RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. NAME OF THE CANDIDATE AND : DR. KAVERAMMA.M.G, ADDRESS D/O GANDHI.M.K, 14#24, NEAR MUTHAPPA TEMPLE, MAHADEVPET ROAD, MADIKERI-571201, KODAGU, KARNATAKA. ------
2. NAME OF THE INSTITUTION : MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE. ------
3. COURSE OF STUDY AND SUBJECT : M.D. ANAESTHESIOLOGY
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4. DATE OF ADMISSION TO THE : 17-05-2012 COURSE
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5. TITLE OF THE TOPIC : “ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND TRACHEAL INTUBATION IN ADULT PATIENTS USING 75mg and 150mg OF ORAL PREGABALIN-A PROSPECTIVE, CONTROLLED, DOUBLE BLIND, COMPARITIVE DOSE FINDING STUDY”
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1 6. BRIEF RESUME OF 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 and haemodynamic responses in the form of laryngosympathetic stimulation, which is manifested by hypertension, tachycardia and arrhythmias. These haemodynamic responses are well tolerated in an otherwise healthy individual, but in patients with hypertension, coronary artery disease, cerebrovascular disease and intracranial aneurysms these transient haemodynamic changes can result in potentially deleterious effects like left ventricular failure, pulmonary edema, myocardial ischemia, ventricular dysrrhythmias and cerebral haemorrhage1.
Attempts were made as early as in 1950s by various investigators to reduce the sympathetic response to laryngoscopy and intubation. These include,
1. deepening the plane of anaesthesia with inhalational and intravenous
anaesthetic agents1.
2. usage of drugs like lidocaine, opioids, vasoactive drugs like sodium
nitroprusside, calcium channel blockers and beta-blockers1.
3. Other drugs especially α – 2 agonists like Clonidine, Dexmedetomidine have
also been used2.
All these drugs have been used with varying results and have not been effective in
completely obtunding the sympathetic response to intubation, for example opiods
and beta blockers predominantly decrease the heart rate, whereas vasodilators and
calcium channel blockers decrease the rise in blood pressure. Many of these agents
2 also have various adverse effects. Hence there is a need for a single drug which can
effectively suppress both the rise in heart rate as well as blood pressure with
minimal adverse effects.
Recently the anti-epileptic drugs Gabapentine and Pregabalin now used
more often for chronic pain are also being used for the attenuation of intubation
response. Both the above mentioned drugs have been found to suppress the
intubation response. Gabapentin is 3-4 times less potent and the bioavailability
when used orally is also less as compared to pregabalin. Onset of action of oral
Pregabalin is one hour 3 whereas it is delayed for Gabapentin. Hence all these
features suggest that it is better to use Pregabalin for suppression of intubation
response instead of Gabapentin.
Pregabalin is available as capsules of 75mg and 150 mg. Not many studies have
tried to find out the minimal dose of Pregabalin that can be used for suppression of
intubation response. Only one study has compared 75 mg and 150mg of
Pregabalin4. Hence a study is required to know the effectiveness of Pregabalin for
suppression of intubation response and also to find the minimal effective dose of
Pregabalin in suppression of haemodynamic response to laryngoscopy and
intubation. Hence the present study is being done.
6.2 REVIEW OF LITERATURE
Oral Pregabalin
Pregabalin, a gabapentinoid compound, is described structurally as (S)-3 aminoethyl-5- methylhexanoic acid. Pregabalin is structurally related to the inhibitory neurotransmitter gamma-
3 aminobutyric acid(GABA), but is not functionally related to it. Pregabalin acts by decreasing the synthesis of neurotransmitter glutamate to act on the central nervous system. It possesses analgesic, anticonvulsant and anxiolytic activity. It is well absorbed and tolerated after oral administration, with peak plasma concentration occurring within 1h.It undergoes negligible hepatic metabolism4.
1.Dr. Patrick Kwan3, in 2006 in review article has described in detail about the pharmacology of
Pregabalin.
Pregabalin [(S)-3-(aminomethyl-5-methylhexanoic acid] is similar to gabapentin but has greater potency. It binds to the alpha-2-delta subunit of the neuronal voltage gated sodium channel, resulting in reduced depolarization-induced calcium influx at the nerve terminals with a consequential decrease in the release of the excitatory neurotransmitters.
It is rapidly and extensively absorbed after oral dosing in the fasting state. Maximal plasma concentration is reached after 1 hour of administration. The oral bioavailability of Pregabalin is high at >90% and is independent of dose. It is excreted virtually unchanged by the kidneys.
2. A. Fassoulaki et al5 in 2006 evaluated the use of Gabapentin in attenuating the pressor response to direct laryngoscopy and tracheal intubation. In this study 46 patients undergoing abdominal hysterectomy for benign disease were randomly allocated to receive Gabapentin
1600mg or placebo capsules at 6 hourly intervals, starting the day (noon) before surgery.
Anaesthesia was induced with propofol and cistatracurium. Systolic, diastolic arterial blood pressures and heart rate were recorded before and after the anaesthetic and 0,1,3,5 and 10 min after tracheal intubation.
4 They found that systolic arterial pressure and diastolic arterial pressure were significantly lower in the Gabapentin control group versus the control group, however heart rate did not differ between the two groups at any time.
3.Kiran.S, Verma D6 et al in 2008 evaluated the use of gabapentin in attenuating pressor response to direct laryngoscopy and tracheal intubation.
In this study 100 patients undergoing elective surgery were randomly allocated to two groups of 50 patients each. Patients in group A received gabapentin 800mg and patients in group B received placebo capsules the night before and on the morning of the surgery. Systolic, diastolic and mean arterial blood pressures and heart rate were recorded before and after the induction of anaesthesia and 0,1,3,5 and 10 min after tracheal intubation.
The results obtained were that there was a decrease in systolic, diastolic, mean arterial pressure were lower in the gabapentin group but tachycardia was not completely eliminated.
4. Indira Kumari et7 al in 2009 conducted a prospective randomized double blind placebo controlled trail of oral Gabapentin for attenuation of haemodynamic response during laryngoscopy and tracheal intubation.
The study was conducted on 78 patients of ASA physical status 1 and 2. Patients were randomly divided into two groups to receive either oral Gabapentin 900mg(Group G) or placebo(Group P), two hours before induction of anaesthesia. Changes in systolic, diastolic and mean blood pressure and heart rate were studied following laryngoscopy and intubation.
5 They found that there was a significant increase in systolic, diastolic and mean blood pressure in Group P as compared to Group G. No significant change in heart rate was documented in both groups.
5.Ashgan Raouf Ali et8 al in 2009 studied the efficacy of preoperative oral Gabapentin in attenuation of neuro-endocrine response to laryngoscopy and endotracheal intubation.
In this study fifty normotensive ASA 1 patients undergoing elective general surgery under general anaesthesia were randomly allocated to one of the two equal groups. Patients were assigned to receive either oral 1200mg Gabapentin(GABA group) or placebo( control group) 2 hours prior to surgery. Mean arterial pressure and the heart rate were recorded before and after induction of anaesthesia as well as at 1,2,3,4,5 and 10 minutes following intubation. Plasma catecholamines were measured before and after induction and at 1 and 5 min after intubation .
The results obtained were that the patients receiving placebo exhibited significant increase in the mean arterial pressure, heart rate and plasma concentration of catecholamines, whereas the increase of mean arterial pressure and heart rate was attenuated in patients treated with gabapentin, but there was no suppression of the increase in catecholamine concentrations in response to tracheal intubation.
6.Kumkum Gupta et al9 in 2011did a comparative evaluation of oral premedication with
Pregabalin or Clonidine for haemodynamic stability during laryngoscopy and laproscopic cholecystectomy.
A total of 180 healthy adult patients of age 35 to 52 years with ASA Grade 1 and 2 were randomized to receive placebo(Group 1), Pregabalin 150mg(Group 2), or Clonidine 200 micrograms(Group 3), given 75 to 90 minutes before surgery as oral premedication. The groups
6 were compared for preoperative sedation, changes in heart rate, mean arterial pressure prior to premedication, before induction, after laryngoscopy.
They concluded that both Pregabalin and Clonidine have sedative and anxiolytic effects as oral premedicants and decreased the need of intraoperative analgesic drug requirement. Clonidine was superior to Pregabalin for the attenuation of the haemodynamic responses, but it increased the incidence of intra operative and post-operative bradycardia. There were no post-operative side effects and no significant differences in the parameters of recovery between the two groups
7.Ayya Syama Sundar et al10 in 2011, studied the effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opiod-sparing effect in patients undergoing off- pump coronary artery bypass grafting.
The study was done to evaluate and compare single pre-operative dose of pregabalin to a placebo regarding haemodynamic responses to laryngoscopy and endotracheal intubation. It was a randomized, double-blind, placebo-controlled, efficacy study. It was a comparison between two groups of 30 each adults. In the control group, the patients were given placebo capsules and in the pregabalin group, the patients were given pregabalin 150mg capsule one hour prior to the surgery. The patients were compared for haemodynamic changes before the start of surgery, after induction,1, 3 and 5 minutes after intubation.
They concluded that a single oral dose of 150mg pregabalin given 1 hour before surgery attenuated the pressor response to tracheal intubation in adults, and was devoid of side effects in the given dose.
7 8.Rastogi Bhawna et al4 in 2012 studied oral Pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation during general anaesthesia.
In a randomized, double blind, placebo controlled study, a total of 90 normotensive consenting adult patients were assigned to three groups of 30 patients each. Group 1 received oral placebo, group 2 oral pregabalin 75mg and group 3 oral pregabalin 150mg one hour prior to induction.
The groups were assessed for pre-operative sedation, haemodynamic changes after the premedication, before and after induction after laryngoscopy and intubation, along with intraoperative haemodynamic stability and post operative side effects.
The study found that there was significant increase in heart rate and mean arterial pressure in Groups 1 & 2 after airway instrumentation, while statistically significant attenuation of mean arterial pressure was seen in Group 3. No significant decrease in the heart rate was observed in any group. There were no post-operative side-effects and no significant differences in the parameters of recovery and awakening time were observed.
They concluded that oral pregabalin premedication had adequately sedated the patients and the haemodynamic pressor response of airway instrumentation was attenuated in a dose related fashion. The premedicated patients were haemodynamically stable perioperatively without prolongation of recovery time and side effects.
6.3 OBJECTIVES OF STUDY:
8 Comparison of two doses, 75mg and 150mg of Pregabalin given orally one hour before induction of general endotracheal anaesthesia in patients posted for elective appendicectomies with regards to
Primary Objective
1) Study the changes in Heart Rate, Systolic Blood Pressure, Diastolic Blood Pressure and
Mean Arterial Pressure associated with Laryngoscopy and intubation.
2.) To find out minimum effective dose of pregabalin to suppress the laryngoscopy and intubation response.
Secondary objectives
1) To study any adverse effects associated with pregabalin administration such as increased
sedation, dizziness, blurred vision and prolonged recovery.
2) To study the requirement of induction dose of Propofol with different doses of Pregabalin.
7. MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
◦ 90 patients aged between 18years to 40years of ASA Class 1and 2, posted for elective appendicectomy surgeries under general anaesthesia at Krishna Rajendra Hospital attached to
Mysore Medical College and Research Institute, Mysore.
◦ The population is divided in to 3 groups of 30 patients in each group.
1).Group C (n=30), is the control group
2).Group P75(n=30), is the Pregabalin 75mg dose group
9 3).Group P150(n=30), is the Pregabalin 150mg dose group
Group C patients will be given the placebo capsule orally one hour prior to induction.
Group P75 patients will be given 75mg Pregabalin capsule orally one hour prior to
induction.
Group P150 patients will be given 150mg Pregabalin capsule orally one hour prior to
induction.
Randomisation of the group is done using sealed envelope method.
The double blind design of the study is assured by the fact that an anaesthesiologist not further involved in the study will be opening the sealed envelopes and issuing the capsules to the patients one hour before the surgery. The patient and the anaesthesiologist conducting the study, doing the observations are thus kept unaware of the content of the capsules.
All the patients of the three groups, with their informed consent, will be given diazepam 10mg orally the night before and will be kept nil per oral 6 hours for solids and two hours for clear fluids. Patients in Group P150- 150mg capsule of Pregabalin, Group P75-75mg capsule of
Pregabalin and Group C patients-Placebo capsule, will be given orally one hour before induction in the pre-operative room(Capsule Pregabalin manufactured by –Company Lyrica) .
All the patients will be connected with non-invasive monitoring – pulse oximetry(SPO2),Non
Invasive Blood Pressure(NIBP) and electrocardiography(ECG) using multiparameter monitor(B-30 GE make). Haemodynamic recordings will be done along with sedation scoring(using Ramsays Sedation Score) after 30 minutes and before shifting. Any side effects like dizziness and blurring of vision will be noted.
