Remifentanil Tapering and Post-adenotonsillectomy Pain in Children

Remifentanil Tapering and Post-adenotonsillectomy Pain in Children: a Randomised, Placebo Controlled, Double Blind Study

Tonsillectomy is the commonest operation of childhood and results in considerable pain.

Remifentanil is a potent, ultra short acting opioid with a long- established safety record in paediatric anaesthesia that is used to provide intraoperative analgesia.

There is evidence from adult studies that remifentanil increases postoperative pain, although this may be ablated if propofol (rather than inhalational anaesthesia) is used or if the remifentanil is tapered rather than abruptly discontinued at the end of surgery.

The analgesic effect of gradual withdrawal of remifentanil at the end of surgery has not been studied in children and may have significant clinical implications.

The primary measure of efficacy will be the dose of fentanyl rescue analgesia in the peri-operative period (1 mcg.kg-1 bolus for >20% increase in pulse, blood pressure or movement intraoperatively or a FLACC(Face, Legs, Arms, Cry, Consolablity) score of >5 in recovery).

Study Overview

• Status: Terminated
• Conditions: Pain; Child, Only; Tonsillectomy; Remifentanil
• Intervention / Treatment: Drug: Remifentanil; Drug: Sodium Chloride 9mg/mL

Detailed Description

Tonsillectomy is one of the commonest childhood operations in the world; approximately 9200 children have their tonsils removed every year in Norway alone.

Postoperative pain following the procedure is significant and notoriously difficult to mange. It´s management is potentially complicated by nausea and the risk of tonsillar infection or re-bleeding. Post-tonsillectomy pain in children is persistent, with 75% of children experiencing significant pain for the first three days and 50% still suffering with significant pain one week after the procedure. As well as delaying recovery, reducing oral intake of food and drink and disturbing sleep, post tonsillectomy pain has been shown to result in more than 50% of patients and their parents consulting their primary care physician in the post operative period, with the ensuing costs to the families and healthcare providers.

It is worth noting, that despite significant postoperative pain and potential complications, recovery after adeno / tonsillectomy is excellent.

The operative nature of tonsillectomy and adenotonsillectomy necessitates the provision of general anaesthesia to the child. The technique must ensure sufficient depth of anaesthesia and analgesia and protection of the airway from blood and surgical debris. Whilst there are a wide variety of anaesthetic techniques employed to achieve these goals,Total Intra Venous Anaesthesia (TIVA) with propofol and remifentanil has been shown in previous studies to be superior to volatile based (gas) anaesthesia, resulting in less post operative nausea and vomiting, less long term adverse behavioural changes, improved quality of emergence from anaesthesia, and less environmental pollution.

The use of remifentanil and propofol TIVA in children is well established and has been in use since at least the year 2000 for children undergoing tonsillectomy. Despite this the effects of remifentanil dosing on post-operative pain has not been studied in children undergoing tonsillectomy, though it may play a significant role.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0456
    • Lovisenberg Diakonale Sykehus
  • Akershus
    • Lørenskog, Akershus, Norway, 1478
      • Akershsus Universitetssykehus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 10 years (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• American Society Anaesthesiology I-II children 1 to 10 years
• Weight over 10.0 Kg
• Presenting for tonsillotomy / tonsillectomy or adenotonsillectomy at Akershus Universitetssykehus, Lørenskog and Lovisenberg Diakonale Hospital, Norway

Exclusion Criteria:

• Children who have had airway surgery previously.
• Children who have had any type of surgery in the previous 12 months.
• Children using chronic pain medication or who have used analgesia in the 24 hours preceding surgery.
• Children who are known to suffer from NSAID sensitive asthma.
• Children with a known allergy to propofol or remifentanil.
• Pre-existing cardiac, renal, liver dysfunction.
• Children or parents who are not fluent in Norwegian or English.
• Children in whom more than three attempts at intravenous cannulation are required or in those who request an inhalational induction or premedication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remifentanil tapering / Placebo abrupt cessation; Syringe one contains Remifentanil 2 mg in 40 ml NaCl 9 mg.ml-1 = 50 µg.ml-1 which will be infused at a rate of 0.9 µg.kg-1.min-1 and Syringe two contains 40 ml NaCl 9 mg.ml-1 at an identical infusion rate. According to randomisation syringe one will then be tapered towards the end of surgery and syringe two abruptly stopped.	Drug: Remifentanil; Syringe containing 40 ml of Remifentanil 50 µg/ml for intravenous administration. In order to maintain double blinding two identical syringes, prepared by pharmacy according to randomisation, will be simultaneously infused. One of the syringes will be abruptly stopped at the end of the operation whilst the other is tapered by stepwise decreases in infusion rate prior to the end of surgery.; Other Names: Ultiva; Drug: Sodium Chloride 9mg/mL; Syringe containing 40 ml of Sodium Chloride 9 mg/ml for intravenous administration. In order to maintain double blinding two identical syringes, prepared by pharmacy according to randomisation, will be simultaneously infused. One of the syringes will be abruptly stopped at the end of the operation whilst the other is tapered by stepwise decreases in infusion rate prior to the end of surgery.; Other Names: Placebo; Normal saline
Placebo Comparator: Placebo tapering / Remifentanil abrupt cessation.; Syringe one contains 40 ml NaCl 9 mg.ml-1 and Syringe two contains Remifentanil 2 mg in 40 ml NaCl 9 mg.ml-1 = 50 µg.ml-1 which will be infused at a rate of 0.9 µg.kg-1.min-1. According to randomization syringe one will be tapered towards the end of surgery and syringe two abruptly stopped.	Drug: Remifentanil; Syringe containing 40 ml of Remifentanil 50 µg/ml for intravenous administration. In order to maintain double blinding two identical syringes, prepared by pharmacy according to randomisation, will be simultaneously infused. One of the syringes will be abruptly stopped at the end of the operation whilst the other is tapered by stepwise decreases in infusion rate prior to the end of surgery.; Other Names: Ultiva; Drug: Sodium Chloride 9mg/mL; Syringe containing 40 ml of Sodium Chloride 9 mg/ml for intravenous administration. In order to maintain double blinding two identical syringes, prepared by pharmacy according to randomisation, will be simultaneously infused. One of the syringes will be abruptly stopped at the end of the operation whilst the other is tapered by stepwise decreases in infusion rate prior to the end of surgery.; Other Names: Placebo; Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intravenous fentanyl consumption in the perioperative period (mcg/kg).	Intravenous fentanyl consumption in the perioperative period (mcg/kg).	From the induction of anaesthesia until discharge from the day case surgical unit.4 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Faces Legs Activity Cry Consolability (FLACC) pain scores at 20,40,60,90 and 120 minutes after the operation to give a Sum of Pain Intensity Differences (SPID).	The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a well validated measurement used to assess pain for children or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. The scale has five criteria, which are each assigned a score of 0, 1 or 2. Thus the face component is scored as 0 for no particular expression or smile, 1 for an occasional grimace and 2 for a constant quivering chin or clenched jaw. The 0-2 score from each of the 5 domains is summated to give a total score between 0 and 10. A lower pain score indicates a better outcome than a high pain score.	From cessation of anaesthesia until 120 minutes after the cessation of anaesthesia.
Parents' Post Operative Pain Measure (PPOMP) on post operative days 1,3,7,10,14 and 28	The Parents' Post Operative Pain Measure (PPOMP) is a well validated 15 point questionnaire used to measure childrens' pain after moderately or severely painful procedures. The parents are asked to complete the survey between particular times each day (e.g between supper and bed time). The questionnaire consists of 15 YES / NO questions such as: "When your child was recovering from surgery between supper and bed time today did s/he... Cry more easily than usual ? YES / NO Refuse to eat? YES/ NO Want to be closer to you than usual? YES / NO. The YES response are scored as 1 and the NO responses scores as 0. The sum score ranges from 0 to 15. A lower pain score indicates a better outcome than a high pain score.	From the cessation of anaesthesia until the 28th day following discharge from the day case surgical unit.

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Investigators: Principal Investigator: Signe Søvik, MD. PhD, University Hospital, Akershus

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2020
• Primary Completion (Actual): August 18, 2023
• Study Completion (Actual): August 18, 2023

Study Registration Dates

• First Submitted: June 13, 2019
• First Submitted That Met QC Criteria: June 20, 2019
• First Posted (Actual): June 21, 2019

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Remifentanil
• Other Study ID Numbers: 2019-001677-81

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: On request and following consultation with the Regional Ethics Committee and the Data Protection Officer at the host institution.

IPD Sharing Time Frame

The data will be available following completion of the study and analysis and publication by the investigating team.

There is no plan to time limit access to the data following this.

• IPD Sharing Access Criteria: On request and following consultation with the Regional Ethics Committee and the Data Protection Officer at the host institution.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No