Morphine IV vs Paracetamol IV in Neonates and Infants After Cardiac Surgery (PACS)

Pediatric Analgesia After Cardiac Surgery; Morphine IV Versus Paracetamol IV After Cardiac Surgery in Neonates and Infants.

The goal of this clinical trial is to compare pain management in neonates and infants under 3 years of age undergoing cardiac surgery with use of cardiopulmonary bypass. Patients will be randomized to either continuous morphine IV (standard) of intermittent paracetamol IV (intervention).

The investigators' hypothesis is that intermittent IV paracetamol is effective as the primary analgesic drug in post-cardiac surgery patients up to 3 years of age and that the use of IV paracetamol will reduce overall morphine requirements.

Study Overview

• Status: Completed
• Conditions: Analgesia; Surgery; Congenital Heart Disease
• Intervention / Treatment: Drug: Morphine; Drug: paracetamol

Detailed Description

Congenital heart disease accounts for almost one third of all congenital anomalies. Surgical intervention is necessary in 55% within the first year of life and in 67% during the first three years of life.

Morphine is the drug of first choice worldwide for pain relief after major surgery in neonates and children. However, morphine can cause unwanted hemodynamic and respiratory reactions and therefore patients could potentially benefit from a non-opioid analgesic.

In a recent randomized controlled trial, intravenous (IV) paracetamol was compared with morphine as a primary analgesic drug in non-cardiac post-operative children up to 1 year. IV paracetamol was equally effective in pain relief, and no difference in rescue analgesics was shown between groups. The IV paracetamol group had a lower cumulative morphine dose the first 48 h after surgery and less adverse drug reactions.

Whether these results also apply to neonates and children after cardiac surgery is unclear. Pharmacokinetic (PK) parameters are assumed to be different in patients during and after cardiac surgery compared with non-cardiac surgery due to use of the cardiopulmonary bypass (CPB).

Hypothesis The investigators' hypothesis is that intermittent IV paracetamol is effective as the primary analgesic drug in post-cardiac surgery patients up to 3 years of age and that the use of IV paracetamol will reduce overall morphine requirements.

This hypothesis is currently being tested at three level-4 PICUs in the Netherlands and Belgium (Erasmus MC-Sophia Rotterdam, Wilhelmina Children's Hospital University Medical Center (UMC) Utrecht, Beatrix Children's Hospital UMC Groningen, University Hospital (UZ) Leuven).

All participants will receive a loading dose of morphine after cardiac surgery. After this, participants will be randomized to either standard care (morphine continuous IV) or intervention group (intermittent paracetamol IV).

Validated pain and sedations assessment tools will be used to adjust pain treatment if necessary. Rescue morphine as available for both groups.

A double blind study design is used, with a dummy saline continuous infusion in the paracetamol group and a dummy saline intermittent infusion in de continuous morphine group.

Study medication is stopped 48 hours after surgery and patients are transferred to open label morphine and paracetamol when applicable.

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent
• Neonates/infants who are 0-36 months old
• Cardiac surgery with the use of CPB.

Exclusion Criteria:

• No informed consent
• Known allergy to or intolerance of paracetamol or morphine
• Administration of opioids in the 24 h prior to surgery
• Hepatic dysfunction defined as three times the reference value of alanine aminotransferase/aspartate aminotransferase (ALAT/ASAT)
• Renal insufficiency at least RIFLE category Risk prior to surgery.

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
Other: morphine; Standard care, continuous morphine IV.	Drug: Morphine; standard care
Active Comparator: paracetamol; intervention group, intermittent paracetamol IV	Drug: paracetamol; paracetamol IV to substitute morphine IV.; Other Names: Acetominophen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively.	dose in micrograms per kilogram	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse drug reactions	Hemodynamic: hypotension or bradycardia, with the need for intervention by means of medication or a fluid bolus; Decreased gastrointestinal motility or intestinal obstruction not directly related to the underlying diagnosis and not previously existing, with the need for intervention; Vomiting; Number of re-intubations (duration 48 hours); Pediatric delirium as measured by the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD, max score is 16/17, higher score more risk of pediatric delirium) or Cornell Assessment of Pediatric Delirium (CAPD, score > 9 gives increased risk of delirium) score.	96 hours
Non-inferiority analysis of comparing the proportion of patients with one or more Numaric Rating Scale (NRS) scores of at least 4 between groups	Numeric rating scale	48 hours
The role of genetic polymorphisms in morphine metabolism	Genes involved in morphine metabolism: UGT2B7, ABCC3, and OCT1	directly before surgery
Concomitant use of sedatives	type and dose	48 hours
mechanical ventilation duration in hours		immediately after surgery
The length of PICU stay	Duration of PICU stay in both groups in days	immediately after surgery
Role of alarmins in the systemic inflammatory response (only at Wilhelmina Children's hospital)	specific nuclear proteins to be determined (IL-1 alfa, IL-33, HMGB1)	48 hours
Analysis of plasma morphine and paracetamo levels in relation to dose after cardia surgery using NONMEM (non-lineair mixed effects modelling).	serum plasma levels of morphine and paracetamol	48 hours

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: KU Leuven; University Medical Center Groningen; UMC Utrecht
• Investigators: Principal Investigator: Enno Wildschut, MD, PhD, Erasmus Medical Center

Publications and helpful links

Helpful Links

• published study protocol

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2016
• Primary Completion (Actual): July 11, 2020
• Study Completion (Actual): July 20, 2020

Study Registration Dates

• First Submitted: March 25, 2023
• First Submitted That Met QC Criteria: May 8, 2023
• First Posted (Actual): May 10, 2023

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: pharmacokinetics; infants; morphine; cardiopulmonary bypass; child; analgesia; neonates; paracetamol; congenital cardiac surgery; congenital heart defect
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Morphine
• Other Study ID Numbers: NL 53085.078.15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study data can be shared with other researchers upon request.
• IPD Sharing Time Frame: not yet decided
• IPD Sharing Access Criteria: upon reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No