COMPARISION OF INTRANASAL DEXMEDETOMIDINE-MIDAZOLAM,DEXMEDETOMIDINE-KETAMINE AND MIDAZOLAM-KETAMINE

FOR PREMEDICATION IN PAEDIATRIC PATIENTS:

A DOUBLE BLINDED RANDOMIZEDTRIAL.

Dissertation submitted to

All India Institute of Medical Sciences

Jodhpur

In partial fulfillment of requirement for the degree ofMD in Anaesthesiology and Critical Care.

Session: January 2018-2021

Candidate:

Dr. Vaishnavi B.D.

Junior Resident

Guide:

Dr. ShilpaGoyal

Associate professor

Co-guide:                                                                                             Co-guide:

Dr. Pradeep Bhatia                                                                      Dr. Ankur Sharma

Professor and Head                                                                     Assistant professor

Co-guide:                                                                                               Co-guide:

Dr. Priyanka Sethi                                                                      Dr. NarenderKaloria

Assistant professor                                                                      Assistant professor

Department of Anaesthesiology and Critical Care

All India Institute of Medical Sciences, Jodhpur

Table of content

·         Synopsis

·         Introduction

·         Review of Literature

·         Aims and Objectives

·         Material and Methods

·         Statistical Analysis

·         Ethical Consideration

·         Bibliography

·         Appendix

SYNOPSIS

Premedication plays an important role in paediatricanaesthesia as it is helpful in decreasing child’s stress and anxiety thus facilitating smooth induction of anaesthesia.Atleast 60% of children experience pre-operative anxiety which can produce aggressive reaction, increased distress in children and parents, may prolong induction of anaesthesia, greater requirement of analgesics, emergence agitation, post-operative psychological and behavioral issue^[1].

Pre-operative anxiety and its effects inintra-operative and post-operative period can be prevented by effective premedication in an acceptable and non –traumatic route inorder to avoid extra stress to the child. It is a double blinded randomized trial, intended to compare the level of separation anxiety from parents by using combination of three different drugs for pre-medication through intranasal route in pediatric agegroup(2-4 years) undergoing surgery under general anesthesia.

INTRODUCTION

Premedication in paediatricanaesthesia aims at relieving preoperative and postoperative anxiety, facilitating good parental separation and smooth induction of anaesthesia. Anxiety and fear in children lead to increased levels of catecholamines in the body, thereby leading to tachycardia, hypertension, tachypnea^[2]. There is also difficulty in intravenous (IV) access, separation from parents and induction of anaesthesia. It can also lower the pain threshold leading to offensive behaviour. Psychological stress because of forced separation can cause nightmares and post-operative behavioral abnormality. Premedication facilitates in overcoming these difficulties. So the route of administration of premedication shouldbe acceptable to the child and non-traumatic. Several studies have been tried to find the best sedative agent and best route of administration. Most commonly used method is IV drug administration. Since IV cannulation is painful; it could lead to long term psychological problem in the child such as refusing contact with health care provider^[3]. Therefore other routes of premedication have been tried like oral, intranasal, nebulization,sublingual , rectal which are non- traumatic. Intranasal premedication has advantage over others as it requires no venous puncture, rich vascularization,good drug permeability and bypasses first pass hepatic metabolism. Hence, it leadsto rapid absorption into systemic circulation and ensuing effective and rapid sedationof children^[4,5]. Intranasal route may have some minor side effects like burning, stinging or irritation inside nose, crusting, running nose, watery eyes, coughing or sneezing. Children have been found to have high acceptability to intranasal route of premedication administration in previous studies .^[5,6,7]

Midazolam and ketamine are most commonly used for premedication in children. Midazolam is a water soluble benzodiazepine known to have a rapid onset and short duration of action but has no analgesic effect and causes respiratory depression. Ketamine produces dissociativeanesthesia that creates a trance like state with properties of sedation ,amnesia and analgesia. Dexmedetomidine is an alpha 2- adreno-receptor agonist has an analgesic and sedative action with no respiratory depression. These three drugs have been compared individually or in combination with individual drug but never thesethree combinations have been compared with each other. Our study aims at assessing the combination of these three premedication drugs in preventing preoperative anxiety in paediatric age group(2-4years) and thus preventing the ill effects of anxiety.

