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RAGIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGLORE ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. NAME OF THE CANDIDATE AND ADDRESS : 2. NAME OF THE INSTITUTION : MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE MYSORE 3. COURSE OF STUDY AND SUBJECT 4. DATE OF ADMISSION TO THE COURSE 5. TITLE OF THE TOPIC DR. G.B.SUMALATHA C/O G.B.VIJAYKUMAR,ASST TEACHER, MCC A BLOCK, 3RD MAIN CHURCH ROAD, #2110, DAVANGERE, KARNATAKA. : M D ANAESTHESIOLOGY : 9th MARCH 2009 : “ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND TRACHEAL INTUBATION IN ADULT PATIENTS WITH A SINGLE INTRAVENOUS DOSE OF 0.6ug/kg OF DEXMEDETOMIDINE” 1 6. BRIEF RESUME OF THE INTENDED WORK 6.1 NEED FOR THE STUDY: Laryngoscopy and endotracheal intubation are employed for safe conduct of general anaesthesia. However both laryngoscopy and intubation are noxious stimuli and are associated with stress responses & haemodynamic responses in the form of laryngosympathetic stimulation which is manifested as hypertension, tachycardia & arrhythmias. These haemodynamic responses are well tolerated in otherwise healthy individuals, but in patients with hypertension, coronary heart disease, cerebrovascular disease & intracranial aneurysm these transient changes can result in potentially deleterious effects like left ventricular failure, pulmonary edema, myocardial ischemia, ventricular dysrhythmias & cerebral haemorrhage1 Attempts were made as early as in 1960’s by various investigators to reduce the sympathetic response to laryngoscopy & intubation. These include: 1. deepening the plane of anaesthesia with inhalational & intravenous anaesthetic agents.1 2. Decreasing the duration of laryngoscopy to less than 15 seconds. 3. usage of drugs like lidocaine, sedatives, opioids, vasoactive drugs like sodium nitroprusside, calcium channel blockers, beta blockers1 and other drugs especially alpha 2 agonists like clonidine & dexmedetomidine.2 Intravenous Dexmedetomidine, a central alpha 2 agonist is being used in anaesthesia practice as a premedicant. The advantages of Dexmedetomidine as premedicant in anaesthesia setting include sedation, analgesia, anxiolysis & improved hemodynamic stability. Because of these beneficial properties it has been found that the minimum alveolar 2 concentration (MAC) of volatile anaesthetics also decreases significantly up to 90% and hence decreases the requirement of anaesthetics.3 It has also been found that it can decrease the haemodynamic response to laryngoscopy and intubation. 4,5 Dexmedetomidine is being used in other countries since many years as premedicant. Since it has been introduced recently in India, (only in2009) and not many studies have been done in our country, there is a need to study the effectiveness of Dexmedetomidine in obtunding the hemodynamic response to laryngoscopy & intubation The present study is aimed at attenuation of haemodynamic response to laryngoscopy & intubation in adult patients with single intravenous bolus dose of Dexmedetomidine 0.6ug/kg given 10 min prior to induction. REVIEW OF LITERATURE 1. Pharmacology & physiology in anaesthesia practice, by Robert K. Stoelting & Simon C. Hillier, Philadelphia, Lippincott Williams and Wilkins ( 4th edition 2006),2 Dexmedetomidine is a highly selective, specific, and potent alpha 2 adrenergic agonist (1,620:1 alpha 2 to alpha 1)(Bloor et al, 1992;Sandler, 1996). This drug is the dextroisomer and pharmacologically active component of medetomidine, which has been used for many years in veterinary practice for its hypnotic, sedative, and analgesic effects. Compared with clonidine, Dexmedetomidine is 7-10 times more selective for alpha 2 receptors and has a shorter duration of action than clonidine. In this regard Dexmedetomidine is considered full agonist at the alpha 2 receptors, whereas clonidine is a partial agonist ,( ratio of alpha 2:alpha 1 activity for clonidine is 220:1)(Sandler,1996). The elimination half time of 3 Dexmedetomidine is 2-3 hours compared with 6-10 hours of clonidine. Dexmedetomidine is highly protein bound (90%) and undergoes extensive hepatic metabolism. As with clonidine, pretreatment with Dexmedetomidine attenuates responses to tracheal intubation, decreases plasma catecholamine concentrations during anaesthesia, decreases perioperative requirements for inhaled anaesthetics and opioids and increases the likelihood of hypotension. Dexmedetomidine decreases MAC for volatile anaesthetics in animals by >90% compared with a plateau effect between 25% to 40% for clonidine. Despite marked dose dependant analgesia and sedation produced by this drug, there is only mild depression of ventilation. The preservation of breathing provides a potential anaesthetic technique for patients with difficult upper airway. 