{"paper_id":"58d97271-e0b4-44dc-9eb1-ef0d63aaa5f3","body_text":"Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial Gerdien Zeilmaker-Roest, Christine de Vries-Rink, Joost van Rosmalen, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3899589/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Apr, 2024 Read the published version in Critical Care → Version 1 posted 8 You are reading this latest preprint version Abstract Background To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0–3 years after cardiac surgery with cardiopulmonary bypass. Methods Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016 - July 2020. Children aged 0–3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if Numeric Rating Scale (NRS) scores for pain exceeded predetermined cutoff values. Primary outcome was weight-adjusted cumulative morphine dose in mcg/kg in the first 48 hours post-operative. For the comparison of the primary outcome between groups, the non-parametric Van Elteren test with stratification by center was used. Results In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median cumulative morphine consumption in the first 48 hours postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7- 856.1) mcg/kg ; P < 0.00001 ). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority analysis of IV paracetamol showed no differences between groups in number of NRS scores indicating pain (p = 0.61). Conclusions In children aged 0–3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the weight-adjusted cumulative morphine consumption in the first 48 hours after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20. Morphine Intravenous Paracetamol Randomized controlled trial Analgesia Child Congenital heart defects Congenital cardiac surgery Figures Figure 1 Background Congenital heart disease is the most frequently diagnosed congenital defect, with a reported total prevalence of 8.0 in 1000 births in Europe.(1) More than half of these patients require surgical intervention during the first 3 years of life. An evidence-based guideline for pain treatment after cardiac surgery in children is lacking. (2) A 2022 guideline for pain and sedation management recommends opioids as primary analgesic in critically ill patients with moderate to severe pain.(3) A 2022 survey including over 200 European PICUs as well as a survey in pediatric cardiac ICUs showed large variation in dose and choice of analgesic drugs.(4, 5) Currently, most centers prescribe at least one opioid as primary analgesic after cardiac surgery.(2) Cardiopulmonary bypass (CPB) may alter pharmacokinetics (PK) after cardiac surgery ).(6) Valkenburg et al. showed that children after cardiac surgery with use of CPB have a lower clearance of morphine and a higher volume of distribution compared with non-cardiac surgery suggesting that children undergoing cardiac surgery with the use of CPB may need adjusted dosages of postoperative analgesics (7, 8) Opioids have been associated with potential serious adverse events, such as hypotension and respiratory depression and risk for opioid tolerance and opioid withdrawal.(9) These occurrences may result in prolonged ICU-stay.(10–13) A possible alternative is paracetamol (acetaminophen), considered a safe drug when used in the age-appropriate dose.(14, 15) In earlier randomized controlled trial, intermittent IV paracetamol proved equally effective as intravenous morphine in children up to one year of age after major non-cardiac surgery. (16) We therefore assumed that IV paracetamol might also benefit children after cardiac surgery. Methods Aims We performed a prospective, multi-center, randomized double-blinded, controlled trial in children aged 0–3 years undergoing cardiac surgery with the use of CPB. The aim of the study was to test the hypothesis that intermittent IV paracetamol administration as primary analgesic after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine dose (in mcg/kg) during the first 48 hours after cardiac surgery. Study design and setting A prospective, multi-center, randomized double-blinded controlled trial conducted in four level-3 PICUs in the Netherlands and Belgium (Erasmus MC-Sophia Rotterdam, Wilhelmina Children’s Hospital UMC Utrecht, Beatrix Children’s Hospital UMC Groningen, the Netherlands and University Hospital Leuven, Belgium). The study was approved by the Erasmus MC Medical Ethics Committee and was registered in the Dutch trial registry under the code NTR5448 as well at the Central Committee on Research Involving Human Subjects (NL 53085.078.15), EudraCT (2015–001835-20-NL/BE), and clinicaltrials.gov (identifier: NCT05853263). Parents or legal guardians of the participating children provided written informed consent prior to any study procedures. The study protocol is published in Trials and available online.(17) Patients Inclusion criteria Children (0–36 months) admitted to the PICU after cardiac surgery with the use of CPB between March 2016 and July 2020 were eligible to participate. Exclusion criteria No informed consent, a known allergy or intolerance for paracetamol or morphine, opioids administered in the 24 hours before surgery, hepatic dysfunction prior to surgery (defined as three times the reference value of alanine/aspartate aminotransferase (ALAT/ASAT)), and/or renal insufficiency defined at least as RIFLE category Risk prior to surgery. Withdrawal criteria: Withdrawn informed consent Signs of hypersensitivity or an allergic reaction to either morphine or paracetamol Re-operation or extracorporeal membrane oxygenation (ECMO) treatment within 48 hours Hepatic dysfunction, defined as three times the reference value of ALAT/ASAT Renal insufficiency defined as RIFLE category Injury Administration of muscle relaxants after surgery for 3 hours or longer Body temperature of 38.5° Celsius after surgery for 6 hours or longer Randomization, blinding and treatment allocation Blocked randomization with randomly chosen block sizes and stratification by center was applied. A biostatistician (JvR) carried out the randomization in advance, with a randomization schedule for each participating center. Participants were assigned a consecutive trial number on the randomization schedule. The randomization schedule was safely stored in the local pharmacy at every center. The hospital pharmacies of all participating centers, but not the physicians, had access to the randomization schedule to ensure concealed allocation. Study medication was prepared at the participating centers by the pharmacy. In case of a medical emergency the pharmacists could be consulted on treatment allocation. To ensure blinding in both groups, a double dummy (intermittent placebo bolus of Sodium chloride (NaCl) 0.9% in a similar volume as the IV paracetamol dose or a continuous placebo infusion of NaCl 0.9% at the same rate as an equivalent morphine continuous infusion) was used. Procedures Peroperative management Peroperative analgosedation in each center was performed per local protocol. Type of analgesics and sedatives were registered in the electronic patient data management system, but not included in the case record form (CRF). Information on the duration of surgery, type of CPB system used, CPB run time, aorta cross clamp time and degree and duration of hypothermia were registered in the CRF. Assessments Trained pediatric ICU nurses applied the Numeric Rating Scale-11 (NRS-11) and COMFORT-Behavior Scale (COMFORT-B) every 2 hours. Both instruments are validated in critically ill children.(18) Pediatric delirium was assessed thrice daily in children requiring sedatives or analgesics for more than 48 hours using the validated SOS-Pediatric Delirium (SOS-PD) scale.(19) All patients were classified according to the Risk-Adjusted Classification for Congenital Heart Surgery (RACHS-1) score.(20) The Pediatric Risk of Mortality (PRISM) lll score (21), combined with the Pediatric Logistic Organ Dysfunction 2 (PELOD-2)(22) were assessed on the day of surgery postoperatively, and postoperative days 1 and 2. Study protocol A loading dose of morphine 100 mcg/kg IV was administered to all patients at the end of surgery. Hereafter, patients were randomized to receive either continuous morphine or intermittent IV paracetamol. Paracetamol was dosed according to the Dutch Pediatric Formulary (loading dosage 20 mg/kg in all patients, maintenance dosage 40 mg/kg/day in neonates and 60 mg/kg/day in all other patients, 4 times daily).(23) Morphine dosing was based on a population PK model-derived dosing regimen, range 3.9 to 16.0 mcg/kg per hour, resulting in similar morphine concentration across children’s age and bodyweight ranges.(9, 17, 24, 25) Pain or discomfort was scored with both the NRS pain scale and COMFORT-B. An open label morphine IV rescue dose (10 mcg/kg in neonates < 10 days, 15 mcg/kg in older patients) was administered if NRS-score ≥ 4. Pain was re-evaluated 10 minutes after the intervention. If pain persisted after three rescue doses, a morphine loading dose of 100 mcg/kg was administered and open label continuous morphine infusion was started at 10 mcg/kg per hour. Open label morphine infusion could be increased to maximum 30 mcg/kg per hour. In case of inadequate analgesia with maximum open label morphine, patients were switched to continuous IV fentanyl. Open label morphine or fentanyl infusion was titrated to effect using the NRS pain scale. In each group, continuous study morphine infusion was decreased on postoperative day 1 if the NRS score < 3 and COMFORT-B score < 10. Study medication was continued until 48 hours after surgery. In patients who met the withdrawal criteria, treatment allocation was de-blinded and trial morphine infusions and/or paracetamol were switched to equivalent open label dose infusions of both paracetamol and morphine and analyzed as intention to treat within their treatment arm. Outcomes The primary endpoint is weight-adjusted cumulative morphine dose in mcg/kg during the first 48 hours postoperatively. Secondary outcomes are: Morphine rescue dose in micrograms per kilogram in the first 48 hours postoperatively, number of patients receiving rescue morphine doses, and number of patients needing rescue morphine continuous infusions. Incidence of adverse drug reactions: Hemodynamic; hypotension or bradycardia, with the need for medication or a fluid bolus Decreased gastrointestinal motility or intestinal obstruction not directly related to the underlying diagnosis and not previously existing obstruction with the need for intervention Vomiting Number of reintubations Pediatric delirium (SOS-PD > 3) Non-inferiority analysis by comparing the proportion of patients with one or more NRS scores of at least 4 between study arms Average COMFORT-B score Concomitant use of sedatives (type and dose) Number of hours on mechanical ventilation Length of PICU stay Secondary outcomes were registered until 48 hours after stop trial medication (96 hours after surgery). Statistical methods Power analysis The power analysis, conducted in a simulation study, is based on a comparison of the primary outcome between groups using a Mann-Whitney test. For the simulation study, data from a previous study were used.