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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA SYNOPSIS OF DISSERTATION “COMPARISON OF SINGLE DOSE OF INTRAVENOUS RAMOSETRON AND RAMOSETRON PLUS DEXAMETHASONE AS PROPHYLACTIC ANTI- PONV IN PATIENTS COMING FOR ELECTIVE ENT SURGERIES-A CLINICAL STUDY” Submitted by Dr. AMITHA.S M.B.B.S. POST GRADUATE STUDENT IN ANAESTHESIOLOGY (M.D.) DEPARTMENT OF ANAESTHESIOLOGY ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA-571448 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION Dr. AMITHA.S D/O K.C.SEENAPPA ‘BELLI CHUKKI’ SIT EXTENSION, 16TH CROSS, GANGOTRI ROAD, TUMKUR, KARNATAKA- 572102 1 NAME OF THE CANDIDATE AND ADDRESS (in block letters) 2. NAME OF THE INSTITUTION ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA. 3. COURSE OF STUDY AND SUBJECT M.D. IN ANAESTHESIOLOGY 4. DATE OF ADMISSION TO COURSE 28TH APRIL 2010 5. “COMPARISON OF SINGLE DOSE OF INTRAVENOUS RAMOSETRON AND RAMOSETRON PLUS DEXAMETHASONE AS PROPHYLACTIC ANTI- PONV IN PATIENTS COMING FOR ELECTIVE ENT SURGERIES-A CLINICAL STUDY” TITLE OF THE TOPIC BRIEF RESUME OF INTENDED WORK 6. 7 6.1 NEED FOR THE STUDY APPENDIX-IA 6.2 REVIEW OF LITERATURE APPENDIX-IB 6.3 OBJECTIVES OF THE STUDY APPENDIX-IC MATERIALS AND METHODS APPENDIX-II 7.1 SOURCE OF DATA APPENDIX-IIA 7.2 METHOD OF COLLECTION OF DATA : (INCLUDING SAMPLING PROCEDURE IF ANY) APPENDIX-IIB 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS, IF SO PLEASE DESCRIBE BRIEFLY. APPENDIX-IIC 7.4 HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3 YES APPENDIX-IID 1 8. LIST OF REFERENCES 9. SIGNATURE OF THE CANDIDATE 10. REMARKS OF THE GUIDE 11 NAME AND DESIGNATION (in Block Letters) APPENDIX - III STUDY WILL BE CONDUCTED AT A.I.M.S. 11.1 GUIDE Prof. Dr. RADHA. M.K. M.B.B.S., M.D. Professor and Head of the Department, Department of Anaesthesiology, AIMS, B.G. Nagara-571448 11.2 SIGNATURE OF THE GUIDE 11.3 CO-GUIDE (IF ANY) NONE 11.4 SIGNATURE - 11.5 HEAD OF DEPARTMENT Prof. Dr. RADHA. M.K. M.B.B.S., M.D. Professor and Head of the Department, Department of Anaesthesiology, AIMS, B.G. Nagara-571448 11.6 SIGNATURE 12 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL 12.2 SIGNATURE 2 APPENDIX-I 6.BRIEF RESUME OF THE INTENDED WORK: APPENDIX –I A 6.1 NEED FOR THE STUDY: Post operative nausea and vomiting complicates the lives of both patients and health care providers. The incidence of PONV varies between 20% and 30% depending on surgical and patient factors1. Nausea is the uncomfortable sensation of impending episode of vomiting it is often associated with prodromal symptoms such as salivation, swallowing, tachycardia etc. Vomiting is a complicated process, mediated by a central co-ordinating “Vomiting Center”, though to reside in the brain stem (close to the Tractus solitarius) called the parvicellular Reticular formation or the emetic center2. This is accompanied by multiple autonomic phenomena including salivation, Shivering and vasomotor changes3,4. During prolonged episodes, marked behavioral changes including lethargy, depression and withdrawal may occur3,4. Hence PONV may prolong recovery, delay patient discharge, increase hospital expenditure 5 and thereby need to prevent the incidence of PONV. Several studies were done in comparing ondansetron, dexamethasone and ondansetron plus dexamethasone as a prophylactic antiemetic therapy in patients undergoing day-case gynecological surgeries. Ondanestron is a selective 5HT3-Receptor antagonist. Dexamethasone reduces inflammation and acts on opioids receptor these drugs act in emetic centre to reduce incidence of PONV and studies showed that combination of drugs would be better in prevention of PONV than use of either drug alone (ondansetron 4mg, dexamethasone 8mg)6. Studies have also being done in comparing ramosetron versus ondansetron for the prevention of PONV in patients undergoing gynecological surgery. Ramosetron is a newer congener of ondansetron having more potency than the latter. 