Users Online: 3532 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size  
Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts | Login 

RSACP wishes to inform that it shall be discontinuing the dispatch of print copy of JOACP to it's Life members. The print copy of JOACP will be posted only to those life members who send us a written confirmation for continuation of print copy.
Kindly email your affirmation for print copies to [email protected] preferably by 30th June 2019.


Table of Contents
Year : 2013  |  Volume : 29  |  Issue : 1  |  Page : 61-65

A prospective, randomized, double blind and placebo-control study comparing the additive effect of oral midazolam and clonidine for postoperative nausea and vomiting prophylaxis in granisetron premedicated patients undergoing laparoscopic cholecystecomy

Department of Anesthesiology, Sir Sunder Lal Hospital, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India

Date of Web Publication10-Jan-2013

Correspondence Address:
Ghanshyam Yadav
Department of Anesthesiology, Sir Sunder Lal Hospital, Institute of Medical Sciences, BHU, Varanasi - 221005, Uttar Pradesh
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-9185.105800

Rights and Permissions

Background: Reduction of postoperative nausea and vomiting (PONV) continues to be a major challenge in perioperative care in spite of introduction of newer antiemetics with better efficacy and safety profiles. Therefore, we evaluated the additive effect of oral midazolam and clonidine for PONV prophylaxis in granisetron premedicated patients undergoing laparoscopic cholecystectomy.
Materials and Methods: In a prospective, randomized fashion, 120 selected cases were randomized into three groups: I, II or III to receive a tablet of midazolam (15 mg, n = 36), clonidine (150 mcg, n = 40), or glucose as placebo (5 g, n = 44) orally, 1 h before anesthesia. Occurrence of PONV along with need for rescue antiemetic during the first postoperative day was compared between groups as a primary outcome.
Results: Episodes of PONV reduced significantly in Group II (15%) as compared to group I and III (22.2%, 59%) at various time points during the period of observation (P = 0.002). Need for rescue antiemetic was significantly lower in group I (13.88%) and II (5%) as compared to group III (52.27%, P < 0.001).
Conclusion: Oral clonidine is better adjuvant for PONV prophylaxis, as compared to midazolam, in granisetron premedicated patients undergoing laparoscopic cholecystectomy.

Keywords: Clonidine, granisetron premedicated, midazolam, PONV prophylaxis

How to cite this article:
Yadav G, Pratihary BN, Jain G, Paswan AK, Mishra LD. A prospective, randomized, double blind and placebo-control study comparing the additive effect of oral midazolam and clonidine for postoperative nausea and vomiting prophylaxis in granisetron premedicated patients undergoing laparoscopic cholecystecomy. J Anaesthesiol Clin Pharmacol 2013;29:61-5

How to cite this URL:
Yadav G, Pratihary BN, Jain G, Paswan AK, Mishra LD. A prospective, randomized, double blind and placebo-control study comparing the additive effect of oral midazolam and clonidine for postoperative nausea and vomiting prophylaxis in granisetron premedicated patients undergoing laparoscopic cholecystecomy. J Anaesthesiol Clin Pharmacol [serial online] 2013 [cited 2021 Jan 18];29:61-5. Available from:

  Introduction Top

Postoperative nausea and vomiting (PONV) continues to be a major compliant after laparoscopic surgeries accounting for about 40 to 77% of cases. [1] There is a rising concern for PONV related complications like aspiration, hypoxia, bleeding, suture dehiscence, patient discomfort, increased hospital stay, and added health care costs. It is widely anticipated that a single antiemetic is less likely to be reasonable measure to prevent PONV than combination of drugs. [2] Many drugs like dexamethasone, droperidol and metoclopramide have been investigated to reduce the risk of PONV. Given the limited antiemetic efficacy of prophylactic antiemetic, Scuderi and coworkers were the first to investigate a multimodal approach in laparoscopic surgery. [3] Oral clonidine premedication was found to reduce vomiting in children after strabismus surgery. [4]

Although clonidine and midazolam are commonly used in adult patients as a premedication but literature review and Medline search did not reveal any study in adult patients, undergoing laparoscopic cholecystectomy, where comparison of additive effect of clonidine and midazolam has been evaluated for PONV prophylaxis in granisetron-premedicated patients. The present study was undertaken to investigate the additive effect of oral midazolam for PONV prophylaxis in granisetron-premedicated patients undergoing laparoscopic cholecystectomy and to compare it with oral clonidine. The primary outcome measure was PONV while secondary outcome measures were mean pulse rate, systolic blood pressure, postoperative visual analog score (VAS) and Ramsay sedation score (RAS).

