Ketofol Versus Dexmedetomidine for Prevention of Emergence Delirium in Pediatric Patients Undergoing Squint Surgeries: A Randomized Controlled Study.
Phase: PHASE1
Conditions: Emergence Delirium
Sponsor: Cairo University

 
 
 
 
Ketofol Versus 
Dexmedetomidine For 
Prevention Of Emergence 
Delirium In Pediatric Patients 
Undergoing Squint Surgeries: 
A Randomized Controlled 
Study. 
 
 
 
16/7/2024

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Table of Contents 
 
Title Page ....................................................................................................................................................... 2 
Study Title……………………………………………………………………………………………………………………………………………2 
Investigators…………………………………………………………………………………………………………………………………………2 
Introduction: ................................................................................................................................................. 3 
Aim of the work ............................................................................................................................................ 4 
Objectives: .................................................................................................................................................... 4 
Hypothesis..................................................................................................................................................... 5 
Ethical Considerations ................................................................................................................................... 5 
Methodology .............................................................................................................................................. 6-9 
I. 
Study design .................................................................................................................................. 6 
II. 
Study setting and location ............................................................................................................. 6 
III. Study population ........................................................................................................................... 6 
IV. Eligibility Criteria ........................................................................................................................... 6 
1. Inclusion criteria ....................................................................................................................... 6 
2. Exclusion criteria ....................................................................................................................... 6 
V. 
Study Procedures ....................................................................................................................... 6-8 
1. Randomization (in RCT only) .................................................................................................... 6 
2. Study Protocol ....................................................................................................................... 7,8 
VI. Study outcomes ................................................................................................................................... 9 
1. Primary outcome ..................................................................................................................... 9 
2. Secondary outcome(s) ............................................................................................................. 9 
Statistical Analysis .................................................................................................................................... 9,10 
I. 
Sample size .............................................................................................................................. 9 
II. 
Statistical analysis .................................................................................................................. 10 
References ............................................................................................................................................. 11,12 
 
 
 

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Title Page 
Study Title 
Ketofol Versus Dexmedetomidine For Prevention Of Emergence Delirium 
In Pediatric Patients Undergoing Squint Surgeries: A Randomized 
Controlled Study. 
Investigators 
Candidate Details 
Name: Muhammad Khalaf Ibrahim Ali 
Affiliation: assistant lecturer of anesthesia ,surgical ICU and pain management at Kasr 
Alainy School Of Medicine. 
Degree: MD 
Phone No: 01032170260 
Email:  dr.mki26413@gmail.com  
Principle Investigator 
Name and Affiliation: Prof. Dr: Karim Kamal Fahim Girgis, MD  
Professor of Anesthesia, Pain management and Surgical ICU Faculty of Medicine, Cairo University. 
               Phone No: 01222457666 
Email:  Karim.Girgis@kasralainy.edu.eg  
Co-investigator (A): 
Name & Affiliation : prof assistant Dr: Hany Mohammed Elhadi Shaukat , MD   
assistant professor of Anesthesia, Pain management and Surgical ICU Faculty of medicine, Cairo 
university 
Phone No :01003066806 
Email: hany.elhadi@kasralainy.edu.eg  
 
Coinvestigator (B): 
Name: Dr.Kareem mohammed Assem Mohammed Nawwar, MD 
Lecturer of Anesthesia, Pain management and Surgical ICU 
Faculty of Medicine, Cairo University 
Phone No: 01003878369 
Email:  drknawwar@yahoo.com  
 
Coinvestigator (C): 
              Name: Mohamed Elsayed AbdelFatah Mohammed, MD 
             Lecturer of Anesthesia, Pain management and Surgical ICU  
             Faculty of Medicine, Cairo University. 
Phone No: 01272288695 
Email: mohyaseen2@gmail.com  
 

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Introduction : 
 