3 The result found to be ramosetron more potent than ondansetron in reducing nausea severity in female patients undergoing gynecological surgery7. In 2003 studies had done, to evaluate the role of dexamethasone in reducing post operative vomiting & pain after pediatric tonsillectomy. Results found that, pre operative dexamethasone 0.5mg/kg i.v. reduced both post operative vomiting & pain in children after electrocautery tonsillectomy 8. Since very few studies were done in comparing Ramosetron & Ramosetron plus dexamethasone we have made an attempt to compare whether Ramosetron alone is sufficient or combination of drugs is effective in prevention of PONV. APPENDIX –I B 6.2 REVIEW OF LITERATURE Post operative nausea and vomiting complicates the lives of both patients and health care providers. The incidence of PONV varies between 20% and 30% depending on surgical and patient factors. Several studies have been made to know the most economical and most preferred drug to be opted to prevent PONV. K.Liu et-al in 19988 did a double blind randomized study to compare the effect of dexamethasone versus placebo on postoperative emesis and pain in a 60 women undergoing general anaesthesia for major gynaecology surgery. Dexamethasone 10mg (group D) or saline (group S) was administered i.v. in a double blind manner during induction of anaesthesia. Post operative pain relief was controlled with bolus doses of morphine using an i.v. patientcontrolled analgesic device, and patients were assessed for incidence of vomiting, sedation score, verbal pain rating score, time to first morphine demand & morphine consumption at 4 4,8,12&24 hr after surgery. Six patients in group D & 19 in group S experience vomiting at least once within 24hr postoperative period; dexamethasone was effective in reducing the overall incidence of vomiting from 63.3% to 20.0% (p<0.01). Other variables were similar between the groups, and the influence of dexamethosone on postoperative pain was minimal. R. Thomas et-al in 20019 performed a prospective randomized, double-blind comparative study of dexamethasone, ondansetron and ondansetron plus dexamethasone as prophylactic antiemetic therapy in patients undergoing day case gynecological surgery. In this study, the effect of combination in comparisons to either of drug alone investigated in day care gynecological surgery. A total of 177 patients were randomized to three groups: dexamethasone8mg, ondansetron 4mg, dexamethasone 8 mg plus ondansetron 4mg. The result found that combination of drug would be better in prevention of PONV than use of either drug alone. Dr.Moktar elhakim et-al in 200310 did a double blind study to evaluate the effects of single dose of dexamethasone on the incidence and severity of post operative vomiting and pain in children undergoing electro cautery tonsillectomy under standardized general anesthesia. About 120 patients were randomly allocated either dexamethasone 0.5mg/kg (maximum 8mg) i.v. or an equivalent volume of saline preoperatively .The incidence of early and late, need for rescue antiemetic time of first oral intake, time of first demand of analgesia & analgesic consumption were compared in both groups. Pain score used includes children’s hospital eastern Ontario pain scale “faces,’’ & a 0-10 visual analogue pain. The results found that Compared with placebo, dexamethasone significantly decreases the incidence of early &late vomiting (p<0.005,p<0.001)respectively. .Fewer patient with dexamethasone group needed antiemetic rescue (p<0.01).the time of first oral intake was shorter, and the time of first dose of analgesic was longer in the dexamethasone group (p<0.01). Pain scores 30 min after 5 extubation were lower (p<0.005) in dexamethasone group. Hence concluded Preoperative dexamethasone 0.5mg/kg iv reduces both post operative vomiting & pain in children after electro cautery tonsillectomy. Aarti Nandkumar Pawar et- al in 200911 did comparative study of single dose intravenous dexamethasone.Ondansetron And Ondansetron Plus Dexamethasone As Prophylactic anti-Emetic therapy in Patients Undergoing Laparoscopic Gynecological Surgery. The study was undertaken on 120 patients in the age group of to 65 years with ASA grades I & II undergoing gynaecologic laparoscopic intervention under general anaesthesia. Group 1 received Inj. Ondansetron 4mg with Inj. Dexamethasone 8mg as single dose I V bolus 5 minutes before induction of anaesthesia. Group 2 received Inj. Ondansetron 4mg as single dose I V bolus 5 minutes before induction of anaesthesia. Group 3 received Inj. Dexamethasone 8mg as single dose I V bolus 5 minutes before induction of anaesthesia. A standard anaesthetic protocol was used in all the patients. 