  Materials and Methods Top

After ethical approval and written informed consent, 120 female patients of American Society of Anesthesiologists physical status 1/2, aged 18-60 years, posted for laparoscopic cholecystectomy in between January 2010 and December 2010 were included in this trial. Exclusion criteria included known hypersensitivity to granisetron, significant systemic disease, obesity (BMI > 35) and patients already on antiemetics, steroids and opioids. Patients with previous history of motion sickness and PONV were included because they are the ones who are likely to get maximum benefit from prophylactic antiemetic therapy.

Using a sealed envelope technique, patients were randomized into three groups: Group I (n = 36): received midazolam 15 mg orally; Group II (n = 40): received clonidine 150 mcg orally; while Group III (n = 44): received glucose 5 g orally. Randomization and study drug administration was done by an investigator not involved in the management of the patients. Two blinded anesthesiologists familiar with the anesthetic technique participated in the procedure. The data collection was done by another investigator blinded to group allocation.

All the patients were administered studied drug as per group allocation, 60 minutes before induction of anesthesia. No antianxiety premedication was given to the patients, preoperatively. Perioperative monitoring included heart rate, oxygen saturation (SpO 2) , electrocardiography, noninvasive blood pressure and end-tidal carbon dioxide concentration (EtCO 2 ). All patients were given granisetron 1 mg intravenous (IV) 10 min before induction. Induction of anesthesia was done with fentanyl 2 mcg/kg and propofol 2 mg/kg IV. Vecuronium bromide 0.1 mg/kg IV was administered to facilitate endotracheal intubation. Ventilation was controlled mechanically and was adjusted to keep EtCO 2 35-40 mmHg. Anesthesia was maintained using 70% nitrous oxide in oxygen and 0.5-1% isoflurane, and intermittent dosage of fentanyl 1 mcg/kg and vecuronium 0.02 mg/kg. At the end of surgery the neuromuscular block was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg IV and patients were transferred to the postanesthesia care unit (PACU). Sedation was assessed by RSS. The events in the recovery room vomiting, pain, heart rate, blood pressure, SpO 2 , respiratory rate, antiemetic and analgesic requirements were recorded at every 30 minutes for the first 2 h and thereafter at 4 h, 6 h, and then 6 hourly up to 24 h. Pain was assessed by using VAS between 0-10; where 0 means no pain and 10 means worst imaginable pain. RSS was assessed by six point scale (1-6): 1- Anxious or restless or both; 2- Cooperative, orientated and tranquil; 3- Responding to commands; 4- Brisk response to stimulus; 5- Sluggish response to stimulus; 6- No response to stimulus. The severity of PONV was graded on a four point ordinal scale from 0 to 3 (0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea with vomiting). For postoperative pain management fentanyl 0.5-1 mcg/kg IV was used in all patients for the first 24 h. All emetic episodes were noted by the blinded anesthesiologist. Total amount of IV metoclopramide used as rescue antiemetic was recorded.

Assuming that average incidence of PONV following laparoscopic cholecystectomy is 70%, to have 80% power α0.05), to detect a reduction to 35%, one would need to study 31 patients per group. Keeping in mind the drop out, we planned to study 36 patients in each group. Demographic and clinical data in three groups were analyzed using independent sample 't' test or Mann Whitney test where appropriate. The occurrence of PONV, rescue antiemetic therapy and rescue analgesic therapy were analyzed with the Chi-square test or the Fisher Exact test. The number of episodes of vomiting that occurred was measured by standard analysis of variance (ANOVA). P-value <0.05 was considered significant.

  Results Top

All 120 patients completed the study without any dropout. There was no significant difference in the demographic profile between the three groups (P > 0.05) [Table 1].
Table 1: Demographic data (Mean ± SD)

Click here to view

Significant reduction in incidence of PONV was observed in the Group II as compared with I and III, 15%, 22.2%, and 59%, respectively (P = 0.002). Requirements of rescue antiemetic in first 24-h postoperative period was more in the Group III (52.27%) as compared with (5%) and (13.88%) in Group II and I, respectively (P < 0.001) [Table 2].
Table 2: Incidence of post - operative nausea and vomiting (PONV) in the three groups atdifferent time intervals (%)

Click here to view

Mean pulse rate was significantly low in Group I and II as compared to Group III (P = 0.003). Overall the mean pulse rate and its variation during the first 6 postoperative hours was lower in Group II and very high in Group III (P = 0.007) [Figure 1]. The mean systolic blood pressure was lower in Group II than Group I and III at all time-points [Figure 2]. The VAS was significantly lower in group I as compared to group II and III (P<0.001) for first hr during postoperative period [Figure 3]. In Group III, RSS at 2 h was lower as compared to Group I and II (P = 0.007) [Figure 4] and [Figure 5].
Figure 1: Mean pulse rate at various time points during postoperative period

Click here to view
Figure 2: Mean systolic blood pressure at various time points during postoperative period

Click here to view
Figure 3: Visual analogue score at various time points during postoperative period

Click here to view
Figure 4: Showing mean Ramsay sedation score (RSS) in Group III at preoperative period was lower as compared to Group I and II

Click here to view
Figure 5: Flow chart of patient studied

Click here to view

  Discussion Top

We observed significant reduction in incidence of PONV in clonidine group as compared to midazolam and placebo group.

Four major neurotransmitter system appear to play important roles in mediating the emetic response viz. dopaminergic, histaminic (H1), cholinergic/muscarinic and serotonergic (5 HT 3 ). As there are four different types of receptors, there are at least four sites of actions at more than one receptor, but the commonly used drugs have a more prominent action at one or two receptors. [5] Midazolam possibly acts as an antiemetic by decreasing dopamine input at the chemoreceptor trigger zone in addition to decreasing anxiety. It may also decrease adenosine reuptake. This leads to an adenosine-mediated reduction in the synthesis, release, and postsynaptic action of dopamine at the chemoreceptor trigger zone. [6],[7] Moreover it may also decrease dopaminergic neuronal activity and 5-hydroxytryptamine (5-HT) release by binding to the γ-amino butyric benzodiazepine complex. [8]

The mechanism of antiemetic effects of clonidine is not known and probably multifactorial. It decreases sympathetic outflow, reduces anxiety, provide sedation and decreases anesthetic and analgesic requirements. [9] High sympathetic tone and catecholamine release may trigger nausea and vomiting. [10],[11] The analgesic effect of clonidine, by a reduced need for opioid as known emetogens, [10],[12] might influence the incidence of PONV.

Clonidine decreases sympathetic tone, attenuates heart rate, arterial blood pressures, and plasma renin activity were lower during and after pneumoperitoneum. [9] Preoperative clonidine decreases intraoperative stress response and improves hemodynamic stability. [9],[13],[14] The hemodynamic effects of midazolam are dose related: the higher the plasma level, the greater the decrease in systemic blood pressure. [15] The mechanism by which midazolam maintain a relatively stable hemodynamic involves the preservation of homeostatic reflex mechanisms. [16]

Apnea and respiratory depression occurs with benzodiazepines in a dose-dependent manner [16] and more likely to occur in the presence of opioids. Clonidine have minimal depressant effects on ventilation and it does not significantly potentiates opioid induced depression of ventilation. [17]

Clonidine use resulted in lower VAS, better pain relief and lesser rescue analgesic requirements. This was possibly because of activation of post-synaptic α2 receptor in substantia gelatinosa of spinal cord, as well as the descending noradrenergic pathway. [18],[19]

Limitations of this study are that we have used nitrous oxide, isoflurane and fentanyl which are known to potentiate emesis. According to the pharmacokinetics of midazolam and clonidine, a different length of preoperative observation was necessary. Different age groups have different emesis potential. We did not use antianxiety premedication, which is also limitation of our study.

This study supports the study done by Mikawa et al. [4] in children which found that clonidine to be better than midazolam. The additive effect of oral midazolam and clonidine for PONV prophylaxis in granisetron-premedicated adult patients undergoing laparoscopic cholecystectomy has not been adequately studied and further research in this field is needed.

To conclude, clonidine has higher antiemetic efficacy than midazolam. Clonidine decreases the sympathetic discharge and act as a preemptive analgesic. Oral clonidine is better adjuvant, than midazolam, for PONV prophylaxis, in granisetron-premedicated patients undergoing laparoscopic cholecystectomy.

  Acknowledgments Top

We would like to thanks the technical staff and others who helped me during this study.