After shifting the patients(after fifty five minutes) into the Operation Theatre(OT), an intravenous(IV) line using 18G cannula, is secured on the non-dominant hand and infusion of
10 Ringer Lactate will be started and non-invasive monitoring continued. Patients will be
premedicated with 1mg of midazolam and 1 microgram / kg body weight of Fentanyl,
intravenously before induction. Pain on injection of Propofol will be prevented by using IV
Injection of 1.5 mg/kg body weight of preservative free 2% lignocaine given 30 seconds before
Propofol.
General anaesthesia will be induced with Propofol 2mg/kg slowly. The end point of induction is taken as loss of eye lash reflex and the dose of Propofol required for induction will be noted. Suxamethonium 1.5 mg /kg IV is used for intubation in all the patients.
All the patients will be intubated with appropriate sized cuffed endotracheal tubes with gentle
laryngoscopy and tracheal position of the tube confirmed by end tidal carbon dioxide(EtCO2)
Anaesthesia will be maintained with Oxygen+Nitrous oxide+Inj.Vecuronium+0.5%Isoflourane
After the surgical procedure patients of all the groups will be reversed with Inj. Neostigmine
2.5mg + Inj. Atropine 1.2mg given intravenously
INCLUSION CRITERIA:
- Adult patients of either sex aged between 18yrs-40yrs weighing between 50-70 kg posted for
elective appendicectomy under general anaesthesia.
-Patients belonging to ASA grade I & II.
EXCLUSION CRITERIA:
1. Patients with hypertension, cardiac, renal, hepatic and cerebral diseases.
2. Patients with difficult airway and obese patients.
3. Patients with endocrinal diseases like hyperthyroidism, hypothyroidism and diabetes
11 mellitus.
4. Patients in ASA Class 3, 4 and 5.
5. Patients posted for emergency appendicectomy.
6. Patients on antiepileptic medications.
7.2 Methods of collection of data:
A. Haemodynamic responses are compared in all the groups by measuring
1. Heart Rate(HR)
2. Systolic Blood Pressure(SBP)
3. Diastolic Blood Pressure(DBP)
4. Mean Arterial Pressure(MAP)
These parameters are measured using automatic Multiparameter monitor (B-30 GE )
at following Intervals
1. before giving the test drug.(Basal Recordings)
2. 30 minutes after giving the test drug
3. before induction(60 minutes after giving the drug)
4. immediately after induction before giving succinylcholine.
5. 1 Minute after Intubation
6. 3 Minutes after Intubation
7. 5 Minutes after Intubation
8. 10 minutes after intubation
9. Every 15 minutes till the end of surgery.
12 B. Post- operative recovery and sedation will be studied.
Time of recovery from anesthesia: ΄It is the interval from injecting the reversal agent till the spontaneous eye opening of the patient’.
Sedation scoring will be done as per Ramsay sedation scale 30 minutes after giving the test drug, pre-induction, and post –operatively after recovery.
Ramsay sedation scale
Score Response 1 Anxious or restless or both 2 Cooperative, oriented and tranquil 3 Responding to commands 4 Brisk response to stimulus 5 Sluggish response to stimulus 6 No response to stimulus
C. The requirement of induction dose of Propofol with different doses of
Pregabalin.
D. Side effects like dizziness and blurring of vision.
SAMPLE SIZE- The sample size was decided in consultation with the statistician and was based on initial pilot study observations, indicating that approximately 20-23 patients should be included in each group in order to ensure a power of 0.80 for detecting clinically meaningful reduction by 10-20% in heart rate and mean arterial blood pressure. Assuming a
5% drop out rate, the final sample size was set at 90 patients, which would permit a type 1 alpha error =0.05, with a type 2 error of beta=0.2 and power of 0.8. The results obtained in
13 the study are presented in a tabulated manner and analysed using Microsoft Excel and SPSS
17 software.
The results of the present study between the three groups will be compared statistically using
‘p’ Value obtained using the above SPSS 17 software.
7.3 Does the study require any investigation / intervention to be conducted on
Patients / human / animals? If so, describe briefly.
NO
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Yes (Copy Enclosed)
8. LIST OF REFERENCES:
1. KING B D, HARRIS,L.C, “Reflex circulatory responses to Direct laryngoscopy and Tracheal intubation performed during General anaesthesia”, Anesthesiology,1951, 12; 556-566
2. STOELTING RK, HILLIER SC, “ Pharmacology and physiology in anaesthetic practice”, Philadelphia, Lippincott Williams and Wilkins,2006,340-344pp
3. Dr.PATRICK KWAN, “Pregabalin: a new drug for epilepsy, neuropathic pain and anxiety”, Medical Bulletin, Vol.2,No.4, April 2006.
4 .Rastogi B, Gupta K, Gupta PK, Agarwal S, Jain M, Chauhan H, “Oral Pregabalin premedication for attenuation of haemodynamic pressor response of airway
14 instrumentation during general anaesthesia: A dose response study. Indian J Anaesth 2012;56:49-54
5. A.Fassoulaki, A.Melemeni, A.Paraskeva and G.Petropoulos, “Gabapentin attenuates the pressor response to direct laryngoscopy and tracheal intubation” BJA 2006;96(6):769-73
6.Kiran S, Verma D, “Evaluation of gabapentin in attenuating pressor response to direct laryngoscopy and tracheal intubation” SAJAA 2008;14(6):43-46
7. Indira Kumari, Vikrant Singh Pathania, “A Prospective, randomized, double blind placebo controlled trail of oral Gabapentin in attenuation of intubation responses during laryngoscopy and tracheal intubation” J Anaesth Clin Pharmacol 2009; 25(4): 439-443
8.Ashgan Raouf Ali, M. El Gohary, H.Salah El-din Ahmawi, H.M.El-Kerdawy and H.H.Essa, “Efficacy of preoperative oral Gabapentin in attenuation of neuro-endocrine response to laryngoscopy and endotracheal intubation” J.MeD.Sci.,2009(1):24-29
9.Kumkum Gupta, Deepak Sharma and Prashant K.Gupta, “Oral premedication with pregabalin or clonidine for haemodynamic stability during laryngoscopy and laparoscopic cholecystectomy: A comparative evaluation” Saudi J Anaesth 2011 Apr-Jun;5(2):179-184.
10.Ayya Syama Sundar, Rajeshkumar Kodali, Sajith Sulaiman, Harish Ravullapalli, Ranjith Karthekeyan, Mahesh Vakamudi, “ The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opiod sparing effect in patients undergoing off-pump coronary artery bypass grafting” Ann Card Anaesth 2012; 15:18-25
9. Signature of the Candidate :
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10. Remarks of the Guide : The sympathetic response to laryngocscopy and intubation requires to be obtunded. Pregabalin being a GABA mimetic drug which is found to inhibit this response, has not been studied much for this purpose. Also there is a requirement of knowing proper dose of Pregabalin for obtunding the intubation response.
Hence this study is very relevant.
11. NAME AND DESIGNATION OF
11.1 Guide : PROF. DR.C.L.GURUDATT M.D.,DA PROFESSOR AND HEAD, 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 :
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11.5 Head of the Department : PROF.DR.C.L.GURUDATT M.D . D.A. PROFESSOR AND HOD DEPARTMENT OF ANAESTHESIOLOGY, MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE.
11.6 Signature of Head of the :
Department
12. REMARKS :
12.1 Remarks of the
Dean and Director :
12.2 Signature :
17 ETHICAL COMMITTEE CLEARANCE
1. TITLE OF DISSERTATION :ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND TRACHEAL INTUBATION IN ADULT PATIENTS USING 75mg AND 150mg OF ORAL PREGABALIN-A PROSPECTIVE, CONTROLLED, DOUBLE BLIND, COMPARITIVE, DOSE FINDING STUDY”
2. NAME OF THE CANDIDATE : DR. KAVERAMMA.M.G
3. SUBJECT : M.D. ANAESTHESIOLOGY
4. NAME OF THE GUIDE : PROF DR.C.L.GURUDATT M.D., DA
DEPARTMENT OF
ANAESTHESIOLOGY,
MYSORE MEDICAL COLLEGE AND
RESEARCH INSTITUTE, MYSORE.
5. APPROVED/NOT APPROVED : APPROVED (If not approved, suggestion)
18 MEDICAL SUPERINTENDENT MEDICAL SUPERINTENDENT KR Hospital Cheluvamba Hospital Mysore Mysore
PROFESSOR AND HOD PROFESSOR AND HOD DEPART MENT OF MEDICINE DEPART MENT OF SURGERY MYSORE MEDICAL COLLEGE AND MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE RESEARCH INSTITUTE, MYSORE
MEDICAL SUPERINTENDENT LAW EXPERT P.K.T.B AND CHEST DISEASES HOSPITAL, MYSORE
DEAN AND DIRECTOR MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, MYSORE.
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