|Year : 2019 | Volume
| Issue : 1 | Page : 16-20
Effect of oral melatonin on patients' anxiety scores and dose requirement of propofol during bispectral index-guided induction of general anesthesia
Nikhil Jain1, Hemlata2, Tanmay Tiwari2, Monica Kohli2, Girish Chandra2, Vinod Kumar Bhatia2
1 Department of Anesthesiology, Netaji Subhash Chandra Bose Medical College, Jabalpur, Madhya Pradesh, India
2 Department of Anesthesiology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||18-Jan-2019|
|Date of Acceptance||05-Feb-2019|
|Date of Web Publication||6-May-2019|
Dr. Tanmay Tiwari
Department of Anesthesiology, King George's Medical University, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Management of preoperative anxiety in surgical patients is usually required for better perioperative hemodynamics and patient management. Various pharmacological and nonpharmacological entities have been used for the management of anxiety. The aim of this study was to analyze the effect of oral melatonin on patient anxiety scores and dose requirement of propofol using bispectral index (BIS)-guided induction of general anesthesia.
Materials and Methods: Sixty patients of American Society of Anesthesiologists physical Status I and II between 18 and 45 years of age scheduled to undergo elective surgery of more than 30 min participated in this study. Patients were divided into control and melatonin groups, comprising 30 patients each. Group M patients received two melatonin tablets (3 mg each) and Group C patients received two placebo tablets 120 min before induction. Anxiety scores using visual analog scale-anxiety at baseline and 120 min, mean dose requirement of propofol, time to attain BIS value of 55 in seconds, and hemodynamic parameters were studied in-between the groups.
Results: There were significant differences between two groups in anxiety scores 120 min after drug dosage (P = 0.0013) with Group M patients with reduced levels of anxiety, and mean requirement of propofol in Group C (104.67 ± 16.34 mg) was found to be statistically significantly higher than Group M (70.67 ± 16.39 mg), P < 0.001. Hemodynamic parameters in terms of heart rate and mean arterial blood pressures were better for Group M in comparison to Group C.
Conclusion: 6 mg of melatonin 120 min before elective surgery can allay anxiety in patients along with reduced dose requirement for propofol for BIS-guided induction of general anesthesia without any adverse effects.
Keywords: Anxiety, bispectral index, general anesthesia, melatonin, premedication, propofol
|How to cite this article:|
Jain N, Hemlata, Tiwari T, Kohli M, Chandra G, Bhatia VK. Effect of oral melatonin on patients' anxiety scores and dose requirement of propofol during bispectral index-guided induction of general anesthesia. Indian Anaesth Forum 2019;20:16-20
|How to cite this URL:|
Jain N, Hemlata, Tiwari T, Kohli M, Chandra G, Bhatia VK. Effect of oral melatonin on patients' anxiety scores and dose requirement of propofol during bispectral index-guided induction of general anesthesia. Indian Anaesth Forum [serial online] 2019 [cited 2019 Aug 22];20:16-20. Available from: http://www.theiaforum.org/text.asp?2019/20/1/16/257680
| Introduction|| |
N-acetyl-5-methoxy-serotonin (melatonin), an endogenous hormone secreted by the pineal gland, is mainly responsible for the circadian rhythm of the human body. Exogenous melatonin has been studied for various indications in anesthesia such as hypnosis, anxiolysis, sedation, and analgesia. It facilitates sleep onset and improves the quality of sleep. Some degree of anxiety in preoperative period is a natural response in view of apprehensions for upcoming surgery. We assumed that inhibitory actions of melatonin on central nervous system may have role in attenuating preoperative anxiety and would also decrease the amount of propofol required to produce an adequate depth of hypnosis at induction when given 120 min before the procedure.
| Methods|| |
This prospective, randomized, double-blinded, and placebo-controlled study was approved by the Institutional Review Board of our hospital and was performed after obtaining consent from all the participating patients. The study included 18-year-old to 45-year-old patients with American Society of Anesthesiologists (ASA) physical Status I and II, who underwent elective surgery of more than 30 min duration under general anesthesia between August 2016 and April 2017.
The exclusion criteria included patients with a history of hypertension, ischemic heart disease, diabetes, bronchial asthma, psychiatric illness, sleep disorders, obesity (Body mass index >30 kg/m2), and patients taking antipsychotic, antidepressants, sedatives, anxiolytics, and anti-epileptic drugs. Pregnant and lactating females were also excluded from the study.
The patients were divided into control (Group C) and melatonin (Group M) groups of 30 participants (n = 30) each by using a computer-generated random number table.
Preoperative anxiety was measured using the visual analog scale for anxiety (VAS-A) ranging between 0 and 10 (0 = completely calm, 10 = the worst possible anxiety) once the patient was taken in the preoperative room and was assigned as A baseline. Group C patients received two placebo tablets of Vitamin D3 orally 120 min before induction with a sip of water, and the Group M patients received two melatonin tablets (3 mg each) 120 min before induction with sip of water in the preoperative room. To ensure that the patients and anesthesiologists were blinded to the group assigned, the study medications were packaged in an identical manner and provided to the anesthesiologist in a thick opaque envelope. No other drug was given in the preoperative room to the patients.
On receiving the patient in the operating room, standard monitoring including an electrocardiogram, noninvasive blood pressure, end-tidal partial pressure of carbon dioxide (ETCO2), bispectral index (BIS) monitoring using BIS™ LoC 2 Channel OEM module from Medtronic using BIS™ Quatro (4 Electrode) Sensor, and peripheral pulse-oximetry (Spo2) were applied to all patients. Intravenous line was established in the nondominant arm, and balanced fluid was infused. Anxiety levels were assessed again using VAS-A once the patient was ready to be induced at operating table and scores were labeled as A-Preinduction.
All the patients were preoxygenated using 100% oxygen for 3 min; injection fentanyl 2 μg/kg was administered intravenously as a premedication. Two minutes after fentanyl administration, an infusion of propofol was initiated at 0.5 mg/kg/min, and the infusion was stopped as soon as BIS value reached to 55. The consumed dose of propofol was measured as an independent marker. We also measured the time from the start of propofol infusion till the decrease in the BIS value to 55.
Once the BIS values reach 55, the anesthetic drug infusion was stopped, and endotracheal intubation with adequate sized tube was facilitated with injection vecuronium bromide 0.1 mg/kg. After confirming bilateral equal air entry, the endotracheal tube was secured. Maintenance of anesthesia was attained using nitrous oxide: oxygen in 50:50 ratio, isoflurane 0.4%, and intermittent doses of 0.02 mg/kg vecuronium bromide. The settings of mechanical ventilation with 50% oxygen-nitrous mixture were also adjusted to maintain the ETCO2 between 35 and 45 mmHg.
At the end of the surgery, the patients received injection neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg intravenously to reverse the residual neuromuscular blockade.
Heart rate (HR), Spo2, systolic, diastolic, and mean blood pressures were recorded before the administration of study drug (baseline), 120 min after baseline (preinduction), after induction, at laryngoscopy, intubation, and at 1, 3, 5, and 10 min after intubation. Induction doses of propofol required for loss of response to verbal commands were also noted in both the groups. The primary outcome of the study was to study dose requirement of propofol for induction of general anesthesia, and secondary objectives were to assess anxiety scores and hemodynamic parameters during intubation and laryngoscopy.
Based on a previous study and considering similar differences in drug usage, the sample size has been calculated using the formula proposed by Snedecor and Cochran.
n = (16σ2/d2) +1
Where σ is the standard deviation and d is the mean difference between two groups. Calculated sample size at 95% confidence and 80% power, is 22 in each group. After adding for a contingency of 20%, we proposed a sample size of 26 in each group. To compensate for dropout cases and shifting from normality in data distribution, a total of 30 cases were studied in each group.
The statistical analysis was done using SPSS (Statistical Package for Social Sciences) Version 15.0 statistical Analysis Software (SPSS Inc., Chicago, IL, USA). To test the significance of two means, the Student's “t”-test was used. To compare the change in a parameter at two different time intervals paired, “t”-test was used. Chi-square test was used to compare the proportional differences among the groups. Mann–Whitney U-test was used to compare nonparameteric data of two groups. P < 0.05 is considered as statistically significant.
| Results|| |
A total of 60 patients fulfilling the inclusion and exclusion criteria were included in the study. Demographic characteristics including age, gender, weight, ASA physical status, duration of surgery, and baseline BIS score were similar between the groups [Table 1] and [Table 2].
[Table 3] shows in between group comparison of requirement of total dose of propofol and time to attain BIS of 55. [Table 4] indicates that there were significant differences between two groups in anxiety scores 120 min after drug dosage.
|Table 3: Comparison of requirement of total dose (mg) of propofol and time to attain bispectral index score of 55|
Click here to view
Mean HR of patients of Group M was found to be higher than that of Group at baseline (84.93 ± 12.39 vs. 80.60 ± 09.40 beats/min) and at preinduction (87.67 ± 14.73 vs. 86.20 ± 11.16 beats/min), but this difference in mean HR was not found statistically significant [Figure 1].
|Figure 1: Comparison of heart rate (beats/min) at different time periods. Data are presented as mean ± Standard deviation|
Click here to view
At rest of the periods of observation, mean HR patients of Group C was found to be higher than that of Group M at laryngoscopy (121.57 ± 08.91 vs. 102.60 ± 13.79 beats/min), at 1 min postintubation (121.30 ± 06.89 vs. 90.17 ± 09.83 beats/min), at 3 min postintubation (112.57 ± 06.11 vs. 82.73 ± 08.08 beats/min), at 5 min postintubation (106.33 ± 05.83 vs. 77.43 ± 08.16 beats/min), at 10 min postintubation (100.93 ± 06.71 vs. 77.20 ± 09.91 beats/min). This difference in mean HR among patients of Group M and Group C was found to be statistically significant.
Mean arterial pressure of patients of Group M was found to be higher than that of Group C at baseline (92.80 ± 7.33 vs. 90.94 ± 10.10 mmHg) and at preinduction (93.60 ± 7.76 vs. 92.40 ± 9.17 mmHg); but, this difference in mean arterial pressure was not found statistically significant. Mean arterial pressure of patients of Group M was found to be higher than that of Group C after induction (75.07 ± 8.00 vs. 69.60 ± 9.03 mmHg); this difference in mean arterial pressure was found statistically significant (P = 0.016) [Figure 2].
|Figure 2: Comparison of mean arterial pressure (mmHg) at different time periods. Data are presented as mean ± Standard deviation|
Click here to view
At rest of the periods of observation, mean arterial pressure of patients of Group C was found to be higher than that of Group M;at laryngoscopy (112.51 ± 07.94 vs. 97.91 ± 10.09 mmHg), at 1 min postintubation (109.99 ± 05.36 vs. 91.71 ± 08.75 mmHg), at 3 min postintubation (105.03 ± 05.67 vs. 85.71 ± 07.33 mmHg), at 5 min postintubation (101.88 ± 04.48 vs. 83.87 ± 07.89 mmHg), and at 10 min postintubation (99.21 ± 06.04 vs. 81.74 ± 05.00 mmHg), this difference in mean arterial pressure among patients of Group M and Group C was found to be statistically significant.
| Discussion|| |
The present study aim was to study the effect of exogenously administered melatonin on the preoperative anxiety scores and dose requirement of propofol during BIS-guided induction of general anesthesia.
Lerner et al. first identified the pineal gland as the source of melatonin in 1958 and also isolated an active factor (N-acetyl-5-methoxytryptamine) from beef pineal extracts. In mammals and humans, circadian rhythm is maintained by the suprachiasmatic nucleus (SCN) of brain hypothalamus, and neural signal from SCN leads to synthesis of melatonin by the pineal gland. Melatonin maintains the circadian rhythm as reported by various studies., Orally administered melatonin is used to alleviate jet lag and fatigue after long flights. Administration of melatonin during daytime results in the induction of fatigue and sleepiness in humans.
The peak effect of exogenous melatonin ranges from 60 to 150 min. Gupta et al. studied the effect of 6 mg melatonin on attenuation of hemodynamic parameters during laryngoscopy and intubation after 120 min, so we also decided to study the effect of 6 mg of melatonin on patients' anxiety and dose requirement of propofol 120 min after drug intake using BIS-guided induction of general anesthesia.
The BIS monitor is validated for measuring the depth of anesthesia. It consists of a sensor, digital signal converter, and monitor. The sensor is placed on the patient's forehead to pick up the electrical signals from the cerebral cortex and transfer them to the digital signal converter. BIS appreciates changes in the electrophysiologic state of the brain during anesthesia. Values of 90–100 are present in awake individuals and values of 0 or flat line are seen with no cortical activity of the brain. According to the manufacturer's guidelines, a BIS value should be kept between 40 and 60 for patients undergoing general anesthesia. We randomly used values of 55 for our study.
In our study, we gave propofol as an infusion and not as bolus and incremental dose fashion to avoid any human error. In our study, there was statistical difference (P < 0.001) in the mean dose requirement of propofol in Group C (104.67 ± 16.34 mg) as compared to Group M (70.67 ± 16.39 mg), and also, time to attain BIS score of 55 in seconds was significantly (P = 0.003) higher in Group C as compared to Group M. Naguib et al. found that oral premedication with 0.2 mg/kg melatonin significantly reduces the propofol and thiopental doses required for loss of responses to verbal commands and eyelash stimulation. In our study, we gave fixed dose of 6 mg of melatonin in our group of patients other than per kg of body weight.
Preoperative anxiety is a universal phenomenon and is multifactorial in origin depending on various exogenous and endogenous factors such as gender, ethnicity, and sociocultural factor. In our study, we found the beneficial effect of melatonin on anxiety scores of patients in melatonin group as compared to the control group at 120 min after baseline just before induction. We used the VAS anxiety score as it is very simple, fast, and manageable, calling for only a few seconds to be administered and scored. Our result further validated the usefulness of melatonin in reducing preoperative anxiety as shown in several studies.,, Preoperative anxiety was present in both the groups during baseline, and it decreased in both the groups at 120 min, and there was significant (P = 0.0013) difference between both groups at 120 min. The anxiolytic effects of melatonin may be related to GABAergic system activation.
Hemodynamic parameters during laryngoscopy and intubation in terms of HR between the groups showed statistically significant (P < 0.001) difference, with mean HR patients of Group C higher than that of Group M at laryngoscopy, at 1 min postintubation, at 3 min postintubation, at 5 min postintubation, and at 10 min post intubation. Similarly, mean arterial pressure of patients of Group C was found to be higher than that of Group M at laryngoscopy, at 1 min postintubation, at 3 min postintubation, at 5 min postintubation, and at 10 min postintubation, and this difference in mean arterial pressure among patients of Group M and Group C was found to be statistically significant (P < 0.001). Laryngoscopy and intubation are the instances which lead to exaggerated sympathetic stimulation, and control of this sympathetic drive is one of the major goals of anesthesia. Gupta et al.'s study also demonstrated similar attenuation of hemodynamic response during laryngoscopy and intubation.
In our study, there were no untoward incidences of bradycardia, cardiac arrhythmias, respiratory depression, nausea, hypotension, anaphylaxis, and drug interactions in any of the group. Limitation of our study was that we took only 6 mg of melatonin as dose and not took different doses of melatonin.
| Conclusion|| |
Melatonin 6 mg when given 120 min before surgery can be an attractive option to allay anxiety and requirement of propofol for BIS-guided induction of general anesthesia. It also provides better hemodynamic control during laryngoscopy and intubation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The visual analog scale allows effective measurement of preoperative anxiety and detection of patients' anesthetic concerns. Anesth Analg 2000;90:706-12.
Turkistani A, Abdullah KM, AlShaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol 2007;24:399402.
Snedecor GW, Cochran WG. Statistical Methods. 8th
ed. Ames: Iowa State Press; 1989.
Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocyteS1. Journal of the American Chemical Society 1958;80:2587.
Levi F, Schibler U. Circadian rhythms: Mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 2007;47:593-628.
Cajochen C, Kräuchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 2003;15:432-7.
Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11-24.
Caspi O. Melatonin for the prevention and treatment of jet lag. Altern Ther Health Med 2004;10:74-8.
Gorfine T, Assaf Y, Goshen-Gottstein Y, Yeshurun Y, Zisapel N. Sleep-anticipating effects of melatonin in the human brain. Neuroimage 2006;31:410-8.
Melatonin. Monograph. Altern Med Rev 2005;10:326-36.
Gupta P, Jethava D, Choudhary R, Jethava DD. Role of melatonin in attenuation of haemodynamic responses to laryngoscopy and intubation. Indian J Anaesth 2016;60:712-8.
] [Full text]
Johansen JW. Update on bispectral index monitoring. Best Pract Res Clin Anaesthesiol 2006;20:81-99.
Naguib M, Samarkandi AH, Moniem MA, Mansour Eel-D, Alshaer AA, Al-Ayyaf HA, et al.
The effects of melatonin premedication on propofol and thiopental induction dose-response curves: A prospective, randomized, double-blind study. Anesth Analg 2006;103:1448-52.
Capuzzo M, Zanardi B, Schiffino E, Buccoliero C, Gragnaniello D, Bianchi S, et al.
Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg 2006;103:121-3.
Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, et al.
Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005;9:41-50.
Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg 2009;108:1146-51.
Wan Q, Man HY, Liu F, Braunton J, Niznik HB, Pang SF, et al.
Differential modulation of GABAA receptor function by mel1a and mel1b receptors. Nat Neurosci 1999;2:401-3.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]