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

Sponsor

Erasmus Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT05853263

Collaborator

KU Leuven (Other), UMC Utrecht (Other), University Medical Center Groningen (Other)

208

Enrollment

Arms

52.4

Actual Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Analgesia Congenital Heart Disease Surgery	Drug: paracetamol Drug: Morphine	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

208 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

prospective, double blind, randomized controlled trial.prospective, double blind, randomized controlled trial.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

double blind, randomized

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 9, 2016

Actual Primary Completion Date :

Jul 11, 2020

Actual Study Completion Date :

Jul 20, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively. [48 hours]
dose in micrograms per kilogram

Secondary Outcome Measures

Incidence of adverse drug reactions [96 hours]
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.
Non-inferiority analysis of comparing the proportion of patients with one or more Numaric Rating Scale (NRS) scores of at least 4 between groups [48 hours]
Numeric rating scale
The role of genetic polymorphisms in morphine metabolism [directly before surgery]
Genes involved in morphine metabolism: UGT2B7, ABCC3, and OCT1
Concomitant use of sedatives [48 hours]
type and dose
mechanical ventilation duration in hours [immediately after surgery]
The length of PICU stay [immediately after surgery]
Duration of PICU stay in both groups in days
Role of alarmins in the systemic inflammatory response (only at Wilhelmina Children's hospital) [48 hours]
specific nuclear proteins to be determined (IL-1 alfa, IL-33, HMGB1)
Analysis of plasma morphine and paracetamo levels in relation to dose after cardia surgery using NONMEM (non-lineair mixed effects modelling). [48 hours]
serum plasma levels of morphine and paracetamol

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 36 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.