5 min prior, the patients received the anti – emetic as per their groups Induction of general anaesthesia was done with Inj. Propofol 2 – 3 mg / kg IV. Intubating conditions were achieved with Inj. Suxamethonium 2 mg / kg I V. Trachea was intubated with appropriate sized cuffed PVC endotracheal tube. General anaesthesia was maintained with O2 + N2O::40:60.,skeletal muscle relaxation was maintained with of Inj. Atracurium 0.5mg / kg as loading dose and 0.05mg/kg as supplemental doses. The duration of anaesthesia, surgery, pneumoperitoneum was noted. Nasogastric tube was introduced after induction & suction of gastric contents was done before recovery & was removed after extubation. The patients were evaluated at regular intervals of time in the post operative period for complaints of nausea, vomiting. The results were found that Combination of Inj. Ondansetron 4mg with Inj. Dexamethasone 8mg proved to be more efficacious over either drug alone. 6 Fujii Y et-al in 199912 compared Ramosetron versus granisetron for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. In this randomized, double-blind study, 80 female patients received 3 mg granisetron and 0.3 mg ramosetron i.v. (n=40 of each) at the completion of surgery. The standardized anesthetic included isoflurane and nitrous oxide in oxygen. The response found that the incidence of patients with no complaints PONV during the first 24 hr after anesthesia was 85% with granisetron and 93% with ramosetron, respectively (P=0.241); the corresponding incidence during the next 24 hr (24-48 hr) after anesthesia was 63% and 90% (P=0.004). No clinically important adverse events due to the study drug were observed in any of the groups. This study showed Ramosetron was more effective than granisetron for prevention of PONV during 0-48 hr after anesthesia for laparoscopic cholecystectomy. Fujii Y et-al in 200013 performed a prospective, randomized, double-blinded study, they evaluated the efficacy of granisetron and ramosetron for preventing postoperative nausea and vomiting (PONV) in major gynecologic surgery. The study consist of No clinically serious adverse events due to the drugs were observed in any of the groups. 120 patients, ASA physical status I or II, aged 23-65 yr, received i.v. granisetron 2.5 mg or ramosetron 0.3 mg (n = 60 each) at the end of surgery. A standard general anesthetic technique and postoperative analgesia were used. The incidence of a complete response, defined as no PONV and no need for another rescue medication, 0-3 h after anesthesia was 87% with granisetron and 90% with ramosetron; the corresponding incidence 3-24 h after anesthesia was 85% and 90%; the corresponding incidence 24-48 h after anesthesia was 70% and 92% (P < 0.05). They concluded that prophylactic therapy with ramosetron is more 7 effective than granisetron for the longterm prevention of PONV after major gynecologic surgery. Fujii Y et-al in 200014 did a prospective, randomized, double-blinded, placebo- controlled trial for Ramosetron in preventing postoperative nausea and vomiting in women undergoing gynecological surgery. The study consist of One hundred twenty women, ASA physical status I or II, aged 21-63 yr, received IV either placebo or ramosetron 0.15, 0.3, or 0.6 mg (n = 30 of each) at the completion of surgery. A standard general anesthetic technique and postoperative analgesia were used. A complete response, defined as no PONV and no need for another rescue antiemetic, during 0-3 h after anesthesia occurred in 40%, 47%, 87%, and 90% of patients who had received placebo and ramosetron 0.15, 0.3, and 0.6 mg, respectively. Corresponding results during 3-24 h after anesthesia were 43%, 50%, 87%, and 90%, and 2448 h after anesthesia were 50%, 53%, 90%, and 93% (P < 0.05). Patients who had received ramosetron 0.3 or 0.6 mg were satisfied compared with those who had received placebo (P < 0.05). There were no serious clinical adverse events caused by the study drug in any of the groups. The report shows that, ramosetron 0.3 mg is an effective antiemetic for preventing PONV during 0-48 h after anesthesia in female patients undergoing gynecological surgery. Increasing the dose to 0.6 mg provided no further benefit. Fujii Y et-al in 200115 performed prospective, randomized, double-blind study, Comparing granisetron versus ramosetron in Prevention of vomiting after tonsillectomy in children: Granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, is effective for the prevention of vomiting after tonsillectomy in children. Ramosetron antagonist of 5- 8 hydroxytryptamione type 3 receptor, has more potent and longer-acting properties than granisetron Ninety pediatric patients, aged 4 to 10 years, received intravenously granisetron 40 microg/kg or ramosetron 6 microg/kg (n = 45 each) at the end of surgery. The same standard general anesthetic technique and postoperative analgesia were used throughout. Emetic episodes and safety assessment were performed during the first 24-hour period and the next 24-hour period after anesthesia. The authors found that Ramosetron is a better antiemetic than granisetron for the long term prevention of postoperative vomiting in children undergoing general aneshesia for tonsillectomy. Fujii Y et-al in 2003 16performed Randomized, double-blind, placebo-controlled, dosedfinding study of the antiemetic effects and tolerability of ramosetron in adults undergoing middle ear surgery the study to determine the minimum effective and tolerable dose of ramosetron needed to prevent postoperative emetic symptoms in adult patients undergoing middle ear surgery. Patients aged more than 20 years scheduled for middle ear surgery were randomized to receive either placebo or ramosetron at 1 of 3 doses (0.15, 0.3, or 0.6 mg), regardless of body weight, i.v. immediately before anesthesia induction. Emetic symptoms (nausea, retching, or vomiting) occurring from 0 to < 24 and 24 to 48 hours after the start of anesthesia were recorded. The authors concluded Ramosetron 0.3 mg, regardless of body weight, was more effective than either ramosetron 0.15 mg or placebo and as effective as ramosetron 0.6 mg for the prevention of emetic symptoms in the first 48 hours after the start of anesthesia in this selected population of adult patients who underwent middle ear surgery. 9 Lee D et-al in 200917 studied the effect of oral and IV ramosetron on postoperative nausea and vomiting in patients undergoing gynecological laparoscopy with total intravenous anesthesia. The study consists of 120 women were allocated randomly to one of three groups (n = 40 in each) to receive saline (control), 0.1 mg oral ramosetron (PO), or 0.3 mg IV ramosetron (IV). Total intravenous anesthesia (TIVA) with propofol and remifentanil was used in all patients. The results concluded that The effect of oral ramosetron 0.1 mg was comparable to that of IV ramosetron 0.3 mg on the prevention of PONV in women undergoing gynecological laparoscopy with TIVA. Both the oral and IV forms were effective at preventing PONV during the first 1 hr after surgery. Kim SI et-al in 200918 studied the Comparison of ramosetron with ondansetron for prevention of postoperative nausea and vomiting in patients undergoing gynaecological surgery. In this prospective, randomized, double-blinded, placebo-controlled study, 162 healthy patients who were undergoing gynecological operation under general anaesthesia using sevoflurane were enrolled. Patients were divided into three groups: the ramosetron group (0.3 mg i.v.; n=54), the ondansetron group (8 mg i.v.; n=54), and the placebo group (normal saline i.v.; n=54). The treatments were given before the end of surgery. The incidence of PONV, severity of nausea, and the use of rescue antiemetic requirements during the first 24 h after surgery were evaluated. The results that found ramosetron 0.3mg i.v. was as effective as ondansetron 8mg i.v. in decreasing incidence of PONV and reducing nausea severity in female patients during first 24 hr after gynaecological surgery. 10 APPENDIX –IC 6.3 OBJECTIVE OF THE STUDY To evaluate and compare the efficacy of Ramosetrone and Ramosetrone with dexamethasone in patient undergoing elective ENT surgery perioperatively period (24 hours). 1. To compare the effficacy of the drugs 2. To compare the vital parameters in terms of Pulse rate,SPO2 and Respiratory rate in each group. 3. To compare the complications if any. 11 APPENDIX-II 7.0 MATERIALS AND METHODS APPENDIX-IIA 7.1 SOURCE OF DATA An open comparative randomised study that will include 60 patients of ASA Grade I and II between 20-40 years of age scheduled for ENT elective surgery under general anaesthesia in Adichunchanagiri Institute of Medical Sciences, Research center and Hospital.B.G.NAGARA-571448. Ethics committee’s permission taken.The total study period will be of 18 months of duration. A thorough preanaesthetic evaluation with relevent and appropriate investigations ordered and done in the selected patients for the following study. Patients wil be divided into two groups of thirty each. Group A - Injection Ramosetrone – 0.3 mg Group B - Injection Ramosetrone-0.3 mg with Injection Dexamethasone-8 mg Premedication:Inj glycopyrolate 0.2mg+ Inj.Midazolam 1mg/kg body wt +Inj.Fentanyl 2 microg/kg body wt will be given and all operations will be performed under general anaesthesia.In Group A prophylactically Inj Ramosetrone was injected and in Group B Inj Ramosetrone with Inj Dexamethasone was injected. Anaesthesia will be induced in with Inj.Thiopentone 5mg/ kg .body.wt.and intubation is achieved with injection Succinyl choline 1.5 mg / kg.body .wt. Maintainance of Anaesthesia will be with inhalation of nitrous oxide 67%+oxygen 33% and halothane 1 % delivered via a Bain coaxial system with controlled 12 ventilation. Muscle relaxation will be facilitated using Inj.Vecuronium bromide 0.02 mg/ kg.body.wt. APPENDIX-II B 7.2 METHOD OF COLLECTION OF DATA INCLUSION CRITERIA 1. Patients belonging to ASA grade 1 & 2 undergoing elective ENT surgical procedures. 2. Patients of either sex, between the age group 20-40 years. 3. Patients Body mass index between 18-25 EXCLUSION CRITERIA 1. Patient refusal. 2. Patients belonging to ASA grade III or IV 3. Patients with previous history of allergy to any anaesthetic agents. 4. Patients with Body mass index more than 1.5 times normal. 5. Patient coming for any emergency surgeries 6. Obstetrics patients coming for elective ENT sugeries. PARAMETERS OBSERVED 1. Vital parameters pulse rate, respiratory rate, blood pressure, SPO2 after induction with either of the drug intra operatively at regular intervals. 2. To study any untoward reaction with either of the drug peri operatively. 3. Time at which first rescue antiemetics administered to either of the patietns group. 4. Frequency of rescue antiemetics administered to the patients. 13 STATISTICAL ANALYSES For this study finally for comparing the efficacy and potency of drugs will be done by standard deviation + 0.5 and with paired “t” students test. P value will be considered significant when it is < 0.05 APPENDIX-II C 7.3 Does the study require any investigation or interventions to be conducted on patients or other animals, if so please describe briefly. NO 14 APPENDIX-II D PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL SECTION A “COMPARISON OF SINGLE DOSE OF INTRAVENOUS RAMOSETRON AND RAMOSETRON PLUS DEXAMETHASONE AS PROPHYLACTIC ANTI- PONV IN PATIENTS COMING FOR ELECTIVE ENT SURGERIES-A CLINICAL STUDY” Dr. AMITHA. S. P.G IN ANAESTHESIOLOGY, ADICHUNCHUNAGIRI INSTITUTE OF MEDICAL SCIENCES.B.G NAGARA, MANDYA DISTRICT -571448 a Title of the study b Principle investigator (Name and Designation) c Co-investigator (Name and Designation) Prof. Dr. RADHA. M.K. M.B.B.S., M.D. Professor and Head of the Department, Department of Anaesthesiology, AIMS, B.G. Nagara-571448 d Name of the Collaborating Department/Institutions Radiology, Biochemistry and Surgical Faculties e Whether permission has been obtained from the heads of the collaborating departments & Institution Section – B Summary of the Project YES APPENDIX - I Section – C APPENDIX – IC Objectives of the study Section – D APPENDIX - II Methodology Where the proposed study will be A undertaken DEPARTMENT OF ANAESTHESIOLOGY, S.A.H. & R.C., B.G.NAGARA B Duration of the Project 18 MONTHS C Nature of the subjects: Does the study involve adult patients? YES Does the study involve Children? NO Does the study involve normal volunteers? NO Does the study involve Psychiatric patients? NO Does the study involve pregnant women? NO 15 D If the study involves health volunteers I. Will they be institute students? NO II. Will they be institute employees? NO III. Will they be Paid? NO IV. If they are to be paid, how much per NA session? E Is the study a part of multi central trial? NO F If yes, who is the coordinator? (Name and Designation) NA Has the trail been approved by the ethics Committee of the other centers? - If the study involves the use of drugs please indicate whether. - I. The drug is marketed in India for the YES indication in which it will be used in the study. II. The drug is marketed in India but not for the indication in which it will be used in the study NA III. The drug is only used for experimental use in humans. NA IV. Clearance of the drugs controller of India has been obtained for: NA Use of the drug in healthy volunteers Use of the drug in-patients for a new NA indication. Phase one and two clinical trials Experimental use in-patients and healthy volunteers. 16 G How do you propose to obtain the drug to be used in the study? - Gift from a drug company - Hospital supplies - Patients will be asked to purchase - Other sources (Explain) NA H Funding (If any) for the project please state - None - Amount - Source - To whom payable NO Does any agency have a vested interest in the I NO out come of the Project? Will data relating to subjects /controls be stored J NO in a computer? Will the data analysis be done by K - The researcher? - The funding agent YES NO L Will technical / nursing help be required form NO the staff of hospital. If yes, will it interfere with their duties? NO Will you recruit other staff for the duration of NO the study? If Yes give details of I. Designation II. Qualification III. Number IV. Duration of Employment NA 17 M Will informed consent be taken? If yes YES Will it be written informed consent: YES Will it be oral consent? NO Will it be taken from the subject themselves? YES Will it be from the legal guardian? If no, give NO reason: N Describe design, Methodology and techniques APPENDIX II Chairman, P.G Training Cum-Research Institute, A.I.M.S., B.G.Nagara. Date : PS : NA – Not Applicable 18 APPENDIX-III 8. LIST OF REFERENCES 1. WATCHA-MF,WHITE-PF.’’Postoperative nausea and vomiting.its etiology,treatment & prevention”.Anesthesiology.77:167-87.1992. 2. ANDREW-PL.Physiology of nausea and vomiting BRITISH JOURNAL OF ANAESTHESIA 69(Suppl):2s-19s.1992. 3. Drugs for emesis,Reflux and digestive disorder.Tripathi KD ,Essentials of medical pharmacolory.6th edition. 4. Sander-Bush E,Mayer SE 5-(Hydroxytryptamine(serotonin);Receptor agonist and antagonist.Bruton LL,Lazo JS,Parker kl. GOODMAN AND GILMAN’S The pharmacology basis of therapeutics.11th edition. 5. WATCHA-MF,WHITE-PF.’’Postoperative nausea and vomiting.its etiology,treatment & prevention”.Anesthesiology.77:161-184.1992. 6. R.Thomas & N.Jones BRITISH JOURNAL OF ANAESTHESIA 87(4);588-92;2001 7. Kim SL, Kim SC et al ;Br J Anaesth. 2009 Oct;103(4):549-53. 8. K.Liu, c.c. Hsu and Y.Y CHA;BJA 1998;80:85-86 9. R. Thomas and N.Jones BJA 87(4);588-92; 2001 10. Mokhtar Elhakim , Naglaa M;CANADIAN JOURNAL OF ANAESTHESIOLOGY 2003;50:4;392-397. 11. Aarti nandakumar Pawar, Manjula sarkar; The internet journal of anaesthesiology ISSN: 1092-406X pg 1-7. 12. Fujii Y, Saitoh Y et al; Can J Anaesth. 1999 Oct;46(10):991-3. 13. Fujii Y, Saitoh Y et al; Anesth Analg. 2000 Apr; 90(4); 1004-7 14. Fujii Y, Saitoh Y et al; Anesth Analg. 2000 Feb;90(2):472-5. 19 TM 15. Fujii Y, Saitoh Y et al; Laryngoscope. 2001 Feb;111(2):255-8. 16. Fujii Y, Hiroyoshi Tanaka Clin Ther. 2003 Dec;25(12):3100-8. 17. Lee D, Kim Jy et al J Anesth. 2009;23(1):46-50. Epub 2009 Feb 22. 18. S.I. Kim, S.C.Kim et al Br J Anaesth. 2009 Oct;103(4):549-53. 20