2. Martina Aho, A.M.Lehinten, O.Erkola et al 6 in the year 1991, conducted a double blind, randomized study in 96 women undergoing abdominal hysterectomy to evaluate the effect of intravenously administered Dexmedetomidine on perioperative hemodynamics & isoflurane requirements. Here they studied the effect of 2 doses of Dexmedetomidine 0.3ug/kg & 0.6ug/kg, fentanyl 2ug/kg & saline as a single intravenous bolus dose which were administered 10 min prior to induction of anaesthesia. They found that in all groups BP & HR increased after tracheal intubation. However increase in BP & HR was significantly less in Dexmedetomidine group which received 0.6µg/kg than in saline group. At the same time they noted that in patients receiving Dexmedetomidine 0.3µg/kg, the increase in HR & BP did not differ from that of saline group. The major findings of this study were that Dexmedetomidine administered before induction at a dose of 0.6µg/kg blunted the tachycardiac response during endotracheal intubation. 4 3. M.L.Jaakola, T.Ali-melkkila, J.Kanto et al5 in year 1992, studied the effect of a single intravenous bolus dose of Dexmedetomidine on intraocular pressure, hemodynamic & sympathoadrenal responses to laryngoscopy & tracheal intubation. The effects were studied in a randomized placebo contolled, double blind trial in 30 ASA I patients undergoing cataract surgery. The groups were allocated to receive Dexmedetomidine 0.6ug/kg and saline placebo intravenous 10 min before induction of anaesthesia, In group receiveing Dexmedetomidine there was 34% reduction in intraocular pressure & 62% reduction in plasma nor-adrenaline concentrations. After intubation maximum heart rate was 18% less in Dexmedetomidine group compared with placebo. They also noted that there was a significant decrease in blood pressure in Dexmedetomidine group. They concluded that Dexmedetomidine may be a useful adjunct in ophthalmic surgery. 4. B.Scheinin, L.Lindgren, T.Randell et al4 in the year 1992, evaluated the effect of Dexmedetomidine in attenuating sympathoadrenal responses to tracheal intubation & requirements of Thiopentone and fentanyl perioperatively. They studied the effect in a randomized placebo controlled, double blind trial in 24 ASA – I patients. Dexmedetomidine 0.6ug/kg or saline was given 10 min before induction of anaesthesia. They concluded that required dose of Thiopentone was significantly smaller in Dexmedetomidine group than in control group. They also concluded that the drug attenuated the cardiovascular responses to laryngoscopy and tracheal intubation. 5. Basar H, Akpinar S, Doganci N et al7 in 2008, evaluated the effects of preanaesthetic single dose Dexmedetomidine on induction, hemodynamic & cardiovascular parameters. The effects were studied in randomized double blind trial in 40 ASA I & II patients scheduled for Cholecystectomy. Patients were divided randomly into two groups to 5 receive 0.5ug/kg of Dexmedetomidine ( Group D) 10 minutes before anaesthesia, slowly over 60 seconds or saline (Group C). Measurements of mean arterial pressure, heart rate, ejection fraction, end diastolic index. Cardiac index & stroke volume index were recorded at every 10 min intervals. The time for patients to “open eyes on verbal command” & post op Aldrete recovery scores were also recorded. In Group C , increase in heart rate & mean arterial pressure(MAP) occurred after endotracheal intubation. In group D heart rate(HR) significantly decreased after Dexmedetomidine. The end diastolic index (EDI), cardiac index(CI), stroke volume index(SVI) and ejection fraction(EF) values were similar in groups D and C.The modified Aldrete recovery scores of patients were similar in groups C and D. They concluded that a single dose of Dexmedetomidine given prior to induction of anaesthesia decreased thiopental requirements without serious hemodynamic effects or any effect on recovery time. 6. Yildiz M, Tavlan A, Tuncer S et al8 in 2006 evaluated the effect of a single preinduction intravenous dose of