(16) Based on this data set, the median cumulative morphine consumption in the control group would be 357 mcg/kg (IQR: 220–605), and was hypothesized that this morphine consumption would be reduced by 30% in the intervention (paracetamol) group. The simulation study showed that using a two-sided significance level of 5%, 86 patients per group would be required to obtain a power of 95%. To account for the effects of stratification by center and missing data, 104 patients per study arm had to be included, 208 in total. Statistical analysis For the comparison of the primary outcome between groups, the non-parametric Van Elteren test with stratification by center was used. Linear regression analysis with group and treatment center as categorical predictor variables was applied for the secondary outcomes. For comparison of the proportion of patients with one or more NRS scores of 4 and higher between the two groups, a non-inferiority analysis was done, using a non-inferiority margin of 20%. The confidence interval was calculated with the method of Klingenberg(26), with adjustment for center. Adverse effects were compared between groups using Fisher exact tests with 95% confidence interval. Level of significance was set to 5%, and all tests were two-sided. Interim analysis and stopping guidelines An international external Data and Safety Monitoring Board (DSMB) composed of an experienced cardiac surgeon, pediatric intensivist and cardio-anesthesiologist together with an independent biostatistician was installed. The study protocol did not contain an interim analysis. The DSMB evaluated inclusion rate and safety of participants (need for rescue morphine and NRS pain scores in both groups) 4 times during the inclusion period and advised us to continue the study without design changes to the protocol. To better assess safety aspects and before patient enrolment, morphine rescue dose in micrograms per kilogram in the first 48 hours postoperatively, number of patients receiving rescue morphine doses, number patients needing rescue morphine continuous infusions and average COMFORT-B scores were added as secondary outcome. Results Patient characteristics Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. The main reasons are noted in the flowchart in Figure 1. The morphine group contained 100 patients versus 94 in the intravenous paracetamol group. The two groups did not significantly differ in patient characteristics and risk of mortality scores (Table 1. Patient characteristics). Underlying cardiac diagnoses are shown in Table 2. Table 1. Patient characteristics Characteristic Paracetamol (n,%) N=94 Morphine (n,%) N=100 Sex, n (%) Male Female 51 (54) 43 (46) 52 (52) 48 (48) Centre, n (%) Erasmus MC-Sophia Rotterdam Wilhelmina Children’s Hospital UMC Utrecht Beatrix Children’s Hospital UMC Groningen University Hospital Leuven 59 (62.8) 14 (14.9) 7 (7.4) 14 (14.9) 61 (61) 14 (14) 8 (8) 17 (17) Age at surgery in months, median (IQR) 5 (3-10) 4 (2-7) Body weight in kg, median (IQR) 5.8 (4.8-8.6) 5.9 (4.5-7.5) CPB duration in min, median (IQR) 98.0 (60-138) 98.5 (79-133) RACHS, n (%) 1 2 3 4 5 6 12 52 22 5 - 3 4 62 20 15 - 0 PRISM III , median (IQR) 15 (9) 16 (9) PIM II, median(IQR) -3,78 (0,58) -3.73 (0,51) PELOD Day 0 Day 1 Day 2 5 (3) 4 (4) 2 (5) 5 (3) 3 (4) 2 (4) Table 2. Underlying cardiac diagnosis per group Intermittent IV paracetamol (n=94) Number (%) VSD 20 (21,3) TOF 16 (17) AVSD 15 (16) ASD 12 (12,7) TGA 7 (7,4) Valve stenosis/insufficientie 6 (6,3) HRHS 5 (5.3) HLHS 4 (4,3) PAPVR 3 (3,2) Hypoplastic aortic arch 2 (2,1) TAPVR 2 (2,1) Other * 2 (2,1) Morphine (n=100) VSD 29 (29) TOF 21 (21) AVSD 12 (12) TGA 10 (10) Hypoplastic aortic arch 5 (5) HLHS 8 (8) Valve stenosis/insufficientie 4 (4) ASD 2 (2) HRHS 2 (2) PAPVR 3 (3) VSD & ASD 2 (2) Other ** 2 (2) *Other: ALCAPA, Ebstein with pulmonary valve atresia. **Other: Truncus arteriosus, TAPVR Abbreviations: VSD: ventricular septal defect, TOF: Tetralogy of Fallot, AVSD: atrioventricular septal defect, ASD: atrial septal defect, TGA: transposition of the Great Arteries, HRHS: hypoplastic right heart syndrome, HLHS: hypoplastic left heart syndrome, TAPVR: total abnormal pulmonary venous return, PAPVR: partial abnormal pulmonary venous return, ALCAPA (anomalous left coronary artery from the pulmonary artery). Twenty-eight patients in the IV paracetamol group and 26 patients in the continuous morphine group were withdrawn from the study after start study medication, most often because of fever. Reasons for withdrawal and time to withdrawal are shown in Table 3. Table 3. Time and reasons for patient withdrawal Endpoint Paracetamol (n=28) Morphine (n=26) Time to withdrawal (hr:min) 21:26 15:11 Reasons for withdrawal, n (%) Fever Parental request Physicians request Trial medication delivery problem ECMO/OR/muscle relaxants 13 (46,4) 2 (7,1) 4 (14,3) 4 (14,3) 5 (17,9) 12 (46,2) 3 (11,5) 6 (23,1) 4 (15,4) 1 (3,8) Study Outcomes The median weight-adjusted cumulative morphine dose in the first 48 hours postoperative in the paracetamol group was 5 times lower (79%) than in the morphine group ( P < 0.001 (Table 4). There were no significant differences between groups in median total rescue morphine consumption in the first 48 hours postoperative, proportion of patients receiving rescue morphine boluses and additional continuous morphine infusions Table 4. Primary and secondary study outcomes Outcome Paracetamol (n=94) Morphine (n=100) P-value Cumulative morphine consumption, median (IQR), mcg/kg* 145.0 (115.0-432.5) 692.6 (532.7- 856.1) <0.001 Rescue morphine dose total, median (IQR), mcg/kg* 29.4 (0-45.7) 30.0 (0-70.9) 0.38 Patients receiving rescue morphine bolus, n (%)* 62 (66.0%) 69 (69.0%) 0.76 Patients receiving rescue morphine bolus and infusions (n)* 40(42.3%) 42 (42.0%) 1.00 Comedication (n)* Midazolam Lorazepam Propofol Fentanyl 76 (80.9%) 5 (5.3%) 26 (27.7%) 8 (8.5%) 77 (77%) 10 (10%) 19 (19%) 10 (10%) 0.59 0.29 0.18 0.81 PICU stay in days, median(IQR)) 3 (2-6) 2 (1-5) 0.10 Duration postoperative mechanical ventilation (median, IQR, hours) 11.8(4.5-45.6) 15.4(5.7-28.8) 0.39 Reintubation (n, %)* 3 (3.2) 2 (2) 0.68 Adverse events** Hemodynamic instability (bradycardia or hypotension) Gastrointestinal (obstruction, obstipation, vomiting) Delirium 22 (23.4%) 3 (3.2%) 3 (3.2%) 28 (28%) 1 (1%) 5 (5%) NRS ≥ 4 at least once (n,%)* 55 (59%) 62 (62%) 0.62 Comfort-B scale scores (median, range)* 12(8-22) 12 (7-20) 0.05 The median weight-adjusted cumulative morphine consumption in the 140 patients who received the study medication for 48 hours was 135.1 (IQR 115.4-395.5) mcg/kg in the IV paracetamol group vs 701.5 (IQR 562.0-854,8) mcg/kg (p<0.001) in the continuous morphine group. The rescue morphine consumption was similar in both groups, 29.9 mcg/kg in the IV paracetamol group vs 30 mcg/kg (p= 0.91) in the continuous morphine group. The percentage of patients needing continuous open label morphine was 36% in the IV paracetamol group vs 32% in the continuous morphine group. Percentage of adverse effects did not significantly differ between treatment groups (Table 4). Hemodynamic instability as predefined occurred was the most frequently adverse effect in both groups; 22 (23%) in the IV paracetamol group versus 28 (28%) in the continuous morphine group (p=0.51). Three patients in IV paracetamol group were re-intubated versus two patients in the continuous morphine group (p= 0.68). Overall median NRS pain scores were 0 (IQR 0-3) vs 0 (IQR 0-5) in the IV paracetamol and continuous morphine group, respectively. The number of patients with one or more NRS scores of 4 or higher was similar in both groups (Table 4). Non-inferiority analysis of all patients with a NRS of 4 or higher fell within the predefined confidence interval of 20%. Discussion In this multi-center RCT, infants below 4 years of age treated with IV paracetamol as primary analgesic after cardiac surgery with CPB received significantly less morphine within the first 48 hours after surgery than did morphine. Their median weight-adjusted morphine dose was 79% lower than that of patients receiving continuous morphine as a primary analgesic. Several studies have shown opioid-sparing effects of intravenous or rectal paracetamol in children of various ages undergoing various types of non-cardiac surgery.(16, 29-32) While these earlier studies showed a 15% to 66% reduction in total morphine consumption, this reduction in total morphine dosing in our cohort was higher at 79%. Differences in study populations and study designs may prevent a true comparison of the results. Whether altered PK or PD in our patient cohort plays a role in our findings is unclear. Morphine has both sedative and analgesic properties. Interestingly, approximately 80% of our included patients in either group needed additional sedatives. This proportion is higher than that in a similar study by Ceelie et al. in non-cardiac surgery patients, in which between 7.9% and 15.2% of patients received additional midazolam (16) and in a similar study by Hoogd et al., in which 37.2% of all patients received additional continuous midazolam.(27) The discrepancy may be explained by the difference in patient ages between the studies: median five months in our study vs. less than one month in the study by Ceelie et al. (16) Older children may need more sedatives to accept intubation and mechanical ventilation, chest tubes and the hospital environment compared to neonates. De Hoogd et al. used much higher morphine doses compared to our study; leading to lower use of other sedatives as morphine itself has a sedative effect as well. Lower or even absent continuous morphine infusions might therefore lead to higher needs for sedatives. We found no difference in midazolam needs between the two study groups, suggesting that sedative needs were not influenced by the morphine infusion. Furthermore, several studies report similar use of midazolam in children following cardiac surgery treated with continuous morphine infusions as found in our study. (36-38) The most common adverse effects of the study drugs were hemodynamic instability which was comparable between groups; 23.4% vs 28.0 % for IV paracetamol and continuous morphine, respectively. Changes in hemodynamic parameters are multifactorial and differentiation between morphine effect or purely cardiac-surgery-related hemodynamic effects is difficult. Adverse effects of IV paracetamol also need to be considered. In a previous study, IV paracetamol was associated with hypotension in 5% of children in the cardiac intensive care unit.(39) This can partially explain why there is no difference in hemodynamic instability between both study groups. Reintubation was rare in both groups and could not be attributed to pharmacologic induced hypopnea or apnea. Length of PICU stay as well as time on mechanical ventilation did not differ between groups: this suggests no adverse respiratory effects of the higher morphine exposure in the continuous morphine group. Gastrointestinal side effects as well as withdrawal syndrome or delirium are side effects that might be more prominent after 96 hours after surgery. Since all patients switched to open label morphine and paracetamol after 48 hours, late onset adverse effects could have been masked or missed due to the short follow-up time. Strengths To the best of our knowledge, this is the first large randomized controlled trial in children under the age of 4 years undergoing cardiac surgery with CPB, and the first to compare IV paracetamol as a primary analgesic postoperatively with the common practice of administering opioids. Limitations About 30% of patients in either group were switched to open label paracetamol and morphine during the study timeframe. In approximately half of these cases the reason was sustained fever after surgery and the need for IV paracetamol to decrease body temperature. Interestingly, fever episodes were similar in both groups. Changing to open label might have actually increased the morphine consumption in patients in the IV paracetamol group who were switched from placebo to open label morphine within 48 hours, thereby reducing the observed difference between the groups. The need for open label paracetamol due to fever does not reflect inadequate pain management and would not be an issue in open label paracetamol treatment. To conclude, administration of intermittent intravenous paracetamol as primary analgesic in children under 4 years of age after cardiac surgery with the use of cardiopulmonary bypass resulted in a substantial reduction of the cumulative morphine consumption in the first 48 hours postoperatively and reduced the need for continuous morphine infusions in almost 60% of all patients treated with IV paracetamol. Considering the similar need for rescue morphine doses and the same median NRS and COMFORT-B scores in both groups, an analgesic treatment protocol incorporating a loading dose of morphine followed by IV paracetamol maintenance doses achieves equally effective postoperative pain relief in these patients independent of diagnosis or type of cardiac surgery. Abbreviations IV Intravenous (P)ICU (Pediatric) Intensive care Units NRS Numeric Rating Scale CPB Cardiopulmonary Bypass PK Pharmacokinetics ALAT Alanine aminotransferase ASAT Aspartate aminotransferase ECMO Extracorporeal Membrane Oxygenation NaCL Sodium Chloride CRF Case record form COMFORT B COMFORT Behavior Scale SOS-PD SOS-Pediatric Delirium RACHS-1 Risk-Adjusted Classification for Congenital Heart Surgery PRISM III The Pediatric Risk of Mortality III PELOD 2 Pediatric Logistic Organ Dysfunction 2 DSMB Data and Safety Monitoring Board Declarations Ethics approval and consent to participate The study was approved by the Erasmus MC Medical Ethics Committee and was registered in the Dutch trial registry under the code NTR5448 as well at the Central Committee on Research Involving Human Subjects (NL 53085.078.15), EudraCT (2015–001835-20-NL/BE), and clinicaltrials.gov (identifier: NCT05853263). Parents or legal guardians of the participating children provided written informed consent prior to any study procedures. The study protocol is published in Trials and available online.(17) Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding This study was funded by ZonMw (The Netherlands Organisation for Health Research and Development), “effective, efficient, safer use of medicines” project (project number 836041016), and the Sophia Foundation for Scientific Research (SSWO) (project number S16–08). Funders had no role in study design or study proceedings, writing of the report, or the decision to submit the report for publication. Funding Greet van den Berghe (ORCID ID: 0000-0002-5320-1362) Methusalem Programme from the Flemish Goverment (METH/14/06) and ERC Advanced Grant (AdvG-2017-785809) from the Horizon 2020 Program of the EU. Authors' contributions GZ made substantial contributions to the conception and design of the work, acquisition, analysis and interpretation of data, drafted and substantively revised the manuscript. CR made substantial contributions to acquisition, analysis and interpretation of data, and drafted the work. JvR made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript. MvD made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript. SdW made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript. CK made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript. EK made substantial contributions to the conception and design of the work, and substantively revised the manuscript. NJ made substantial contributions to the conception and design of the work, and substantively revised the manuscript. MK made substantial contributions to the conception and design of the work, and substantively revised the manuscript. SM made substantial contributions to acquisition, analysis and interpretation of data, and substantively revised the manuscript. GvdB made substantial contributions to the conception and design of the work, and substantively revised the manuscript. RH made substantial contributions to acquisition, analysis and interpretation of data, and substantively revised the manuscript. DV made substantial contributions to the conception and design of the work, and substantively revised the manuscript. AB made substantial contributions to the conception and design of the work, analysis and interpretation of data, drafted and substantively revised the manuscript. DT made substantial contributions to the conception and design of the work, analysis and interpretation of data, drafted and substantively revised the manuscript. EW made substantial contributions to the conception and design of the work, acquisition, analysis and interpretation of data, drafted and substantively revised the manuscript. All authors read and approved the final manuscript Acknowledgements The authors would like to acknowledge all medical and support staff from participating hospitals, and in particular the research nurses without whom this study would have been have difficult to execute. References Dolk H, Loane M, Garne E, European Surveillance of Congenital Anomalies Working G. 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Valentine K, Cisco MJ, Lasa JJ, Achuff BJ, Kudchadkar SR, Staveski SL. A survey of current practices in sedation, analgesia, withdrawal, and delirium management in paediatric cardiac ICUs. Cardiol Young. 2023:1-6. van Saet A, de Wildt SN, Knibbe CA, Bogers AD, Stolker RJ, Tibboel D. The effect of adult and pediatric cardiopulmonary bypass on pharmacokinetic and pharmacodynamic parameters. Curr Clin Pharmacol. 2013;8(4):297-318. Ferrari F, Benegni S, Marinari E, Haiberger R, Garisto C, Rizza A, et al. Vancomycin concentrations during cardiopulmonary bypass in pediatric cardiac surgery: a prospective study. Perfusion. 2022;37(6):553-61. Mian P, Valkenburg AJ, Allegaert K, Koch BCP, Breatnach CV, Knibbe CAJ, et al. Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass. J Clin Pharmacol. 2019;59(6):847-55. Egbuta C, Mason KP. Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit. J Clin Med. 2021;10(9). Burgart AM, Char D. The opioid crisis should lead pediatric anesthesiologists to a broader vision of opioid stewardship. Paediatr Anaesth. 2019;29(11):1078-80. Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122-32. Harris J, Ramelet AS, van Dijk M, Pokorna P, Wielenga J, Tume L, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42(6):972-86. da Silva PS, Reis ME, Fonseca TS, Fonseca MC. Opioid and Benzodiazepine Withdrawal Syndrome in PICU Patients: Which Risk Factors Matter? J Addict Med. 2016;10(2):110-6. Cook SF, Roberts JK, Samiee-Zafarghandy S, Stockmann C, King AD, Deutsch N, et al. Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation. Clin Pharmacokinet. 2016;55(1):107-19. Mian P, Knibbe CAJ, Calvier EAM, Tibboel D, Allegaert K. Intravenous Paracetamol Dosing Guidelines for Pain Management in (pre)term Neonates Using the Paediatric Study Decision Tree. Curr Pharm Des. 2017;23(38):5839-49. Ceelie I, de Wildt SN, van Dijk M, van den Berg MMJ, van den Bosch GE, Duivenvoorden HJ, et al. Effect of Intravenous Paracetamol on Postoperative Morphine Requirements in Neonates and Infants Undergoing Major Noncardiac Surgery A Randomized Controlled Trial. Jama-Journal of the American Medical Association. 2013;309(2):149-54. Zeilmaker-Roest GA, van Rosmalen J, van Dijk M, Koomen E, Jansen NJG, Kneyber MCJ, et al. Intravenous morphine versus intravenous paracetamol after cardiac surgery in neonates and infants: a study protocol for a randomized controlled trial. Trials. 2018;19(1):318. Giordano V, Edobor J, Deindl P, Wildner B, Goeral K, Steinbauer P, et al. Pain and Sedation Scales for Neonatal and Pediatric Patients in a Preverbal Stage of Development: A Systematic Review. JAMA Pediatr. 2019;173(12):1186-97. Ista E, Te Beest H, van Rosmalen J, de Hoog M, Tibboel D, van Beusekom B, et al. Sophia Observation withdrawal Symptoms-Paediatric Delirium scale: A tool for early screening of delirium in the PICU. Aust Crit Care. 2017. Cavalcanti PE, Sa MP, Santos CA, Esmeraldo IM, Chaves ML, Lins RF, et al. Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for Cardio- Thoracic Surgery (STS-EACTS) mortality score. Rev Bras Cir Cardiovasc. 2015;30(2):148-58. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med. 1996;24(5):743-52. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F, et al. PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013;41(7):1761-73. Formulary DP. [Available from: www.kinderformularium.nl. Krekels EH, Tibboel D, de Wildt SN, Ceelie I, Dahan A, van Dijk M, et al. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet. 2014;53(6):553-63. Wang C, Sadhavisvam S, Krekels EH, Dahan A, Tibboel D, Danhof M, et al. Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. Clin Drug Investig. 2013;33(7):523-34. Klingenberg B. A new and improved confidence interval for the Mantel-Haenszel risk difference. Stat Med. 2014;33(17):2968-83. de Hoogd S, Goulooze SC, Valkenburg AJ, Krekels EHJ, van Dijk M, Tibboel D, et al. Postoperative breakthrough pain in paediatric cardiac surgery not reduced by increased morphine concentrations. Pediatr Res. 2021;90(6):1201-6. Penk JS, Lefaiver CA, Brady CM, Steffensen CM, Wittmayer K. Intermittent Versus Continuous and Intermittent Medications for Pain and Sedation After Pediatric Cardiothoracic Surgery; A Randomized Controlled Trial. Crit Care Med. 2018;46(1):123-9. Hong JY, Kim WO, Koo BN, Cho JS, Suk EH, Kil HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy. Anesthesiology. 2010;113(3):672-7. Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. ANESTHESIOLOGY. 1999;91(2):442-7. Ali S, Sofi K, Dar AQ. Comparison of Intravenous Infusion of Tramadol Alone with Combination of Tramadol and Paracetamol for Postoperative Pain after Major Abdominal Surgery in Children. Anesth Essays Res. 2017;11(2):472-6. Patel AK, Gai J, Trujillo-Rivera E, Faruqe F, Kim D, Bost JE, et al. Association of Intravenous Acetaminophen Administration With the Duration of Intravenous Opioid Use Among Hospitalized Pediatric Patients. JAMA Netw Open. 2021;4(12):e2138420. Hartman ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: A systematic review. Pediatric Critical Care Medicine. 2009;10(2):246-55. Nasr VG, DiNardo JA. Sedation and Analgesia in Pediatric Cardiac Critical Care. Pediatr Crit Care Med. 2016;17(8 Suppl 1):S225-31. Wolf AR, Jackman L. Analgesia and sedation after pediatric cardiac surgery. Paediatr Anaesth. 2011;21(5):567-76. Borenstein-Levin L, Hochwald O, Ben-Ari J, Dinur G, Littner Y, Eytan D, et al. Same baby, different care: variations in practice between neonatologists and pediatric intensivists. Eur J Pediatr. 2022;181(4):1669-77. Valkenburg AJ, Goulooze SC, Breatnach CV, Mathot RAA, Tibboel D, van Dijk M, et al. Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study. Pediatr Crit Care Med. 2021;22(4):e259-e69. Amula V, Vener DF, Pribble CG, Riegger L, Wilson EC, Shekerdemian LS, et al. Changes in Anesthetic and Postoperative Sedation-Analgesia Practice Associated With Early Extubation Following Infant Cardiac Surgery: Experience From the Pediatric Heart Network Collaborative Learning Study. Pediatr Crit Care Med. 2019;20(10):931-9. Achuff BJ, Moffett BS, Acosta S, Lasa JJ, Checchia PA, Rusin CG. Hypotensive Response to IV Acetaminophen in Pediatric Cardiac Patients. Pediatr Crit Care Med. 2019;20(6):527-33. Additional Declarations No competing interests reported. Supplementary Files PACStrialprotocol.pdf consortchecklistPACStrial.pdf Cite Share Download PDF Status: Published Journal Publication published 30 Apr, 2024 Read the published version in Critical Care → Version 1 posted Editorial decision: Revision requested 22 Feb, 2024 Reviews received at journal 21 Feb, 2024 Reviews received at journal 09 Feb, 2024 Reviewers agreed at journal 01 Feb, 2024 Reviewers invited by journal 01 Feb, 2024 Editor assigned by journal 28 Jan, 2024 Submission checks completed at journal 28 Jan, 2024 First submitted to journal 26 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-3899589\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":269779387,\"identity\":\"9636c50a-e4d6-451a-afe3-f9e63aa057c1\",\"order_by\":0,\"name\":\"Gerdien Zeilmaker-Roest\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIie3QoWoDMRjA8S8EUnMPkMLYPcEgNXHb7VHuOOiZikHNwcTqztz8lUKfoerUROCgZ/oAKZm4ikVVrC5iYmlrahImJ/KXX/jxJQEIhf5r6QsABUDD7fDOT9iFYHY7jPxrroTQP5H4eXQYBtbG4+pdl6ePp+ShKb42Bj6dZCIgZylTk1XU832j86yVM76vQbvJArbUErSmU6IigVMuZ0QBdB6CKmNJso41mf+It4TLQntJDJjYH1PZihKCQXSolSn3EoYJPl8sX9ZTPK5Fn7W7o30L82ypqsPJlOqx6bfo24jXhPeFlqbs7p1bOsfcBeyWhfssFAqFQtd+AWpeWF/ACZzjAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Erasmus MC-Sophia Children’s Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Gerdien\",\"middleName\":\"\",\"lastName\":\"Zeilmaker-Roest\",\"suffix\":\"\"},{\"id\":269779388,\"identity\":\"a58e5ccd-7b6b-4e14-9435-2dc5c12bbf7d\",\"order_by\":1,\"name\":\"Christine de Vries-Rink\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Erasmus MC\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Christine\",\"middleName\":\"\",\"lastName\":\"de Vries-Rink\",\"suffix\":\"\"},{\"id\":269779389,\"identity\":\"491b63fb-a4ac-4a59-91b3-1aa5603f6895\",\"order_by\":2,\"name\":\"Joost van Rosmalen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Erasmus MC\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Joost\",\"middleName\":\"van\",\"lastName\":\"Rosmalen\",\"suffix\":\"\"},{\"id\":269779391,\"identity\":\"2297e964-f0de-4267-80ef-45f7f2cbb4a8\",\"order_by\":3,\"name\":\"Monique van Dijk\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Erasmus MC\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Monique\",\"middleName\":\"van\",\"lastName\":\"Dijk\",\"suffix\":\"\"},{\"id\":269779393,\"identity\":\"886816da-45db-4623-8f78-b8173b93fbce\",\"order_by\":4,\"name\":\"Saskia N. de Wildt\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Radboud University Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Saskia\",\"middleName\":\"N.\",\"lastName\":\"de Wildt\",\"suffix\":\"\"},{\"id\":269779396,\"identity\":\"eb992eba-b4f3-48e7-871c-8b9af4ca2965\",\"order_by\":5,\"name\":\"Catherijne A. J. Knibbe\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Leiden University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Catherijne\",\"middleName\":\"A. J.\",\"lastName\":\"Knibbe\",\"suffix\":\"\"},{\"id\":269779398,\"identity\":\"db412a17-ef04-4dda-b118-255830b7a46a\",\"order_by\":6,\"name\":\"Erik Koomen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wilhelmina Children's Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Erik\",\"middleName\":\"\",\"lastName\":\"Koomen\",\"suffix\":\"\"},{\"id\":269779399,\"identity\":\"b2b2f446-1186-4e04-80fd-ef3955d75796\",\"order_by\":7,\"name\":\"Nicolaas J. G. Jansen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wilhelmina Children's Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nicolaas\",\"middleName\":\"J. G.\",\"lastName\":\"Jansen\",\"suffix\":\"\"},{\"id\":269779401,\"identity\":\"10c0596f-cc46-45e5-aa30-488349299075\",\"order_by\":8,\"name\":\"Martin C. J. 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J.\",\"lastName\":\"Kneyber\",\"suffix\":\"\"},{\"id\":269779402,\"identity\":\"5f967065-b649-428a-9316-4aa8d6da815c\",\"order_by\":9,\"name\":\"Sofie Maebe\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UZ Leuven\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sofie\",\"middleName\":\"\",\"lastName\":\"Maebe\",\"suffix\":\"\"},{\"id\":269779403,\"identity\":\"972226ab-6423-4d79-8449-db3d1c01f752\",\"order_by\":10,\"name\":\"Greet van den Berghe\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UZ Leuven\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Greet\",\"middleName\":\"van den\",\"lastName\":\"Berghe\",\"suffix\":\"\"},{\"id\":269779404,\"identity\":\"faa4e3d5-3a2e-4d3c-b331-8880a785a918\",\"order_by\":11,\"name\":\"Renata Haghedooren\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UZ Leuven\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Renata\",\"middleName\":\"\",\"lastName\":\"Haghedooren\",\"suffix\":\"\"},{\"id\":269779405,\"identity\":\"3ed39fcb-721f-4ce1-a6d9-d126512ad78f\",\"order_by\":12,\"name\":\"Dirk Vlasselaers\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UZ Leuven\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Dirk\",\"middleName\":\"\",\"lastName\":\"Vlasselaers\",\"suffix\":\"\"},{\"id\":269779406,\"identity\":\"cebc764d-b476-495e-8db8-4ce64808516f\",\"order_by\":13,\"name\":\"Ad J.J.C. 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Wildschut\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Erasmus MC-Sophia Children’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Enno\",\"middleName\":\"D.\",\"lastName\":\"Wildschut\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-01-26 09:44:34\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3899589/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3899589/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s13054-024-04905-3\",\"type\":\"published\",\"date\":\"2024-04-30T23:57:34+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":50458258,\"identity\":\"80ed09bc-45d0-4c5c-8ea7-638cb436d29b\",\"added_by\":\"auto\",\"created_at\":\"2024-01-31 20:09:11\",\"extension\":\"jpeg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":412886,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eStudy flowchart\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3899589/v1/c35409d4bf083ad26e74e30b.jpeg\"},{\"id\":55697397,\"identity\":\"38b29fac-ca46-4c04-82d1-26e724500b41\",\"added_by\":\"auto\",\"created_at\":\"2024-05-02 02:11:31\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":819661,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3899589/v1/1e2c24e4-f61f-4736-bb33-6a8af555f920.pdf\"},{\"id\":50458256,\"identity\":\"eefeb611-64f0-4bf4-99bb-b4e31eae6269\",\"added_by\":\"auto\",\"created_at\":\"2024-01-31 20:09:11\",\"extension\":\"pdf\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":1746997,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"PACStrialprotocol.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3899589/v1/cb199e938701875b65c5a2e3.pdf\"},{\"id\":50458257,\"identity\":\"754dbc4b-02db-4804-bfd5-87aa716dc4d4\",\"added_by\":\"auto\",\"created_at\":\"2024-01-31 20:09:11\",\"extension\":\"pdf\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":149921,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"consortchecklistPACStrial.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3899589/v1/79b8250e9b10b4f33bee228a.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eCongenital heart disease is the most frequently diagnosed congenital defect, with a reported total prevalence of 8.0 in 1000 births in Europe.(1) More than half of these patients require surgical intervention during the first 3 years of life.\\u003c/p\\u003e \\u003cp\\u003e An evidence-based guideline for pain treatment after cardiac surgery in children is lacking. (2) A 2022 guideline for pain and sedation management recommends opioids as primary analgesic in critically ill patients with moderate to severe pain.(3)\\u003c/p\\u003e \\u003cp\\u003eA 2022 survey including over 200 European PICUs as well as a survey in pediatric cardiac ICUs showed large variation in dose and choice of analgesic drugs.(4, 5) Currently, most centers prescribe at least one opioid as primary analgesic after cardiac surgery.(2)\\u003c/p\\u003e \\u003cp\\u003eCardiopulmonary bypass (CPB) may alter pharmacokinetics (PK) after cardiac surgery ).(6) Valkenburg et al. showed that children after cardiac surgery with use of CPB have a lower clearance of morphine and a higher volume of distribution compared with non-cardiac surgery suggesting that children undergoing cardiac surgery with the use of CPB may need adjusted dosages of postoperative analgesics (7, 8)\\u003c/p\\u003e \\u003cp\\u003eOpioids have been associated with potential serious adverse events, such as hypotension and respiratory depression and risk for opioid tolerance and opioid withdrawal.(9) These occurrences may result in prolonged ICU-stay.(10\\u0026ndash;13)\\u003c/p\\u003e \\u003cp\\u003eA possible alternative is paracetamol (acetaminophen), considered a safe drug when used in the age-appropriate dose.(14, 15) In earlier randomized controlled trial, intermittent IV paracetamol proved equally effective as intravenous morphine in children up to one year of age after major non-cardiac surgery. (16) We therefore assumed that IV paracetamol might also benefit children after cardiac surgery.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eAims\\u003c/p\\u003e \\u003cp\\u003eWe performed a prospective, multi-center, randomized double-blinded, controlled trial in children aged 0\\u0026ndash;3 years undergoing cardiac surgery with the use of CPB. The aim of the study was to test the hypothesis that intermittent IV paracetamol administration as primary analgesic after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine dose (in mcg/kg) during the first 48 hours after cardiac surgery.\\u003c/p\\u003e \\u003cp\\u003eStudy design and setting\\u003c/p\\u003e \\u003cp\\u003eA prospective, multi-center, randomized double-blinded controlled trial conducted in four level-3 PICUs in the Netherlands and Belgium (Erasmus MC-Sophia Rotterdam, Wilhelmina Children\\u0026rsquo;s Hospital UMC Utrecht, Beatrix Children\\u0026rsquo;s Hospital UMC Groningen, the Netherlands and University Hospital Leuven, Belgium).\\u003c/p\\u003e \\u003cp\\u003e The study was approved by the Erasmus MC Medical Ethics Committee and was registered in the Dutch trial registry under the code NTR5448 as well at the Central Committee on Research Involving Human Subjects (NL 53085.078.15), EudraCT (2015\\u0026ndash;001835-20-NL/BE), and clinicaltrials.gov (identifier: NCT05853263).\\u003c/p\\u003e \\u003cp\\u003e Parents or legal guardians of the participating children provided written informed consent prior to any study procedures. The study protocol is published in \\u003cem\\u003eTrials\\u003c/em\\u003e and available online.