     Emergence delirium (ED) is a common postoperative complication in pediatrics 
characterized by disorientation, confusion, alterations in perception such as 
hypersensitivity to stimuli, inconsolable crying and moaning(1,2,3 ). The incidence of 
ED among pediatric population ranges from 25% to 80%, with high frequency in 
preschool children aging between 2- 6 years old (1,2,3). There are many risk factors 
contributing to ED including : patient age, preoperative anxiety, inadequate adaptive 
behavior, separation from parents, anesthetic drugs side effects, sudden arousal in 
unfamiliar enivronment and type of surgical operation including ophthalmological 
operations(strabismus surgeries)(3,4). 
Emergence delirium appeared to be accompanied by unpreferable consequences as the 
child may remove intravenous devices, urinary catheter and surgical drain and may 
cause injury to surgical site. Child with  ED need more care and delayed discharge 
from PACU(1,2). Accordingly, prevention of such complication is mandatory. To 
achieve this goal, Administration of adjunctive anesthetic agents including propofol, 
benzodiazepines, opioids, gabapentin, ketamine, clonidine, or dexmedetomidine may 
help in reducing the risk of emergence delirium in pediatric patients (5-7). 
Dexmedetomidine is a selective α2 receptor agonist known to have potent analgesic, 
sedative and anxiolytic effect, mainly due to binding to and stimulation of α2 
receptors in the brain preventing activation of sympathetic system. Furthermore, it 
activates the same receptors in the dorsal horn of spinal cord leading to substance b 
release that have strong analgesic action (8,9). On the other hand, Ketamine is a 
noncompetitive antagonist of the N-methyl-D-aspartic acid (NMDA) receptor that 
have dose dependent hypnotic, analgesic and amnesic effects(10).  However, being a 

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low-cost drug, ketamine has undesirable side effects like postoperative nausea, 
vomiting, laryngospasm, and desaturation (11). 
Propofol is an anesthetic agent, with hypnotic and sedative effects of rapid onset short 
duration that allows rapid recovery, utilized for induction and maintenance of general 
anesthesia.   Many studies demonstrated that propofol administrations for maintenance 
of anesthesia remarkably reduces incidence of ED (12). Considering that there is a 
synergistic clinical action between propofol and ketamine (ketofol) which has been 
used to prevent ED. Therefore, their doses decrease and undesirable side effects are 
reduced (13). 
Despite many previous studies investigated effectiveness of adjunctive anesthetic 
agents in prevention of ED, there is lack of studies that focused on comparison 
between the efficacy of Dexmedetomidine and Ketefol in decreasing incidince of ED 
in preschool pediatric  population undergoing eye surgeries , a previous study 
conducted a clinical trial on dexmedetomidine versus ketofol when given as a single 
bolus dose 10 minutes before  the end of suregery in pediatric patients aged from 3 to 
6 years old  who underwent orthopedic surgeries under sevoflurane based General 
anesthesia(14),  another one compared Dexmedetomidine versus Ketofol as a single 
bolus dose given 10 minutes  before the end of surgery in  pediatric population aged 
from 3 to 10 years old underwent oropharyngeal and urological operations(15) .  
In this randomized controlled study, we will compare between efficacy of 
Dexmedetomidine vesus Ketofol for prevention of ED used as continous infusion 
through operation in pediatric patients aging from 2 to 6 years old undergoing squint 
surgeries .  
 
        

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Aim of the work 
         The aim of the study is to compare the effectiveness of ketofol for the prevention 
of emergence delirium in pediatric patients undergoing squint surgery, in comparison 
to dexmedetomidine. 
Objectives : 
• 
To compare the incidence of ED between children who received ketofol with 
those who received dexmedetomidine. 
• 
To compare the adverse effect profile associated with both drugs regarding the 
effect on heart rate, mean arterial pressure, recovery time, nausea, and vomiting. 
Hypothesis 
      We hypothesize that Ketofol, due to the combined effect of ketamine and propofol 
will be as effective as dexmedetomidine in preventing ED in pediatric patients 
undergoing squint surgery. 
Ethical Considerations 
     The study protocol will be implemented after the approval by the Institutional 
Research Ethics Committee and then written informed consent will be obtained from 
all patients before enrollment into the study. 
Methodology 
 
 
I.
Study design 
           A prospective randomized controlled double blinded study. 
 
II.
Study setting and location 
         The study will be conducted at the Specialized Children Hospital (Abo El-Rish),    
         Cairo University. 

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III. Study population 
All pediatric patients aged 2 to 6 years with ASA physical status I and II 
scheduled for squint surgery will be included in the study. 
 
