TITLE: Efficacy of intravenous midazolam versus clonidine as premedicants on bispectral index guided propofol induction of anesthesia in laparoscopic cholecystectomy: A randomized control trial

  ABSTRACT.BACKGROUND:
Midazolam and clonidine are preferred premedicants whose effects are not restricted to the preoperative period. In addition, these premedicants significantly modulate not only the intraoperative requirements of the anesthetic agents, but also the postoperative outcome. We aim to compare the efficacy of both the agents in view of premedication, induction characteristics, hemodynamic changes and postoperative complications utilizing bispectral index (BIS) using propofol anesthesia.

ABSTRACT.MATERIALS AND METHODS:
The type of this study was randomized control trial conducted on patients undergoing laparoscopic cholecystectomy under general anesthesia with endotracheal intubation. Study included 105 patients of either sex aged 20-60 years. The patients were randomly allocated into three groups: Intravenous midazolam (Group 1), clonidine (Group 2), and normal saline (Group 3) (control). The initial value of BIS and Ramsay Sedation Score, dose of propofol required for induction were noted in each group and monitored for pulse rate, electrocardiograph, noninvasive blood pressure, and BIS.

ABSTRACT.RESULTS:
The requirement of propofol ranged from 40 to 150 mg. Mean requirement was maximum in Group 3 (109.43 ± 20.14 mg) and it was minimum in Group 1 (78.57 ± 22.15 mg). A significant reduction in consumption of propofol with the use of midazolam (P < 0.001) and clonidine (P < 0.001) was observed. Both premedicants partially attenuates laryngoscoy and intubation response along with reduction in the incidence of postoperative complications.

ABSTRACT.CONCLUSION:
Both clonidine and midazolam contributed equally in lowering propofol consumption. Reduction in the induction dosage of propofol and hemodynamic variations were also observed to be similar with the use of midazolam or clonidine as premedicants. Both provide a beneficial effect in relation to recovery and less postoperative complications. However clonidine premedication was found to be more effective in preventing post operative shivering and can be recommended in routine practice.

BODY.INTRODUCTION:
Surgery and anesthesia is a stressful condition and are associated with stimulation of neuroendocrinal pathway, producing various hemodynamic effects, which may be harmful to patient. Methods to decrease these effects include maintaining an adequate depth of anesthesia to prevent these hemodynamic effects, or to give some pharmacological preparation to the patients, which will modify the response of anesthetic drug.[12]  Use of midazolam as premedicant during induction showed significant reduction in propofol dose, low maintenance requirements of anesthetics, less airway irritability, and blood pressure (BP) increase.[3] Administration of clonidine preoperatively has been shown to potentiate the effects of anesthetics[4] and decreases the requirement of propofol.[5] However, clinically optimized focusing of drug administration to a specific need of patient with bi-spectral index (BIS) monitoring results in reduced dosage of anesthetic agents and faster recovery of consciousness.[6]  Although clonidine and midazolam are commonly used premedicants, but literature review and MEDLINE search did not reveal much study in adults where comparison of both these premedicants have been evaluated by BIS guided propofol dose requirement for anesthesia induction, so this study was planned to determine the efficacy of these commonly used premedicants on propofol requirement for anesthesia induction using BIS analysis, sedative and their hemodynamic effects.

BODY.MATERIALS AND METHODS:
A randomized control trial (RCT) was conducted in the Department of Anesthesiology, Pain Management and Intensive Care, after Ethical Committee Clearance. The RCT included 105 patients undergoing laparoscopic cholecystectomy under general anesthesia with endotracheal intubation. Patients with American Society of Anesthesiologists Grades III and IV, using central nervous system (CNS) depressants, patients having any other chronic medical or surgical illness, cardiac illness, pregnant females, and the patients with anticipated difficult airway were excluded from the trial.

BODY.MATERIALS AND METHODS.SAMPLE SIZE:
Calculation of sample size was done on the basis of findings from a previous study[7] considering reduction in propofol dose as a main parameter. A difference between the groups of more than 20-25% will be considered as a practical significant. Using α = 5% and β = 80%, 27 found the minimum required sample size to be 27. To make study more appropriate 35 samples were considered.  After obtained informed consent, the patients were premedicated with tablet diazepam 10 mg and tablet pantaprozole 40 mg night before surgery. Intravenous (i.v.) access was established in nondominant hand in the ward and in the waiting area of the operating room. Patients were randomly allocated into three groups of 35 patients each by computer generated randomization number. The group received following medicines:  
Group 1: Injection midazolam, 50 μg/kg diluted to total volume of 5 ml, injected slow i.v. 20 min prior to surgeryGroup 2: Injection clonidine, 1.5 μg/kg to make a total volume of 5 ml, injected slow i.v. 20 min prior to surgeryGroup 3: Normal saline 5 ml (control group) was injected slow i.v. 20 min prior to surgery.
  All the patients were monitored for respiratory depression utilizing pulse oximetry (SpO2 <92%), respiratory rate <10/min, sedation using Ramsay Sedation Score, (R) and BP.  The patients were monitored for noninvasive BP, electrocardiograph, pulse rate (Philips Sure Signs VM8) and BIS using BIS sensor and A-2000 BIS monitor XP platform (Aspect Medical Systems, Cambridge, MA, USA) standard anesthesia induction was done utilizing injection fentanyl 2 μg/kg followed by infusion of propofol (Fresofol 1%, Fresenius Kabi, Fresenius Kabi India Pvt.Ltd.Fifth Floor, A-wing, Ashoka Plaza, Pune-Nagar Road, Survey No. 32/2,Vadgaon Sheri, Viman Nagar, Pune- 411014, Maharashtra, India) at 30 mg/kg/h until BIS stabilized at 48 ± 2 and remained stable for that. Once the desired BIS value was reached, propofol infusion was switched off and total dose of propofol was noted. The patients were mechanically ventilated with 66% N2O in O2 (Dräger-PrimusGermany) and sevoflurane ≤1.5% for 3 min.after giving injection vecuronium. The value of BIS and hemodynamic parameters were noted at the time of loss of consciousness, at the time of intubation and thereafter every minute for first 10 min after intubation. The observer was blinded to the premedicant being given to the patient. Anesthesia was maintained with 66% nitrous oxide in oxygen, sevoflurane dial concentration of ≤1.5%, intermittent vecuronium and fentanyl. No dose of fentanyl was administered once the gall bladder was dissected out from the liver bed. No antiemetic was administered to any group of patient. Sevoflurane was switched off on commencing of closure of skin incision. The patients were administered aqueous solution of injection diclofenac 75 mg i.v. before extubation. Neuromuscular blockade was reversed with injection neostigmine (0.05 mg/kg) mixed with injection glycopyrolate (0.02 mg/kg). A gentle oral suctioning was done and patient extubated. No neuromuscular monitoring was used in our study. The patients were shifted to postanesthesia care unit. The patients were also assessed for postoperative pain, nausea, vomiting, and shivering. The primary outcome of this study was to compare the propofol dose consumption for anesthesia induction with i.v. clonidine and midazolam premedication, whereas the secondary outcome was to evaluate the preoperative sedation status BP, heart rate (HR) changes during laryngoscopy and endotracheal intubation, postoperative nausea and vomiting (PONV), postoperative shivering, and postoperative pain between the groups.

BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Data analysis was performed using SPSS version 21. Quantitive data were expressed in terms of mean ± standard deviation. Propofol dose was analyzed by using ANOVA followed by Bonferroni correction. Repeated measure ANOVA was used to compare the hemodynamic parameters at different time interval group. P < 0.05 was considered as statistically significant.

BODY.RESULTS:
The demographic parameters were comparable among three groups [Table 1]. Mean dosage of propofol used in mg/kg were 78.57 ± 22.15 in Group 1, 80.14 ± 20.81 in Group 2 and 109.43 ± 20.14 in Group 3 [Table 2] to achieve a BIS value of 48 ± 2 for induction. A significant propofol sparing effect was noted with the use of midazolam (P < 0.001) and clonidine (P < 0.001). Though propofol consumption was less clinically with midazolam premedication compared with clonidine, but it was not statistically significant (P = 0.761).   Table 1 Demographic profiles and baseline characteristics of patients   Table 2 Comparison of three groups for mean dose of propofol required   Among hemodynamic variables such as HR, systolic BP (SBP) and diastolic BP (DBP), the increase in HR was significantly lower in both the study groups (Groups 1 and 2 P < 0.05) as compared to Group 3. The HR was elevated after intubation in all groups with lowest in Group 2. SBP and DBP were comparable among three groups. All the three groups showed elevated BIS values at the time of intubation, changes were minimum in midazolam group and the difference was found to be statistically significant as compared to control group. However, no statistically significant difference in BIS values was found among the study groups (1 and 2) [Table 3].  Table 3 Hemodynamic parameters and BIS value changes   Preinduction Ramsay Sedation Score was 2 in all the groups; however, the readings of BIS varied [Table 4].  Table 4 BIS value in different groups   Postoperative complications were comparable except for reduced incidence of shivering in patients receiving clonidine (5.7%) as compared to those in Group 1 (22.9%) and Group 3 (40%), thus showing a statistically significant intergroup difference (P = 0.003). Majority of subjects complained of mild pain in all the three groups showing no statistically significant intergroup difference (P > 0.05). Incidence of PONV was comparable among Groups 1 and 2 (11.4%) (P = 0.089), though the incidence was more than twice (28.6%) in Group 3 [Table 5].  Table 5 Comparison of postoperative complications in different groups 