(17)\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatients\\u003c/h2\\u003e \\u003cp\\u003eInclusion criteria\\u003c/p\\u003e \\u003cp\\u003eChildren (0\\u0026ndash;36 months) admitted to the PICU after cardiac surgery with the use of CPB between March 2016 and July 2020 were eligible to participate.\\u003c/p\\u003e \\u003cp\\u003eExclusion criteria\\u003c/p\\u003e \\u003cp\\u003eNo informed consent, a known allergy or intolerance for paracetamol or morphine, opioids administered in the 24 hours before surgery, hepatic dysfunction prior to surgery (defined as three times the reference value of alanine/aspartate aminotransferase (ALAT/ASAT)), and/or renal insufficiency defined at least as RIFLE category Risk prior to surgery.\\u003c/p\\u003e \\u003cp\\u003eWithdrawal criteria:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eWithdrawn informed consent\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eSigns of hypersensitivity or an allergic reaction to either morphine or paracetamol\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eRe-operation or extracorporeal membrane oxygenation (ECMO) treatment within 48 hours\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eHepatic dysfunction, defined as three times the reference value of ALAT/ASAT\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eRenal insufficiency defined as RIFLE category Injury\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eAdministration of muscle relaxants after surgery for 3 hours or longer\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eBody temperature of 38.5\\u0026deg; Celsius after surgery for 6 hours or longer\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRandomization, blinding and treatment allocation\\u003c/h2\\u003e \\u003cp\\u003eBlocked randomization with randomly chosen block sizes and stratification by center was applied. A biostatistician (JvR) carried out the randomization in advance, with a randomization schedule for each participating center. Participants were assigned a consecutive trial number on the randomization schedule. The randomization schedule was safely stored in the local pharmacy at every center. The hospital pharmacies of all participating centers, but not the physicians, had access to the randomization schedule to ensure concealed allocation. Study medication was prepared at the participating centers by the pharmacy. In case of a medical emergency the pharmacists could be consulted on treatment allocation. To ensure blinding in both groups, a double dummy (intermittent placebo bolus of Sodium chloride (NaCl) 0.9% in a similar volume as the IV paracetamol dose or a continuous placebo infusion of NaCl 0.9% at the same rate as an equivalent morphine continuous infusion) was used.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eProcedures\\u003c/h2\\u003e \\u003cp\\u003ePeroperative management\\u003c/p\\u003e \\u003cp\\u003ePeroperative analgosedation in each center was performed per local protocol. Type of analgesics and sedatives were registered in the electronic patient data management system, but not included in the case record form (CRF). Information on the duration of surgery, type of CPB system used, CPB run time, aorta cross clamp time and degree and duration of hypothermia were registered in the CRF.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssessments\\u003c/h2\\u003e \\u003cp\\u003eTrained pediatric ICU nurses applied the Numeric Rating Scale-11 (NRS-11) and COMFORT-Behavior Scale (COMFORT-B) every 2 hours. Both instruments are validated in critically ill children.(18)\\u003c/p\\u003e \\u003cp\\u003ePediatric delirium was assessed thrice daily in children requiring sedatives or analgesics for more than 48 hours using the validated SOS-Pediatric Delirium (SOS-PD) scale.(19)\\u003c/p\\u003e \\u003cp\\u003eAll patients were classified according to the Risk-Adjusted Classification for Congenital Heart Surgery (RACHS-1) score.(20) The Pediatric Risk of Mortality (PRISM) lll score (21), combined with the Pediatric Logistic Organ Dysfunction 2 (PELOD-2)(22) were assessed on the day of surgery postoperatively, and postoperative days 1 and 2.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy protocol\\u003c/h2\\u003e \\u003cp\\u003eA loading dose of morphine 100 mcg/kg IV was administered to all patients at the end of surgery. Hereafter, patients were randomized to receive either continuous morphine or intermittent IV paracetamol. Paracetamol was dosed according to the Dutch Pediatric Formulary (loading dosage 20 mg/kg in all patients, maintenance dosage 40 mg/kg/day in neonates and 60 mg/kg/day in all other patients, 4 times daily).(23) Morphine dosing was based on a population PK model-derived dosing regimen, range 3.9 to 16.0 mcg/kg per hour, resulting in similar morphine concentration across children\\u0026rsquo;s age and bodyweight ranges.(9, 17, 24, 25)\\u003c/p\\u003e \\u003cp\\u003ePain or discomfort was scored with both the NRS pain scale and COMFORT-B. An open label morphine IV rescue dose (10 mcg/kg in neonates\\u0026thinsp;\\u0026lt;\\u0026thinsp;10 days, 15 mcg/kg in older patients) was administered if NRS-score\\u0026thinsp;\\u0026ge;\\u0026thinsp;4. Pain was re-evaluated 10 minutes after the intervention. If pain persisted after three rescue doses, a morphine loading dose of 100 mcg/kg was administered and open label continuous morphine infusion was started at 10 mcg/kg per hour. Open label morphine infusion could be increased to maximum 30 mcg/kg per hour. In case of inadequate analgesia with maximum open label morphine, patients were switched to continuous IV fentanyl. Open label morphine or fentanyl infusion was titrated to effect using the NRS pain scale. In each group, continuous study morphine infusion was decreased on postoperative day 1 if the NRS score\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 and COMFORT-B score\\u0026thinsp;\\u0026lt;\\u0026thinsp;10. Study medication was continued until 48 hours after surgery. In patients who met the withdrawal criteria, treatment allocation was de-blinded and trial morphine infusions and/or paracetamol were switched to equivalent open label dose infusions of both paracetamol and morphine and analyzed as intention to treat within their treatment arm.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eOutcomes\\u003c/h2\\u003e \\u003cp\\u003eThe primary endpoint is weight-adjusted cumulative morphine dose in mcg/kg during the first 48 hours postoperatively.\\u003c/p\\u003e \\u003cp\\u003eSecondary outcomes are:\\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eMorphine rescue dose in micrograms per kilogram in the first 48 hours postoperatively, number of patients receiving rescue morphine doses, and number of patients needing rescue morphine continuous infusions.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eIncidence of adverse drug reactions:\\u003c/p\\u003e \\u003cp\\u003e \\u003col style=\\\"list-style-type:lower-alpha;\\\"\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eHemodynamic; hypotension or bradycardia, with the need for medication or a fluid bolus\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eDecreased gastrointestinal motility or intestinal obstruction not directly related to the underlying diagnosis and not previously existing obstruction with the need for intervention\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eVomiting\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eNumber of reintubations\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ePediatric delirium (SOS-PD\\u0026thinsp;\\u0026gt;\\u0026thinsp;3)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eNon-inferiority analysis by comparing the proportion of patients with one or more NRS scores of at least 4 between study arms\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eAverage COMFORT-B score\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eConcomitant use of sedatives (type and dose)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eNumber of hours on mechanical ventilation\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eLength of PICU stay\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003eSecondary outcomes were registered until 48 hours after stop trial medication (96 hours after surgery).\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eStatistical methods\\u003c/h3\\u003e\\n\\u003cp\\u003ePower analysis\\u003c/p\\u003e \\u003cp\\u003eThe power analysis, conducted in a simulation study, is based on a comparison of the primary outcome between groups using a Mann-Whitney test. For the simulation study, data from a previous study were used.(16) Based on this data set, the median cumulative morphine consumption in the control group would be 357 mcg/kg (IQR: 220\\u0026ndash;605), and was hypothesized that this morphine consumption would be reduced by 30% in the intervention (paracetamol) group. The simulation study showed that using a two-sided significance level of 5%, 86 patients per group would be required to obtain a power of 95%. To account for the effects of stratification by center and missing data, 104 patients per study arm had to be included, 208 in total.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eFor the comparison of the primary outcome between groups, the non-parametric Van Elteren test with stratification by center was used. Linear regression analysis with group and treatment center as categorical predictor variables was applied for the secondary outcomes.\\u003c/p\\u003e \\u003cp\\u003eFor comparison of the proportion of patients with one or more NRS scores of 4 and higher between the two groups, a non-inferiority analysis was done, using a non-inferiority margin of 20%. The confidence interval was calculated with the method of Klingenberg(26), with adjustment for center. Adverse effects were compared between groups using Fisher exact tests with 95% confidence interval. Level of significance was set to 5%, and all tests were two-sided.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eInterim analysis and stopping guidelines\\u003c/h2\\u003e \\u003cp\\u003eAn international external Data and Safety Monitoring Board (DSMB) composed of an experienced cardiac surgeon, pediatric intensivist and cardio-anesthesiologist together with an independent biostatistician was installed. The study protocol did not contain an interim analysis. The DSMB evaluated inclusion rate and safety of participants (need for rescue morphine and NRS pain scores in both groups) 4 times during the inclusion period and advised us to continue the study without design changes to the protocol. To better assess safety aspects and before patient enrolment, morphine rescue dose in micrograms per kilogram in the first 48 hours postoperatively, number of patients receiving rescue morphine doses, number patients needing rescue morphine continuous infusions and average COMFORT-B scores were added as secondary outcome.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003ePatient characteristics\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. The main reasons are noted in the flowchart in Figure 1.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe morphine group contained 100 patients versus 94 \\u0026nbsp;in the intravenous paracetamol group. The two groups did not significantly differ in patient characteristics and risk of mortality scores (Table 1. Patient characteristics). Underlying cardiac diagnoses are shown in Table 2.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1. Patient characteristics\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"604\\\" style=\\\"margin-right: calc(2%); width: 98%;\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCharacteristic\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eParacetamol (n,%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eN=94\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMorphine (n,%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eN=100\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSex, n (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Male\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Female\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;51 (54)\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;43 (46)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e52 (52)\\u003c/p\\u003e\\n \\u003cp\\u003e48 (48)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCentre, n (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Erasmus MC-Sophia Rotterdam\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Wilhelmina Children’s Hospital UMC Utrecht\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Beatrix Children’s Hospital UMC Groningen \\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eUniversity Hospital Leuven\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\" class=\\\"fr-cell-handler fr-selected-cell\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e59 (62.8)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e14 (14.9)\\u003c/p\\u003e\\n \\u003cp\\u003e7 (7.4)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e14 (14.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\" class=\\\"fr-cell-fixed fr-selected-cell\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e61 (61)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e14 (14)\\u003c/p\\u003e\\n \\u003cp\\u003e8 (8)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e17 (17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAge at surgery in months, median (IQR)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e5 (3-10)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e4 (2-7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBody weight in kg, median (IQR)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e5.8 (4.8-8.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e5.9 (4.5-7.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCPB duration in min, median (IQR)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e98.0 (60-138)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e98.5 (79-133)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRACHS, n (%)\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;1\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;2\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;3\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;4\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;5\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;6\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003cp\\u003e52\\u003c/p\\u003e\\n \\u003cp\\u003e22\\u003c/p\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003cp\\u003e-\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003cp\\u003e62\\u003c/p\\u003e\\n \\u003cp\\u003e20\\u003c/p\\u003e\\n \\u003cp\\u003e15\\u003c/p\\u003e\\n \\u003cp\\u003e-\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePRISM III , median (IQR)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e15 (9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e16 (9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePIM II, median(IQR)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e-3,78 (0,58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e-3.73 (0,51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"49.917355371900825%\\\" valign=\\\"top\\\" style=\\\"width: 64.8318%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePELOD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Day 0\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Day 1\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;Day 2\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.140495867768596%\\\" valign=\\\"top\\\" style=\\\"width: 20.6274%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e5 (3)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (4)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"26.94214876033058%\\\" valign=\\\"top\\\" style=\\\"width: 14.3834%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e5 (3)\\u003c/p\\u003e\\n \\u003cp\\u003e3 (4)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2. Underlying cardiac diagnosis per group\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" align=\\\"\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eIntermittent IV paracetamol (n=94)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNumber (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eVSD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e20 (21,3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTOF\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e16 (17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAVSD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e15 (16)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eASD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e12 (12,7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTGA\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e7 (7,4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eValve stenosis/insufficientie\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e6 (6,3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHRHS\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e5 (5.3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHLHS\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e4 (4,3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePAPVR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e3 (3,2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHypoplastic aortic arch\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2,1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTAPVR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2,1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eOther *\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2,1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMorphine (n=100)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eVSD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e29 (29)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTOF\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e21 (21)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAVSD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e12 (12)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTGA\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e10 (10)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHypoplastic aortic arch\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e5 (5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHLHS\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e8 (8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eValve stenosis/insufficientie\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e4 (4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eASD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHRHS\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePAPVR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e3 (3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eVSD \\u0026amp; ASD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"66.66666666666667%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eOther **\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"33.333333333333336%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2 (2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e*Other: ALCAPA, Ebstein with pulmonary valve atresia.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e**Other: Truncus arteriosus, TAPVR\\u003c/p\\u003e\\n\\u003cp\\u003eAbbreviations: VSD: ventricular septal defect, TOF: Tetralogy of Fallot, AVSD: atrioventricular septal defect, ASD: atrial septal defect, TGA: transposition of the Great Arteries, HRHS: hypoplastic right heart syndrome, HLHS: hypoplastic left heart syndrome, TAPVR: total abnormal pulmonary venous return, PAPVR: partial abnormal pulmonary venous return, ALCAPA (anomalous left coronary artery from the pulmonary artery).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTwenty-eight patients in the IV paracetamol group and 26 patients in the continuous morphine group were withdrawn from the study after start study medication, most often because of fever. Reasons for withdrawal and time to withdrawal are shown in Table 3.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 3. Time and reasons for patient withdrawal\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"57.11159737417943%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eEndpoint\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.00656455142232%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eParacetamol (n=28)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.88183807439825%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eMorphine (n=26)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"57.11159737417943%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eTime to withdrawal (hr:min)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.00656455142232%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e21:26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.88183807439825%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e15:11\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"57.11159737417943%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eReasons for withdrawal, n (%)\\u003c/p\\u003e\\n \\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eFever\\u003c/li\\u003e\\n \\u003cli\\u003eParental request\\u003c/li\\u003e\\n \\u003cli\\u003ePhysicians request\\u003c/li\\u003e\\n \\u003cli\\u003eTrial medication delivery problem\\u003c/li\\u003e\\n \\u003cli\\u003eECMO/OR/muscle relaxants\\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.00656455142232%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e13 (46,4)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (7,1)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (14,3)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (14,3)\\u003c/p\\u003e\\n \\u003cp\\u003e5 (17,9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.88183807439825%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e12 (46,2)\\u003c/p\\u003e\\n \\u003cp\\u003e3 (11,5)\\u003c/p\\u003e\\n \\u003cp\\u003e6 (23,1)\\u003c/p\\u003e\\n \\u003cp\\u003e4 (15,4)\\u003c/p\\u003e\\n \\u003cp\\u003e1 (3,8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStudy Outcomes\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe median weight-adjusted cumulative morphine dose in the first 48 hours postoperative in the paracetamol group was 5 times lower (79%) than in the morphine group (\\u003cem\\u003eP \\u0026lt; 0.001\\u003c/em\\u003e (Table 4).