Intravenous Acetaminophen For Postoperative Pain in the Neonatal Intensive Care Unit (IVA POP NICU)

Intravenous Acetaminophen For Postoperative Pain in the Neonatal Intensive Care Unit: A Feasibility Randomized Controlled Trial

The goal of this pilot randomized clinical trial is to determine the effect of the addition of IV acetaminophen to opioid-based pain regimes for infants admitted to the neonatal intensive care unit (NICU) after surgery.

This is a pilot trial; the main goals are to make sure our study methods work before performing a larger study.

The main clinical aims are:

1. Determine if adding IV acetaminophen reduces pain
2. Determine if adding IV acetaminophen reduces opioid use
3. Determine if adding IV acetaminophen reduces complications

Participants will be randomized to two groups:

Comparator: Fentanyl and IV acetaminophen Control: Fentanyl and placebo

Patients will receive either IV acetaminophen or placebo at regular intervals for seven days after surgery. Patients will be followed daily during that period. Charts will be reviewed at 90-days for final outcomes.

Study Overview

• Status: Recruiting
• Conditions: Pain; Pain, Postoperative
• Intervention / Treatment: Drug: Acetaminophen; Drug: Placebo

Detailed Description

Purpose: Opioid use in neonates is associated with short and long-term adverse events. Multi-modal pain control offers the ability to control pain while reducing opioid exposure. This topic has been relatively unexamined in preterm and term neonates. Specifically, this trial aims to evaluate the effect of adding IV acetaminophen to standard opioid-based pain regimes in neonates in the neonatal intensive care unit (NICU) undergoing major abdominal and thoracic surgery.

Objectives: The primary aim of the proposed study is to determine the feasibility and cost of conducting a multicenter, randomized control trial to compare the efficacy of IV acetaminophen and fentanyl, to fentanyl and saline placebo, in terms of reduction of postoperative pain, opioid use, adverse events. The primary outcome is feasibility; secondarily, efficacy and safety will be assessed.

Design: This single-center, parallel-arm, placebo-controlled, fully blinded, randomized controlled external feasibility trial will enroll patients admitted in the neonatal intensive care unit (NICU) who have undergone major, thoracic, or abdominal surgery. Patients will be randomized 1:1, with parallel allocation to receive acetaminophen and fentanyl or fentanyl and saline placebo. All study staff, clinical staff and guardians will be blinded. As this is a pilot study, no sample size will be calculated, however; we aim to enroll 60 patients. A sample size calculation will be completed for the full RCT if it is deemed feasible from the results of this study. Patients will be followed for the day of surgery and the following 7 postoperative days (192 hours) and have their charts reviewed at 90 days.

Impact: The results of this study will be used to determine the feasibility of conducting a multi-center RCT to assess the effect of IV acetaminophen on fentanyl infusions in postoperative neonatal patients. The effect of IV acetaminophen for postoperative pain in preterm neonates has yet to be studied, this trial would generate novel insights into its efficacy. The prolonged follow-up period would also provide novel insights into recovery throughout the entire perioperative period.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Victoria Archer, MD; Phone Number: 506-721-9285; Email: vicki.archer@medportal.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Recruiting
      • McMaster Children's Hospital
      • Contact: Victoria Archer, MD; Phone Number: 5067219285; Email: vicki.archer@medportal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Neonates, admitted to McMaster Children's Hospital NICU
2. Has had major open, thoracic or abdominal surgery (see appendix 1, table 6).
3. Informed consent obtained from guardian(s)

Exclusion Criteria:

1. Hepatic dysfunction

   • AST, ALT or Bilirubin > 3x upper limit of normal
   • INR ≥ 3.0 or PT greater than 20s regardless of vitamin K administration

2. Renal dysfunction

   • Increase in serum creatinine ≥ 2x baseline (baseline: lowest value in first 5 days of hospitalization)
   • Urine output < 0.5 mL/kg/h for ≥ 12h
3. Allergy or intolerance to acetaminophen or fentanyl
4. Acetaminophen administration within 24 hours of the end of surgery
5. Nerve blocks or epidurals
6. Refusal or withdrawal of consent
7. Enrolment in another competing trial
8. No later than 12 hours after the end of surgery
9. 12 months post gestational age or greater in age
10. Birthweight greater or equal to 2,500g.
11. Discharged from the McMaster NICU

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
Active Comparator: Comparator; Standard of care + IV acetaminophen: Baseline fentanyl infusion, with dosage escalations, deescalations, and additional boluses and analgesics (excluding oral or rectal acetaminophen) determined by the patient's physician (this represents standard of care at this institution) with the addition of IV acetaminophen every 4 or 6 hours at weight-appropriate doses based on the patient's gestational age.	Drug: Acetaminophen; IV acetaminophen will be added to standard of care opioid based pain regimes.
Placebo Comparator: Placebo; Standard of care + placebo: Baseline fentanyl infusion, with dosage escalations, deescalations, and additional boluses and analgesics (excluding oral or rectal acetaminophen) determined by the patient's physician (this represents standard of care at this institution) with the addition of an IV saline placebo every 4 or 6 hours at a rate which would mimic their dose of acetaminophen.	Drug: Placebo; In control group placebo will be added to standard of care opioid based pain regimes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Mean number of patients randomized per month	through study completion, an average of 1.5 years
Follow up rate	Number of patients followed in completion from postoperative day 0 to 7	90 days
Medication compliance	Number of patients who received at least 80% of doses of study drugs at the correct dose and interval	7 days
Blinding index	Responses of nurse's physician's, and research staff's guess of group assignment (control vs treatment) compared to actual group assignment	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily fentanyl consumption	Fentanyl consumption will be recorded for each patient for each 24-hour period in the study period. Will be recorded in mcg/kg.	daily for 7 days
Total fentanyl consumption	Daily fentanyl consumption will be added together for the entire study period to determine the total amount of fentanyl consumed in mcg/kg.	7 days
Daily Consumption of other analgesics	Consumption of other analgesics will be recorded for each patient for each 24-hour period in the study period. Will be recorded in mg or mcg /kg.	daily for 7 days
Total consumption of other analgesics	Daily consumption of other analgesics will be added together for the entire study period to determine the total amount of fentanyl consumed in mg or mcg/kg.	7 days
Invasive ventilation	Length of time requiring intubation	90 days
Non-invasive ventilation	Length of time requiring CPAP, BiPAP, or supplemental oxygen	90 days
Enteral feeds	Time to first enteral feeds and time to full enteral feeds (using NICU's calculated goal feed)	90 days
Bowel movement	Time to first bowel movement	90 days
Glycerin suppository use	Number of patients requiring one or more glycerin suppositories	90 days
Length of stay	with discharge destination	90 days
Postoperative Pain	Measured by the N-PASS Pain Scale as units on the scale (scale ranges from 0-10)	every 6 hours for entire study period (7 days after surgery)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vomiting	Number of patients with ≥ 1 episode of vomiting documented	7 days
NG/Vygone	Number of patients, mean duration	90 days
Reintubation	Number of patients	90 days
Apnea	Number of patients with oxygen saturation less than 94% or RR less than 20 breaths/min for more than 30 seconds	7 days
Naloxone administration	Number of patients	7 days
Bradycardia	Number of patients with HR less than 100 for more than 30 seconds	7 days
Hypotension	Number of patients with SBP less than 60, or requiring vasoactive medication	7 days
Foley catheterization	Number of patients, mean duration	7 days
Feeding intolerance	Number of patients: feeds stopped or decreased due to vomit/increased gastric output, or if diagnosed by the treating team	7 days
Hepatic injury	Number of patients with hepatic injury as defined in the protocol	90 days
Mortality	all cause mortality	90 days

Collaborators and Investigators

• Sponsor: McMaster Children's Hospital
• Investigators: Principal Investigator: Mark Walton, MD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2023
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 25, 2023
• Last Update Submitted That Met QC Criteria: April 24, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: pain; surgery; acetaminophen; postoperative; infant; neonate; paracetamol; tylenol
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 14887-GRA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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