Review of Literature

Mostafa et al^[8], in 2012 published a study comparing premedication with intranasal dexmedetomidine(1mg/kg), midazolam(0.2mg/kg) and ketamine(5mg/kg) in 96 children of age 2-8 years undergoing bone marrow biopsy and aspirate. They concluded that dexmedetomidine group achieved a faster sedation score at a point of 10 minutes, then all groups achieved a comparable sedation score at a point of 25 minutes, both dexmedetomidine and midazolam group had better sedation score than ketamine group at 30 minutes. Children achieved child-separation score grade 1 was significantly higher in dexmedetomidine group than in midazolam and ketamine groups.

Gyanesh et al^[5]in 2014 published a study in 150 children of age 1-10years undergoing MRI, comparing intranasal dexmedetomidine and intranasal ketamine as premedication. They concluded that dexmedetomidine and ketamine were equally effective by intranasal route.

Sheta et al^[9] in 2014 published a study in 72 children aged 1-3 years undergoing complete dental rehabilitation, comparing intranasal dexmedetomidine and intranasal midazolam. They found that intranasal dexmedetomidine(1mg/kg) is safe and effective alternative for premedication in children, it resulted in superior sedation in comparison to intranasal midazolam (0.2mg/kg).

Khatavkar et al^[6] in 2014 published a study comparing intranasal midazolam (0.15mg/kg) with ketamine(1mg/kg) and intranasal midazolam(0.2mg/kg) in 60 children aged 1-12 years .They concluded that intranasal premedication allows rapid and predictable sedation in children. Both the groups provide good level of sedation but quality of sedation, analgesia,and comfort is significantly better in midazolam with ketamine group.

Wang et al ^[10]in 2014 published a study comparing two doses of dexmedetomidine (1mg/kg and 2mg/kgintranasally) effects on sedation, attenuation of cardiovascular and arousal response during anesthesia induction and intubation in pediatric patients. They concluded that intranasal dexmedetomidine (2mg/kg) administered 30 minutes before induction of anesthesia, provides considerable effect to attenuate the increasing MAP caused by intubation response, produce optimal sedation, more favorable anesthesia induction course in pediatric patients. Premedication of intranasal dexmedetomidine is a considerable way to blunt cardiovascular and arousal response to endotracheal intubation.

Narendra et al^[11], in 2015 published a study comparing intranasal ketamine(5mg/kg) and intranasal midazolam(0.2mg/kg) in 50 children aged 1 to 10years. They concluded that both midazolam and ketamine are an effective pediatric premedication through intranasal route, midazolam has an early onset of sedation and is associated with fewer side effects.

Jia et al^[12]in 2017 published a study in which total of 135 children aged 2-5 years scheduled for eye surgery were randomly allocated to receive intranasal dexmedetomidine 2.5mg/kg  (group D) ,oral ketamine 3mg/kg and intranasal dexmedetomedine 2mg/kg (group DK) or oral ketamine 6mg/kg (group K) 30 mins before surgery. They came to a conclusion that intranasal dexmedetomidine and oral ketamine produce satisfactory parent separation and more successful venous cannulation, allowing children to smoothly accept induction of general anesthesia.

Bhat , Santhosh , Annigeri et al^[13] in 2018 published a study in which 54 children aged 1-6 years scheduled for elective minor surgery were allocated to receive intranasal dexmedetomidine 1mg/kg and another group received dexmedetomidine 1mg/kg and ketamine 2mg/kg intranasally. They concluded that dexmedetomedine as premedicant in children provide acceptable parenteral separation and decreases emergence agitation , however mask acceptance in operating room is poor. Combination of dexmedetomidine and ketamine does not increase the success of premedication.

Gharde et al^[14], published  study in 2018 in 60 children aged 1-10 years  evaluating the efficacy of intransal midazolam (0.2mg/kg ),ketamine (10mg/kg) and their mixture of premedication ( midazolam – 0.1mg/kg , ketamine- 7.5mg/kg ) in children with tetralogy of fallot undergoing intracardiac repair. They concluded that intranasal ketamine is an effective method of premedication than intranasal midazolam and the combination of two provides no benefit as compared to ketamine alone, but is better than midazolam alone.

Kumar et al ^[15], in 2018 published a study in 60 children aged 2-12years comparing efficacy of intranasal dexmedetomidine (1mg/kg) vs oral midazolam (0.5mg/kg), they concluded that intransaldexmedetomidine  produced a superior sedation score at separation and induction but normal behavior scores in comparision  to oral midazolam in pediatric patients.

Gupta et al^[2], in 2018 published a study in 60 children aged 1-8 years scheduled for elective brain MRI , randomly assigned to the intranasal dexmedetomidine ( 1mg/kg)  or intranasal midazolam (0.2mg/kg). They found that intranasal dexmedetomidine results in more successful parental separation and yields a higher sedation level at a time of induction of anesthesia than intranasal midazolam as premedication, with negligible side effects, however its onset of action is relatively prolonged.

Justification of the study:

Hence, literatures suggest that intranasal route is potential alternative and effective route of premedication for paediatric patients. Many studies have been done comparing the intranasal pre-medication drugs individually or an individual premedication drug is compared with combination of premedication drugs using certain scales to assess sedation and parental separation. Many studies have shown that combination of premedication drugs have superior effect than individual drug^[6,15].As there has been no single study comparing the three different combination of intranasally administered drugs as a premedication that is why the present study will be done.

AIMS AND OBJECTIVES

AIM: 

To compare three different combinations of intranasally administered drugs for premedication in children undergoing surgeries under general anesthesia.

OBJECTIVES:

PRIMARY: To assess anxiety level at separation from the parents after 30 minutes of administration of intranasal premedication.

SECONDARY: To assess the  level of sedation , ease of iv cannulation , mask acceptance after 30 minutes of administration of intranasal premedication.

MATERIAL AND METHODS:

STUDY SETTING:

Patients included in the study group will be intervened in the preoperative period till mask acceptance in the Department of Anesthesiology and Critical Care, AIIMS, Jodhpur.

STUDY DESIGN:

A Double Blinded,Randomized trial

STUDY PARTICIPANTS:

INCLUSION CRITERIA:

Paediatric patients of age 2-4 yearsbelonging to ASA 1 posted for elective surgeries under general anaesthesia.

EXCLUSION CRITERIA:

1.Parent refusal.

2. Patients with recent history and active nasal bleeding.

3. Patients with nasal mass.

4. Patients with active URI.

5. Patients with history of pyschiatric illness.

6. Patients with cardiac arrhythmia and congenital heart disease.

7. Patients with raised ICT and raised IOP.

8. Patients with history of allergy to drugs been used.

9.Children who fail to achieve parental separation even after 30 minutes of pre-medication.

Sampling and Sample size:

The study will be done on 150 patients considering anxiolysis(Calm at separation) as 30% in midazolam group and 63.3% in midazolam + ketamine group (Khatavkar SS 2014)^[7], we estimate a sample size of 49 per group at 98.3% confidence interval(after applying Bonferroni correction to 95% confidence interval for three group comparision), 70% power and 10% contingency.

The patients will be randomly divided into three groups of 50 each and will be allocated to the group by computer random number table method as follows.

1. Group A(DM): Patients pre-medicated with 1µg/kg dexmedetomidine and 0.15mg/kg midazolam intranasally.

2. Group B(DK): Patients pre-medicated with 1µg/kg dexmedetomidine and 2mg/kg ketamine intranasally.

3. Group C (MK): Patients pre-medicated with 0.15mg/kg midazolam and 2mg/kg ketamine intranasally.

METHODOLOGY

Pre-anesthetic check-up will be done for these patients prior to surgery.Patients will be kept fasting as per the standard protocol.The procedure of premedication will be explained to the patient’s attendant.Informed written consent will be taken from parents or nearest kin.

Pre-sedation behavior is assessed on 4 point scale(1=calm, cooperative, 2=anxious but reassurable, 3=anxious but not reassurable , 4= crying or resisting).

All study drugs will be prepared by an independent investigator not involved in the observation or administration of anaesthesia. Each drug will be administered by an observer completely blind to the study and to the group allocation of the child.  This observer will also record the pre-sedation scores. The attending anaesthesiologistswill be blinded to the study drug and the master codes and will collect rest of data.

In all the groups, the drug will be given 30 mins before surgery using 1ml tuberculin syringe and the drug will be  deposited in both the nostrils equally with child in recumbent position.Saline will be added to make the total volume to 1 ml.

The signs of nasal irritation (stingy and scratchy nose, watering of nose and eyes) will be observed.

Continuous monitoring of heart rate and SpO₂ and mean arterial pressure will be done in pre-operative period and will be recorded every 5 minutes for 30 minutes.

At 30 minutes after intranasal dose, sedation,ease of separation from parents and iv cannulation will be evaluated by using following scores.

Parent –separation anxiety scale:

·         Patient unafraid,cooperative ,asleep=1

·         Slight fear or crying, quiet with reassurance =2

·         Moderate fear,crying not quiet with reassurance =3

·         Crying need for restraint =4

Sedation score:

·         Agitated = 4

·         Awake=3

·         Drowsy=2

·         Asleep=1

Ease of ivcannulation:

·         No reaction =1

·         Minor resistance= 2

·         Fights without success = 3

·         Fights with success = 4

Mask acceptance with 100% O₂ for pre-oxygenation on OT table will also be assessed as per the following score.

MAS (Mask acceptance scale):

·         Unafraid, cooperative ,accepts mask readily= 1

·         Slight fear of mask , easily reassured  = 2

·         Moderate fear of mask,not calmed with reassurance =3

·         Terrified , crying and combative = 4

Statistical analysis plan:

Data will be entered and analysed using SPSS IBM software version 22 (IBM SPSS Advanced statistics, Chicago, IL, USA) 

Nominal data will be described using frequency and percentages and compared using chi square test or Fischer Exact test. 

Ordinal Data will be described using Median and Interquartile Range (IQR) and compared using Mann-Whiteney U test.

Continuous data will be described using mean +/- SD and compared using unpaired t test. 

P value of <0.05 will be considered as statistically significant. 

ETHICAL CONSIDERATIONS

• The study is ethical as all the three combination of premedication and the route of administration of premedication have been used in the previous studies are standard and safe.
• Informed written consent will be taken from patient’s attendant in  English/Hindi language.
• They will be given full information about the study & the procedure they are undergoing.
• Strict confidentiality about the patient information will be maintained

BIBLIOGRAPHY

1.      Litke J, Pikulska A, Wegner T. Management of perioperative stress in children and parents. Part I – The preoperative period. Anaesthesiol Intensive Ther.2012;44:165‐9.

2.      Gupta A, Dalvi NP, Tendolkar BA. Comparison between intranasal dexmedetomidine and intranasal midazolam as premedication for brain magnetic resonance imaging in pediatricpatientA prospective randomized double blind trial.J AnaesthesiolClinPharmacol. 2017;33:236-240.

3.      Watson AT, Visram A. Children’s preoperative anxiety and postoperative behaviour. PaediatrAnaesth 2003; 13: 188-204.


4.      Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. AnesthProg 1993; 40: 63-6.

5.      Gyanesh P, Haldar R, Srivastava D, Agrawal PM, Tiwari AK, Singh PK.Comparison between intranasal dexmedetomidine and intranasal ketamine as premedication for procedural sedation in children undergoing MRI:a double blind, randomized, placebo-controlled trial.J Anesth. 2014;28:12-8.

6.      Khatavkar SS, Bakhshi RG   .      Comparison of nasal Midazolam with Ketamine versus nasal Midazolam as a premedication in children. Saudi J Anaesth. 2014 ;8:17-21.

7.      Bhat R, Santhosh MC, Annigeri VM, Rao RP

Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study. Anesth Essays Res. 2016;10:349-55.

8.      Mostafa MG, MorsyKM.Premedication with intranasal dexmedetomidine, midazolam and ketamine for children undergoing bone marrow biopsy and aspirate.Egyptian Journal Of Anaesthesia 2013;29:131-5.

9.      Sheta SA, Al-Sarheed MA, AbdelhalimAA. Intranasal dexmedetomidine vs midazolam for premedication in childrenundergoing complete dental rehabilitation:a double-blinded randomizedcontrolled trial. PaediatrAnaesth. 2014 Feb;24:181-9.

10.  Wang SS, Zhang MZ, Sun Y, Wu C, Xu WY, Bai J, Cai MH, Lin L. The sedative effects and the attenuation of cardiovascular and arousal responsesduring anesthesia induction and intubation in pediatric patients: a randomizedcomparison between two different doses of preoperative intranasaldexmedetomidine.PaediatrAnaesth. 2014;24:275-81.

11.  Narendra PL, Naphade RW, Nallamilli S, Mohd S. A comparison of intranasal ketamine and intranasal midazolam for pediatric premedication. Anesth Essays Res 2015;9:213-8.

12.  Jia JE, Chen JY, Hu X, Li. WXA randomised study of intranasal dexmedetomidine and oral ketamine for premedication in children. Anaesthesia. 2013;68:944-9.

13.  Gharde P, Chauhan S, Kiran U. Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair.Ann Card Anaesth. 2006;9:25-30.

14.  Kumar L, Kumar A, Panikkaveetil R, Vasu BK, Rajan S, Nair SG. Efcacy of intranasal dexmedetomidine versus oral midazolam for paediatric premedication. Indian J Anaesth2017;61:125-130.

15.  Zanaty OM, El Metainy SA. A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. AnesthAnalg 2015;121:167‐71.

Appendix -1

All India Institute of Medical Sciences

Jodhpur, Rajasthan

Informed Consent Form

Title of Dissertation : COMPARISION OF INTRANASAL DEXMEDETOMIDINE-MIDAZOLAM, DEXMEDETOMIDINE-KETAMINE AND MIDAZOLAM-KETAMINE FOR PREMEDICATION IN PAEDIATRIC PATIENTS : A DOUBLE BLINDED RANDOMIZED TRIAL.

Name of PG Student                                   : Dr.Vaishnavi B.D.

Telephone no:9620810873

Patient/Volunteer Identification No.         :           ______________

I, _________________                   F/o or M/o ______________________________

R/o________________________________________________________________

give my full, free, voluntary consent for my child to be a part of the study “COMPARISION OF INTRANASAL DEXMEDETOMIDINE-MIDAZOLAM, DEXMEDETOMIDINE-KETAMINE AND MIDAZOLAM-KETAMINE FOR PREMEDICATION IN PAEDIATRIC PATIENTS : A DOUBLE BLINDED RANDOMIZED TRIAL.”the procedure and nature of which has been explained to me in my own language to my full satisfaction. I confirm that I have had the opportunity to ask questions.

I understand that my child’s participation is voluntary and I am aware of my right to opt out of the study at any time without giving any reason.

I understand that the information collected about my child and any of my child’s medical records may be looked at by responsible individual from AIIMS Jodhpur or from regulatory authorities. I give permission for these individuals to have access to my child’s records.

Date : ________________                                                 ________________________

Place : ________________                                         Signature/Left thumb impression

This to certify that the above consent has been obtained in my presence.

Date : ________________                                                 _______________________

Place : ________________                                                           Signature of PG Student

1.    Witness 1                                                                  2. Witness 2

Signature                                                                  Signature

Name: _______________________                                Name: ________

Address : _____________________                               Address : ________

Appendix -2

All India Institute of Medical Sciences

Jodhpur, Rajasthan

Participant information sheet

Title of study:COMPARISION OF INTRANASAL DEXMEDETOMIDINE-MIDAZOLAM, DEXMEDETOMIDINE-KETAMINE AND MIDAZOLAM-KETAMINE FOR PREMEDICATION IN PAEDIATRIC PATIENTS : A DOUBLE BLINDED RANDOMIZED TRIAL.

Name of the principal investigator :Dr.Vaishnavi B.D.

                                                        PG Anaesthesiology & Critical Care

AIIMS Jodhpur

9620810873

I have been explained in my own understanding language by the Principal Investigator that they are doing this study “Comparision of intranasal dexmedetomidine-midazolam, dexmedetomidine-ketamine and midazolam-ketamine for premedication in paediatricpatients : a double blinded randomized trial “ and the risk and benefits associated with it.

I have been informed that I can withdraw my child from the study at any time.

The data obtained from my child will be used for the purpose of the study only. All my child’s records will be kept confidential .

Patient name and Registration ID :

Signature of the parent/guardian :

Appendix -3

Presedationbehaviour is assessed on 4 point scale

Appendix -4

Parent –separation anxiety scale :

Appendix -5

Sedation score :

Appendix -6

Ease of iv cannulation:

Appendix -7

MAS ( mask acceptance scale ):

Appendix -8

PROFORMA

S.No.                          Date:                   

Thesis Title :COMPARISION OF INTRANASAL DEXMEDETOMIDINE-MIDAZOLAM, DEXMEDETOMIDINE-KETAMINE AND MIDAZOLAM-KETAMINE FOR PREMEDICATION IN PAEDIATRIC PATIENTS: A DOUBLE BLINDED RANDOMIZED TRIAL

IPD Serial no/Sticker:

Presedation behavior scale:

Any side effects of intranasal administration : (yes / no )

Scores At 30 minutes :

Sedation score :

Parent –separation anxiety scale :

Ease of iv cannulation:

MAS ( Mask acceptance scale ):