Comparative efficacy of oral gabapentin versus melatonin for attenuation of haemodynamic response to direct laryngoscopy and endotracheal intubation

Introduction: Several drugs have been tried and used to attenuate the haemodynamic response to direct laryngoscopy and endotracheal intubation. In this study, we have compared the efficacy of Gabapentin and Melatonin, an endogenous hormone, in attenuating the haemodynamic response to direct laryngoscopy and endotracheal intubation. Materials and Methods: 60 patients of ASA physical status I and II scheduled to undergo elective surgeries were randomly allocated to three groups: the Control group, Melatonin group and Gabapentin group. Placebo, 6mg melatonin, or 300mg gabapentin respectively were administered orally to the patients in the three groups 120min before surgery. Pre-operative anxiety score, induction dose of propofol and the patient’s heart rate and blood pressure were recorded. The haemodynamic parameters were recorded every minute for 5 minutes after intubation and then at 10 and 15min after intubation. Results: Patients in the study groups were found to have significantly reduced pre-operative anxiety scores and dose of propofol required for induction was also significantly lower than control. Heart rate was found to be significantly lower in the study groups at all time points. Systolic blood pressure was significantly lower in the study groups at 1, 2, 3, 4, 10 and 15min after intubation. Diastolic and Mean blood pressures were significantly lower in the study groups at 1 and 2min after intubation. Post-hoc tests showed no significant differences between the two study groups. Conclusion: Both melatonin and gabapentin are effective in attenuating the haemodynamic response to direct laryngoscopy and endotracheal intubation. Both drugs are also effective in reducing pre-operative anxiety and also reduce the induction dose of propofol. © 2020 Published by Innovative Publication. This is an open access article under the CC BY-NC license (https://creativecommons.org/licenses/by-nc/4.0/)


Introduction
Direct laryngoscopy and endotracheal intubation are very potent noxious stimuli. They provoke adrenergic responses leading to marked increases in heart rate and blood pressure. This puts a strain on the heart and is especially detrimental in patients who have diagnosed or undiagnosed Coronary Artery Disease. Several drugs have been found to be useful in attenuating the haemodynamic response to intubation. But the search is still on for a drug which can give consistent results with minimum side effects.
Gabapentin was introduced as an antiepileptic but proved to be effective in controlling neuropathic pain. The drug is well tolerated with limited side-effect. 1 More recently gabapentin has been used in randomized controlled trials to treat acute postoperative pain and to reduce the postoperative opioid requirements. 2 While using gabapentin as premedication for patients undergoing elective surgeries, it was noticed that these patients were also haemodynamically stable. Subsequently, studies have demonstrated that gabapentin attenuates the pressor response to direct laryngoscopy and endotracheal intubation. 3,4 Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone secreted by the pineal gland. Exogenous administration of melatonin facilitates sleep onset and improves the quality of sleep. Melatonin is a safe drug with minimal side effects and is classified under the heading of "dietary supplement". Melatonin administered pre-operatively has been found to reduce anxiety in patients undergoing surgery. 5,6 Attenuation of haemodynamic responses to endotracheal intubation 7,8 and reduction of induction dose of propofol 9 with preoperatively administered melatonin has been demonstrated in recently published studies.
We decided to compare the effects of gabapentin and melatonin pre-medication on the haemodynamic response to direct laryngoscopy and endotracheal intubation.

Materials and Methods
After obtaining Institutional Ethical Committee Approval, patients were enrolled for this study. The study was done in 60 patients who were randomly allocated to three groups using a computer generated random number

Preparation and procedure 2.3.1. Preoperative
Routine preoperative assessment was done as for all elective surgeries. Patients were explained about the study in their own language and written informed consent to participate in the study was obtained. 2 hr before the start of surgery, the patient was administered the oral pre-medication according to his/her group allocation. Patients in group C were administered placebo, those in group M were administered tab. Melatonin 6mg, and those in group G were administered tab. Gabapentin 300mg. The tablets were kept in identical opaque envelopes labelled only with the study number and were administered by the pre-operative room nurse. The patient, the anaesthesiologist conducting the case and the investigator conducting the study were unaware of the group allocation of the patients.
The pre-operative anxiety score of the patient was recorded using the VAS Anxiety scale 10 2 hours after administration of the study drug.

Intraoperative
Routine monitoring was done with ECG, pulse oximetry and NIBP. Baseline HR and Blood Pressure were noted (systolic, diastolic and mean).
Venous access was secured with an 18G venous canula. All patients received preloading with 500ml of Ringer Lactate before induction of anesthesia. Inj fentanyl 2µg/kg intravenously was administered to all patients.
After pre-oxygenating with 100% oxygen for 4 mins, induction of anaesthesia was started with inj. Propofol (10mg/ml). Propofol was administered 20mg every 15 sec till anaesthesia was induced. The end point of induction was taken as loss of verbal contact. Thereafter, after checking the adequacy of mask ventilation, inj Atracurium 0.5mg/kg was administered for achieving neuromuscular blockade. Patient's lungs were ventilated with 33% oxygen in nitrous oxide through face mask for 4min before intubation.
Intubation was done using Macintosh laryngoscope. Portex cuffed endotracheal tube size 7.0mm ID was used for female patients and size 8.0mm ID for male patients. Heart rate and blood pressure were recorded after induction, and every 1 min for 5 min and at 10 and 15 min after intubation.

Observations and Results
The Normality of the variables was tested with the Shapiro-Wilk test /Kolmogorov Smirnov tests of normality. ANOVA followed by Post Hoc Multiple Comparisons test were carried out for comparisons of Normally distributed data. Group comparisons of values of skewed data were made with Kruskall Wallis test. Categorical variables were compared using the Chi-Square test or Fisher's exact test. A p-value < 0.05 was considered significant. All the statistical tests were two-sided and were performed at a significance level of α = 0.05. Analyses were conducted using IBM SPSS STATISTICS (version 22.0).
There was no statistically significant difference observed in the patients of the three groups with respect to Age, Sex Distribution, Weight and ASA Physical Status.
There was a significantly reduced Anxiety Score (pvalue <0.001) observed in the study groups compared to the control group. Post-hoc test showed no difference between the two study groups.
Induction dose of Propofol (mg/kg) was found to be significantly reduced (p-value 0.001) in the study groups compared to the control group. Post-hoc test showed no difference between the two study groups.
Heart rate was found to be significantly lower at all time points, namely baseline, post-induction, post-intubation     1min, 2min, 3min, 4min, 5min, 10min and 15min in the study groups as compared to the control group. Also, posthoc test showed that patients in the Melatonin group had lower heart rates than the Gabapentin group at all time points after intubation.
The baseline and post-induction Systolic Blood Pressures were comparable in the three groups. The study groups were found to have significantly lower Systolic Blood Pressures at 1, 2, 3, 4, 10 and 15 min after intubation. Post-hoc test did not show any difference between the two study groups.
Diastolic Blood Pressure was comparable in the three groups at Base-line and post-induction. At 1 min and 2 min post-intubation, there was a significantly lower Diastolic Blood Pressure in the study groups. There was, however, no difference between the two study groups.
The three groups had comparable Mean Blood Pressures at Base-line and post-induction. At 1 min and 2 min postintubation, there was a significantly lower Mean Blood Pressure in the study groups. There was, however, no difference between the two study groups.

Discussion
Fassoulaki et al 3 studied the effect of gabapentin premedication on the pressor response to direct laryngoscopy and tracheal intubation. Gabapentin in the dose of 1600 mg at 6 hourly intervals starting the day (noon) before surgery was found to attenuate the pressor response but not the tachycardia associated with laryngoscopy and tracheal intubation. In our study, Gabapentin attenuated both the tachycardia as well as the hypertension associated with laryngoscopy and tracheal intubation. Memis et al 4 compared the effects of gabapentin on arterial pressure and heart rate at induction of anaesthesia and tracheal intubation in a randomized double-blind study. They concluded that given 1 h before operation, gabapentin 800 mg blunted the arterial pressure and heart rate increase due to endotracheal intubation. These results are consistent with those of our study. In our study, the reduction in heart rate was found to be more significant with both melatonin and gabapentin pre-medication.
Gupta et al 7 studied the role of melatonin in attenuation of haemodynamic responses to laryngoscopy and intubation. Melatonin in the dose of 6mg given 120min before surgery was found to be an effective drug for attenuation of cardiovascular responses to laryngoscopy and endotracheal intubation. These results are consistent with those of our study.
Mohamed et al 8 studied the effects of melatonin premedication on the hemodynamic responses and perfusion index during laryngoscopy and endotracheal intubation. Melatonin in the dose of 6mg or 9mg given 1 hr before surgery was found to significantly decrease the hemodynamic parameters and perfusion index in response to direct laryngoscopy and endotracheal intubation. In this study, patients receiving melatonin were also found to have lower preoperative anxiety scores. These results are consistent with those of our study where we have found significantly reduced pre-operative VAS anxiety scores in patients receiving melatonin or gabapentin, when compared to placebo.
In a study done by Turkistani et al, 9 melatonin premedication, in an oral dose of either 3 or 5 mg, reduced the required dose of propofol to achieve a BIS score of 45, reflecting a sufficient level of hypnosis for tracheal intubation without prolongation of postoperative recovery room stay. In our study, the induction dose of propofol was found to be significantly reduced in patients receiving both melatonin and gabapentin.

Source of Funding
None.

Conflict of Interest
None.