efficacy of ketamine gargle 40 mg and benzydamine hcl 0

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Subekti et al., Efficacy of ketamine gargle 40 mg and benzydamine HCl 0.075%in reducing post intubation sore throat

J Med SciVolume 44, No.2, June 2012: 1 - 9

* corresponding author: [email protected]

Efficacy of ketamine gargle 40 mg andbenzydamine HCl 0.075% in reducingpost intubation sore throat

Eko Bambang Subekti1*, MuhdarAbubakar2, Djayanti Sari21Ibnu Sutowo District Hospital, Baturaja, Ogan Komering Olu, South Sumatra, 2Depart-ment of Anesthesiology and Reanimation, Faculty of Medicine, Universitas Gadjah Mada,Yogyakarta, Indonesia

ABSTRACTSore throat is a frequent complication in postoperative patients under general anesthesia whichis performed with endotracheal tube intubation. This effect occurs because of mucosal irritationand damage and airways inflammation due to a lubricant gel on laryngoscopy or an emphasis ofendotracheal tube cuff. This study was conducted to compare the efficacy of ketamine 40 mggargle with benzydamine HCl 0.075% gargle in reducing post intubation of sore throat prior tothe insertion of endotracheal tube. A prospective randomized double blind controlled clinicaltrial enrolled patients aged 18-50 years with physical status of ASA I and II whounderwent elective surgery with general anesthesia in Dr. Sardjito General Hospital, Yogyakarta.Subjects were divided into 2 groups. 50 patients of group A were given 30 mL ketamine gargle40 mg and 51 patients of group B were given 30mL benzydamine HCl gargle 0.075%. The sorethroat was measured whenever the patients were fully awake, 2 hours and 4 hours post-extubationwith Canbay score (no pain, mild pain, moderate pain and severe pain). There was a significantdifference (p<0.01) in sore throat incidence of both groups especially at fully awake and 2hours post-extubation; 20% in group A versus 66.7% in group B at fully awake and 16% ingroup A versus 58,8% in group B at 2 hours of post-extubation. However, there was not anysignificant difference in sore throat incidence of both groups at 4 hours post-extubation(p=0.394). In conclusion, giving ketamine gargle 40 mg 5 minutes before intubation is moreefficient in reducing sore throat after endotracheal tube-general anesthesia compared withbenzydamine HCl 0.075% at fully awake and 2 hours post-extubation.

ABSTRAKNyeri tenggorok merupakan komplikasi yang sering terjadi pada pasien pascaoperasi dengananestesi umum menggunakan intubasi pipa endotrakeal. Efek ini terjadi karena iritasi, kerusakanmukosa dan peradangan jalan napas akibat lubrikan gel pada laringoskopi atau penekanan daribalon pipa endotrakeal. Penelitian ini bertujuan membandingkan daya guna obat ketamin kumur40 mg dan obat kumur benzydamine HCl 0,075 % untuk mengurangi nyeri tenggorok pascaintubasisebelum pemasangan pipa endotrakeal. Penelitian ini merupakan uji klinis tersamar ganda denganmelibatkan pasien berusia 18-50 tahun dengan status fisik ASA I dan II yang menjalani operasielektif dengan anestesi umum di Rumah Sakit Umum Dr. Sardjito Yogyakarta. Subyek dibagimenjadi 2 kelompok, 50 pasien kelompok A diberi 30 mL ketamin kumur 40 mg dan 51 pasienkelompok B diberi 30mL benzydamine HCl kumur 0,075%. Nyeri tenggorok diukur setelahpasien sadar penuh, 2 jam dan 4 jam pasca operasi dengan skor Canbay (tidak ada nyeri, nyeriringan, nyeri sedang dan nyeri berat). Hasil penelitian menunjukkan adanya perbedaan kejadiannyeri tenggorok yang bermakna (p<0,01) pada kedua kelompok yaitu pada saat pasien mulaisadar penuh (20% pada kelompok A dan 66,7% pada kelompok B), dan 2 jam pasca ekstubasi(16% pada kelompok A dan 58, 8% pada kelompok B). Tidak ada perbedaan yang bermakna (p= 0,394) mengenai kejadian nyeri tenggorok antara grup A dan B pada 4 jam pasca ekstubasi.

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J Med Sci, Volume 44, No. 2, June 2012: 1-9

Sebagai kesimpulan, pemberian ketamin obat kumur 40 mg 5 menit sebelum intubasi lebihberdayaguna dalam mengurangi nyeri tenggorok pasca anestesi umum dengan pipa endotrakealdibandingkan dengan obat kumur benzydamine HCl 0,075% pada saat sadar penuh dan 2 jampasca ekstubasi.

Keywords : endotracheal tube - sore throat - ketamine gargle - benzydamine HCl gargle

INTRODUCTION

Incidence of sore throat is a frequentcomplaint by the patients after undergoingsurgery with general anesthesia using anendotracheal tube, which causes the patients tofeel uncomfortable in the throat area. This effectoccurs because there are mucosal irritation anddamage and inflammation in the airway whichare caused either by the gel as a lubricant andthe emphasis of laryngoscopy or endotrachealtube balloon.1,2 The mechanism of this incidenceof sore throat is due to trauma to the tonsils,pharynx, larynx and trachea that causes a localinflammatory response and pain.3

An endotracheal intubation action in thegeneral anesthesia is necessary to ensure airwaypatency and ensure that inhalation agents runand maintain the anesthesia. However, theaction to secure airway with endotracheal tubewill give some side effects with postoperativesore throat. An anesthesiologist is responsibleto minimize side effects of sore throat causedby the use of endotracheal tube. Eventhough thecomplications are rare, postoperative sorethroat can lead to morbidity and dissatisfactionfor the postoperative patients.4

Some actions have been conducted toreduce the incidence of postoperative sore throatcomplications with general anesthesia using anendotracheal tube both through non-pharmacological and pharmacological actions.The non-pharmacological actions can beperformed partly by using an endotracheal tubewith smaller size, providing a lubricant geldissolved in water of the endotracheal tube

balloon, inserting an endotracheal tube after thepatients have been completely relaxed with theircondition after induction of a jaw thrustpredictor is conducted without motoricresponses and reflexes of the airway, insertingendotracheal pipes after the vocal cordscompletely opened, suctioning the oropharynxarea with caution, reducing the pressure on theendotracheal tube balloon and performingextubation after endotracheal tube balloon iscompletely deflated.3,4

The pharmacological actions to reduce thesore throat can be conducted by providingbeclomethasone inhalation, intravenous andtopical steroids, giving medication withintravenous non-steroid anti-inflammatory drug(NSAID), intravenous ketamine, gargling withazulenesulphonate, benzydamine HCl, oralketamine and oral aspirin.5

The use of mouthwash before endotrachealintubation treatment is reported to reduce theincidence of sore throat. Canbay et al.4 andRudra et al.6 reported that ketamine garglesignificantly attenuates postoperative sore throat(POST) with no drug-related side effects.Ketamine is a rapidly acting anesthetic andanalgesic agent that has been used as generalanesthesia for more than 30 years. Now ketaminehas been used as new analgesic for peripheralpain. The existing ionotropic glutamatereceptor, such as N-methyl-D-aspartate(NMDA) receptor, on peripheral sensory axonscan be the basis of ketamine-induced analgesiaat peripheral.7,8

Agarwal et al.9 reported that benzydaminehydrochloride gargles significantly reduces the

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incidence and severity of POST. In addition, areview of clinical trials concluded thatbenzydamine HCl can be used as a treatmentoption for the oropharynx disorders and thepharynx, especially during post-intubation.10

Benzydamine HCl is included into the group oftopical NSAIDs that are widely used as the anti-inflammatorydrugs for the mouth. BenzydamineHCl reduces the prostaglandin (PGE2 and PGI2)synthesis in gingival fibroblasts, partly at thelevel of phospholipase A2, by diminishing theliberation of arachidonic acid (AA) fromphospholipids, and partly at the level ofcyclooxygenase.11

This study was conducted to compare theefficacy of ketamine 40 mg gargle withbenzydamine HCl 0.075% gargle in reducingpost intubation sore throat prior to the insertionof endotracheal tube.

