Intravenous Acetaminophen For Postoperative Pain in the Neonatal Intensive Care Unit

Study Overview
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Brief Summary
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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: Determine if adding IV acetaminophen reduces pain Determine if adding IV acetaminophen reduces opioid use 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.

Detailed Description
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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.

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

Conditions
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Pain, Pain, Postoperative

Intervention / Treatment
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* Drug: Acetaminophen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates, admitted to McMaster Children's Hospital NICU Has had major open, thoracic or abdominal surgery (see appendix 1, table 6). Informed consent obtained from guardian(s) Exclusion Criteria: Hepatic dysfunction AST, ALT or Bilirubin > 3x upper limit of normal INR ≥ 3.0 or PT greater than 20s regardless of vitamin K administration 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 Allergy or intolerance to acetaminophen or fentanyl Acetaminophen administration within 24 hours of the end of surgery Nerve blocks or epidurals Refusal or withdrawal of consent Enrolment in another competing trial No later than 12 hours after the end of surgery 12 months post gestational age or greater in age Birthweight greater or equal to 2,500g. Discharged from the McMaster NICU

Ages Eligible for Study
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Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized to the control or comparator group. There will be 60 patients enrolled, with 30 patients per arm.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Comparator<br>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<br>* IV acetaminophen will be added to standard of care opioid based pain regimes.<br>|
| Placebo Comparator: Placebo<br>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<br>* In control group placebo will be added to standard of care opioid based pain regimes.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, acetaminophen, neonate, infant, tylenol, paracetamol, postoperative, surgery