BODY.DISCUSSION:
Our study demonstrated equal efficacy of midazolam and clonidine as premedicants in sparing propofol dose. Midazolam attenuates cardiovascular response to laryngoscopy and intubation nearly as well as clonidine except for HR. Premedicaton with clonidine is better than midazolam in preventing postoperative shivering. We found 28.20% decrease with the use of 0.05 mg/kg i.v. midazolam and 26.70% reduction with the use of 1.5 μg/kg i.v. clonidine in propofol dose. This decrease in the dose of propofol with the use of midazolam or clonidine has also been shown by other authors, though the decreased was variable. This variation may be attributed to the higher doses of oral clonidine being used for preoperative sedation 4-5 μg/kg in the previous studies,[489101112] while we used only 1.5 μg/kg i.v.[71314] observed mean reduction in the propofol doses after midazolam pretreatment, more than our study, the reason, which may be attributed to this difference is relatively younger age group of the patients in our study. This study supports that induction doses of propofol required were less with midazolam premedication as compared to clonidine clinically, which could be due to the fact that both propofol and midazolam have been known to have a depressive effect on the CNS via GABA-A receptor-mediated inhibition, and share a common receptor or exert effect on the GABA-A receptor.[15]  The BIS monitor is a well-established monitor for measuring depth of anesthesia.[16]  Target-controlled infusion provides a precise blood concentration of propofol, but due to its unavailability in our setup at the time of study, we used the infusion of propofol at the rate of 30 mk/kg/h in lieu of the study of Mi[17] and study conducted in our department by Arya S et al.[18]  Clonidine is more effective in blunting the reflex tachycardia associated with laryngoscopy and endotracheal intubation, reduced intra-operative labiality of BP, HR as well as decrease in dosage of narcotics and their supplementations. The inhibitory effects of clonidine on central monoaminergic system as possible cause for the above finding.[19] Similar findings were seen in the other studies.[202122] However, we inferred that neither clonidine nor midazolam premedication completely block the cardiovascular response to laryngoscopy and tracheal intubation due to the mechanical stimuli from the larynx and base of the tongue and their effect is dose dependent.  The potentially beneficial anesthetic - sparing effect of alpha-2 agonists may be negated by bradycardia and hypotension. A study has shown bradycardia and bradypnea only with 5 μg/kg that is higher than the dose used in our study. The activation of presynaptic alpha-2 adrenoreceptors in peripheral nervous terminations inhibits norepinephrine exocytosis partially explaining the hypotensive and bradycardia-inducing effects of such receptor agonists.[23]  Bispectral index value increases significantly after tracheal intubation.[24] Such response can be reduced by premedication with midazolam or clonidine, which is in agreement with the findings of Paris et al.[8]  We observed no association between preinduction BIS value and Ramsay Sedation Score. Similar to the findings of Mason et al., Malviya et al., and Shields et al.[252627] Another interesting aspect seen in control group was that 11 patients had a value of BIS <90 at the time of first reading of BIS. The exact cause is not known; however, Paris et al., in their study also noticed similar observations, they correlated this to the use of preoperative diazepam, which has got longer half-life received a night before surgery as regular premedication as per their hospital policy.[8] We also gave tablet diazepam 10 mg at night before surgery to all our patients.  In this study, the incidence of shivering was least with use of clonidine as premedicant. This has been attributed to the well-known antishivering effects of clonidine at three levels: Hypothalamus, locus coeruleus and spinal cord. As postulated by Basker et al., and Bergendahl et al.[2829]  Clonidine also affords an advantage of reduction in PONV, although many workers have reported the antiemetic property of clonidine, the mechanism by which it acts warrants further investigation.[30]  Our study also confirmed that the analgesic and sedative effects of clonidine are most likely dose dependent. Other researchers have found decreased requirement of analgesics postoperatively with the use of clonidine premedication,[313233] failure to get such response may be due to the lower dose of clonidine used by us.  The limitations of our study were that:  
We have compared the patients with the younger age group with the range of age being 34 ± 10 years. A wider range of age would have given an idea of influence of age of patient on the dosage of propofol with the use of premedicantsUnavailability of target-controlled infusion in our set up at the time of study which provides a precise blood concentration of propofolWe did not estimate the level of stress hormones at the time of anesthesia induction and intubation, which would have given a better idea of changes in stress level after premedication.


BODY.CONCLUSION:
To conclude, midazolam and clonidine pretreatment provides adequate sedation, has dose sparing effect on propofol, partially blunts hemodynamic responses and decreases PONV. In addition, clonidine also demonstrated superiority in reducing postoperative shivering. However, considering the fact that different route, dosing, combinations and time interval between premedication and intubation might affect the efficacy of drugs; hence, further studies are recommended to find out the optimal dose and route to get the best results.

Question: Compared to normal saline (Group 3) (control) what was the result of midazolam (Group 1) on consumption of propofol?
Evidence: Majority of subjects complained of mild pain in all the three groups showing no statistically significant intergroup difference (P > 0.05).
Answer: significantly decreased