MATERIALS AND METHODS

SubjectsOne hundred and one patients who

underwent elective surgery withgeneral anesthesia in Dr. Sardjito GeneralHospital, Yogyakarta were enrolled in thisprospective randomized double blind controlledclinical study. Patients were divided into 2groups. 50 patients of group A were given 30mL ketamine gargle 40 mg and 51 patients ofgroup B were given 30 mL benzydamine HClgargle 0.075%.

The inclusion criteria were men or womenbetween the age 18-64 years old, with the BodyMass Index (BMI) <30 kg/m2, physical statusASA I-II, elective surgical procedures with thesupine position to be performed under generalanesthesia with endotracheal intubation,duration of operation not more than 2 hours, noprediction for the intubation difficulty, andagreed to participate in the study. The exclusioncriteria in this study were the patients with

hypertension history and heart disease, surgeryon the airway, abdomen with the nasogastrictube which is required to install, patients withpain history of sore throat, hyperactive historyon the airway such as asthma, common cold,respiratory tract infection, history of allergy todrugs used in this study. While the criteria ofdrop-out was an attempt of intubation more than60 seconds, allergy medications used duringsurgery.

Study protocolAfter the patients arrival in the operating

room, the infusion of crystalloid at ½ fluid asreplacement of 1 hour fasting was admnisteredintravenously with the catheter IV no. 18 in alarge peripheral vein. Furthermore, patientswere randomly allocated to one of two groups.Group A received ketamine gargle 40 mg andgroup B received benzydamine HCl 0.075% 15mL.All medications were made into 30 mLwithdistilled water which was placed into anopaque bottle. The investigators and patientswere blinded to the medications given to thepatients. The patients were taught how to garglefor 30 seconds, therefore patients could gargleproperly and the mouthwash wet thehypopharynx and nosopharynx areas. Standardsfor patient monitoring during anesthesia i.e.electrocardiogram, blood pressure, meanarterial blood pressure (MAP), heart rate (HR)and oxygen saturation (SpO2) were initiated.

Five minutes after gargling with themouthwash, the patients were premedicated withmidazolam 0.05 mg/kgBW IV co-induction. Thiswas followed by IV induction with propofol 2mg/kg BW at a constant rate infusion 1.5 mg/kg/minute three minutes later until the negativereflect of eyelash, gave the ventilation foroxygen 100% with facemask. Endotrachealintubation was facilitated by injection ofrocuronium 0.6 mg/kg BB and then blood

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pressure, MAP, HR and SpO2 were monitored90 seconds later.

Endotracheal intubation was performedafter ensuring that the patient was completelyrelaxed, when just thrust predictor showed nomotoric response and airways reflect. Theendotracheal was intubated with the high volumelow pressure plastic pipe no 7 for females andno 7.5 for males. The cuff was inflated with airand cuff pressure was maintained around 22 cmof water with intracuffpressuremanometer. Theblood pressure, MAP, HR and SpO2 weremonitored again one minute later.

Anesthesia was maintained using 50% N2Oin 50% O2 and isoflurane. Ondansetron 4 mg IVand ketorolac 30 mg were administered 30minutes before the sugery was finished. At theend of surgery, N2O was stopped. Before thepatients were conscious as indicated with noairway reflexes but showed free of the muscleparalyzing, adequate breathing, stablehemodynamics, endotracheal extubation wasperformed followed with the 100% oxygenationby facemask until the patients opened their eyeswith mild stimuli. The patients were thentransferred to the postanesthesia care unit.

After the patients were fully conscious asindicated with the Ramsay score of 2, thepatients were interviewed by a blinded observerto assess POST. Kappa (ê) agreement test wasconducted between interobservers before beinginvolved in this study. The POST was assessedat 0, 2 and 4 hours after at patients arrival inthe postanesthesia care unit. The POST wasgraded on a four-point scale (0-3) as describedby Canbayet al.4 as follows: 0 as no sore throat,1 as mild sore throat (complains of sore throatonly on asking), 2 as moderate sore throat(complains of sore throat on his/her own) and

3 as severe sore throat (change of voice orhoarseness, associated with throat pain). Theside effects due to the the medications ingestionwere also monitored.

This research protocol has been approvedby Medical and Health Research EthicsCommittee, Faculty of Medicine, UniversitasGadjah Mada, Yogyakarta.

