Clinical trial NCT05853263: Morphine IV vs Paracetamol IV in Neonates and Infants After Cardiac Surgery
Official title: Pediatric Analgesia After Cardiac Surgery; Morphine IV Versus Paracetamol IV After Cardiac Surgery in Neonates and Infants.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Analgesia
Congenital Heart Disease
Surgery
Keywords: morphine
paracetamol
neonates
infants
child
analgesia
congenital heart defect
cardiopulmonary bypass
congenital cardiac surgery
pharmacokinetics
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: KU Leuven
name: UMC Utrecht
name: University Medical Center Groningen
First posted: 2023-05-10
Enrollment: 208
Sex: ALL
Minimum age (years): 1
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: prospective, double blind, randomized controlled trial.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively.
timeFrame: 48 hours
Secondary outcomes:
measure: Incidence of adverse drug reactions
timeFrame: 96 hours
measure: Non-inferiority analysis of comparing the proportion of patients with one or more Numaric Rating Scale (NRS) scores of at least 4 between groups
timeFrame: 48 hours
measure: The role of genetic polymorphisms in morphine metabolism
timeFrame: directly before surgery
measure: Concomitant use of sedatives
timeFrame: 48 hours
measure: mechanical ventilation duration in hours
timeFrame: immediately after surgery
measure: The length of PICU stay
timeFrame: immediately after surgery
measure: Role of alarmins in the systemic inflammatory response (only at Wilhelmina Children's hospital)
timeFrame: 48 hours
measure: Analysis of plasma morphine and paracetamo levels in relation to dose after cardia surgery using NONMEM (non-lineair mixed effects modelling).
timeFrame: 48 hours
Other outcomes:
Locations:
Study officials:
affiliation: Erasmus Medical Center
name: Enno Wildschut, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: