laryngoscopy and endotracheal intubation are considered potent noxious stimuli which provoke haemodynamic responses leading to a marked increase in heart rate and blood pressure . however , these events are especially detrimental in individuals who have limited myocardial reserve due to coronary artery disease , cardiac dysrhythmias , congestive heart failure , hypertension , cardiomyopathy and geriatric age group . hence , it is mandatory to take measures to attenuate these pressor responses . the mechanisms of these haemodynamic alterations are somatovisceral reflexes due to sympathetic stimulation . during intubation of trachea , the laryngeal and tracheal sensory receptors are stimulated which result in the release of endogenous catecholamines resulting in tachycardia and hypertension . since the invention of laryngoscopy and endotracheal intubation , various drug regimens and techniques have been used from time to time to attenuate these stress responses . some of such agents being opioids ( fentanyl , alfentanil ) , calcium channel blockers ( verapamil , diltiazem ) , sympatholytics ( clonidine , dexmedetomidine and methyldopa ) , beta blockers ( esmolol , propranolol ) , benzodiazepines ( midazolam , alprazolam ) , barbiturates , propofol , pregabalin and peripheral vasodilators ( sodium nitroprusside , nitroglycerine ) . however , each agent has some limitations such as respiratory depression , hypotension , tachycardia , bradycardia , rebound hypertension or allergic reactions . melatonin ( n - acetyl-5-methoxytryptamine ) is an endogenous sleep - regulating hormone secreted by pineal gland . it is different from benzodiazepines and their derivatives in that it produces natural sleep pattern and does not lead to impairment of cognitive functions . various researchers have used this drug in different dose patterns as premedication in both adults as well as children . it has been mainly studied in view of pre - operative anxiolysis , sedation in intensive care unit , pre - operative cognitive and psychomotor functions . we assumed that its inhibitory actions on central nervous system responsible for sedation and anxiolysis may have role in attenuating haemodynamic responses to laryngoscopy and intubation . based on this , we made a hypothesis that melatonin can provide haemodynamic stability during laryngoscopy and intubation when given 120 min before the procedure . the primary objective was to study the changes in blood pressure during laryngoscopy and intubation . this prospective randomised double - blind study was conducted after obtaining permission from the hospital ethical committee and informed patient consent . group m ( melatonin group ) received oral melatonin tablets 6 mg ( two tablets of 3 mg each ) , administered 120 min before surgery . each patient received either drug based on the generated list in a thick opaque , similar looking envelope by the pre - operative nurse . vitamin d3 tablets were used as placebo and looked similar to melatonin tablets . moreover , the study drugs were administered by nurse in the pre - operative area , and she was unaware of the study . inclusion criteria were patients belonging to the american society of anesthesiologists ( asa ) physical status grade i and ii , age 2045 years of either gender and surgery requiring general anaesthesia for duration longer than 30 min . exclusion criteria were diabetes , hypertension , psychiatric illness , intake of antipsychotics , sedatives , anxiolytics and antiepileptic drugs ; sleep disorders , obesity and drug allergy . likewise , patients with anticipated difficult intubation and those requiring more than one attempt or more than 20 s for laryngoscopy were excluded from the study . the pregnant and lactating females were also excluded from the study . in the pre - operative room , the study drugs were administered with a sip of water 120 min before surgery . continuous monitoring of the pulse rate , respiratory rate , blood pressureand arterial oxygen saturation ( spo2 ) was done in the pre - operative period at an interval of 5 min by the nurse posted in the pre operative room . on receiving the patient in the operation theatre , routine monitoring was commenced which included heart rate , electrocardiogram , arterial spo2 , non - invasive blood pressure ( nibp ) and end - tidal carbon dioxide ( etco2 ) . induction was attained with intravenous propofol 2 mg / kg intravenously mixed with preservative - free lignocaine hydrochloride . succinylcholine was given intravenously 2 mg / kg to facilitate endotracheal intubation with proper sized well - lubricated cuffed endotracheal tube by the same person each time . maintenance of anaesthesia was attained with inhalation of isoflurane 1 minimum alveolar concentration ; nitrous oxide : oxygen 40:60 . muscle relaxation was attained with vecuronium bromide administered in the dose of 0.060.08 mg / kg intravenously as loading dose and one - fourth of the initial dose as maintenance doses . intravenous infusion of injection diclofenac sodium 75 mg was administered slowly 15 min before completion of surgery for post - operative analgesia . after completion of the surgery , neostigmine 50 g / kg and injection glycopyrrolate 10 g / kg were administered intravenously to reverse the residual neuromuscular blockade . haemodynamic parameters such as heart rate : systolic , diastolic and mean blood pressures were recorded before the administration of drug ( baseline ) , 120 min after administration of study drug ( just before induction ) , immediately after induction , at laryngoscopy and intubation , just after laryngoscopy and intubation and at 1 , 3 , 5 and 10 min thereafter . in the post - anaesthesia care unit , the patients received the standard post - operative care including oxygen administration via face mask at 46 l / min and monitoring of heart rate , nibp , respiratory rate and spo2 . we observed for any episodes of nausea , vomiting , dizziness , headache , respiratory depression , arrhythmias , bradycardia , hypotension and restlessness till 24 h postoperatively . the primary outcome was maintenance of systolic blood pressure within 10% of baseline values at laryngoscopy and intubation . the secondary outcomes were minimal respiratory depression ( spo2 < 90% , respiratory rate < 12/min ) , bradycardia ( heart rate < 20% of baseline ) and hypotension ( systolic blood pressure < 20% of baseline ) in the post - operative period . ratio and interval scale data were summarised as a mean and standard deviation , whereas nominal scale data as ratio and proportions . nominal scale data were analysed using fisher 's exact test , whereas unpaired t - test was used for between - group comparison of ratio and interval scale data . for within - group comparison of ratio and interval scale data , repeated - measures anova and post hoc bonferroni t - tests were used . as the bonferroni 's test is very conservative post hoc test , the conventional p < 0.05 was selected even for multiple comparisons . sample size was calculated at 80% study power and alpha error of 0.05 assuming a standard deviation of 6.5 mmhg in systolic blood pressure after 2 h of 6 mg melatonin per oral administration as per results of pilot study conducted before this study on ten patients . for difference of 5 mmhg to be detected in mean systolic blood pressures between the groups , 28 patients in each group were required as sample size . it was further enhanced and rounded off to thirty patients in each group as the final sample size for the present study . both the study groups were identical in terms of age , gender distribution , weight , asa status and duration of surgery [ table 1 ] . systolic blood pressure was higher from baseline values in control group during laryngoscopy and intubation . thereafter , this increase persisted at all points of time until 10 min ( p < 0.0001 ) . in the melatonin group , there was no rise and the patients were stable at all points of time after the administration of the study drug ( p < 0.0001 ) [ table 2 ] . similar trends were observed for diastolic and mean blood pressure ( p < 0.0001 ) [ tables 3 and 4 ] . systolic blood pressure at various points of time ( mmhg ) diastolic blood pressure at various points of time ( mmhg ) mean blood pressure at various points of time ( mmhg ) in the control group , there was a rise in heart rate from baseline values at laryngoscopy which attained statistical significance at 1 min and persisted thereafter till 10 min . in the melatonin group , there was a rise in heart rate from baseline values at the time of laryngoscopy , but it was not statistically significant and returned to previous values within 1 min . thereafter , it was maintained at lower values at all points of time till 10 min after laryngoscopy and intubation ( p < 0.0001 ) [ table 5 ] . heart rate at various points of time ( beats / min ) in the control group , one patient had nausea and vomiting ; two patients were agitated and restless in the immediate post - operative period . in the melatonin group , the present study is aimed at assessing the role of melatonin in attenuating haemodynamic responses to laryngoscopy and intubation . melatonin ( n - acetyl-5-methoxytryptamine ) is a pineal gland hormone which controls the circadian rhythm . it has been used for sleep disorders , jet lag , perioperative anxiolysis and sedation , cognitive and psychomotor functions . we assumed that its inhibitory actions on central nervous system responsible for sedation and anxiolysis may have a role in attenuating haemodynamic responses to laryngoscopy and intubation . rosenberg et al . studied the role of perioperative melatonin in the modification of surgical stress response indicating that melatonin has sympatholytic activity . based on this , we made a hypothesis that melatonin can provide haemodynamic stability during laryngoscopy and intubation when given 120 min before the procedure . we performed a pilot study in which we did not observe the desired effects with 3 mg but with 6 mg oral melatonin and not at 90 min but after a period of 120 min and our patients were tranquil and haemodynamically stable . we observed that in melatonin group , systolic blood pressure was lower than baseline values at all points of time till 10 min after intubation as compared to the control group in which there was a significant rise . compared the role of oral melatonin 6 mg and 9 mg with placebo administered 1 h before surgery in attenuating pressor response to laryngoscopy and intubation . they observed that there was a reduction of blood pressure with regard to systolic , diastolic and mean blood pressure ; and perfusion index in both melatonin groups as compared to the placebo group . the blood pressure lowering effect may be attributed to the specific binding of melatonin to melatonin receptors in the blood vessels , interfering with the vascular response to catecholamines . it may interfere with the peripheral as well as central autonomic system , causing a reduction in adrenergic outflow and resulting catecholamine levels . furthermore , it may induce relaxation of arterial wall smooth muscle by enhancing the availability of nitric oxide . in addition , it may also act via specific receptors melatonin type 1 or melatonin type 2 located peripherally in the blood vessels and centrally in blood pressure regulating area of the brain . it also has free radical scavenging effect leading to dilatation of blood vessels , and it may work via epigenetic mechanism at area postrema in the brain . the blood pressure lowering effect could also be due to the sedative action of orally administered melatonin . the sedative effect is mainly due to binding at gaba - a receptor and exerting its anaesthetic effect . we observed that heart rate was also lower than baseline values at all points of time in melatonin group as compared to the control group . however , in a similar study , no difference was observed in the changes of heart rate in the melatonin groups as compared to the placebo group . the heart rate lowering effect of melatonin may be attributed to its anxiolytic actions . it also has analgesic effects as observed by various investigators and this may also contribute to the haemodynamic stability . moreover , the magnitude of the haemodynamic responses is directly proportional to the duration of laryngoscopy and to the force applied during laryngoscopy . hence , those patients requiring more than one attempt and more than 20 s for laryngoscopy were not to be included in the study . since this study is regarding haemodynamic responses and antihypertensive agents desensitise the autonomic receptors , diabetic patients usually have some degree of autonomic neuropathy , as age progresses blood vessel wall gets atherosclerosis . all these may interfere with the results ; hence , these patients were excluded from the study . in our series of patients , there were no significant side effects such as bradycardia , arrhythmias , respiratory depression , restlessness , nausea and drug interactions . very high doses up to 300 mg / day orally for 2 years have been administered safely . even in children doses up to 20 mg have been used without any significant side effects apart from sedation . dizziness , headache and irritability may be seen in some patients with use of very high doses in some previous studies of melatonin done for its anxiolytic action . thus , proving that melatonin is a useful drug for use as an adjunct in anaesthesia . the role of melatonin in anaesthesia and critical care has been elaborately discussed in the literature ; it has been mentioned as a wonder drug with a wide spectrum of beneficial uses in anaesthesia and critical care including antioxidant and neuroprotective properties besides hypnosis , anxiolysis , analgesia and others . the use of melatonin for attenuation of haemodynamic responses before laryngoscopy and intubation is superior to few other drugs studied for the same purpose . for instance , melatonin is superior to dexmedetomidine since the latter is associated with significant bradycardia and hypotension . on the other hand , esmolol has more selective action on heart rate than blood pressure . as compared to remifentanil . the limitations of our study were that we did not compare different doses of melatonin and effects at different time intervals of administration of melatonin . we also did not assess sedation and anxiety scores and did not perform psychoanalytic tests in the post - operative period , extubation responses and plasma norepinephrine levels . pre - treatment with 6 mg melatonin administered orally 120 min before induction of anaesthesia is effective for attenuating haemodynamic responses to laryngoscopy and intubation .
background and aims : laryngoscopy and endotracheal intubation are considered as potent stimuli which lead to an increase in heart rate and blood pressure . 
 melatonin ( n - acetyl-5-methoxytryptamine ) has been studied for pre - operative anxiolysis and sedation in intensive care unit . 
 we made a hypothesis that melatonin can provide haemodynamic stability during laryngoscopy and intubation when given 120 min before the procedure.methods:sixty american society of anesthesiologists physical status grade i and ii patients of either gender , 2045 years old , 4065 kg body weight , scheduled to undergo elective surgical procedures under general anaesthesia were assigned into two equal groups - group c ( control ) and group m ( melatonin ) . 
 they received oral placebo or melatonin tablets 6 mg , respectively , 120 min before surgery . 
 the haemodynamic parameters were recorded preoperatively , during laryngoscopy and endotracheal intubation and thereafter at 1 , 3 , 5 and 10 min . 
 unpaired t - test was used for between - group comparison of ratio and interval scale data . for within - group 
 comparison of ratio and interval scale data , repeated - measures anova and post hoc bonferroni t - tests were used.results:it was observed that in the control group , there was a significant increase in heart rate and blood pressure at laryngoscopy and intubation and persisted till 10 min post - intubation . in melatonin group 
 , there was an insignificant increase in heart rate at the time of laryngoscopy and intubation which however settled within 1 min post-intubation.conclusion:melatonin is an effective drug for attenuation of cardiovascular responses to laryngoscopy and endotracheal intubation .