Statistical analysisDemographic data were presented as mean

± standard deviation (SD) and analyzed withone t-test for continuous variables and Mann-Whitney U test for categorical variables. Theincidence of postoperative symptos wasanalyzed by Chi-square test, whereas theseverity of symptoms was analyzed by theMann-Whitney U test. All statistical analysiswere perfermored with SPSS. Probability value(p) <0.05 was considered significant.

RESULTS

This study involved 101 patients consistingof 50 patients who gargled with ketamine 40mg and 51 patients who gargled withbenzydamine HCl 0.075 %. The characteristicsof patients of both group are presented inTABLE 1. Weight, height, BMI, anestheticduration, recovery conscious, sex and type ofsurgery were similar among the two groups,except the patients’age andASAphysical status.The age of patients receiving ketamine wasyounger than those receiving benzydamine HCl.The ASA physical status I of patients receivingketamine was higher than those receivingbenzydamine HCl. Conversely, the ASAphysical status II of patients receiving ketaminewas lower than those receiving benzydamineHCl.

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TABLE 1. Characteristics of patients of ketamine and benzydamine groups

The incidence of POST at 0, 2, and 4 hourspost-extubation on ketamine and benzydamineHCl groups is presented in FIGURE 1. Theincidence of POST on ketamine group at 0 and2 hours post-extubation was significantly lower

than benzydamine HCl group (p=0.001).However, at 4 hours post-extubation nosignificant difference in the incicidence ofPOST of both groups was observed (p=0.394).

FIGURE 1. The incidence of POST at 0, 2, and 4 hours post-extubationon ketamine and benzydamine HCl groups; * significantlydifferent p<0.05

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The severity of POST at 0, 2, and 4 hourspost-extubation on ketamine and benzydamineHCl groups is presented in TABLE 2.Significantly, more patients suffered severePOST on ketamine group at 0 and 2 hours post-

extubation compared with benzydamine HClgroup. However, the severity of POST wassimilar between ketamine group andbenzydamine HCl group.

TABLE 2. The severity of POST at 0, 2, and 4 hours post-extubation on ketamineand benzydamine HCl groups

Changes in blood pressure, diastolic bloodpressure, MAP, HR and SpO2 of the patientsafter entering operating room, at pre intubationand 1 min post intubation are presented inTABLE 3. No significant changes of patientshemodynamic were observed in between both

ketamine and benzydamine HCl groups(p>0.05), except the MAP at pre intubation thatshowed the MAP of patients ketamine groupwere lower than those receiving benzyldamineHCl.

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TABLE 3. Changes in blood pressure, diastolic blood pressure, MAP, HR and SpO2

of the patient at entered operating room, pre intubation and 1 min postintubation on ketamine and benzydamine HCl

SBP: sistolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial bloodpressure; HR: heart rate; SPO2: oxygen saturation; *significantly different

DISCUSSION

Postoperative sore throat (POST) is acommon occurrence after surgery under generalanesthesia using endotracheal tube. The POSTmay disappear after a few hours, but can occuragain for two days or more.12 Despite being aminor complication, POST contributes to post-operative morbidity and patient dissatisfaction.Some nonpharmacological and pharmacologicalintervention have been used for attenuatingPOST with variable success. In pharmaco-logical intervention, beclomethasone inhalation,azulene sulfonate gargle and some NSAID such

as tenoxicam and aspirin have been used toreduce POST.4,9 In this study, the efficacy ofketamine 40 mg and benzyldamine HCl 0.075%that administered prior to the endotrachealintubation for attenuating POST have beeninvestigated. The findings of this study may beused as an altervative pharmacological interven-tion to reduce POST in general anesthesia withendotracheal intubation.

The contributing factors influencing theincidence and severity of POST have beencontrolled in this study. The weight, height, BMI,anesthetic duration, recovery conscious, sex and

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type of surgery between ketamine group andbenzydamine HCl group were similar (p>0.05),except the patients age andASAphysical status(p<0.05). Although the patients age weredifferent, it was not correlated with POST asreported by Canbay et al. 4 while the ASAphysical status has neve been correlated withPOST in some studies.4,9 In addition, the suctionof mucus from the patients’ oropharynx wasconducted one time carefullyusing the same typeof endotracheal tube with size and high volumelow pressure no 7 for female and no 7.5 formale. The intracuff pressure was measured onthe initial endotracheal intubation andmaintained around 22 cm of water withintracuffpressuremanometer.

