Clinical trial NCT03781505
Conditions: Postoperative Analgesia
Sponsor: Aga Khan University
Start date: 2019-01-31; Completion date: 2022-05-01
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate whether the addition of intravenous paracetamol with caudal ropivacaine leads to better quality of postoperative recovery in patients undergoing hypospadius repair than caudal ropivacaine alone. The quality of recovery will be judged by postoperative analgesia requirement and lesser agitation in the postoperative period.

Detailed description:
After obtaining approval from Ethical Review Committee (ERC) of Aga Khan University Hospital Karachi (AKUH) and inform about the study to primary surgeon (who ever doing the surgical procedure on this time), informed written consent will be obtained from the parents of patients fulfilling the inclusion criteria schedule for surgical procedures on the day before surgery. Assent will be obtained from older children.

The patients will be assigned to one of the two groups by randomization through sealed opaque envelope technique. The envelopes will be prepared using a computer generated randomization table. Randomization envelopes will be used in consecutive order.

Patients will be allocated to either placebo group, who will not receive intravenous paracetamol, or group who will receive intravenous paracetamol.

All patient will be given general anesthesia as per standard of care. Anaesthesia will be standardized as follow. Anaesthesia will be induced by the inhalational route with application of facemask with 8% sevoflurane in 50% oxygen-nitrous oxide mixture. Airway will be managed by laryngeal mask airway (LMA) of appropriate size as recommended by manufacturer and anesthesia will be subsequently maintained with Minimum alveolar concentration 1-2% sevoflurane in 40% oxygen-nitrous mixture with spontaneous ventilation via LMA. Heart rate (HR), noninvasive blood pressure, core body temperature (oral/nasal probe), end-tidal carbon dioxide (ETCO2) and oxygen saturation by pulse oximetry (SpO2) will be monitored throughout.

After induction of anaesthesia, patients will be turned to lateral position and maximum safe dose of ropivacaine will be calculated (3mg/kg) and documented. After all aseptic measures, butterfly needle (size 23 gauge) will be inserted into the sacral hiatus. A total volume of 1 ml/kg of 0.25% ropivacaine solution will be injected in caudal space. The time of performing block will be noted. The success of caudal analgesia will be assessed by monitoring the parameters like heart rate (HR) and blood pressure (BP) in response to incision. In case of tachycardia (\>20% from baseline) and hypertension (\>20% from baseline), the concentration of sevoflurane will be adjusted. If tachycardia persists for more than 5 minutes despite increasing the sevoflurane concentration, rescue analgesia in the form of fentanyl 1mcg/kg will be administered.

Study drugs will be prepared and dispatch by Clinical Trial Unit (CTU) pharmacy. Eligible consecutive randomized patients belonging to study group will receive intravenous paracetamol approximately about an hour before the end of surgery with a dose of 15mg/kg over 15 to 20 minutes. While the patients belonging to other group will receive placebo. Time of intravenous paracetamol administration will be noted.

After emergence, the children will be taken to the postanesthesia care unit (PACU) where parents will be called to stay with their child. Time of arrival in the recovery room will be noted.The Mean arterial pressures (MAP), heart rate HR, oxygen saturation by pulse oximetry (SPO2), respiratory rate (RR), sedation, agitation, quality and duration of analgesia will be recorded at 15 and 30 minutes and will be followed by 1, 2, 4, and 6 hours following recovery from anaesthesia.

The analgesic status of the patient will be evaluated by trained Research Assistant in the PACU and in the ward by using Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). This includes crying, facial expression, verbal response, touching the wound and torso and leg movement. It is given in the Appendix.

Sedation will be assessed using a five point scale (0: awake; 1: mild sedation; 2: sleeping, but able to wake; 3: in deep sleep, unable to wake). These observations will be recorded by the same investigator blinded to the medication administered. Same observer will perform the measurements for all patients. A pain score lower than 4 will be considered adequate analgesia. Rescue analgesia will be provided by 0.1 mg/kg i.v. morphine in divided doses (0.025 mg aliquots) and time of doses will be noted on the form.