  References Top

1.Boehler M, Mitterschiffthaler G, Schlager A. Korean hand acupressure reduces postoperative nausea and vomiting after gynecological laparoscopic surgery. Anesth Analg 2002;94:872-5.  Back to cited text no. 1
2.Apfel CC, Laara E, Koivuranta M. A simplified risk scores for predicting postoperative nausea and vomiting. Anesthesiology 1999;91:693-700.  Back to cited text no. 2
3.Scuderi PE, James RL, Harris L, Mims GR III. Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000;91:1408-14.  Back to cited text no. 3
4.Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995;42:977-81.  Back to cited text no. 4
5.Paxton DL, McKay CA, Mirakin KR. Prevention of nausea and vomiting after day care gynaecological laparoscopy. Anaesthesia 1995;501:403-6.  Back to cited text no. 5
6.Reitan J, Porter W, Braunstein M. Comparison of psychomotor skills and amnesia after induction of anesthesia with midazolam or thiopental. Anesth Analg 1986;65:933-7.  Back to cited text no. 6
7.Hartgraves P, Primosch R. An effect of oral and nasal midazolam for pediatric dental sedation. J Dent Child 1994;61:175-81.  Back to cited text no. 7
8.Paul S, Marangos P, Skolnick P. The benzodiazepine-GABA-chloride ionophore receptor complex: Common site of minor tranquilizer action. Biol Psychiatry 1981;16:213-29.  Back to cited text no. 8
9.Laisalmi M, Koivusalo AM, Valta P. clonidine provides opioid-sparing effect, stable hemodynamics, and renal integrity during laparoscopic cholecystectomy. Surg Endosc 2001;15:1331-5.  Back to cited text no. 9
10.Watcha MF, White PF. Postoperative nausea and vomiting: Its etiology, treatment, and prevention. Anesthesiology 1992;77:162-84.  Back to cited text no. 10
11.Jenkins LC, Lahay D. Central mechanisms of vomiting related to catecholamine response: Anaesthetic implication. Can Anaesth Soc J 1971;18:434-41.  Back to cited text no. 11
12.Anderson BJ, Ralph CJ, Stewart AW, Barber C. The dose-effect relationship for morphine and vomiting after day-stay, tonsillectomy in children. Anaesth Intensive Care 2000;28:155-60.  Back to cited text no. 12
13.Joris JL, Chiche JD, Canivet JL. Hemodynamic changes induced by laparoscopy and their endocrine correlates: Effects of clonidine. J Am Coll Cardiol 1998;32:1389-96.  Back to cited text no. 13
14.Aho M, Lehtinen AM, Laatikainen T. Effects of intramuscular clonidine on hemodynamic and plasma beta-endorphin responses to gynecologic laparoscopy. Anesthesiology 1990;72:797-802.  Back to cited text no. 14
15.Sunzel M, Paalzow L, Berggren L, Eriksson I. Respiratory and cardiovascular effects in relation to plasma levels of Midazolam and diazepam. Br J Clin Pharmacol 1988;25:561-9.  Back to cited text no. 15
16.Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: Pharmacology and uses. Anesthesiology 1985;62:310-24.  Back to cited text no. 16
17.Bailey PL, Sperry RJ, Johnson GK. Respiratory effects of Clonidine alone and combined with morphine in humans. Anesthesiology 1991;74:43-8.  Back to cited text no. 17
18.Curatolo M, Schnider TW, Petersen-Felix S. A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia. Anesthesiology 2000;92:325-37.  Back to cited text no. 18
19.Paech MJ, Pavy TJ, Orlikowski CE. Postoperative epidural infusion: A randomized, double-blind, dose-finding trial of clonidine in combination with bupivacaine and fentanyl. Anesth Analg 1997;84:1323-8.  Back to cited text no. 19


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]

This article has been cited by

Stability and Compatibility of Ramosetron with Midazolam in 0.9% Sodium Chloride Injection for Postoperative Nausea and Vomiting Administration

Jingsheng Xia,Peng Chen
Drug Design, Development and Therapy. 2020; Volume 14: 1169
[Pubmed] | [DOI]
2 Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery
Dallas Duncan,Ashwin Sankar,W Scott Beattie,Duminda N Wijeysundera
Cochrane Database of Systematic Reviews. 2018;
[Pubmed] | [DOI]
3 What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials
Miguel Carlos Sanchez Munoz,Marc De Kock,Patrice Forget
Journal of Clinical Anesthesia. 2017; 38: 140
[Pubmed] | [DOI]
4 Effect of Clonidine on Hemodynamic Responses During Laparoscopic Cholecystectomy
Yi Zhang,Xi Zhang,Yu Wang,Jiefeng Zhang
Surgical Laparoscopy, Endoscopy & Percutaneous Techniques. 2017; 27(5): 335
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
   Materials and Me...
   Article Figures
   Article Tables

 Article Access Statistics
    PDF Downloaded541    
    Comments [Add]    
    Cited by others 4    

Recommend this journal