To avoid the presence of bias betweenobservers, kappa () agreement test wasconducted three weeks before study was started.Five residents who would be observers wereinvolved in this test. The kappa agreement testresult showed that thevalue interobserver was0.75 and 0.40.75. It was indicated thatthe moderate and substantial agreement betweeninterobserver were obatained in this test andcan be involved in this study.

The incidence of POST on patientsreceiving ketamine 40 mg gargle at 0 and 2 hourspost-extubation (20% and 16%) wassignificantly lower than those receivingbenzydamine HCl 0.075 gargle (66.7% and58.8%) (FIGURE 1). It was indicated thatketamine 40 mg gargle was more effective forattenuating POST compared with benzydamineHCl 0.075% in patients undergoing anesthesiawith endotracheal intubation. However, theincidence of POST for 4 hours post-extubationwas not significantly different on patientsreceiving ketamine 40 mg gargle (10%)compared to those receiving benzydamine HCl0.075% gargle (15.7%).

The incidence of POST on both patientsreceiving ketamine 40 mg and benzydamine HCl

0.075% were reduced in time-dependentmanner. It can be explained that noxious stimuliintensity (painful stimuli) derived fromanesthetic procedure such as laryngoscopy andendotracheal tube cuff pressure would becompesated by the body after several hours. Inaddition, administration of postoperativeanalgesic could reduce painful stimuli. In thisstudy, ketorolac 30 mg as postoperativeanalgesic was given 30 minutes before theoperation was completed.

The incidence of POST in patientsundergoing anesthesia with tracheal intubationhas been reported by some authors. Canbay etal.4 reported that the incidence of POST inTurkey was 30-40%, while in India theincidence of POST was 40%. In this study theincidence of POST was lower (16-20%) thanthose previous studies. Some contributingfactors for the incidence of POST have beenreported, including race, age, sex, type ofsurgery, large tracheal tube, cuff design, intracuff pressure, postoperative analgesicadministration, installation of naso gastric tube(NGT), and suctioning procedures.13,14

Ketamine is initially developed asanesthetic agent, however in low (subanes-thetic) doses, ketamine is widely used as ananalgesic in the treatment of both acute andchronic pain. The analgesic effect of ketamineis primarily based on the antagonism of NMDAreceptor.15,16 Besides acting on the NMDAreceptor, ketamine also acts on nicotinic,muscarinic and opioid receptors.17 Meanwhilethe benzyldamine HCl is a topical NSAID thathas analgesic, local anesthetic, antiinflammatoryand antimicrobial properties.18 Thesemechanism of actions of benzyldamine HCl maybe mediated by the prostaglandin system.19Bothof ketamine and benzyldamine HCl have beenused in reducing the incidence and severity ofPOST. Differences in their pharmacodynamicsand pharmacokinetics may contribute in the

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efficacy of these drugs to reduce POST ingeneral anesthesia with endotracheal intubation.

The hemodynamic changes of patients afterentering the operating room, at pre-intubationand one minute post intubation were monitored.No significant hemodynamic changes of patientswere observed on both ketamine andbenzydamine HCl groups (p>0.05), except theMAP at pre intubation where the MAP ofpatients in ketamine group were lower than thosereceiving benzyldamine HCl. However, thisMAP value was still in normal range (70-110mmHg). The stability of the patients’hemodynamic changes might be a consequenceof the smooth insertion conducted, and completerelaxation in patients as indicated by the absenceof motoric response and air ways after a jawthrust.

CONCLUSION

It can be concluded that ketamine 40 mggargle is more effective for attenuating theincidence and severity of POST compared withbenzydamine HCl 0.075% in patientsundergoing anesthesia with endotrachealintubation.

ACKNOWLEDGEMENT

Authors would like to thank all patients whohave participated in this study. We also thankall observers for their valuable assistance inscoring of POST.

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efficacy of ketamine gargle 40 mg and benzydamine hcl 0

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