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CLINICAL INVESTIGATION
Year : 2007  |  Volume : 51  |  Issue : 6  |  Page : 510-514 Table of Contents     

Antiemetic effects of granisetron versus dexamethasone in clonidine premedicated children undergoing strabismus surgery


1 MD, Assistant Professor, Department of Anaesthesia & Intensive care and Post Graduate Institute of Medical Education & Research, Chandigarh, India
2 MS, Opthalmology, Assistant Professor, Department of Anaesthesia & Intensive care and Post Graduate Institute of Medical Education & Research, Chandigarh, India
3 MD, D. Ac, MAMS, FAMS, Ex-Professor & Head, Department of Anaesthesia & Intensive care and Post Graduate Institute of Medical Education & Research, Chandigarh, India

Date of Acceptance20-Oct-2007
Date of Web Publication20-Mar-2010

Correspondence Address:
Indu Sen
Post box No 1519, PGI Campus, Sector-12-A, Chandigarh-160012
India
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Source of Support: None, Conflict of Interest: None


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In a prospective, double blind, randomized trial, 120 children, aged 3-8 years,ASAI-II, undergoing strabismus repair were randomly divided into three groups (n = 40 each). Oral clonidine premedication (4gg.kg-1) was administered to all the patients two hours prior to surgery. Soon after induction of anaesthesia, Group G patients were administered intravenous granisetron (40gg.kg­1 ), Group D intravenous dexamethasone (150gg.kg-1) and group S received 4ml normal saline. Postoperatively, children were continuously monitored and assessed half-hourly till discharge and then after 24 hours for vomiting and pain. The overall incidence of postoperative emesis was lower (15.4%) in the Group G compared with the Group D (21.6%) in the first 24 hours (P>0.05). The Group S had a highest incidence of postoperative vomiting ((37%) P value < 0.0324 compared to group G). The frequency of early vomiting was highest in the S group. Both G and D groups showed better control of delayed emetic episodes. We observed that in children who were premedicated with clonidine, both IV granisetron or dexamethasone were efficacious in reducing the incidence and severity of POV in day-care strabismus surgery.

Keywords: POV, Ambulatory surgery, Strabismus surgery, Granisetron, Dexamethasone, Clonidine


How to cite this article:
Sen I, Brar G S, Chari P. Antiemetic effects of granisetron versus dexamethasone in clonidine premedicated children undergoing strabismus surgery. Indian J Anaesth 2007;51:510-4

How to cite this URL:
Sen I, Brar G S, Chari P. Antiemetic effects of granisetron versus dexamethasone in clonidine premedicated children undergoing strabismus surgery. Indian J Anaesth [serial online] 2007 [cited 2020 Aug 5];51:510-4. Available from: http://www.ijaweb.org/text.asp?2007/51/6/510/61189


   Introduction Top


Post-operative nausea and vomiting (PONV) con­tinues to be a clinical problem with unacceptably high incidence. The reported incidence of PONV after stra­bismus surgery ranges from 44-88% without antiemetic prophylaxis [1],[2] . Oral clonidine is a safe and effective premedicant. [3] Granisetron is a long acting selective 5HT 3 receptor antagonist. Drug has been found to be safe and effective for antiemetic prophylaxis in children. [4],[5] In sur­gical settings, a single prophylactic dose of dexam­ethasone has been found to be cost effective anti­emetic as compared to placebo. [6] Though all these drugs are commonly used in children, on literature review and medline search, we did not come across any study in paediatric patients undergoing strabismus repair where efficacy of granisetron or dexamethasone in clonidine premedicated children has been evaluated for the pre­vention of postoperative emesis.


   Methods Top


After approval by hospital ethics committee and parents/guardians informed consent, we conducted a pro­spective randomized double blind trial in 120 healthychil­dren of either sex, aged 3-8 years,undergoing elective strabismus correction surgery.Patients with known hy­persensitivity to serotonin antagonists & those who had received antiemetics (eg. phenothiazines, scopolamine) or steroids 24 hours prior to surgery were excluded. However, we included patients with previous history of motion sickness and POV, because they are the ones who are likely to get maximum benefit from prophylac­tic antiemetic therapy.All the children fasted 6 hours for solids and 3 hours for liquids. Premedication consisted of oral clonidine (4tg.kg -1 ) two hours prior to surgery. Peri-operative monitoring included heart rate, oxygen saturation, electrocardiography, noninvasive blood pres­sure and end-tidal carbon dioxide concentration (EtCO 2 ). Induction of anaesthesia was done with either sleep dose of intravenous propofol or halothane inhalation (in chil­dren not willing for intravenous cannulation), followed by atracurium (0.5mg.kg -1 ) to facilitate endotracheal in­tubation.Ventilation was controlled mechanically and was adjusted to keep EtCO 2 35-40 mmHg using a mixture of 70% nitrous oxide in oxygen and halothane.All children received 1tg.kg -1 fentanyl at induction and no more opio­ids were given during or after the operation.

Using a closed envelope technique, children were randomly assigned to one of the three groups to receive 4 ml of an intravenous solution before surgical proce­dure started. This solution consisted of granisetron 40gg.kg -1 (Group G), dexamethasone 150gg.kg -1 (Group D) or 4ml normal saline (Group S). For postoperative analgesia IV paracetamol 15mg.kg -1 was administered intra-operatively to all the children. At the completion of surgery, neostigmine (0.05 mg.kg -1 ) and glycopyrrolate (0.01 mg.kg -1 ) were given intravenously to reverse muscle paralysis. Sedation was assessed by the Univer­sity of Michigan Sedation Scale {UMSS [7] (Appendix I)} The events in the recovery room (vomiting, pain, antiemetics & analgesics requirements) were continu­ously monitored and recorded every half hourly for four hours or until the patient achieved the discharge criteria. Intensity of nausea was also noted whenever reported by the children. All observations were made by an anaesthesiologist, who was not aware of patients' group assignments.The number of episodes of vomiting or retching were recorded as no vomiting (0), one emetic episode (1), two or more bouts of vomiting (2). All emetic episodes were noted by the blinded anaesthesiologist in first four hours and by parents/guardians in next 20 hours. Vomiting occurring within first four hours was consid­ered as early vomiting and from 4-24 hour as delayed vomiting. Rescue antiemetic therapy consisted of intra­venous metoclopramide (0.2mg.kg -1 ), till the patient could take oral feeds, and tablet metoclopramide afterwards. Need for intravenous metoclopramide as rescue anti­emetic was recorded. Pain was evaluated by incidence and {FLACC scale (Appendix II)} [8]. A score of 7 or >7 was considered severe, 3-6 = moderate and < 3 = mini­mal. Rescue analgesia was given when the pain score was >3. Oral intake was restrained for 2 hours after recovery from anaesthesia. Duringthis period, small quan­tities of clear liquids were allowed on child's request.[Additional file 1]

The discharge criteria were based on the criteria for fast tracking out patients after ambulatory surgery.Time to meet discharge criteria was recorded. However, it is our institute policy to keep all the patients in PACU for four hours post-surgery. At the time of discharge tablet paracetamol SOS was prescribed and the telephone num­bers of all the guardians were noted.All patients were rou­tinely examined by the ophthalmologist in the evening clinic on first postoperative day. Guardians were provided with a postcard each and were requested to handover the same to the operating surgeon, after recording the occurrence of vomiting episodes. Pain,anti-emetics & analgesics require­ments after discharge and details of untoward events were assessed by interviewing the parent/guardian.[Additional file 2]

Statistical Analysis: Assuming that average inci­dence of postoperative emesis following strabismus sur­gery is 70%, to have 80% power (oo = 0.05), to detect a reduction to 35%, one would need to study 31 patients per group. Keeping in mind the drop-outs, we planned to study 40 patients in each group. Demographic and clini­cal data in three groups were analyzed using indepen­dent samples t-test or the Mann Whitney-U test where appropriate. The occurrence of postoperative emetic episodes, 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 were measured by a standard analysis of variance (ANOVA). The occurrence of vomiting af­ter discharge was analyzed using a contingency table. P value of <0.05 was considered significant.All values were expressed as mean + S.D. and number (%).


   Results Top


Nine of the 120 patientsenrolled were excluded from the data analysis because of protocol alteration or incom­plete data. Patients in the three groups were comparable with regards to age, weight and history of motion sick­ness/ POV. Anaesthesia time, administration of propofol vs halothane for induction, intraoperative haemodynamic variables, duration of surgery, number of muscles repaired and quantity of intravenous fluids administered intraoperatively were also compared.[Table 1]­

Complete response defined as no POV and no ad­ministration of rescue antiemetic medication during the first 24 hours afteranaesthesia was seen in 75.7%, (84.6% in granisetron group, 78.4% in dexamethasone group and 62.9% in saline group, P< .0324 for G vs S). Incidence of early and delayed vomiting alongwith need for rescue antiemetics is shown in [Table 2].

Children receiving granisetron vomited less frequently than those receiving dexamethasone or saline. The over­all incidence of emesis was higher in S group (37%) than in D and G group (21.6% & 15.4%) respectively. Analy­sis of results at various time intervals showed that 7 epi­sodes of vomiting were observed in first hour after sur­gery in S group as compared to 4 & 3 episodes in D and G groups respectively. Combination of granisetron or dex­amethasone with oral clonidine resulted in significant re­duction in the number of patients experiencing delayed vomiting. In the late postoperative period, no patient in the D and G group vomited whereas 3 episodes of vomiting were documented in S group. Severe emesis occurred in only one patient in S group. A smaller percentage of pa­tients received rescue antiemetics in G & D group as com­pared to S group. (5.1 %, 5.4% & 23% respectively). Severe emesis occurred in only one patient in S group [Table 3].

The pain scores in the three groups at all times did not show any difference and need for rescue analgesia did not differ. The average time to attain discharge crite­ria were comparable in D & G groups. One patient in S group had to be observed for longer period (>4hr) and was admitted on the request of parents. Eight patients (S­3, D-1, G- 4) had constipation on first postoperative day. No other clinically significant deleterious effects with regards to headache, dizziness, drowsiness or sedation were noticed in any of the children.


   Discussion Top


The etiology and consequences of postoperative emesis are complex and multi-factorial. [2],[9],[10],[11],[12],[13],[14],[15] The patients undergoing ophthalmologic surgeries involving manipu­lation of extraocular muscles are more prone to develop postoperative nausea and vomiting because of oculoemetic reflex. [9] Given the detrimental effects of postoperative vomiting and inherent risk of this compli­cation related to ophthalmological surgeries, any factor that would decrease the incidence or prevalence of POV would be highly useful. The concept of balanced antiemesis has been put forth in the recent years & multi-modal management approach has been suggested. [16] This includes combination therapy with antiemetic medica­tions acting at different neuroreceptor sites, less emetogenic anaesthesia techniques, adequate intrave­nous hydration and adequate pain control. However, the results of numerous antiemetics studied for prevention of PONV are divergent and inconsistentand high costs of antiemetic drugs limit their use. [1],[2],[3],4[],[5],[6],[9],[10],[11],[12],[13],[14],[15].

In this double-blind randomized trial, overall inci­dence of postoperative emesis was 24.3%, and we had included patients with history of motion sickness and previous POV. Patients with an acute complete response (ACR), defined as no emetic episodes and no rescue medication within 24 h of study drug administration were 84.6% in granisetron group, 78.4% in dexamethasone group and 62.9% in saline group (P < .0324 for G vs S ). Considering the high likelihood of developing postopera­tive emesis without prophylaxis in patients undergoing strabismus correction surgeries, we did not consider it ethical to include a placebo arm in the study. All the pa­tients received oral clonidine which is a safe and effec­tive premedicant and also reduces the incidence of vom­iting. [3],[12] An anecdotal report has revealed that there were no deaths in 11 toddlers ingesting clonidine accidentally in doses of 10-150gg.kg -1 . [17] Handa etal have shown that pretreatment with oral clonidine 4gg.kg -1 enhances the antiemetic effects of propofol when compared with midazolam 0.4 mg.kg -1 . [18] Though, Gulhas et al [19] could not find any such difference in a similar study compar­ing oral clonidine 4gg.kg -1 with placebo. Incidence of vomiting in our clonidine saline group was 37%, where we had included patients with previous history of post­operative vomiting. Untoward haemodynamic effects of clonidine premedication for eg. bradycardia (heart rate < 60/min) requiring pharmacological management were not observed. Demographic profile, surgical procedure, duration of anaesthesia and surgery were comparable in the three groups. Few of our patients were induced with halothane as they did not want to be pricked even after the application of EMLA cream. The number of pa­tients induced with propofol versus halothane were com­parable amongst three groups.

After the introduction of selective 5-HT 3 receptor antagonist ondansetron, several of its congeners have appeared, namely, granisetron, tropisetron, dolasetron and ramosetron. Of these granisetron received FDA approval for use in the prevention of PONV in August 2002. [20] Granisetron is claimed to be superior to traditional anti­emetic agents for prevention of PONV [13] . In the present study, in an adjusted cohort of > 100 POV-free patients (PFP),Granisetron-clonidineand dexamethasone-clonidine combination proved to be more effective to clonidine-sa­line combination (84.6 ,78.4% and 37%). Dose of study antiemetics chosen were based upon results of previously published studies on paediatric strabismus surgery under general anaesthesia [3],[6],[15]. Thus, the difference in incidence and severity of vomiting can be attributed to class of study drugs administered. However, routine use of granisetron has been criticized because of the high cost. Antiemetic prophylaxis with single dose of dexamethasone is known to decrease incidence of PONV. [6] Splinter et al [21] while comparing the effects of ondansetron alone vs dexam­ethasone with ondansetron found that incidence of post­operative vomiting was reduced to 9% in combination group. Their patients received oral midazolam premedi­cation 20-30 minutes before surgery. Incidence of vomit­ing in our combination groups is 15.4 & 21.6%. These results are comparable to other studies considering that 21.6 % patients had previous history of POV or motion sickness. [4],[11],[13],[14] .

In the recovery room, the vital signs and pain scores were similar in the three groups. Since the initial prophy­laxis in this study included a 5HT 3 antagonist or dexam­ethasone, we instituted rescue antiemetic therapy from a different class, i.e. intravenous metoclopramide. [22],[23] None of our patients required a second dose of metoclopramide.

We recognize the limitations of our study. Few of our patients were induced with halothane as they did not want to be pricked even after the application of EMLA cream. But the number of patients induced with propofol versus halothane was not statistically significant amongst three groups and none of our patients received propofol infusion for the maintenance of anaesthesia. Secondly, due to non-availability of paediatric laryngeal mask airways (when the study was conducted), all our children were intubated endotracheally, using non-depolarizing muscle relaxant (atracurium) and were reversed with neostigmine at the completion of procedure. However, this was a com­mon factor in all the three groups. Currently, we are using spontaneous ventilation techniques with paediatric LMA insertion for airway management in squint repair surger­ies, and this has further reduced the incidence of postoperative emesis. Thirdly, all our patients were extubated within one hour whereas time of onset of action of dex­amethasone is two hours. [24] Probably, preoperative admin­istration of dexamethasone in this group of patients may be more effective in reducingthe incidence of POV. Lastly, as both verbal expression of discomfort as well as retro­spective reporting of experiences is unreliable, assessment of nausea is difficult in children. Hence, only postopera­tive emesis was statistically evaluated in our study.

In conclusion, we observed that both IV granisetron or dexamethasone when combined with oral clonidine were equally efficacious in reducing the inci­dence and severity of POV in day-care strabismus sur­gery. The need for rescue antiemetics was lower in the combination treatment groups. All the patients, who re­ceived intraoperative antiemetic therapy could be dis­charged home within the proposed time of four hours. This may have economic implications. Both granisetron and dexamethasone were equally efficacious in the pre­vention of delayed POV. However low costs of dexam­ethasone and clonidine make this combination a preferred choice in the present cost-conscious scenario. Further studies in large group of clonidine premedicated chil­dren using a combination of granisetron and dexam­ethasone along with a propofol-based anaesthetic may help to achieve the target of zero postoperative eme­sis. Dose and time of administration of antiemetics in such combinations need to be defined.