Analgesia requirement in the postoperative period will be define as a CHEOPS score of 7 or more. Time to the first analgesic requirement will be calculated as the time from the performance of caudal block to the first analgesic dose administered.

Complications like motor block, hypotension and urinary retention will be monitored and recorded in the postoperative period. Modified Bromage Scale will be used to assess motor block i.e 0= No block, 1= Able to move legs, 2= Unable to move legs.

Adverse effects:

Adverse Events are defined as 'Any untoward medical occurrence in a trial patient to whom a research treatment or procedure has been administered, including occurrences which are not necessarily caused by or related to that treatment or procedure.

Adverse effects associated with the paracetamol are rare \<1/10000, which includes malaise, increased level of hepatic transaminases and hypersensitivity reaction.

The following data will be collected by an observer in postoperative period: age, weight, height, surgical time, anesthesia time, recovery time, discharge time, need to increase sevoflurane concentration after incision, the need for rescue analgesia in operating room (OR) and PACU, time of voiding urine and time of taking oral fluids, while subjective complaint of heaviness in legs will be asked from children above 3 years only.

SAMPLE SELECTION Inclusion criteria

1. Age 3-10 years
2. American Society of Anesthesiologist class I and II
3. Undergoing hypospadias repair surgery

Exclusion criteria

1. Coagulopathy
2. Aspirin or any other analgesic ingestion in the preceding week
3. Preexisting neurological or spinal disease
4. Hepatic, renal disease and malnutrition

Arms: arm 1: Paracetamol is widely accepted and most commonly used as an adjuvant for postoperative analgesia. It also improves the quality of recovery by attenuating the pain associated with the surgical position. Adverse effects associated with the paracetamol are rare \<1/10000, which includes malaise, increased level of hepatic transaminases and hypersensitivity reaction. It has been studied in combination with caudal analgesia with bupivacaine through the rectal route 7,8 with variable results.

Caudal anaesthesia is effective in alleviating pain below the umbilicus. Also if the caudal block is administered at the beginning of surgery, the effect will start wearing off 2 to 3 hours post surgery. Administration of paracetamol towards end of surgery may help with both these issues. In this study we aim to investigate the effect of adding intravenous paracetamol in combination with caudal analgesia with ropivacaine, hoping that it may improve quality of postoperative analgesia and recovery. arm 2: Intravenous Normal Saline with Caudal Ropivacaine
Interventions: intervention 1: Paracetamol +caudal ropivacaine intervention 2: Placebo
Intervention descriptions: intervention 1: Paracetamol + Ropivacaine intervention 2: Caudal ropivacaine

Protocol documents:
Prot_SAP_000.pdf: 
 
Title of study: Effect of Intravenous Paracetamol in combination with caudal ropivacaine 
on quality of postoperative recovery in paediatric patients undergoing hypospadias repair. 
 
Institute: Department of Anaesthesiology, Aga Khan University Hospital. 
 
Clinical Trial Registration: NCT03781505 
 Date: 28th June 2018 
 
 
 
 
 
 
 
 
 
 
 
 
INTRODUCTION 


Postoperative pain control in paediatric population is a challenge because of difficulty in 
communication and, if not controlled can lead to agitation and lead to physical and emotional 
effects.1 Caudal analgesia has been frequently used in combination with general anaesthesia for 
both intraoperative and postoperative pain control in infraumbilical surgeries. It provides 
analgesia of 4 to 8 hours duration.2 Several adjuvants have been used with local anesthetics to 
improve quality and prolong effects. These include; opioids,3 clonidine,4 ketamine,5 epinephrine 2 
and neostigmine.6  
Paracetamol is widely accepted and most commonly used as an adjuvant for postoperative 
analgesia. It also improves the quality of recovery by attenuating the pain associated with the 
surgical position and is not associated with complications seen by other adjuvants like narcotics. 
Adverse effects associated with the paracetamol are rare <1/10000, which includes malaise, 
increased level of hepatic transminases and hypersensitivity reaction. It has been studied in 
combination with caudal analgesia with bupivacaine through the rectal route 7,8 with variable 
results. 
Caudal anaesthesia is effective in alleviating pain below the umbilicus but may not counteract 
pain due to positioning. Also if the caudal block is administered at the beginning of surgery, the 
effect will start wearing off 2 to 3 hours post surgery. Administration of paracetamol towards end 
of surgery may help with both these issues. In this study we aim to investigate the effect of 
adding intravenous paracetamol in combination with caudal analgesia with ropivacaine, hoping 
that it may improve quality of postoperative analgesia and recovery. 
 
 
OBJECTIVE 
To investigate whether the addition of intravenous paracetamol with caudal ropivacaine leads to 
better quality of postoperative recovery in patients undergoing hypospadius repair than caudal 
ropivacaine alone. The quality of recovery will be judged by postoperative analgesia requirement 
and lesser agitation in the postoperative period. 
 


Operational Definitions:  
Postoperative analgesia requirement: 
The time from the performance of caudal block to the first analgesic dose administered 
postoperatively. Quality of analgesia will be monitored by CHEOPS scale. 
Postoperative Agitation: 
A state of consciousness in which the child is inconsolable, irritable, uncooperative, typically 
thrashing  or crying. 
 
Hypothesis:  
Ho: There is no difference in treatment of intravenous paracetamol to caudal ropivacaine and 
caudal ropivacaine alone in term of mean time of first analgesic requirement.  
HA: There is difference in treatment of intravenous paracetamol to caudal ropivacaine and caudal 
ropivacaine alone in term of mean time of first analgesic requirement. 
 
MATERIAL AND METHODS 
STUDY DESIGN: 
A prospective, double-blind, randomized controlled study. 
SETTING: 
 This study will be conducted in Postanaesthesia care unit (PACU) and paediatric surgical ward 
of Aga Khan University Hospital, Karachi. 


DURATION OF STUDY: 
The duration of study is 6 to 12 months after approval of   ERC. 
SAMPLE SIZE: 
The sample size estimation is based on“the time of first analgesic requirement” of patients. A 
previous study on similar outcome by OZYUVACI reported a first analgesic requirement time in 
caudal alone was 3020±39.28 minutes.8 For the purpose of sample size calculation, we 
considered that a clinically important difference in first analgesic requirement time would be a 
10% absolute increment in the intravenous paracetamol in combination with caudal ropivacaine 
compared with the caudal alone. We calculated that 29 patients per group would be required for 
an experimental design incorporating two equal-sized groups, using an alpha =0.05 and beta 
=0.2. To minimize any effect of data loss, we will recruiting 32 patients in each group into our 
study assuming a 10% dropout rate. 
 
SAMPLING TECHNIQUE: 
Non-Probability Consecutive sampling. 
SAMPLE SELECTION 
Inclusion criteria 
1. Age 3–10 years 
2. ASA I and II 
3. Undergoing hypospadias repair surgery  
 
Exclusion criteria 
1. Coagulopathy 
2. Aspirin or any other analgesic ingestion in the preceding week 
3. Preexisting neurological or spinal disease  
4. Hepatic, renal disease and malnutrition 


5. Severe hypovolemia 
6. Uncontrolled convulsions  
7. Refusal of the parents 
8. Local Skin infection at the puncture site  
9. Allergy to local anesthetics 
10. Patient previously involved in other studies  
METHOD 
After obtaining approval from Ethical Review Committee (ERC) of Aga Khan University 
Hospital Karachi (AKUH) and inform about the study to primary surgeon (who ever doing the 
surgical procedure on this time), informed written consent will be obtained from the parents of 
patients fulfilling the inclusion criteria schedule for surgical procedures on the day before 
surgery. Assent will be obtained from older children. 
The patients will be assigned to one of the two groups by randomization through sealed opaque 
envelope technique. The envelopes will be prepared using a computer generated randomization 
table. Randomization envelopes will be used in consecutive order. The randomisation process 
will follow the CONSORT guidelines [A]. 
Patients will be allocated to either placebo group, who will not receive intravenous paracetamol, 
or group who will receive intravenous paracetamol. 
All patient will be given general anesthesia as per standard of care. Anaesthesia will be 
standardized as follow. Anaesthesia will be induced by the inhalational route with application of 
facemask with 8% sevoflurane in 50% oxygen-nitrous oxide mixture. Airway will be managed 
by LMA of appropriate size as recommended by manufacturer and anesthesia will be 
subsequently maintained with (MAC 1–2%)  sevoflurane in 40% oxygen-nitrous mixture with 
spontaneous ventilation via LMA. Heart rate, noninvasive blood pressure, core body temperature 
(oral/nasal probe), end-tidal carbondioxide (ETCO2) and SpO2 will be monitored throughout. 
 
After induction of anaesthesia, patients will be turned to lateral position and maximum safe dose 
of ropivacaine will be calculated (3mg/kg) and documented. After all aseptic measures, butterfly 
needle (size 23 guage) will be  inserted into the sacral hiatus. A total volume of 1 ml/kg of 0.25% 


ropivacaine solution will be injected in caudal space. The time of performing block will be 
noted. The success of caudal analgesia will be assessed by monitoring the parameters like heart 
rate and blood pressure in response to incision. In case of tachycardia (>20% from baseline) and 
hypertension (>20% from baseline), the concentration of sevoflurane will be adjusted. If 
tachycardia persists for more than 5 minutes despite increasing the sevoflorane concentration, 
rescue analgesia in the form of fentanyl 1mcg/kg will be administered. 
Study drugs will be prepared and dispatch by CTU pharmacy. Eligible consecutive randomized 
patients belonging to study group will receive intravenous paracetamol approximately about an 
hour before the end of surgery with a dose of 15mg/kg over 15 to 20 minutes. While the patients 
belonging to other group will receive placebo. Time of intravenous paracetamol administration 
will be noted. 
 
After emergence, the children will be taken to the postanesthesia care unit (PACU) where 
parents will be called to stay with their child. Time of arrival in the recovery room will be 
noted.The MAP, HR, SPO2, respiratory rate (RR), sedation, agitation, quality and duration of 
analgesia will be recorded at 15 and 30 min and will be followed by 1, 2, 4, and 6 h following 
recovery from anaesthesia. 
 
The analgesic status of the patient will be evaluated by trained Research Assistant in the PACU 
and in the ward by using Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS). This 
includes crying, facial expression, verbal response, touching the wound and torso and leg 
movement. It is given in the Appendix. 
 
 Sedation will be assessed using a five point scale (0: awake; 1: mild sedation; 2: sleeping, but 
able to wake; 3: in deep sleep, unable to wake). These observations will be recorded by the same 
investigator blinded to the medication administered. Same observer will perform the 
measurements for all patients. A pain score lower than 4 will be considered adequate analgesia. 
Rescue analgesia will be provided by 0.1 mg/kg i.v. morphine in divided doses (0.025 mg 
aliquots) and time of doses will be noted on the form. 
 


Analgesia requirement in the postoperative period will be define as a CHEOPS score of 7 
(Should be 4) or more. Time to the first analgesic requirement will be calculated as the time from 
the performance of caudal block to the first analgesic dose administered.  
Complications like motor block, hypotension and urinary retention will be monitored and 
recorded in the postoperative period. Modified Bromage Scale will be used to assess motor block 
i.e 0= No block, 1= Able to move legs, 2= Unable to move legs.  
Adverse effects 
Adverse Events are defined as ‘Any untoward medical occurrence in a trial patient to whom a 
research treatment or procedure has been administered, including occurrences which are not 
necessarily caused by or related to that treatment or procedure (18).’ 
Adverse effects associated with the paracetamol are rare <1/10000, which includes malaise, 
increased level of hepatic transminases and hypersensitivity reaction.  
Serious Adverse Events 
Serious Adverse Events are defined as an untoward event that: Results in death; Is life-
threatening*; Requires hospitalization** or prolongation of existing hospitalization; Results in 
persistent or significant disability or incapacity; Or, is otherwise considered medically significant 
by the Investigator (18).  
*The term “life-threatening” refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. ** Patients must be formally admitted – waiting in out-patients or A&E does 
not constitute an SAE (even though this can sometimes be overnight). Similarly, planned 
hospitalizations that clearly are not related to the condition under investigation or 
hospitalizations/prolongation of hospitalization due to social reasons should not be considered as 
SAEs (18). 
 
