European Journal of Cardiovascular Medicine

Postoperative nausea and vomiting (PONV) is the most common complication of surgery and  anaesthesia [1], it is the second most common complaint after postoperative pain in anaesthesia  practice[2],leadingtoadverseconsequencesincludingpatientdissatisfaction,unexpectedprolongationin-hospitalstay, and subsequent delayin return to work[3].

Laparoscopicsurgeriesrequirecarbondioxideinsufflationresultinginpneumoperitoneumandanincrease in intra-abdominal pressure, which is a significant risk factor for inciting nausea and vomiting [4].

PONV may lead to dehydration and electrolyte imbalance Extremely forcefully omitingcan lead to wound dehiscence and even ruptureoftheoesophagus. Various anti-emetic drugs, such as antihistaminics (e.g., hydroxyzine), butyrophenones(e.g.,droperidol),andgastrokineticagents(e.g.metoclopramide)havebeenusedtoreducetheincidenceof PONV, but some of the older anti-emetics are associated with undesirable side-effects [5,6].Failureofmonotherapywiththeaboveagentshasbeenreportedtobesignificant,andacombinationoftwoantiemeticdrugs,withdifferentsitesofaction,hasbeensuggestedtoprovidebetterprophylaxis against PONV.

DexamethasoneandondansetronhavebeenfoundtoreducePONVsignificantlyafterlaparoscopicsurgerieswhen compared with placebo[7,8,9]. Ondansetron, a 5-

Hydroxytryptamine3 receptor antagonist, antagonizes the action of 5-HT at 5-

HT3receptorsonvagalafferentneuronsthatinnervatethegastr

ointestinaltractand5-Hydroxytrptamine 3 receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system. Ondansetron has a plasma half-life of 4 hours and is, therefore, more effective when it is given at the end of a surgical procedure instead of immediately after induction anesthesia.

Since 1981, dexamethasone has been reported to be effective in reducing the incidence of emesisin patients undergoing chemotherapy [10,11,12].The antiemetic effect of dexamethasone was reported to be equal to or better than the 5-HT3 receptor antagonists such as ondansetron and granisetron. Recently, dexamethasone has also been reported to be effective in reducing the incidence of postoperative nausea and vomiting in paediatric patients undergoing tonsillectomy,adenoidectomy, and strabismus surgery [13-17] and in women undergoing major gynecological procedures [18-21].

Thisstudyisbeingconductedtofindoutthecomparativeefficacyoftheondansetrondexamethasonecombination, ondansetron alone, and dexamethasone alone in control of PONV.

This randomized, prospective, double blinded clinical trial was conducted after approval by theethicalandscientificcommitteeandobtainingwritteninformedconsent. A total of 120 (40 in each arm) patients of either sex, aged 18-75 years, American Society of Anaesthesiology physicalstatus(ASAPS) Iand II who were scheduled for elective laparoscopic surgeries were included in the study. The sample size was calculated considering the unexposed with outcome as 12% and exposed with outcome as 28%, using Open Epi Software. Those patients with a history of motion sickness, diabetes, pregnancy, coexisting gastrointestinal pathology, psychiatric disturbance, smokers, chronic antiemetic medications, previously on opiates within 48 h before surgery, suffering from pre-operative emesis or pregnant or patients taking anti-histamines, anxiolytics, sedatives, and anti-emetics or with a known history of drug allergy, hypersensitivity to anti-emetics or suffering from ear disease and vertigo at the time of surgery and history of post-operative emesis were excluded from the study.

The study participants were randomly allocated into Group O, Group D, and Group OD using a computer -generated table. Concealment of allocation was done using sealed envelope method. Allpatientsunderwentapre-anaesthesiaassessmentbeforesurgeryandinformedwritten consent was obtained. No pre-medication was given and the patients were kept nil orally(NPO) from midnight to the day of surgery.(O-Ondansetron, D-Dexamethasone and OD-both On dansetron and Dexamethasone).

In the operating room, patients belonging to Group OD received ondansetron 4mg with dexamethasone 8mg IV one minute before induction, Group D received dexamethasone 8mg intravenous (IV) before induction, and Group O received ondansetron 4mg IV alone before induction. Afterpre-oxygenationwith100%oxygen, allthreegroupsreceivedfentanyl2g/kgi.v.Anaesthesia was induced with Propofol (2mg/kg), and tracheal intubation was achieved with atracurium(0.5mg/kg).Intraoperative muscle relaxation was achieved with a maintenance dose atracurium (0.2mg/kg).

Mechanical ventilation was done to maintain end-tidal carbon dioxide of 35 - 40 mmHg.Anaesthesiawasmaintainedwithisofluraneandnitrousoxide. Attheendofthesurgery, anaesthesiawasdiscontinuedandresidualneuromuscularblockadewasreversedwithi.v.neostigmine(0.05mg/kg)and glycopyrrolate(0.01mg/kg).Patientswereshiftedtotherecoveryroomwheretheywereobservedforthepresence of nauseaor vomiting and the requirement of rescueanti-emetics for the first 6 hours.

Metoclopramide 10mg IV was used as rescue medication in case of nausea that lasted for morethan 15 minutes or an episode of vomiting. The data was collected through structured proforma. Drugswerelabeledefficaciousifnonauseaandvomitingoccurred6hourspost-operativelyasperthe operative definition and no rescue anti-emetic was used.

Statistical analysis:

The data were entered in MS Excel and analyzed using SPSS22.0-Software. The descriptive statistics included frequencies, proportions and percentages for categorical variables while the continuous variables were analyzed in mean, median and standard deviation. Chi – square test was used to analyze inferential statistics for categorical variables. Normally distributed continuous data was analyzed using ANOVA test. A p-valueof0.05was considered as thelevel of significance.

The clinical parameters and demographic characteristics of the patient such as age, gender, weight, ASA physical status, diagnosis and type of surgery are given in Table-1. The groups arecomparable (p>0.05) with respect to the patient characteristics.

Table 2 shows the incidence of nausea at 0 -1 hour and 1 – 6 hours among the three groups. Theincidenceofnauseafrom0to1houris7.5%inOndansetrongroup,20%inDexamethasone group and 2.5% in Ondansetron and Dexamethasone group. The chi-squareresult shows that there is a significant difference between the groups with respect to theincidenceofnauseafrom0to1hour(chi-square =7.222,P= 0.027). The incidence of nausea from 1 to 6 hour is 22.5% in Ondansetron group, 7.5% inDexamethasonegroupand5%inOndansetronandDexamethasonegroup.Thechi-squareresult shows that there is a significant difference between the groups with respect to the incidence ofnauseafrom1to6hour(chi-square =6.954,P=0.031).

The incidence of vomiting at 0 -1 hour and 1 – 6 hours among the three groups. The incidence of vomiting from 0 to 1 hour is 5% in the Ondansetron group, 17.5% in the Dexamethasone group, and 2.5% in Ondansetron and Dexamethasone group. The chi-square result shows that there is a significant difference between the groups with respect to theincidenceofvomitingfrom0to1hour(chi-square=6.764,P=0.034). The incidence of vomiting from 1 to 6 hours is 17.5% in the Ondansetron group, 5% in the Dexamethasone group, and 2.5% in Ondansetron and Dexamethasone group. The chi-square result shows that there is a significant difference between the groups with respect to the incidence of vomiting from 1to6 hours(chi-square=6.764,P=0.034).

Table 3 shows the correlation between overall incidence of nausea and vomiting with the three groups. 52.5% of patients had overall incidence of nausea and vomiting in Ondansetron group,50% of patients had overall incidence of nausea and vomiting in Dexamethasone group and12.5%ofpatientshadoverallincidenceofnauseaandvomitinginOndansetronandDexamethasone group. Chi-square test shows that there is a significant difference between ingroups with respect to the overall incidence of nausea and vomiting (Chi-square = 16.992, P <0.001).

Table 4 depicts the correlationbetweenthenumberofrescuesantiemeticsrequiredineachgroup. 30% of patients needed rescue antiemetic in Ondansetron group, 27.5% of patients needed rescue antiemetic in Dexamethasone group and none of the patients needed recueantiemetic in Ondansetron and Dexamethasone group. Chi-square test shows that there is a significant difference between ingroups with respect to the number of rescue antiemetic  required(Chi-square=14.307,P<0.001).

Adverse effects

The side effects commonly associated with the use of ondansetron and dexamethasone areheadache, diarrhoea, and constipation.In this study, 2 patients in the ondansetron group,1patientinthedexamethasonegroup,and1patientintheondansetronplusdexamethasonehadheadache. The headache was mild in all the patients. Hence there was no clinicallysignificantincidenceofanycomplicationassociatedwitheitherofthetwodrugsusedforprophylaxisinourstudy.

Table 1: Characteristics of the patients undergoing laparoscopic surgery.

Chi-Square Test, ANOVA Test

Table 2: Incidence of nausea and vomiting (0 – 1 hour) and (1 – 6 hour) among the three groups

Chi-Square Test

Table 3: CorrelationbetweenOverallIncidenceofnauseaandvomitingwithGroups

Chi-Square Test

Table 4: Correlationbetweenthenumberofrescuesantiemeticsrequiredineachgroup

Chi-Square Test

Postoperativenauseaandvomitingisacommonsequelofgeneralanaesthesiaandaleadingcauseof delayed discharge and unanticipated hospital admissions following ambulatory surgery. Itcanbeverydistressingtothepatient, sometimesmorethanthesurgeryitself,anditcanresultinseveralcomplicationslikeabdominalpain,tachycardia,sweating,andincreasedriskofaspirationdehydration, wound disruption, and gastric aspiration. Plenty of antiemetic drugs are availablethese days which include anticholinergic drugs (scopolamine, atropine), antihistaminic drugs(diphenhydramine hydroxzine), dopamine antagonist drugs (promethazine, prochlorperazineandmetoclopramide),5HT3receptorantagonists(ondansetron,dolasetronandgranisetron)andsteroids(dexamethasone).Inspiteofplentyofantiemeticdrugsavailable,nosingleagentis100%effectiveagainstPONV.AccordingtoSAMBAguidelines,PONVismultifactorialduringlaparoscopic surgeries, so, a combination of different groups of antiemetics is generally preferredtocontrolpostoperativenauseaandvomiting [22,23].SAMBAguidelinesforPONV

[24]asfollows:1.IdentifypatientsatriskforPONV;2.EmploymanagementstrategiestoreducePONVrisk;3.EmployonetotwoprophylacticmeasuresinadultsatmoderatePONVrisk;4.Usemultipleinterventions in patients at high PONV risk; 5. Administer prophylactic antiemetic therapy tochildren at high risk using combination therapy; 6. Provide antiemetic therapy to patients withPONV who did not receive prophylactic therapy or in whom prophylaxis failed.Therapy shouldbewith a drugfrom adifferentclassthan which failed to provideprophylaxis.

Thecurrentstudycomparedtheefficacyofondansetron4mg,dexamethasone8mg,andacombination of ondansetron 4 mg and dexamethasone 8mg in the prevention of PONV afterlaparoscopiccholecystectomy.Theincidenceofpostoperativenauseaandvomitingwerenotedintwo-time framesaftersurgeryi.e.01hrs,16hrs.AhmedNetalstudied67patientsreceivingacombinationofondansetronanddexamethasoneforthepreventionofpostoperativenauseaandvomitingfollowinglaparoscopiccholecystectomy[25]Theyobservednonauseaandvomitingin85%of patients.They concluded that the combination antiemesis was more effective against PONV.Ourresultsarecomparablewithrespecttotheondansetronanddexamethasonecombination.BanoFetalstudiedondansetron4mgplusdexamethasonecombinationwithdexamethasone8mgalonein patients undergoing laparoscopic cholecystectomy[26].

They found that 81.6% of patients didn'thave nausea and vomiting post-operatively in the combination group, while 60.4% of patients didnot complain of either nausea or vomiting in the dexamethasone group.They concluded that thecombinationantiemesisofondansetronplusdexamethasonewasmoreeffectivethandexamethasone alone for prophylaxis against PONV.Bhattarai B et al compared the efficacyand safety of ondansetron 4mg with or without dexamethasone 4mg given as prophylaxis forPONV in 100 (50 in each group) adult patients undergoing laparoscopic surgery[27].They concludedthat the combination anti-emesis of ondansetron plus dexamethasone was more effective thanondansetron alone for prophylaxis against PONV.They found that a complete response occurredin 92% of patients in the combination group. The results of the current study seem statisticallycomparable. Ahsan et al studied the efficacy of ondansetron 4mg plus dexamethasone 8mg andondansetron 4 mg alone for prophylaxis against PONV in 100 ASA I and II patients undergoinglaparoscopic cholecystectomy with general anaesthesia[28]. They found that complete response (nonausea and emesis episode during the 6-hour post-operative period) occurred in 88% of patientsin the ondansetron and dexamethasone group, and in 72% of patients in the ondansetron group.Theyconcludedthatprophylacticcombinationanti-emesisiseffectiveagainstPONV.Theresultsof thecurrent studyseemstatisticallycomparable.

GautamBetalconductedastudythatcompared theefficacyofondansetronanddexamethasonecombinationversusondansetronanddexamethasonealoneforprophylaxisofpostoperativenauseaand vomiting following laparoscopic cholecystectomy[29].Complete response occurred in 89.4%patientsofcombinationgroup.Rescueantiemeticswererequiredin8.5%patientsofthecombinationgroup.Theyconcludedthatthecombinationantiemesisofondansetronplusdexamethasone was more effective than ondansetron and dexamethasone alone for prophylaxisagainst PONV.The results of the current study were comparable with respect to the combinationgroup was 87.5% versus 89.4%.Our results were comparable with respect to rescue antiemetictherapy incombinationgroup 0% vs8.5%.Kumaret alcomparedthe preventing role ofondansetron,dexamethasone,andondansetronplusdexamethasonecombinationforpostoperative 

nausea and vomiting after laparoscopic cholecystectomy[30].A complete response showed thatpatients had no nausea and vomiting during the postoperative period was 90% in the combinationgroup, 65% in ondansetron, and 70% in the dexamethasone group. Rescue antiemetics in thepostoperativeperiodwererequiredin35%patientsofondansetrongroup,30%inthedexamethasone group, and no rescue antiemetic was required in the combination group.  

Theyconcluded that an antiemetic drug combination was more effective than an antiemetic drug aloneagainst PONV following laparoscopic cholecystectomy.Our result was comparable with respecttothecombination groupi.e.87.5%vs90%andnorescueantiemeticrequiredinthecombinationgroup was similarto ourcurrent study.

We conclude from our study that the combination of Ondansetron and Dexamethasone is moreeffectiveforcontrolofPONVthanOndansetronandDexamethasonealoneasprophylaxisagainst PONV followinglaparoscopicsurgeryandthatDexamethasonealoneisnoteffectiveinpreventingearly PONV. In addition, Ondansetron alone is less effective against late PONV compared tocombinedOndansetronand Dexamethasonetherapy.

Authors contribution

Dr.Kalasree-Design,writingthemanuscript,andinterpretationofdata.

Dr.-Concept, manuscript review, andfinal approval.

Dr.NagalingamNatarajan-DefinitionofintellectualcontentandLiteraturesearch.

Dr.GopalakrishnanKuppusamy-Writingthemanuscript,datacollection,andstatisticalanalysisDr.Parthiban Nagaraj- paper writing and correspondence

CONFLICTSOFINTEREST

None.

AUTHORS FUNDING

Nofinancialinterestinanypartofthestudy.

ETHICALCOMMITTEEAPPROVAL

Ethical committee and Clinical trial registry-India approval were obtained.

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