|6. Brief resume of intended work:
6.1) Need for 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 haemodynamic stress responses in the form of laryngo-sympathetic stimulation which is manifested as hypertension, tachycardia and arrhythmias. These haemodynamic responses are well tolerated in otherwise healthy individuals, but in patients with hypertension, coronary heart disease, cerebrovascular disease and intracranial aneurysm these transient changes can result in potentially deleterious effects like left ventricular failure, pulmonary edema, myocardial ischemia, ventricular dysrrhythmias and cerebral haemorrhage.1
Attempts were made as early as in 1960’s by various investigators to reduce the sympathetic response to laryngoscopy and intubation. These include,
Deepening the plane of anaesthesia with inhalational & intravenous anaesthetic agents2.
Decreasing the duration of laryngoscopy to less than 15 seconds.
Usage of drugs like lidocaine, sedatives, vasoactive drugs like sodium nitroprusside, calcium channel blockers, beta blockers2 and other drugs especially alpha 2 agonists like clonidine & dexmedetomidine.3
Intravenous Dexmedetomidine, a central alpha 2 agonist is being used in anaesthesia practice as a premedicant. The advantages of dexemedetomidine as premedicant in anaesthesia setting include sedation, analgesia, anxiolysis and improved haemodynamic stability4. Because of these beneficial properties,it has been found that it can decrease the haemodynamic response to laryngoscopy and intubation.4 It has also been found that the minimum alveolar concentration (MAC) of volatile anaesthetics also decreases significantly up to 90% and hence decreases the requirement of anaesthetics.
Dexmedetomidine is being used in other countries since many years as premedicant. Since it has been introduced recently in India (2009), and not many studies have been done in our country, there is a need to study the effectiveness of dexmedetomidine in attenuating the haemodynamic response to laryngoscopy and intubation.
Various studies have used Dexmedetomidine in the dose of 0.6µg/kg body weight5,6 and 1µg/kg body weight7,8 as intravenous bolus for attenuating the haemodynamic response.There is need to know whether 0.6µg/kg body weight or 1µg/kg body weight is the ideal dose for attenuation of haemodynamic response to laryngoscopy and endotracheal intubation. Hence, the present study is aimed at comparing the effectiveness of two different doses of intravenous Dexmedetomidine, 0.6µg/kg body weight and 1µg/kg body weight for attenuating haemodynamic response to laryngoscopy and endotracheal intubation .
6.2) Review of literature:
1.Martina Aho,et al in the year 19915,conducted a double blind ,randomized study in 96 women undergoing abdominal hysterectomy to evaluate the effect of intravenously administered Dexmedetomidine on perioperative haemodynamics and isoflurane requirements.Here they studied the effect of 2 doses of Dexmedetomidine 0.3μg/kg body weight and 0.6μg/kg body weight ,fentanyl 2μg/kg body weight and saline as a single intravenous bolus dose which were administered 10 min prior to induction of anaesthesia.They found that in all groups blood pressure(BP) and heart rate(HR) increased after tracheal intubation.However increase in BP and HR was significantly less in Dexmedetomidine group which received 0.6μg/kg body weight than in saline group.At the same time they noted that in patients receiving Dexmedetomidine 0.3μg/kg body weight,the increase in HR and BP did not differ from that of saline group.The major findings of this study was that Dexmedetomidine administered before induction at a dose of 0.6μg/kg body weight blunted haemodynamic response during tracheal intubation.
2.B.Scheinin B. et al in the year 19926 ,evaluated the effect of Dexmedetomidine in attenuating sympathoadrenal responses to tracheal intubation and requirements of Thiopentone and fentanyl perioperatively.They studied the effects in a randomized placebo controlled,double blind trial in 24 ASA-1 patients.
Dexmedetomidine 0.6μg/kg body weight 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.
3.Pharmacology and physiology in anaesthesia practice , by Robert K.Stoelting and Simon C. Hillier,philladelphia,Lippincott Williams and Wilkins(4th edition 2006) 2
Dexmedetomidne is a highly selective,specific,and potent alpha 2 adrenergic agonist (1,620:1:: alpha 2 to alpha 1).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(220:1::alpha 2:alpha 1).the elimination half time of 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. .Isoflurane MAC was decreased by 35% and 48% by Dexmedetomidine plasma concentrations of 0.3ng/ml & 0.6ng/ml,respectively. Despite marked dose dependent 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
4.Yildiz M,Tavlan A,et al in 20067 evaluated the effect of a single preinduction dose of Dexmedetomidine 1μg/kg body weight on cardiovascular responses resulting from laryngoscopy and tracheal intubation,need for anaesthetic agent & perioperative haemodynamic stability.Here 50 patients scheduled for minor surgery were randomized in to two groups, Dexmedetomidine group and 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 study found out that the dose of Thiopentone was decreased by 39% and MAC of Sevoflurane was decreased by 92% during intubation, in Dexmedetomidine group compared with placebo group.The increase in BP and HR in Dexmedetomidine group was significantly less compared to placebo group.
.Hence, they concluded that perioperative administration of a single dose of Dexmedetomidine resulted in sedation,blunted the haemodynamic response to laryngoscopy and intubation, reduced opioids and anaesthetic requirements.
5.Esra Sagiroglu,et al in 20109,compared the clinical effects of two different doses of Dexmedetomidine on attenuation of haemodynamic responses to laryngoscopy and tracheal intubation.A double blinded,randomized study conducted in 60 ASA 1 and 2 patients scheduled for elective gynaecological surgery..Two groups of 30 patients each were selected.Group 1 patients received Dexmedetomidine 1μg/kg body weight in 10 min and Group 2 patients received 0.5μg/kg body weight in 5 min.They found that HR and BP were significantly lower in group 1 patients when compared to group 2.. There was no difference between the groups with respect to quality scores of tracheal intubation,position of vocal cords,jaw relaxation and movement of the limbs .
They concluded that Dexmedetomidine 1μg/kg body weight is more effective than 0.5μg/kg body weight in attenuating haemodynamic responses to laryngoscopy and tracheal intubation .
6.Varshali M Keniya, et al in the year 20118 studied the efficacy of Dexmedetomidine in attenuating symphathoadrenal response to tracheal intubation and analysed reduction in intraoperative anaesthetic requirement.The study was conducted in 60 ASA class I and II patients, divided into two groups of 30 patients each, aged between 18-65 years scheduled for elective surgery of duration of 3 hours or more.Group C received isoflurane-opioid saline anaesthesia,Group D,instead of saline recieved Dexmedetomidine in a dose of 1μg/kg body weight over a period of 10min, prior to induction. Dexmedetomidine infusion was continued in a dosage of 0.2-0.7μg/kg/hr till the start of skin closure.
There was decrease in the dose requirement of Thiopentone by 30%, decrease in Isoflurane
requirement by 32% and also decrease in fentanyl requirement by 33% in Group D.HR and
BP were significantly less in Group D when compared to Group C.So, they concluded that
perioperative infusion of Dexmedetomidine is effective in attenuating symphathoadrenal
responses to laryngoscopy and intubation and also has significant anaesthetic and opioid
6.3) Objectives of study:
a) .To compare the effectiveness of two doses of Dexmedetomidine ,0.6μg/kg body weight and 1μg/kgbody weight in attenuating hemodynamic response - heart rate,systolic blood pressure,diastolic blood pressure & mean arterial pressure, to laryngoscopy and endotracheal intubation.
a)To study the changes in heart rate,systolic blood pressure,diastolic blood pressure and mean arterial pressure associated with laryngoscopy & intubation..
b)To study the effects of Dexmedetomidine in decreasing the requirements of Thiopentone as induction agent and also Vecuronium Bromide as muscle relaxant.
c).To study any adverse effects associated with the administration of Dexmedetomidine, such as perioperative hypotension,bradycardia,postoperative recovery and postoperative execessive sedation.
7) Materials and Methods:
7.1) Source of data:
Ninety patients aged between 18 years and 55 years of either sex belonging to ASA class I and class II posted for various elective surgeries at Krishnarajendra and Cheluvamba hospitals attached to Mysore medical college and research institute, Mysore, will be randomly selected for the study. The study will be conducted from November 2011 to July 2013.
7.2 METHODS OF COLLECTION OF THE DATA
Data will be collected in prescribed proforma meeting the objectives of the study.The study population(90 patients) is randomly divided by computer generated numbers into 3 groups with 30 patients in each group (n=30).
Group A :(n=30) will receive 0.6µg/kg body weight of Dexmedetomidine intravenously.
Group B: (n=30) will receive 1µg/kg body weight of Dexmedetomidine intravenously.
Group C :(n=30) will receive normal saline intravenously. .
Healthy adult patients aged between 18 – 55 yrs posted for elective surgeries.
Patients belonging to ASA Class I & II
Age<18 yrs and >55yrs.
Patients belonging to ASA class III and above.
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.
Patients coming for emergency surgeries.
Pregnant females .