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThere were no significant differences between groups in median total rescue morphine consumption in the first 48 hours postoperative, proportion of patients receiving \\u0026nbsp;rescue morphine boluses and additional continuous morphine infusions\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 4. Primary and secondary study outcomes\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eOutcome\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003eParacetamol (n=94)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003eMorphine (n=100)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003eP-value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eCumulative morphine consumption, median\\u003c/p\\u003e\\n \\u003cp\\u003e(IQR), mcg/kg*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e145.0\\u003c/p\\u003e\\n \\u003cp\\u003e(115.0-432.5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e692.6\\u003c/p\\u003e\\n \\u003cp\\u003e(532.7- 856.1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eRescue morphine dose total, median\\u003c/p\\u003e\\n \\u003cp\\u003e(IQR), mcg/kg*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e29.4\\u003c/p\\u003e\\n \\u003cp\\u003e(0-45.7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e30.0\\u003c/p\\u003e\\n \\u003cp\\u003e(0-70.9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.38\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003ePatients receiving rescue morphine bolus, n (%)*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e62 (66.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e69 (69.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.76\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003ePatients receiving rescue\\u003c/p\\u003e\\n \\u003cp\\u003emorphine bolus and infusions (n)*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e40(42.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e42 (42.0%)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e1.00\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eComedication (n)*\\u003c/p\\u003e\\n \\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eMidazolam\\u003c/li\\u003e\\n \\u003cli\\u003eLorazepam\\u003c/li\\u003e\\n \\u003cli\\u003ePropofol\\u003c/li\\u003e\\n \\u003cli\\u003eFentanyl\\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e76 (80.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e5 (5.3%)\\u003c/p\\u003e\\n \\u003cp\\u003e26 (27.7%)\\u003c/p\\u003e\\n \\u003cp\\u003e8 (8.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e77 (77%)\\u003c/p\\u003e\\n \\u003cp\\u003e10 (10%)\\u003c/p\\u003e\\n \\u003cp\\u003e19 (19%)\\u003c/p\\u003e\\n \\u003cp\\u003e10 (10%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e0.59\\u003c/p\\u003e\\n \\u003cp\\u003e0.29\\u003c/p\\u003e\\n \\u003cp\\u003e0.18\\u003c/p\\u003e\\n \\u003cp\\u003e0.81\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003ePICU stay in days, median(IQR))\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e3 (2-6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e2 (1-5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eDuration postoperative mechanical ventilation (median, IQR, hours)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e11.8(4.5-45.6)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e15.4(5.7-28.8)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.39\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eReintubation (n, %)*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e3 (3.2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e2 (2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.68\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eAdverse events**\\u003c/p\\u003e\\n \\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eHemodynamic instability (bradycardia or hypotension)\\u003c/li\\u003e\\n \\u003cli\\u003eGastrointestinal (obstruction, obstipation, vomiting)\\u003c/li\\u003e\\n \\u003cli\\u003eDelirium\\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e22 (23.4%)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3 (3.2%)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3 (3.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e28 (28%)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1 (1%)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e5 (5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eNRS ≥ 4 at least once (n,%)*\\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e55 (59%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e62 (62%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.62\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"40.93097913322632%\\\" valign=\\\"top\\\" style=\\\"width: 60.5625%;\\\"\\u003e\\n \\u003cp\\u003eComfort-B scale scores (median, range)*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"17.81701444622793%\\\" valign=\\\"top\\\" style=\\\"width: 14.0625%;\\\"\\u003e\\n \\u003cp\\u003e12(8-22)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.829855537720707%\\\" valign=\\\"top\\\" style=\\\"width: 14.2441%;\\\"\\u003e\\n \\u003cp\\u003e12 (7-20)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.42215088282504%\\\" valign=\\\"top\\\" style=\\\"width: 10.9863%;\\\"\\u003e\\n \\u003cp\\u003e0.05\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eThe median weight-adjusted cumulative morphine consumption in the 140 patients who received the study medication for 48 hours was 135.1 (IQR 115.4-395.5) mcg/kg in the IV paracetamol group vs 701.5 (IQR 562.0-854,8) mcg/kg (p\\u0026lt;0.001) in the continuous morphine group. The rescue morphine consumption was similar in both groups, 29.9 mcg/kg in the IV paracetamol group vs 30 mcg/kg (p= 0.91) in the continuous morphine group. The percentage of patients needing continuous open label morphine was 36% in the IV paracetamol group vs 32% in the continuous morphine group.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePercentage of adverse effects did not significantly differ between treatment groups (Table 4). Hemodynamic instability as predefined occurred was the most frequently adverse effect in both groups; 22 (23%) in the IV paracetamol group versus 28 (28%) in the continuous morphine group (p=0.51).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThree patients in IV paracetamol group were re-intubated versus two patients in the continuous morphine group (p= 0.68).\\u003c/p\\u003e\\n\\u003cp\\u003eOverall median NRS pain scores were 0 (IQR 0-3) vs 0 (IQR 0-5) in the IV paracetamol and continuous morphine group, respectively. The number of patients with one or more NRS scores of 4 or higher was similar in both groups \\u0026nbsp;(Table 4). Non-inferiority analysis of all patients with a NRS of 4 or higher fell within the predefined confidence interval of 20%.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this multi-center RCT, infants below 4 years of age treated with IV paracetamol as primary analgesic after cardiac surgery with CPB received significantly less morphine within the first 48 hours after surgery than did morphine. Their median weight-adjusted morphine dose was 79% lower than that of patients receiving continuous morphine as a primary analgesic.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eSeveral studies have shown opioid-sparing effects of intravenous or rectal paracetamol in children of various ages undergoing various types of non-cardiac surgery.(16, 29-32)\\u0026nbsp;While these earlier studies showed a 15% to 66% reduction in total morphine consumption, this reduction in total morphine dosing in our cohort was higher at 79%. Differences in study populations and study designs may prevent a true comparison of the results. Whether altered PK or PD in our patient cohort plays a role in our findings is unclear.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eMorphine has both sedative and analgesic properties. Interestingly, approximately 80% of our included patients in either group needed additional sedatives. This proportion is higher than that in a similar study by Ceelie et al. in non-cardiac surgery patients, in which between 7.9% and 15.2% of patients received additional midazolam\\u0026nbsp;(16)\\u0026nbsp;and in a similar study by Hoogd et al., in which 37.2% of all patients received additional continuous midazolam.(27)\\u0026nbsp;The discrepancy may be explained by the difference in patient ages between the studies: median five months in our study vs. less than one month in the study by Ceelie et al. (16) Older children may need more sedatives to accept intubation and mechanical ventilation, chest tubes and the hospital environment compared to neonates. De Hoogd et al. used much higher morphine doses compared to our study; \\u0026nbsp;leading to lower use of other sedatives as morphine itself has a sedative effect as well.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eLower or even absent continuous morphine infusions might therefore lead to higher needs for sedatives. We found no difference in midazolam needs between the two study groups, suggesting that sedative needs were not influenced by the morphine infusion. Furthermore, several studies report similar use of midazolam in children following cardiac surgery treated with continuous morphine infusions as found in our study.\\u0026nbsp;(36-38)\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe most common adverse effects of the study drugs were hemodynamic instability which was comparable between groups; 23.4% vs 28.0 % for IV paracetamol and continuous morphine, respectively. Changes in hemodynamic parameters are multifactorial and differentiation between morphine effect or purely cardiac-surgery-related hemodynamic effects is difficult. Adverse effects of IV paracetamol also need to be considered. In a previous study, IV paracetamol was associated with hypotension in 5% of children in the cardiac intensive care unit.(39)\\u0026nbsp;This can partially explain why there is no difference in hemodynamic instability between both study groups.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eReintubation was rare in both groups and could not be attributed to pharmacologic induced hypopnea or apnea. Length of PICU stay as well as time on mechanical ventilation did not differ between groups: this suggests no adverse respiratory effects of the higher morphine exposure in the continuous morphine group. Gastrointestinal side effects as well as withdrawal syndrome or delirium are side effects that might be more prominent after 96 hours after surgery. Since all patients switched to open label morphine and paracetamol after 48 hours, late onset adverse effects could have been masked or missed due to the short follow-up time.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eStrengths\\u003c/p\\u003e\\n\\u003cp\\u003eTo the best of our knowledge, this is the first large randomized controlled trial in children under the age of 4 years undergoing cardiac surgery with CPB, and the first to compare IV paracetamol as a primary analgesic postoperatively with the common practice of administering opioids.