AnalgesiaPACSNCT05853263
Morphine IV vs Paracetamol IV in Neonates and Infants After Cardiac Surgery
A study testing paracetamol and Morphine in people with Analgesia and Congenital Heart Disease, run by Erasmus Medical Center.
Trial 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). Read more about this study
- Who is it for?
- Ages 1 day to 36 months
- Conditions the study is for
- Analgesia, Congenital Heart Disease, Surgery
- What is being tested?
- paracetamol and Morphine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 208 participants
- Where
- No sites listed yet
- Study dates
- 9 Mar 2016to 20 Jul 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 36 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Informed consent
- Neonates/infants who are 0-36 months old
- Cardiac surgery with the use of CPB.
Who cannot join
- 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.
About this study
Official title: 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.
Read the 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.
- Conditions
- Analgesia, Congenital Heart Disease, Surgery
- Being tested
- paracetamol, Morphine
- Keywords
- morphine, paracetamol, neonates, infants, child, analgesia, congenital heart defect, cardiopulmonary bypass, congenital cardiac surgery, pharmacokinetics
- Medical subject headings
- Agnosia, Heart Defects, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
paracetamolDrug
Also called Acetominophen
paracetamol IV to substitute morphine IV.
MorphineDrug
standard care
| Study group | Role | What they receive |
|---|---|---|
| morphine | Other | Standard care, continuous morphine IV. Receives: Drug: Morphine |
| paracetamol | Active comparator | intervention group, intermittent paracetamol IV Receives: Drug: paracetamol |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively.
dose in micrograms per kilogram
Measured: 48 hours
Secondary outcomes (8)
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.
Measured: 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
Measured: 48 hours
The role of genetic polymorphisms in morphine metabolism
Genes involved in morphine metabolism: UGT2B7, ABCC3, and OCT1
Measured: directly before surgery
Concomitant use of sedatives
type and dose
Measured: 48 hours
mechanical ventilation duration in hours
Measured: immediately after surgery
The length of PICU stay
Duration of PICU stay in both groups in days
Measured: 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)
Measured: 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
Measured: 48 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 May 2023
- Study start9 Mar 2016
- Primary completion11 Jul 2020
- Study completion20 Jul 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for AnalgesiaStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- prospective, double blind, randomized controlled trial.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 208 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- KU Leuven, UMC Utrecht, University Medical Center Groningen
- Responsible party
- Principal investigator, Gerdien (G.A.) Zeilmaker-Roest, Erasmus Medical Center
- Investigators
- Enno Wildschut, MD, PhD, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05853263
- Sponsor's protocol ID
- NL 53085.078.15
- Acronym
- PACS
- Status last verified
- May 2023
- First submitted
- 25 Mar 2023
- Last updated
- 10 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Study data can be shared with other researchers upon request.
Publications
Zeilmaker-Roest G, de Vries-Rink C, van Rosmalen J, van Dijk M, de Wildt SN, Knibbe CAJ, Koomen E, Jansen NJG, Kneyber MCJ, Maebe S, Van den Berghe G, Haghedooren R, Vlasselaers D, Bogers AJJC, Tibboel D, Wildschut ED. Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial. Crit Care. 2024 Apr 30;28(1):143. doi: 10.1186/s13054-024-04905-3.
PubMed 38689310
Study at a glance
From the registry record, last updated by the sponsor on 10 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pediatric Analgesia After Cardiac Surgery; Morphine IV Versus Paracetamol IV After Cardiac Surgery in Neonates and Infants.
- ClinicalTrials.gov ID
- NCT05853263
- Acronym / sponsor ID
- PACS / NL 53085.078.15
- Conditions
- Analgesia, Congenital Heart Disease, Surgery
- Keywords
- morphine, paracetamol, neonates, infants, child, analgesia, congenital heart defect, cardiopulmonary bypass
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 208 participants (actual)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Collaborators
- KU Leuven, UMC Utrecht, University Medical Center Groningen
- Study start
- 9 Mar 2016 (actual)
- Primary completion
- 11 Jul 2020 (actual)
- Study completion
- 20 Jul 2020 (actual)
- First posted
- 10 May 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- prospective, double blind, randomized controlled trial.
| Arm | Type | Receives |
|---|---|---|
| morphine | Other | Drug: MorphineStandard care, continuous morphine IV. |
| paracetamol | Active comparator | Drug: paracetamolintervention group, intermittent paracetamol IV |
Who may qualify
- Ages
- 1 day to 36 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Informed consent
- Neonates/infants who are 0-36 months old
- Cardiac surgery with the use of CPB.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| paracetamolAlso: Acetominophenparacetamol IV to substitute morphine IV. | Drug | paracetamol |
| Morphinestandard care | Drug | morphine |
Primary outcome
The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively.
Time frame: 48 hours
dose in micrograms per kilogram
8 secondary outcomes
Incidence of adverse drug reactions
Time frame: 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
Time frame: 48 hours
The role of genetic polymorphisms in morphine metabolism
Time frame: directly before surgery
Concomitant use of sedatives
Time frame: 48 hours
mechanical ventilation duration in hours
Time frame: immediately after surgery
The length of PICU stay
Time frame: immediately after surgery
Role of alarmins in the systemic inflammatory response (only at Wilhelmina Children's hospital)
Time frame: 48 hours
Analysis of plasma morphine and paracetamo levels in relation to dose after cardia surgery using NONMEM (non-lineair mixed effects modelling).
Time frame: 48 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 May 2023.
- Derived from this study: PubMed 38689310Zeilmaker-Roest G, de Vries-Rink C, van Rosmalen J, van Dijk M, de Wildt SN, Knibbe CAJ, Koomen E, Jansen NJG, Kneyber MCJ, Maebe S, Van den Berghe G, Haghedooren R, Vlasselaers D, Bogers AJJC, Tibboel D, Wildschut ED. Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial. Crit Care. 2024 Apr 30;28(1):143. doi: 10.1186/s13054-024-04905-3.
- published study protocolLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Study data can be shared with other researchers upon request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Enno Wildschut, MD, PhD principal investigator
Erasmus Medical Center
Questions about this trial
What is this clinical trial studying?
A study testing paracetamol and Morphine in people with Analgesia and Congenital Heart Disease, run by Erasmus Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 May 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary outcome measure is weight-adjusted cumulative morphine dose in the first 48 hours post-operatively. (time frame: 48 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05853263, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2023.