Dexmedetomidine 1 ug/kg on cardiovascular responses resulting from laryngoscopy & tracheal intubation, need for anaesthetic agent & perioperative haemodynamic stability. Here fifty patients scheduled for minor surgery were randomized in to two groups, Dexmedetomidine group & placebo group, n=25 in each group. During and after drug administration, the Ramsay sedation scale was applied every 5 min., haemodynamic parameters and adverse effects were recorded every 10 min for 1 hour after surgery. The results were, during intubation the need for thiopental and sevoflurane concentration were decreased by 39% & 92% respectively in Dexmedetomidine group compared with placebo group. In all groups blood pressure & heart rate increased after tracheal intubation; both were significantly reduced in Dexmedetomidine group than in 6 placebo group. Hence they concluded that preoperative administration of single dose of Dexmedetomidine resulted in progressive increase in sedation, blunted the haemodynamic response to laryngoscopy and reduced opioids and anaesthetic requirements. OBJECTIVES 1. To study changes in heart rate, systolic blood pressure, diastolic blood pressure & mean arterial blood pressure associated with laryngoscopy & intubation. 2. To evaluate the efficacy of Dexmedetomidine in the dose of 0.6ug/kg as a single bolus dose in attenuating hemodynamic response to laryngoscopy & tracheal intubation in adult patients. 3. To study the effect of Dexmedetomidine in decreasing the requirements of induction agent, Thiopentone. 4. To study any adverse effects associated, such as perioperative hypotension, bradycardia, post op recovery & post op excessive sedation. MATERIALS & METHODS Source of Data 100 patients aged between 18yrs and 50yrs of ASA class I for various elective surgeries requiring general anaesthesia at Krishnarajendra & Cheluvamba hospital attached to Mysore medical college & Research institute, Mysore, will be randomly selected for the study. This prospective, randomized, double blind study will be conducted from Nov 2009 to July 2011. The study population will be divided into 2 groups of 50 patients each. a. Group D ( n=50) = Dexmedetomidine group b. Group C ( n=50) = control group 7 Preoperative assessment will be done for each patient and written consent will be taken. Patients will be premedicated on the night before surgery with Tablet Ranitidine 150mg and Tablet Alprazolam 0.5mg. Intravenous line obtained with 18 guage cannula The study drug Dexmedetomidine will be given to group ‘D’ as a bolus dose of 0.6ug/kg diluted in normal saline to 5 ml and injected intravenously slowly over one minute, 10 minutes before induction. Group C patients will be given 5ml of normal saline, 10 min before induction. The double blind design of study is assured by the fact that an anesthesiologist not further involved in the study prepared syringes immediately before induction of anaesthesia. The syringes are marked Dexmedetomidine/placebo together with the name of the patient. The anaesthesiologist responsible for the anaesthetic technique is thus kept unaware of the content of the syringes. Both the groups will be premedicated with 0.2 mg glycopyrollate, 1 mg midozolam & 15 mg pentazocine given intravenously before induction. General anaesthesia will be induced with 2.5% Thiopentone in incremental doses till the eyelash reflex is lost. The loss of eyelash reflex is taken as criteria for end of induction. The dose of Thiopentone required for induction is noted down in both the groups. Succinylcholine 1.5mg/kg is given for intubation.Both groups of patients will be intubated with appropriate sized cuffed endotracheal tubes with gentle laryngoscopy. Anaesthesia will be maintained with oxygen + nitrous oxide + Inj Vecuronium bromide + 0.5% halothane. After the surgical procedure patients of both the groups will be reversed with Inj.Neostigmine 2.5mg + Inj Glycopyrollate 0.5mg intravenously. INCLUSION CRITERIA 8 - Healthy adult patients aged between 18 – 50 yrs - Patients belonging to ASA class I EXCLUSION CRITERIA - Patients with hypertension, cardiac, renal, hepatic & cerebral diseases, - Patients with difficult airway and obese patients - Patients with endocrinal diseases like hyperthyroidism, hypothyroidism and diabetes mellitus. METHODS OF COLLECTION OF DATA A. Hemodynamic responses are compared in both groups by measuring 1. Heart rate 2. Systolic blood pressure 3. diastolic blood pressure 4. mean arterial pressure These parameters are measured using automatic multiparameter monitor at following intervals 1. Before giving the test drug 2. After administration of test drug at 2 min, 5 min & 8 min. 3. Just before induction 4. After induction 5. After intubation at 1 min, 3min, 5 min & 10 min 6. Heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure every 10 min throughout the surgery. B. Post operative recovery and sedation will be studied. 9 Time of recovery from anaesthesia is the interval from injecting the reversal agent to the spontaneous eye opening. Sedation scoring will be done as per Ramsay sedation scale: Score response 1 anxious or restless or both 2 co-operative, oriented & tranquil 3 responding to commands 4 brisk response to stimulus 5 sluggish response to stimulus 6 no response to stimulus The results of intended study between the two groups will be compared statistically using ‘p’ value obtained from Student‘t’ test. 7.2 Does the study require any investigation/intervention to be conducted on patients/human/animals? If so describe briefly. No 7.3 Has ethical clearance been obtained from your institution in case of 7.3? Yes obtained. (copy enclosed) 8.LIST OF REFERENCES 10 1. King BD, Harris LC, “Reflex circulatory responses to Direct laryngoscopy and Tracheal intubation performed during General anaesthesia”, Anesthesiology, 1951;12: 556-566 2. Stoelting RK, Hiller SC, “ Pharmacology and physiology in anesthetic practice”, Philadelphia, Lippincott Williams and Wilkins,2006,340 3. Bloor BC, Ward DS, Belleville JP, Maze M. Effects of intravenous dexmedetomidine in humans. II Haemodynamic changes. Anaesthesiology 1992;77:1134-1142. 4. Scheinin B, Lindgren L, Randell T, Scheinin H, Scheinin M. Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone & peroperative fentanyl. British journal of anaesthesiology 1992;68:126-131 5. Jakola ML, Ali-Melkkila T, Kanto J, Kallio A, Scheinin H, Scheinin M. Dexmedetomidine reduces intraocular pressure, intubation response and anaesthetic requirements in patients undergoing ophthalmic surgery. British journal of anaesthesiology 1992;68:570-575 6. Martina Aho, Lehinten AM, Erkola O, Kallio A, Korttila K. The effects of intravenously administered dexmedetomidine on perioperative hemodynamics and isoflurane requirements in patients undergoing abdominal hysterectomy. Anaesthesiology 1991;74:997-1002 7. Basar H, Akpinar S, Doganci N, Buyukkocak U, Kaymak C et al. The effects of preanaesthetic, single-dose dexmedetomidine on induction, hemodynamic, and cardiovascular parameters. Journal of clinical anaesthesia,2008 Sep;20(6):431-436 8. Yildiz M, Tavlan A, Tuncer S, Reisli R, Yosunkaya A, Otelcioglu S. Effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation, perioperative haemodynamics and anaesthetic requirements. Drugs R D 2006;7:43-52 11 9. Signature of the Candidate : 10. Remarks of the Guide : 11. NAME AND DESIGNATION OF 11.1 Guide : Dr.ARUNA T.M. ASSISTANT PROFESSOR DEPARTMENT OF ANAESTHESIOLOGY MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE 11.2 Signature of Guide : 11.3 Co-guide (if any) : 11.4 Signature of Co-Guide : 12 11.5 Head of the Department : PROF.DR.C.L.GURUDATT M.D . D.A. PROFESSOR AND HEAD DEPARTMENT OF ANAESTHESIOLOGY, MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE 11.6 Signature of Head of the Department : 12. REMARKS 12.1Remarks of the Dean and Director 12.2 Signature : : 13 ETHICAL COMMITTEE CLEARANCE 1. TITLE OF DISSERTATION : “ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND TRACHEAL INTUBATION IN ADULT PATIENTS WITH A SINGLE INTRAVENOUS BOLUS DOSE OF 0.6 µg / kg BODY WEIGHT OF DEXMEDETOMIDINE.” 2. NAME OF THE CANDIDATE : DR.G.B.SUMALATHA 3. SUBJECT : M.D. ANAESTHESIOLOGY 4. NAME OF THE GUIDE :Dr.ARUNA T.M. ASSISTANT PROFESSOR DEPARTMENT OF ANAESTHESIOLOGY MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE 5. APPROVED/NOT APPROVED (If not approved, suggestion) : APPROVED 14 MEDICAL SUPERINTENDENT MEDICAL SUPERINTENDENT KR Hospital Mysore Cheluvamba Hospital Mysore PROFESSOR AND HOD PROFESSOR AND HOD Depart ment of medicine Mysore Medical College and Research institute, Mysore Department of Surgery Mysore Medical College and Research institute, Mysore MEDICAL SUPERINTENDENT P.K.T.B and CHEST DISEASES HOSPITAL, MYSORE LAW EXPERT DEAN AND DIRECTOR MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE 15