PROTOCOL

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

“COMPARISON OF TWO DIFFERENT DOSES OF ORAL MIDAZOLAM

PREMEDICATION ON INDUCTION DOSE AND CHARACTERISTICS OF

PROPOFOL: A DOUBLE BLIND STUDY”

Name of the candidate : DR. RAMMURTHY

Guide : Dr. SUDHIR HEGDE

Course and Subject : M.D. ( ANAESTHESIOLOGY )

Department of Anaesthesiology,

Father Muller Medical College,

1

Kankanady, Mangalore – 575002 .

2009

Rajiv Gandhi University of Health Sciences, Karnataka Bangalore

ANNEXURE II

PROFORMA FOR REGISTRATION OF THE SUBJECT FOR DISSERTATION

1. NAME OF THE CANDIDATE AND

ADDRESS

DR. RAMMURTHY

P.G. RESIDENT

FR MULLER MEDICAL COLLEGE,

KANKANADY,

MANGALORE-575002

2. NAME OF THE INSTITUTION FR. MULLER MEDICAL COLLEGE,

KANKANADY,

MANGALORE – 575002

3. COURSE OF STUDY AND

SUBJECT

M.D. (ANAESTHESIOLOGY)

4. DATE OF ADMISSION TO COURSE 17-04-2009

5. TITLE OF THE TOPIC

2

COMPARISON OF TWO DIFFERENT DOSES OF ORAL MIDAZOLAM

PREMEDICATION ON INDUCTION DOSE AND CHARACTERISTICS

OF PROPOFOL : A DOUBLE BLIND STUDY

6.BRIEF RESUME OF THE INTENDED WORK:

6.1 NEED FOR THE STUDY:

Propofol is the most frequently used intravenous anesthetic today. Propofol

is used for induction and maintenance of anesthesia, as well as for sedation in and

out side the operating room.

Though propofol has replaced thiopental as inducing agent because of its

smooth induction, rapid and more complete awakening after induction, it

produces significant cardiorespiratory depression at doses used for induction.

Studies have shown that the induction dose of propofol can be reduced with

out compromising its beneficial effects by midazolam premedication. Also it has

been shown that midazolam acts in synergy with propofol1, 2.

Since not many studies with oral midazolam as premedication have been

conducted and no similar study has been done in our institution, we have

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undertaken this study to compare the effects of two different doses3 of oral

midazolam premedication on induction characteristics of propofol .

6.2 REVIEW OF LITERATURE:

1.In 1991 – Short & Chui studied iv midazolam and propofol for induction of

anesthesia in 200 unpremedicated female patients undergoing elective

gynecological surgery. In the first part of the study, dose response relationship

was established for propofol and midazolam given individually.Patients were

assessed for hypnosis and anesthesia. In the second part, propofol and

midazolam combination was given and a decrease in ED50 of propofol by

52% was noted. In addition, there was no significant hemodynamic changes

in propofol midazolam or in the combination.

2.In 1992, McClune et al, gave iv midazolam or propofol for induction of

anesthesia to 140 ASA I or ASA II patients (18-60yrs) ED50 values were

obtained by probit analysis for the loss of response to command, loss of eye

lash reflex, lack of response to application of mask.Propofol alone had ED50

of 1.25mg/kg, 1.61mg/kg, 1.5mg/kg. When administered after midazolam

premedication, there was 50% reduction in of ED50 of propofol. Apnoea,

defined as absence of ventilation for 60s, occurred in 4 patients in propofol

group and in 1 patient in propofol and midazolam group.

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3.In 2002;Jones et al.,compared the effects of midazolam co induction with

propofol predosing on induction dose requirements of propofol in 60 elderly

patients posted for urological surgery.Midazolam group showed a significant

reduction in propofol dose requirements for induction than the propofol group.

4.Tzabar et al., in 1996, studied 80 patients who received an i.v. bolus of

midazolam (either 0, 1, 2 or 4mg) 4min before a propofol infusion.

Anaesthesia was successfully induced in 3mins in 45% of patients receiving no

midazolam.This rose to 70%, 85% and 95% in the groups receiving 1, 2 and

4mg midazolam boluses respectively.A fall in arterial blood pressure was

noted in all the groups but there was no significant difference in between the

groups.

6.3 AIMS AND OBJECTIVES:

1. To study the effects of two different doses of oral midazolam

premedication on induction dose and characteristics of propofol.

7. MATERIALS AND METHODS:

7.1 Source of data:

The study will be conducted at Father Muller Medical College Hospital,

Mangalore, and the study period will be from August 2009 to July 2011.

7.2 Design of the Study:

The type of study will be a randomized, prospective double blind study.

7.3 Method of data collection (including sampling technique):

Inclusion Criteria:

Adult patients of either sex, of ASA grade I or II, falling between the age

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group of 20-50 yrs with the weights ranging from 40-70kg, presenting for elective

surgery under general anesthesia will be included in the study, after obtaining a

written and informed consent.

Exclusion criteria:

1. Patients with the history of asthma

2. Patients with history of cardiac or hepatic disorders

3. Patients who are taking centrally acting drugs like benzodiazepines,

antidepressants.

4. Patients who are on beta blockers.

5. Patients with history of allergy to propofol or midazolam.

6. Pregnant women.

Plan of the Study:

Following approval of institutional ethical committee, 60 adult patients will be

taken up for the study. All the patients will be evaluated thoroughly on the

previous day of surgery and a written and informed consent will be obtained.

Pre operative investigation:

All patients shall undergo following investigation

1. Hemoglobin

2. Random blood sugar

3. Blood urea, Serum creatinine and Serum electrolytes

4. ECG for patients above 40 yrs.

All patients will be kept nil orally over night and will receive 0.1mg/kg oral

diazepam on the night before surgery.

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Details of the study:

The patients (subjects) will be randomly divided in to 2 groups.

Anesthesiologist 1 blinded to the induction sequence will administer the oral

midazolam premedication to both the groups.

1. Group A - will receive 1 oral midazolam tablet (7.5mg) 45 min before

surgery.

2. Group B - will receive 2 oral midazolam tablets(15mg)45mins before

surgery.

In the operating room,iv line will be secured with 18G cannula and pulse

oximeter,non invasive blood pressure and ECG monitors will be connected.

Base line heart rate,blood pressure,SpO2 will be recorded before induction

and will be repeated at intervals of 60s for the remainder of the

study.Hypotension is defined as decrease in mean arterial pressure more than

25% of baseline and will be treated with iv fluids and mephenteramine 6mg

bolus iv and bradycardia is defined as heart rate less than 50/min and will be

treated with atropine 0.6mg bolus iv.

Anesthesiologist 2 blinded to the premedication

doses will conduct the induction sequence. Before induction,the degree of

sedation will be assessed with the help of Ramsay sedation scale.

Ramsay sedation scale:

1.Patient is anxious and agitated or restless.

2.Patient is cooperative,oriented and tranquil.

3.Patient responds to commands only.

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4.Patient exhibits brisk response to light glabellar tap or loud auditory

stimulus.

5.Patient exhibits a sluggish response to light glabellar tap or loud auditory

stimulus.

6.patient exhibits no response.

After this, infusion of 1% propofol(mixed with xylocard 2mg/ml of propofol)

will be started at a rate of 300ml/hr (50mg/min)4 and patients will be assessed

for 3 clinical end points.

1.patients will be asked to raise their hand at the onset of infusion and the

end point will be taken as the time (and hence the dose of propofol)at which

patients drop their hands.

2.Similarly it will be also calculated for the next end point , the loss of eye

lash reflex.

3.Following this, painful stimulus will be applied every5s in the form of

trapezius muscle squeeze and response in the form of movements will be

observed5.The infusion will be stopped as soon as the patient shows no

movement to the trapezius squeeze and time will be recorded thus completing

the study.

Then injection fentanyl(1mcg/kg) will be given and the

tracheal intubation will be facilitated by succinyl choline (1mg/kg) .The heart

rate,blood pressure response to the intubation will be noted. Anesthesia will

be maintained with nitrous oxide and oxygen in the ratio of 5:3 ,0.25-0.5%

halothane and vecuronium 0.04mg/kg bolus and 0.02mg/kg supplemental

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doses using IPPV and Bains circuit. Monitoring during anesthesia will be

continued with ECG, pulse oximetry and non invasive blood pressure

measurements.

At the end of the surgery patients will be reversed with

neostigmine (0.05mg/kg) and atropine (0.02mg/kg).

Data analysis

Collected data will be analyzed by paired and unpaired ‘t’ test, Data will be

summarized and presented in the form of mean, S.D. percentages and by

diagrams. A confidence interval will be calculated for the doses at which the end

points will be achieved.

7.3 Does the study require any investigations or interventions to be

conducted on patients or other humans? No

7.4 Has ethical clearance been obtained from your institution? Yes

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8References:

1. Short T.G. Chui PT. Propofol and Midazolam act synergistically in

combination British Journal of Anaesth 1991, 67: 539-45.

2. Mc Clune S,McKay AC,Wright PMC, Patterson CC ,Clarke

RSJ:Synergistic interaction between midazolam and propofol.British

Journal of Anaesthesia 1992;69:240-245.

3. Tzabar , Brydon C, Gillies GW. Induction of anesthesia with midazolam

and a target – controlled propofol infusion. Anestehsia 1996 ; 51 : 536-8.

4. Jones NA, Elliott S, Knight J.A comparison between midazolam

coinduction and propofol predosing for induction of anaesthesia in

elderly.Anesthesia 2002;57(7):649-653.

5. Stansky,Donald R,Steven LS “Measuring depth of anesthesia”chapter31

1

in Miller’s Anesthesia.Miller RD,Phaladelphia:The Curtis Centre.

9 Signature of the Candidate

10. Remarks of the Guide

11. Name & Designation of

11.1 Guide

11.2 Signature

Dr. SUDHIR HEGDE MD

PROFESSOR

DEPARTMENT OF ANAESTHESIOLOGY

FR. MULLER MEDICAL COLLEGE

MANGALORE - 575002

11.3 Co Guide

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11.4 Signature

11.5 Head of the Department

11.6 Signature

Dr. MAHABALA. T.H. MD

PROFESSOR AND HEAD

DEPARTMENT OF ANAESTHESIOLOGY

FR. MULLER MEDICAL COLLEGE

MANGALORE - 575002

12. 12.1 Remarks of the Chairman and Principal

12.2 Signature

PROFORMA

TO STUDY THE EFFECTS OF TWO DIFFERENT DOSES OF ORAL MIDAZOLAM ON INDUCTION DOSE AND CHARACTERISTICS OF PROPOFOL:A DOUBLE BLIND STUDY

NAME:

AGE: SEX: WEIGHT:

PRE ANESTHETIC CHECKUP: HR: BP:

RS: CVS:

ASA PHYSICAL STATUS:

1

PREMEDICATION:

TIME OF ADMINISTRATION OF T.MIDAZOLAM:

RAMSAY SEDATION SCORE:

TIME OF ONSET OF PROPOFOL INFUSION:

DOSE AND TIME AT WHICH PATIENT DROPPED HAND:

DOSE AND TIME AT WHICH LOSS OF EYELASH REFLEX WAS NOTED:

DOSE AND TIME AT WHICH THERE WAS NO MOVEMENT TO TRAPEZIUS SQUEEZE:

VARIABLES Baseline (0min)

1min post infusion

2min 3min 4min 5min

1.HRBRADYCARDIA(+/-)2.MAPHYPOTENSION(+/-)3.SpO2

1