IV. Eligibility Criteria  
 
1. Inclusion criteria 
 
• 
All pediatric patients aged 2 to 6 years. 
• 
Both sexes. 
• 
ASA physical status I and II. 
• 
Patients undergoing squint surgery. 
 
2. Exclusion criteria 
• 
Refusal of parents. 
• 
Patient sensitivity to any of the study medications. 
• 
Known neurological disease that can affect the assessment of ED 
postoperatively. 
 
V.
Study Procedures 
 
1. Randomization (in RCT only) 
 
   A computer-generated sequence will be used for randomization and opaque 
envelopes will be used for concealment.   
The investigator is the anesthesiologist who will prepare all the syringes with the 
study drugs and will prepare them in wrapped aluminum foils and sealed opaque 
envelope technique. which will be provided to another investigator just before 
administering them to the children. Monitoring and data collection will be done by a 
resident who is unaware of the study drugs and allocation. 
 
 

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Study Protocol 
 
        All patients meeting the inclusion criteria will be assessed for adequate fasting 
(except for oral clear liquids intake 2 hours before surgery, all children will fast for 6 
hours.). Patients will attend in the preparation room one hour before the operation to 
get a preoperative checkup, as well as their age and body weight will be recorded. 
Premedicated by intramuscular injection of atropine 0.02 mg/Kg and midazolam 0.2 
mg/Kg. On arriving the operating room, standard monitors including SpO2, ECG, and 
noninvasive blood pressure ((Dräger infinity vista XL). will be applied. Inhalational 
induction using Sevoflurane 5% will be performed, and after the loss of consciousness 
intravenous cannula will be inserted. Atropine 0.01 mg/kg will be administered, and 
appropriate sized endotracheal tube will be inserted after muscle relaxation using 
atracurium 0.5 mg/kg. Maintenance of anesthesia using 2% Sevoflurane in 50% O2 
will be started, and its dose will be adjusted according to the measured pulse and mean 
arterial pressure (MAP), which was kept within 20% of their basal values, with the 
goal of keeping the BIS measurement between (40-60) and atracurium top-ups of 
0.1mg/kg was given every 30 minutes for neuromuscular blockade. and controlled 
ventilation will be applied, aiming for EtCO2 to be between 32-34 mmHg. using 
(G.E-Datex-Ohmeda, Avance CS2, USA) anesthesia machine. Then patients will be 
randomized to either group A or group B. 
Group A: 
Five minutes after securing the airway, dexmedetomidine infusion will be started at a 
rate of 0.2 mcg/kg/hr. 
Group B: 
Five minutes after induction; Ketofol (ketamine to propofol ratio 1:4) will be infused 
at a rate of 0.6 ml/kg/hr. Ketofol will be prepared by adding 40 mg of ketamine to 160 
mg of propofol and diluted to 20 ml with normal saline 0.9%. 
 
The hemodynamic data, including heart rate and arterial pressure, will be documented 
every five minutes and any intraoperative complications including bradycardia, 
hypotension will be managed and documented. Ten minutes before the conclusion of 
the surgery the infusion in both groups will be stopped.  All patients will receive 
15mg/kg paracetamol IV. 

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After finishing the surgical procedure, sevoflurane will be discontinued, and the 
neuromuscular block will be reversed via neostigmine (0.05 mg/kg) and atropine (0.02 
mg/kg). The patient will be extubated when he/she is fully awake, expressing eye-
opening and purposeful movement, in addition to maintaining good tidal volume. 
Then, the patients will be transferred to the PACU, where they receive O2 via a face 
mask to maintain oxygen saturation above 95%. 
During their stay at PACU, delirium will be assessed at 5, 10, 15, 20, 25, and 30 
minutes following extubation via the Pediatric Anesthesia Emergence Delirium scale 
(PAED) (Table 1), and ED will be established when the child have a score of 10 or 
more. If the child has a score of 10 or more, rescue sedation will be done via propofol 
1 mg/kg. (14,17) 
The postoperative pain will be assessed via the Face, Legs, Activity, Cry, and 
Consolability (FLACC) scale 0 = Relaxed and comfortable,1–3 = Mild discomfort, 4–
6 = Moderate pain, 7–10 = Severe discomfort/pain. IV Fentanyl (1 μgm /kg) will be 
administered if the child expressed a score of 3 or more. (16) 
  
Criteria 
Not 
at all 
Just a 
little 
Quite 
a bit 
Very 
much 
Extremely Score 
The child makes eye 
contact with the 
caregiver/parent. 
4 
3 
2 
1 
0 
 
The child’s actions are 
purposeful. 
4 
3 
2 
1 
0 
 
The child is aware of 
his/her surrounding. 
4 
3 
2 
1 
0 
 
The child is restless. 
0 
1 
2 
3 
4 
 
The child is inconsolable. 
0 
1 
2 
3 
4 
 
Total score. 
 
 
 
 
 
 
 
Table 1. Pediatric Anesthesia Emergence Delirium (PAED) Scale Score. The PAED scale consists of 5 criteria 
that are scored using a 5-point scale. The scores of each criterion are added to make a total score. The maximum 
achievable score is 20. A score of ≥10 has 64% sensitivity and 86% specificity for the diagnosis of ED. A score 
of >12 100% sensitivity and 94.5% specificity for the diagnosis of ED (17). 
 
 
 
Both pulse and MAP will be recorded at PACU on arrival, then at 5 and 10 minutes, 
then every 10 minutes until the discharge.  

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Any 
postoperative 
complications 
including 
bradycardia, 
hypotension 
or 
hypersensitivity reaction will be recorded. The incidence of postoperative vomiting, 
together with the duration of stay in PACU will be recorded. 
 
Children were monitored in the PACU for all the above parameters until discharge 
and criteria of discharge are :  
1. Fully awake 
2. Calm 
3. Stable hemodynamics 
4. PAED scale < 10 
5. Oxygen saturation > 92% on room air. 
 
VI. Study outcomes 
 
 
1. Primary outcome 
The incidence of postoperative ED using PAED scale at time of admission to 
         
PACU in both groups. 
 
2. Secondary outcome(s) 
 Intraoperative vital signs So2 (%), HR (bpm) and MAP (mmhg) on admission to OR 
and every 5 minutes intraoperative.  
 Incidence of Intraoperative complications (bradycardia and hypotension)  
 PAED scale at 5, 10, 15, 20, 25 and 30 minutes after extubation.  
 Total dose of rescue sedation by propofol (mg) at PACU.  
 FLACC scale at PACU. 
 Total dose of rescue analgesia (mic).  
 Postoperative hemodynamics So2 (%), HR (bpm) and MAP (mmhg) after 5 and 10 
minutes after admission to PACU then every 10 minutes till discharge.  
 Incidence of postoperative nausea and vomiting. 

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 Length of stay in the PACU (minutes). 
 
 
Statistical Analysis 
 
I.
Sample size 
 Sample size was calculated using G*Power version 3.1.9.2 (Kiel University, Kiel, 
Germany) software; based on our primary outcome ED could occur in 
dexmedetomidine group and ketofol group with PAED score 1.55±2.195, and 
4.70±3.988 respectively (8); a total sample of 46 patients (23 in each group) were 
required to achieve a power (1–β) of 90%, and type I α error of 0.05. Six patients were 
added to compensate for any drop out. Thus, the final sample was 26 patients in each 
group; with total 52 patients. 
 
II.
Statistical analysis 
All collected data will be revised for completeness and accuracy. Pre coded data will 
be entered on the computer using the statistical package of social science software 
program, version 26 (SPSS) to be statistically analyzed. Data will be summarized 
using: Mean and SD for quantitative variables and Number and percent for qualitative 
variable. 
Comparison between qualitative variables will be done using chi square test. While 
independent T test for quantitative variable which will be normally distributed and 
non-parametric Mann-Whitney tests for quantitative variables which will be not 
normally distributed. One-way Anova will be used to compare quantitative variables 
between more than two categories for quantitative variable which will be normally 
distributed and nonparametric Kruskal-Wallis tests for quantitative variables which 
will not be normally distributed. Pearson or Spearman Correlation will be performed 
to explore correlations between the continuous variables. P value <0.05 will be 
considered significant. 
 
 

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