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. Group A Patients will be given intravenous Dexmedetomidine 0.6 g/kg body weight diluted in 10 ml normal saline using syringe infusion pump over 10 minutes,10 minutes before induction . Group B patients will be given intravenous Dexmedetomidine 1.0 g/kg body weight diluted in 10 ml normal saline , using syringe infusion pump over 10 minutes,10 minutes before induction. Group C patients will be given 10 ml of normal saline intravenously using syringe infusion pump over 10 minutes, 10 minutes before induction .
The double blind design of the study will be assured by the fact that an anesthesiologist not further involved in the study prepared syringes containing study drugs before induction of anaesthesia. The syringes are marked Dexmedetomidine-0.6/Dexmedetomidine-1/placebo together with the name of the patient. The anaesthesiologist responsible for the anaesthetic technique is thus kept unaware of the contents of the syringes.The observing anaesthesiologist and the patients are thus blinded for the study drug.
All the three groups will be premedicated with 0.2 mg glycopyrolate, 1 mg midozolam & fentanyl 1µg/kg body weight given intravenously before induction.
General anaesthesia will be induced with 2.5% Thiopentone in incremental doses of 25 mg every 10 secs till the eyelash reflex is lost. The loss of eyelash reflex will be taken as criteria for end of induction. The dose of Thiopentone required for induction is noted down in all the three groups. Succinylcholine 1.5mg/kg body weight will be given for intubation.One minute after succinylcholine, patients will be intubated with appropriate sized cuffed endotracheal tubes with gentle laryngoscopy done within 15 seconds. Anaesthesia will be maintained with oxygen + nitrous oxide + 1 % isoflurane+ Inj Vecuronium bromide- 0.05mg/kg body weight as initial dose and 0.5mg as and when required. After the surgical procedure, patients will be reversed with Inj. Neostigmine 2.5 mg + Inj Glycopyrolate 0.5mg intravenously.The total dose of Vecuronium bromide used for the procedure will be noted.
PARAMETERS TO BE STUDIED
A. Hemodynamic responses are compared in all three 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- STAR PLUS-LARSEN & TOUBRO INDIA LIMITED, at following intervals.
Before giving the test drug
After administration of test drug at 2 min, 5 min .
Just before induction
After intubation at 1 min, 5 min & 10 min
Heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure every 10 min afterwards throughout the surgery.
B. Post operative recovery and sedation will be studied.
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.
Anxious or restless or both
Co-operative, oriented & tranquil
Responding to commands
Brisk response to stimulus
Sluggish response to stimulus
No response to stimulus
The results of the intended study between the three groups will be compared statistically using ‘p’ value obtained from Student ‘t’ test / ANOVA.
7.3 Does the study require any investigation / intervention to be conducted on patients / human / animals? If so describe briefly.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Yes obtained. (Copy enclosed)
8) List of references:
1. King BD, Harris LC, “Reflex circulatory responses to Direct laryngoscopy and Tracheal intubation performed during General anaesthesia”, Anesthesiology, 1951;12:556-566.
2. Ronald D.Miller,Lars I.Eriksson,Lee A.Fleisher,Jeanine P.Wiener-Kronish,William L.Young,”Miller’s anesthesia”seventh edition; 1585-1600.
3. Stoelting RK, Hiller SC, “Pharmacology and physiology in anesthetic practice”, Philadelphia, Lippincott Williams and Wilkins, 2006,340.
4. Bloor BC, Ward DS, Belleville JP, Maze M.“Effects of intravenous dexmedetomidine in humans. II Haemodynamic changes”. Anaesthesiology 1992;77:1134-1142.
5. Martina Aho, Lehinten AM, Erkola O, Kallio A, Korttila K. “The effects of intravenously administered dexmedetomidine on perioperative hemodynamics and isoflurance requirements in patients undergoing abdominal hysterectomy”. Anaesthesiology 1991;74:997-1002.
6. Scheinin B, Lingren L, Randell T, Scheinin H, Scheinin M, “Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone & preoperative fentanyl.” British journal of anaesthesiology 1992; 68:126-131.
7. Yildiz M, Tavlan A, Tuncer S, Reisli R, Yosunkaya A, Otelcioglu S. “Effect of dexmedetomidine on haemodynamic response to laryngoscopy and intubation, perioperative haemodynamics and anaesthetic requirements”, Drugs R D 2006;7:43-52.
8. Varshali M Keniya, Sushma Ladi, Ramesh Naphade, “ Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement” Indian Journal of Anaesthesia, Vol. 55, Issue 4, July – Aug 2011, 352-357.
9. A.Esra Sagiroglu MD, Melek Celik MD, Zeynep Orhon MD, Serdar Yuzer MD, Betul Sen MD, “Different Doses of Dexmedetomidine on Controlling Haemodynamic responses to tracheal Intubation”, Internet Journal of Anesthesiology, 2010, Vol 27, No. 2.