 
   References Top

1.Abramowitz MD, Oh TH, Epstein BS, et al. The antiemetic effect of droperidol following outpatient strabismus surgery in children.Anesthesiology 1983; 59:579-83.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Bose J B, Watcha M F. Post operative nausea and vomiting in pediatric patients. Br J Anaesth 1999;83:104-17.  Back to cited text no. 2      
3.Nishina K, Mikawa K, Shiga M, et al. Clonidine in paediatric anaesthesia. PaediatrAnaesth 1999;9:187-202.  Back to cited text no. 3      
4.Fujji Y, Tanaka H, Toyooka H. Granisetron and dexamethasone provide more improved prevention of postoperative emesis than granisetron alone in children. Can JAnaesth 1996;43 : 1229-32.  Back to cited text no. 4      
5.Munro HM, Celia C, Errico D, et al. Oral granisetron for strabismus surgery in children. Can J Anaesth 1999;46:45-48.  Back to cited text no. 5      
6.Subramaniam B, Madan R, Sadhasivam, S et al. Dexamethasone is a cost-effective alternative to ondansetron in preventingPONV after paediatric strabismus repair. Br J Anaesth 2001;86:84-9.  Back to cited text no. 6      
7.Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in children undergoing computed tomography. Validity and re­liability of the University of Michigan Sedation Scale(UMSS).Br J Anaesth 2002;88:241-5.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatric Nursing 1997; 23: 293-7.  Back to cited text no. 8  [PUBMED]    
9.Hardy JF, Charest J, Girouard G, et al. Nausea and vomiting after strabismus surgery in pre-school children. Can Anaesth Soc J 1986; 33: 57-62.  Back to cited text no. 9  [PUBMED]    
10.Baines D. Post operative nausea and vomiting in children. PaediatrAnaesth 1996;6:7-14.  Back to cited text no. 10      
11.Lin DM, Furst SR, Rodarte A. A double-blind comparison of metoclopramide and droperidol for prevention of emesis fol­lowing strabismus surgery. Anesthesiology 1992; 76: 357-61.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Bergendahl H,lonnqvist PA, Eksborg S. Clonidine in pediatric anesthesia: review of the literature and comparison with ben­zodiazepine for premedication.ActaAnaesthesiol Scand 2006; 50:135-43.  Back to cited text no. 12      
13.Loewen PS, Marra CA, Zed PJ. 5-HT 3 receptor antagonists vs traditional agents for prophylaxis of postoperative nausea and vomiting. Can J Anaesth 2000;47 :1008-18.  Back to cited text no. 13  [PUBMED]    
14.Yoshitaka Fujii, Hidenori Toyooka H, Tanaka H.Agranisetron­droperidol combination prevents postoperative vomiting in children.Anesth Analg 1998;87:761-5.  Back to cited text no. 14      
15.Henzi I, Walder B , Tramer MR. Dexamethasone for the pre­vention of postoperative nausea and vomiting :A quantitative systematic review. Anesth Analg 2000; 90:186-94.  Back to cited text no. 15      
16.Hefferman AM, Rowbotham DJ. Post-operative nausea and vomiting - time for balanced antiemesis? [Editorial; Comment]. Br J Anaesth 2000; 85: 675-77.  Back to cited text no. 16      
17.Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Crit Care Med 1990; 18: 1124-8.  Back to cited text no. 17  [PUBMED]    
18.Handa F, Fujji Y. The efficacy of oral clonidine premedication in the prevention the postoperative vomiting in children fol­lowing strabismus surgery. Paediatr Anaesth 2001;11:71-4  Back to cited text no. 18      
19.Gulhas N, TurkozA, Durmus M, et al. Oral clonidine premedica­tion does not reduce postoperative vomiting in children undergo­ing strabismus surgery.ActaAnaesthesiol Scand 2003; 47:90-3.  Back to cited text no. 19      
20.Tan M. Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacotherapy 2003;4:1563-71.  Back to cited text no. 20      
21.Splinter WM, Rhine EJ L. Low-dose ondansetron with dexam­ethasone more effectively decreases vomiting in children than does high-dose ondansetron. Anesthesiology 1998;88:72-5.  Back to cited text no. 21      
22.Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. New Engl J Med 2004; 350:2441-51.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]  
23.Henzi I, Walder B, Tramer MR. Metoclopramide in the pre­vention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth 1999; 83: 761-71.  Back to cited text no. 23      
24.Wang JJ, Ho ST, Tzang JI, et al. The effect of timing of dexam­ethasone administration on its efficacy as aprophylactic anti­emetic for postoperative nausea and vomiting. Anesth Analg 2000; 91: 136-39.  Back to cited text no. 24      



 
 
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