 


The following data will be collected by an observer in postoperative period: age, weight, height, 
surgical time, anesthesia time, recovery time, discharge time, need to increase sevoflurane 
concentration after incision, the need for rescue analgesia in OR and PACU, time of voiding 
urine and time of taking oral fluids, while subjective complaint of heaviness in legs will be asked 
from children above 3 years only. 
Data and Record handling: 
The data would be handled by the primary investigator and hard copies of the data will be saved 
by a lock and key method and soft copies will be saved on a computer and the data will be 
password protected. Due to regulatory requirement this data will be saved for 15 years.  The 
study and data would be published after it has been approved as a dissertation by the CPSP and 
identity of the subjects will be kept confidential. 
The study will be monitored by the supervisors and samples will be randomly picked for 
protocol compliance, ethical standards, regulatory compliance and data quality at the clinical 
site, including review of records, consent forms and Performa are up to the mark. 
 
Data Analysis Procedure:  
Statistical analyses will be performed using SPSS 19.0 (SPSS Inc., Chicago, IL). Point 
estimation will be computed as mean ± SD or number of patients (%). A normality test will be 
performed using Kolmogorov–Smirov and Shapiro–Wilk tests. Continuous variables with a 
normal distribution will be analyzed using independent sample t test, and non-normal data will 
be analyzed by Mann Whiney U test.  Categorical data will be analyzed by chi-square test or 
fisher exact test.  A P value 0.05 was considered significant. 
 
 
 
 
 
 
 


 
 
 
 
 
REFERENCES 
 
1. Miller RD. Anesthesia. 7th ed. [United States]: Elsevier Science Health Science div; 
2010. 
 
2. Samuel M, Hampson-Evans D, Cunnington P. Prospective to a randomized double-blind 
controlled trial to assess efficacy of double caudal analgesia in hypospadias repair. J Ped 
Surg 2002; 37: 168–174. 
 
3. Gauntlett I. A comparison between local anaesthetic dorsal nerve block and caudal 
bupivacaine with ketamine for paediatric circumcision. Paediatr Anaesth 2003; 13: 38–
42. 
 
4. Sharpe P, Klein JR, Thompson JP et al. Analgesia for circumcision in a paediatric 
population: comparison caudal bupivacaine plus two doses of clonidine. Paediatr Anaesth 
2001; 11: 695–700. 
 
5. Lee HM, Sanders GM. Caudal ropivacaine and ketamine for postoperative analgesia in 
children. Anaesthesia 2000; 55: 806– 810. 
6. Turan A, Memis D, Basaran UM et al. Caudal ropivacaine and neostigmine in pediatric 
surgery. Anesthesiology 2003; 98: 719– 722. 
7. Mercan A et al. When to add supplemental rectal paracetamol for postoperative analgesia 
with caudal bupivacaine in children? A prospective, double-blind, randomized study. 
Pediatric Anesthesia 2007; 17: 547–551. 


8. Ozyuvaci E et al. Evaluation of adding preoperative or postoperative rectal paracetamol 
to caudal bupivacaine for postoperative analgesia in children. Pediatric Anesthesia 2004 
;14: 661–665. 
 
 
 
S. No:         ____ 
PROFORMA 
Subject ID            ____________     
Age (years)          __________     
Date of birth        ____________ 
Weight (kg)          ______________                                                                           
Date of Surgery   _____________ 
Gender               M                     F 
OPERATING ROOM 
Baseline ParametersChange in parameters (20%) 
• 
Heart Rate            _________                          _____________ 
• 
Blood Pressure      _________                          _____________  
• 
Maximum safe dose of Ropivacaine (3mg/kg)    ____________________ 
• 
Dose of Ropivacaine administered                     ____________________ 
• 
Time of performing Caudal Block    ____________________ 
• 
Anesthesia Time:         Induction ________       Ready for surgery _______ 
• 
Surgical Time:             Skin Incision _______    Skin Dressing ___________ 
• 
Increase in Sevoflorane concentration    Y                       N 


• 
Rescue Analgesia                                  Y                       N 
     If Yes; 
• 
Analgesia _________    Dose ________    Time of Administration _________ 
 
RECOVERY ROOM 
• 
Time of Arrival in RR:_________ 
• 
Rescue Analgesia (If CHEOPS >4)      Y                       N 
     If Yes; 
• 
Analgesic _________    Dose ________    Time of Administration _________ 
• 
Time of voiding urine: _____________ 
• 
Complaint of leg heaviness (age > 3 years):   Y                       N 
• 
Time of taking oral fluids: __________ 
• 
Recovery Time:       ____________ 
• 
Discharge Time:      ___________ 
MODIFIED BROMAGE SCALE 
Baseline 
30 min 
1 Hour 
2 Hour 
4Hour 
  0= No motor Block       0= No motor Block       0= No motor Block       0= No motor Block       0= No motor Block       
1= Can flex knee, 
move foot, but cannot 
raise leg 
1= Can flex knee, 
move foot, but cannot 
raise leg 
1= Can flex knee, 
move foot, but cannot 
raise leg 
1= Can flex knee, 
move foot, but cannot 
raise leg 
1= Can flex knee, 
move foot, but cannot 
raise leg 
2 =Can move foot 
only   
2 =Can move foot 
only   
2 =Can move foot 
only   
2 =Can move foot 
only   
2 =Can move foot only   
3 =Cannot move foot 
3 =Cannot move foot 
3 =Cannot move foot 
3 =Cannot move foot 
3 =Cannot move foot 


or knee 
or knee 
or knee  
or knee 
or knee 
 
Total Score: 
Baseline:      30 min:       1st Hour:     2nd Hour:       4th Hour:    
SEDATION SCORE 
Baseline 
30 min 
1 Hour 
2 Hour 
4Hour 
  0= Awake           
  0=Awake 
  0= Awake 
  0= Awake           
  0= Awake           
1= Mild Sedation 
1= Mild Sedation 
1= Mild Sedation 
1= Mild Sedation 
1= Mild Sedation 
2 =Sleep but able to 
awake   
2 =Sleep but able to 
awake   
2 =Sleep but able to 
awake   
2 =Sleep but able to 
awake   
2 =Sleep but able to 
awake   
3 = Deep sleep, 
unable to awake 
3 = Deep sleep, 
unable to awake 
3 = Deep sleep, 
unable to awake 
3 = Deep sleep, 
unable to awake 
3 = Deep sleep, unable 
to awake 
 
Total Score: 
Baseline:      30 min:       1st Hour:     2nd Hour:       4th Hour: 
 
CHEOPS PAIN SCALE 
Parameter 
Finding 
Point 
15 min 
 
30 min 
 
1 hr 
2 hrs 
4 hrs 
6 hrs 


CRY 
no cry 
0 
 
 
 
 
 
 
 
crying, moaning 
1 
 
 
 
 
 
 
 
scream 
2 
 
 
 
 
 
 
FAICAL 
smiling 
0 
 
 
 
 
 
 
 
composed 
1 
 
 
 
 
 
 
 
grimace 
2 
 
 
 
 
 
 
CHILD VERBAL 
positive 
0 
 
 
 
 
 
 
 
none or other complain 
1 
 
 
 
 
 
 
 
Pain Complaint 
2 
 
 
 
 
 
 
TORSO 
neutral 
0 
 
 
 
 
 
 
 
Shifting, tense, upright 
1 
 
 
 
 
 
 
 
restrained 
2 
 
 
 
 
 
 
LEGS 
neutral 
0 
 
 
 
 
 
 
 
kick, squirm, drawn-up 
1 
 
 
 
 
 
 
 
restrained 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Score = ______  Research Assistant Name and Signature:    
 


Date: