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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. NAME OF THE CANDIDATE AND ADDRESS 2. NAME OF THE INSTITUTION 3. COURSE OF STUDY & SUBJECT 4. DATE OF ADMISSION TO THE COURSE 5. Dr. RAJESH.R.NAYAK. POST GRADUATE STUDENT DEPARTMENT OF ANAESTHESIOLOGY, BANGALORE MEDICAL COLLEGE & RESEARCH INSTITUTE, BANGALORE - 560002 BANGALORE MEDICAL COLLEGE AND RESEARCH INSTITUTE DOCTOR OF MEDICINE IN ANAESTHESIOLOGY 06 - 06 – 2013 TITLE OF THE TOPIC: A COMPARATIVE STUDY OF DESFLURANE REQUIREMENT AND RECOVERY CHARACTERISTICS IN ENTROPY GUIDED GENERAL ANAESTHESIA WITH OR WITHOUT DEXMEDETOMIDINE INFUSION. 6. BRIEF RESUME OF THE INTENDED WORK 6.1 NEED FOR THE STUDY: Desflurane is a new inhalational anaesthetic with lowest blood gas solubility coefficient and hence associated with faster recovery times. It is also said to be more economical as it reduces the stay in the operating room. However desflurane is considered to be more expensive than other volatile anaesthetics1. Hence, studies on reduction in its consumption have gained more importance. 1 Dexmedetomidine is a highly selective alpha 2 adrenoceptor agonist, which possesses hypnotic , sedative, anxiolytic, sympatholytic and analgesic properties without producing significant respiratory depression2,3. Sedative and hypnotic drugs have the ability to reduce both the anaesthetic and opioid requirements.,4,5,6 Although experience with alpha 2 agonists as sole anaesthetic is limited, these drugs reduce anaesthetic requirement6. Its sympatholytic effect decreases mean arterial pressure (MAP) and heart rate (HR) by reducing norepinephrine release,8,9. By using entropy we can measure the adequacy of depth of anaesthesia. The difference between the response entropy and state entropy should be less than 10. Studies evaluating the effect of dexmedetomidine infusion on consumption of desflurane anaesthesia using entropy are sparse. In our study we decided to evaluate the effect of continuous infusion of dexmedetomidine on the requirement of desflurane and its recovery characteristics while continuously monitoring entropy. 6.2 REVIEW OF LITERATURE: Earl M Stry and coworkers studied the emergence and recovery characteristics of desflurane versus sevoflurane in morbidly obese surgical patients. They studied 50 morbidly obese patients(BMI >35 and ASA physical status II-III) requiring gastrointestinal bypass surgery via open laparotomy. Patients were randomized to receive desflurane and sevoflurane for maintenance of anaesthesia. They concluded that recovery after prolonged anaesthesia with desflurane is shorter than with sevoflurane anaesthesia10. Keles and coworkers studied balanced anaesthesia with dexmedetomidine added to desflurane or sevoflurane in spinal surgery. Sevoflurane and desflurane inhalational anaesthetics were used for fast track neuroanaesthesia. Dexmedetomidine is used to provide analgesia, sedation and hemodynamic stability. One hundred patients of ASA I-II aged between 18-65 were randomly divided into two groups. Following the standard anaesthesia induction group (D+D) (n=50) received 2-4% desflurane + 0.2mcg per kg per hr dexmedetomidine and group (S+D) (n=50) received 1-3% sevoflurane +0.2 mcg per kg per hr dexmedetomidine in 60% N2O for anaesthesia management. Extubation time and fast track criteria & Aldrete criteria were evaluated in the operating room, at the 5th and 10th minute and in the postanaesthetic care unit at the 5th, 15th and 25th minutes. They concluded that balanced anaesthesia with desflurane & 2 dexmedetomidine combination is superior to sevoflurane & dexmedetomidine in extubation and time to reach fast track criteria and aldrete criteria in spinal surgery. S.K. Tsai and others studied recovery in 25 adult patients of ASA I undergoing elective orthopedic procedure after anaesthesia with 0.65 MAC desflurane (n=16) and isoflurane (n =9) with 60 % nitrous oxide in oxygen. Early emergence from anaesthesia was assessed in the operating room by measuring time to spontaneous movement, cough, response to painful pinch, tracheal extubation ,opening of eyes and stating correct name, age and body parts. The return of cognitive functions in the late recovery phase was assessed in the post-anaesthesia care unit (PACU) by post-anaesthesia recovery scores (PARS), the Trieger dot test (TDT) and the digit substitution test (DST). Recovery times were not increased by increased duration of desflurane anaesthesia. The desflurane patients showed no delirium, minimal sedation and less shivering during the entire postoperative course. They concluded that desflurane anaesthesia was superior to isoflurane anaesthesia, not only in emergence, but also in the recovery of cognitive functions. Aliyeva A and coworkers studied the effect of 2 different doses of dexmedetomidine on desflurane consumption and hemodynamic parameters. Sixty patients aged 18-60 were divided into 3 groups. Group A received 1mcg /kg of dexmedetomidine infusion, group B received 0.5 mcg/kg of dexmedetomidine infusion and group C received physiological saline solution. During operation hemodynamic parameters, desflurane consumption were recorded. It is concluded that administration of dexmedetomidine as 1mcg/kg and 0.5 mcg/kg infusion decreased desflurane consumption by 45 % compared to control group11. Shin HW and coworkers studied the effect of dexmedetomidine infusion at 1 mcg/kg on sevoflurane consumption during general naesthesia. Forty two patients of ASA status I and II undergoing gynaecological surgery with anticipated operation time of 2 hrs, were randomly assigned to receive dexmedetomidine 1mcg/kg (Dex group) or saline (Control group) intravenously over 10 min before anaesthetic induction. After tracheal intubation with propofol 2mg/kg,cisatracurium 0.15 mg/kg intravenous, anaesthesia was maintained with sevoflurane,O2 50 %, N2O 50%. It was concluded that preanaesthetic dexmedetomidine 1mcg/kg single infusion decreased the sevoflurane consumption without the change of recovery times12. Robert J Fragen et Al studied the effect of dexmedetomidine on the minimum alveolar concentration of sevoflurane in adults aged55 to 70 years. Forty five adults aged between 55-70 years with ASA grade I and II were enrolled in this study. They Concluded that 3 Dexmedetomidine 0.7 ng/ml decreased the MAC of sevoflurane by 17%, whereas there was no difference between the placebo and the dexmedetomidine 0.39 ng/ml group13. 6.3 6.3 AIM AND OBJECTIVES OF THE STUDY: To study the effect of dexmedetomidine infusion on desflurane consumption, recovery characteristics and side effects in entropy guided general anaesthesia. 7 MATERIAL AND METHODS: 7.1 SOURCE OF DATA: a) Study Site Victoria hospital And Bowring and Lady Curzon Hospitals attached to Bangalore Medical College and Research Institute . b) Study Duration The study will be done between November 2013 to May 2015 c) Design Of Study Prospective, randomized, control trial, double blind study. . d) Sample Size Keeping the power of study as 80% and confidence limit at 95%,to detect a 20% change in desflurane consumption, the minimum sample size required is 12 in each group. We have included 25 patients in each group. Patients classified as per American Society of Anesthesiologists (ASA) classes I and II scheduled for elective surgery under general anaesthesia will be studied. The patients will be randomly allocated into two groups of 25 each. 4 e) Inclusion criteria 1) Patients who give informed written consent.(annexure I) 2) Patients aged between 18 to 45 years. 3) Patients belonging to ASA Grade I and Grade II. f) exclusion criteria: 1) An allergy to adrenergic agonists. 2) A history of uncontrolled hypertension. 3) Heart block greater than first degree. History of uncontrolled hypertension. 4) A history of alcohol or drug abuse. 5) Clinically significant neurologic, cardiovascular, renal, hepatic, gastrointestinal diseases. 7.2 METHOD OF COLLECTION OF DATA: 1) Sampling method: After obtaining informed written consent from patients, patients will be randomly divided into 2 groups Group D : Dexmedetomidine group – patients Group P: Control group-Patients. MATERIALS AND METHODS: With a minimum Fasting state of 6-8 hours before anaesthesia IV access will be obtained and standard monitoring will consist of Electrocardiography (ECG), pulse Oximetry, Noninvasive Blood pressure(NIBP), Entropy sensor, Neuromuscular transmission indicator(NMT) and capnography. The spectral entropy will be measured with a plug in Datex ohmeda entropy S/5 module. All patients will be pre-oxygenated