenuated better DL and intubation.[25]

Esmolol was found less effective for attenuation of hypertensive response to laryngoscopy and intubation than dexmedetomidine in neurosurgical patients.[26] Neither pressure nor HR response was attenuated by esmolol.

Bradycardia was observed in one patient in esmolol group. Two patients of labetalol group had hypotension. Bradycardia was treated with injection atropine 0.3 mg and for treatment of hypotension injection mephentermine 6 mg IV was given. These three cases were excluded from the study. Moreover, three other patients were recruited to complete the study.

With both intra- and inter-group comparison, labetalol found to be better for the attenuation of HR, SBP, DBP, mean arterial pressure, and RPP during and after laryngoscopy and endotracheal intubation. The hemodynamic parameters were relatively more stable in labetalol group intraoperatively as compared to esmolol and lignocaine.

CONCLUSION

Laryngoscopy and endotracheal intubation is invariably associated with increase in hemodynamic variables. Labetalol 0.25 mg/kg is an effective and safe drug to be used for attenuation of sympathomimetic responses to endotracheal intubation. Esmolol 0.5 mg/kg and lignocaine 1 mg/kg are also effective to some extent and are safe.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.