with 100% oxygen for 3 minutes and inj.Midazolam 0.05mg/kg IV, inj.Fentanyl 2micrograms/kg IV will be administered. Dexmedetomedine group (D) patients will be given a loading dose of inj.Dexmedetomedine 1microgm/kg IV made to 20ml with normal saline, over 10 minutes. Anaesthesia will be induced with inj. Propofol in successive 30mg doses every 2 minutes until RE drops to 60,and will be 5 confirmed with loss of response to verbal commands .Control group(C) patients will receive similar volume of normal saline 0.9% over 10 minutes, and anesthesia will be induced with inj.Propofol in the same manner as in group (D). Additional dose of inj.Propofol 20-30 mg bolus will be given until no increase in entropy values is observed. Both groups will receive inj.Vecuronium 0.1mg/kg IV to facilitate tracheal intubation. A maintenance dose of inj. Dexmedetomedine infusion at 0.5microgm/kg/hour made to 20 ml with normal saline, will be administered till the end of surgery. Anaesthesia will be continued with Desflurane in 60% nitrous oxide in oxygen and ventilated to maintain end tidal CO2 between 35-40mmHg. Desflurane concentration will be adjusted according to entropy parameters for adequate depth of general anaesthesia and also clinical variables like HR, NIBP, Mean arterial pressure(MAP). Adequate muscle relaxation will be guided by NMT monitor. Entropy values will be recorded atbaseline before induction, after induction, before intubation, 1minute after intubation and every 5minutes thereafter, along with all other vital parameters till the end of surgery. Fresh gas flow will be at 6L/minute until the difference between inspiratory and expiratory Desflurane concentration is less than 20% and then the FGF rate will be reduced to 1.5L/minute. Infusion of Dexmedetomedine will be stopped 30 minutes prior to expected time of completion of surgery. Desflurane administration will be cut off at the beginning of skin closure and the fresh gas flow will be increased to 6L/minute oxygen at the end of the skin closure. This would define the beginning of recovery period. Residual neuromuscular blockade will be reversed with inj.Neostigmine 0.5mg/kg and inj.Glycopyrrolate 0.005mg/kg and patient will be extubated after recovery of adequate respiratory effort and muscle power. Age, sex, body weight, duration of surgery (minutes), duration of anaesthesia (minutes) will be recorded. Parameters observed. 1.Total and hourly Desflurane consumption. 2.Entropy parameters, Systolic blood pressure SBP, Diastolic blood pressure DBP, Mean Arterial Pressure MAP, Heart rate will recorded intra-operatively at baseline before induction, after induction, before intubation, 1minute after intubation and every 5minutes thereafter 3.Time for extubation 4.Ramsay sedation Score(annexure II) and modified aldrete score (annexure III)after extubation. Statistical analysis: Parametric data will be assessed with Independent sample T test and paired T test. Benferroni’s correction applied as appropriate .Non parametric data will be assessed with Chi square test and Fischer exact test. 7.3 Does the study require any investigation or intervention to be conducted on patients or 6 other humans or animals? If so please describe briefly. A) It does not require any intervention on animals. B) Investigations only on patients that are routine for the study with their consent. 7.4 Has ethical clearance has been obtained from your institution in case of 7.3? YES 8 LIST OF REFERENCES: 1. Edmond I-Eger II Inhalational anaesthetics uptake and distribution ; Millers Anaesthes Lavs I Ericsson. Lee A. Fleischer Jeanine P. Weiner-Kronish. William L. Young. Churchill Livingstone Elsvier ; Philadelphia. 7th edition 2005. Page 554-558. 2. Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative,amnestic and analgesic prpperties of small-dose Dex infusion..Anaesth Analg2000;90:699-705 3. Talke P, Richardson CA, Scheinin M, Fisher DM. Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine. Anesth Analg 1997;85:1136 – 428. 4.Aantaa R,Taakola ML,Kallio A,Kanto J.Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine. Anaesthesiology 1997;86;1055-1060 5. Aho M, Erkola O, Kallio A, Scheinin H, Korttila K. Dexmedetomidine infusion for maintenance of anesthesia in patients undergoing abdominal hysterectomy. Anaesth Analog 1992 6.tanski DR: Monitoring depth of anesthesia. In: Miller RD (ed): Anesthesia, 4th ed. New York: Churchill Livingstone, 1994:1127–59. 7.David .B . Glick.The autonomic nervous system.Millers anaesthesia.Editors .Lavs I Ericsson.Lee A. Fleischer Jeanine P. Weiner-Kronish. William L. Young. Churchill Livingstone Elsvier ; Philadelphia. 7th edition 2005. Page 285. 8.Talke p. Chen R, Thomas B, Aggarwall A, Gottelib A, Thorborg P, Heard S, Chung A,Son SI,Kallio A . The hemodynamic and adrenergic effects of perioperative dexmedetomidine 7 infusion after vascular surgery. Anaesth Analg 2000;90:834-839. 9.Guler G,Akin Z, Tosun E,Eskiatascoly,Mizrak A,Boyaci A.Single dose dexmedetomidine attenuates airway and circulatory reflexes during extubation. Acta Anaesthesiol scand 2005;49:1088-1091 10. Earl M Strum and coworkers . Anaes Analg 2004;99:1848-1854. 11. Aliveya A and coworkers. Erciyes Medical Journal 2009 Vol 31 No 2 pages 110-118. 12.Shin HW and coworkers Korean J of Anaesthesiol 2013 Aug ;65(2): 114-120. 13.Robert J Fragen & Paul. C. Fitzgerald. Journal of clinical Anae Vol II Sep 1999 pages 442446. 8 9. SIGNATURE OF THE CANDIDATE 10. REMARKS OF THE GUIDE 11. 11.1 11.2 NAME AND DESIGNATION OF GUIDE DR. HARSOOR SIDHARAMESHWAR PROFESSOR & HEAD DEPARTMENT OF ANAESTHESIOLOGY. BMC&RI SIGNATURE 11.3 CO-GUIDE ( IF ANY ) 11.4 SIGNATURE 11.5 HEAD OF THE DEPARTMENT 11.6 SIGNATURE 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL 12.2 SIGNATURE DR. HARSOOR SIDHARAMESHWAR PROFESSOR & HEAD DEPARTMENT OF ANAESTHESIOLOGY. BMC&RI 9 ANNEXURE I INFORMED WRITTEN CONSENT A single randomized double-blind trial to study the effect of desflurane consumption and recovery characteristics in entropy guided general anaesthesia with or without dexmedetomidine infusion. You are invited to take part in this research study. The information in this document is meant to help you decide whether or not to take part. Please feel free to ask if you have any queries or concerns.You are being asked to participate in this study being conducted in Department of Anaesthesiology,Victoria hospital/Bowring and Lady Curzon hospital,Bangalore Medical College and Research Institute because you satisfy our eligibility criteria which are: (1)Age between 18 to 50 years (2)No contraindication to the use of the agent to be used in the study, which means absence of any systemic disease, not on any long term steroids. You will be one of the 50 patients we plan to recruit in this study. You will be assigned to either of the two study groups. One group of patients will receive standard medications, which are injection glycopyrolate,injection midazolam,injection fentanyl,injection thiopentone,injection succinyl choline,injection vecuronium, desflurane inhalation plus normal saline while other group of patients will receive standard medications and dexmedetomidine infusion. What is the purpose of research? Desflurane is an inhalational anaesthetic commonly used now-a-days. It has many advantages over other inhalational anaesthetics. It undergoes minimal metabolism. It can be safely used in liver and kidney disorders. It can be safely used in old age patients. It is beneficial in long duration surgeries. When desflurane is used as an inhalational anaesthetic extubation time and eye opening time are shorter. Totally hospital stay is found to be less. But desflurane is said to be expensive. By using dexmedetomidine infusion we can reduce the consumption of desflurane. The studies on effect of dexmedetomidine infusion on desflurane consumption and recovery characteristics in entropy guides general anaesthesia are limited. So in this study we want to establish that desflurane requirement will be reduced and there will be early recovery when dexmedetomidine infusion is used. We have obtained permission from the Institutional Ethics Committee for conducting this study. 10 Possible risks to you The study drug is a well established treatment, and so far, in earlier studies with this dosage given, has not demonstrated any side effects. Possible benefits to you You are not expected to get any benefit from being on this research study, other than the treatment benefit and free investigations/tests. Possible benefits to other people The results of the research may provide benefits to the society in terms of advancement of medical knowledge and/or therapeutic benefit to future patients. The alternatives you have If you do not wish to participate, you have the alternative of getting the standard treatment for your condition. Confidentiality of the information obtained from you You have the right to confidentiality regarding the privacy of your medical information (personal details, results of physical examinations, investigations, and your medical history). By signing this document, you will be allowing the research team investigators, other study personnel, institutional ethics committee, if required. The results of clinical tests and therapy performed as part of this research may be included in your medical record. The information from this study, if published in scientific journals or presented at scientific meetings, will not reveal your identity. How will your decision to not participate in the study affect you? Your decision not to participate in this research study will not affect your medical care or your relationship with the investigator or the institution. Your doctor will still take care of you and you will not lose any benefits to which you are entitled. Contact persons For further information/questions,you can contact us at the following address Dr.Harsoor Sidharameshwar Professor and HOD Department of Anaesthesiology.BMC & RI Dr.Rajesh. R. Nayak,PG student,Department of Anaesthesiology,BMC&RI 11 I, Mr/Mrs/Ms ,exercising my own free willpower of choice, hereby give consent for myself as an object in the clinical study “A COMPARATIVE STUDY OF DESFLURANE ENTROPY CONSUMPTION GUIDED GENERAL AND RECOVERY ANAESTHESIA CHARACTERISTICS WITH OR IN WITHOUT DEXMEDETOMIDINE INFUSION conducted by Dr.Harsoor Sidharameshwar, Dr.Rajesh.R. Nayak. Department of Anaesthesiology, Victoria hospital/ Bowring and Lady Curzon hospital, Bangalore Medical college and Research Institute. The attending doctors have informed me to my satisfaction and in a language best understood by me, the purpose of this study, the materials to be used during the course of this study as well as the side effects/ complications associated with the methods/tools to be used. I shall not hold the doctors or the staff responsible for any untoward consequences. I am also aware of my right to opt out of the study without prejudice to further treatment at any time during the course of the study without having to give any reasons to do so. Signature of attending doctor : Date : Signature/Left thumb impression of patient Signature of witness : Date : 12 ANNEXURE II VAS (Visual Analogue Scale) Pain severity will not be at rest ,in supine position and also on exertion using peak flow. Pain severity will be noted at 2, 6hours and 24 hours post operatively. It will be noted for Incisional, Visceral and shoulder pain. Inj Diclofenac 75mg intravenously will be given on demand as rescue analgesic. 13 ANNEXURE III RAMSAY SEDATION SCALE 1- anxious and agitated, restless 2- co-operative, oriented, tranquil 3- responsive to verbal commands, drowsy 4- “asleep”, responsive to light stimulation(loud noise, tapping) 5- asleep, slow response to stimulation 6- no response to stimulation ANNEXURE IV MODIFIED ALDRETE SCORE Level of consciousness Score Awake and oriented 2 Arousable with minimal stimulation 1 Responsive only to tactile stimulation 0 Physical activity Able to move all extremities on command 2 Some weekness in movement of extremities 1 Unable to voluntarily move extremities 0 Hemodynamic stability Blood pressure ,15% of baseline MAP value 2 Blood pressure 15-30 % of baseline MAP value 1 Blood pressure 30% below baseline MAP value 0 14 Respiratory stability Able to breathe deeply 2 Tachypnea with good cough 1 Dyspneic with weak cough 0 Oxygen saturation status Maintains value .90% on room air 2 Requires supplemental oxygen (nasal prongs ) 1 Saturation 90 % with syupplemental oxygen 0 Postoperative pain assessment None or mild discomfort 2 Moderate to severe pain controlled with iv analgesics 1. Persistent severe pain 0 Postoperative emetic symptoms None or mild nausea with no active vomiting 2 Transient vomiting or retching 1 Persistent moderate to severe nausea and vomiting 0. Total score 14 MAP 5 mean arterial pressure. References 1. Aldrete JA. The post-anaesthesia recovery 15