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eLimitations\\u003c/p\\u003e\\n\\u003cp\\u003eAbout 30% of patients in either group were switched to open label paracetamol and morphine during the study timeframe. In approximately half of these cases the reason was sustained fever after surgery and the need for IV paracetamol to decrease body temperature. Interestingly, fever episodes were similar in both groups. Changing to open label might have actually increased the morphine consumption in patients in the IV paracetamol group who were switched from placebo to open label morphine within 48 hours, thereby reducing the observed difference between the groups. The need for open label paracetamol due to fever does not reflect inadequate pain management and would not be an issue in open label paracetamol treatment.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTo conclude, administration of intermittent intravenous paracetamol as primary analgesic in children under 4 years of age after cardiac surgery with the use of cardiopulmonary bypass resulted in a substantial reduction of the cumulative morphine consumption in the first 48 hours postoperatively and reduced the need for continuous morphine infusions in almost 60% of all patients treated with IV paracetamol. Considering the similar need for rescue morphine doses and the same median NRS and COMFORT-B scores in both groups, an analgesic treatment protocol incorporating a loading dose of morphine followed by IV paracetamol maintenance doses achieves equally effective postoperative pain relief in these patients independent of diagnosis or type of cardiac surgery.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eIV\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Intravenous\\u003c/p\\u003e\\n\\u003cp\\u003e(P)ICU \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;(Pediatric) Intensive care Units \\u0026nbsp;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNRS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Numeric Rating Scale\\u003c/p\\u003e\\n\\u003cp\\u003eCPB\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Cardiopulmonary Bypass\\u003c/p\\u003e\\n\\u003cp\\u003ePK\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Pharmacokinetics\\u003c/p\\u003e\\n\\u003cp\\u003eALAT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Alanine aminotransferase\\u003c/p\\u003e\\n\\u003cp\\u003eASAT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Aspartate aminotransferase\\u003c/p\\u003e\\n\\u003cp\\u003eECMO\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Extracorporeal Membrane Oxygenation\\u003c/p\\u003e\\n\\u003cp\\u003eNaCL \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Sodium Chloride\\u003c/p\\u003e\\n\\u003cp\\u003eCRF\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Case record form\\u003c/p\\u003e\\n\\u003cp\\u003eCOMFORT B\\u0026nbsp; \\u0026nbsp;\\u0026nbsp;COMFORT Behavior Scale\\u003c/p\\u003e\\n\\u003cp\\u003eSOS-PD\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;SOS-Pediatric Delirium\\u003c/p\\u003e\\n\\u003cp\\u003eRACHS-1\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Risk-Adjusted Classification for Congenital Heart Surgery\\u003c/p\\u003e\\n\\u003cp\\u003ePRISM III\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;The Pediatric Risk of Mortality III\\u003c/p\\u003e\\n\\u003cp\\u003ePELOD 2 \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Pediatric Logistic Organ Dysfunction 2\\u003c/p\\u003e\\n\\u003cp\\u003eDSMB \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Data and Safety Monitoring Board\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cu\\u003eEthics approval and consent to participate\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was approved by the Erasmus MC Medical Ethics Committee and was registered in the Dutch trial registry under the code NTR5448 as well at the Central Committee on Research Involving Human Subjects (NL 53085.078.15), EudraCT (2015\\u0026ndash;001835-20-NL/BE), and clinicaltrials.gov (identifier:\\u0026nbsp;NCT05853263). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eParents or legal guardians of the participating children provided written informed consent prior to any study procedures. The study protocol is published in \\u003cem\\u003eTrials\\u003c/em\\u003e and available online.(17)\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eConsent for publication\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAvailability of data and materials\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eCompeting interests\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that they have no competing interests\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eFunding\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was funded by ZonMw (The Netherlands Organisation for Health Research and Development), \\u0026ldquo;effective, efficient, safer use of medicines\\u0026rdquo; project (project number 836041016), and the Sophia Foundation for Scientific Research (SSWO) (project number S16\\u0026ndash;08). Funders had no role in study design or study proceedings, writing of the report, or the decision to submit the report for publication.\\u003c/p\\u003e\\n\\u003cp\\u003eFunding Greet van den Berghe (ORCID ID: 0000-0002-5320-1362)\\u003c/p\\u003e\\n\\u003cp\\u003eMethusalem Programme from the Flemish Goverment (METH/14/06) and ERC Advanced Grant (AdvG-2017-785809) from the Horizon 2020 Program of the EU.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAuthors\\u0026apos; contributions\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eGZ made substantial contributions to the conception and design of the work, acquisition, analysis and interpretation of data, drafted and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eCR made substantial contributions to acquisition, analysis and interpretation of data, and drafted the work.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eJvR made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eMvD made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eSdW made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eCK made substantial contributions to the conception and design of the work, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eEK made substantial contributions to the conception and design of the work, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eNJ made substantial contributions to the conception and design of the work, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eMK made substantial contributions to the conception and design of the work, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eSM made substantial contributions to acquisition, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eGvdB made substantial contributions to the conception and design of the work, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eRH made substantial contributions to acquisition, analysis and interpretation of data, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eDV made substantial contributions to the conception and design of the work, and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eAB made substantial contributions to the conception and design of the work, analysis and interpretation of data, drafted and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eDT made substantial contributions to the conception and design of the work, analysis and interpretation of data, drafted and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eEW made substantial contributions to the conception and design of the work, acquisition, analysis and interpretation of data, drafted and substantively revised the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors read and approved the final manuscript\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAcknowledgements\\u003c/u\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors would like to acknowledge all medical and support staff from participating hospitals, and in particular the research nurses without whom this study would have been have difficult to execute.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eDolk H, Loane M, Garne E, European Surveillance of Congenital Anomalies Working G. Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005. Circulation. 2011;123(8):841-9.\\u003c/li\\u003e\\n\\u003cli\\u003eZeilmaker-Roest GA, Wildschut ED, van Dijk M, Anderson BJ, Breatnach C, Bogers A, et al. An international survey of management of pain and sedation after paediatric cardiac surgery. BMJ Paediatr Open. 2017;1(1):e000046.\\u003c/li\\u003e\\n\\u003cli\\u003eSmith HAB, Besunder JB, Betters KA, Johnson PN, Srinivasan V, Stormorken A, et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med. 2022;23(2):e74-e110.\\u003c/li\\u003e\\n\\u003cli\\u003eDaverio M, von Borell F, Ramelet AS, Sperotto F, Pokorna P, Brenner S, et al. Pain and sedation management and monitoring in pediatric intensive care units across Europe: an ESPNIC survey. Crit Care. 2022;26(1):88.\\u003c/li\\u003e\\n\\u003cli\\u003eValentine K, Cisco MJ, Lasa JJ, Achuff BJ, Kudchadkar SR, Staveski SL. A survey of current practices in sedation, analgesia, withdrawal, and delirium management in paediatric cardiac ICUs. Cardiol Young. 2023:1-6.\\u003c/li\\u003e\\n\\u003cli\\u003evan Saet A, de Wildt SN, Knibbe CA, Bogers AD, Stolker RJ, Tibboel D. The effect of adult and pediatric cardiopulmonary bypass on pharmacokinetic and pharmacodynamic parameters. Curr Clin Pharmacol. 2013;8(4):297-318.\\u003c/li\\u003e\\n\\u003cli\\u003eFerrari F, Benegni S, Marinari E, Haiberger R, Garisto C, Rizza A, et al. Vancomycin concentrations during cardiopulmonary bypass in pediatric cardiac surgery: a prospective study. Perfusion. 2022;37(6):553-61.\\u003c/li\\u003e\\n\\u003cli\\u003eMian P, Valkenburg AJ, Allegaert K, Koch BCP, Breatnach CV, Knibbe CAJ, et al. Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass. J Clin Pharmacol. 2019;59(6):847-55.\\u003c/li\\u003e\\n\\u003cli\\u003eEgbuta C, Mason KP. Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit. J Clin Med. 2021;10(9).\\u003c/li\\u003e\\n\\u003cli\\u003eBurgart AM, Char D. The opioid crisis should lead pediatric anesthesiologists to a broader vision of opioid stewardship. Paediatr Anaesth. 2019;29(11):1078-80.\\u003c/li\\u003e\\n\\u003cli\\u003eTobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122-32.\\u003c/li\\u003e\\n\\u003cli\\u003eHarris J, Ramelet AS, van Dijk M, Pokorna P, Wielenga J, Tume L, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42(6):972-86.\\u003c/li\\u003e\\n\\u003cli\\u003eda Silva PS, Reis ME, Fonseca TS, Fonseca MC. Opioid and Benzodiazepine Withdrawal Syndrome in PICU Patients: Which Risk Factors Matter? J Addict Med. 2016;10(2):110-6.\\u003c/li\\u003e\\n\\u003cli\\u003eCook SF, Roberts JK, Samiee-Zafarghandy S, Stockmann C, King AD, Deutsch N, et al. Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation. Clin Pharmacokinet. 2016;55(1):107-19.\\u003c/li\\u003e\\n\\u003cli\\u003eMian P, Knibbe CAJ, Calvier EAM, Tibboel D, Allegaert K. Intravenous Paracetamol Dosing Guidelines for Pain Management in (pre)term Neonates Using the Paediatric Study Decision Tree. Curr Pharm Des. 2017;23(38):5839-49.\\u003c/li\\u003e\\n\\u003cli\\u003eCeelie I, de Wildt SN, van Dijk M, van den Berg MMJ, van den Bosch GE, Duivenvoorden HJ, et al. Effect of Intravenous Paracetamol on Postoperative Morphine Requirements in Neonates and Infants Undergoing Major Noncardiac Surgery A Randomized Controlled Trial. Jama-Journal of the American Medical Association. 2013;309(2):149-54.\\u003c/li\\u003e\\n\\u003cli\\u003eZeilmaker-Roest GA, van Rosmalen J, van Dijk M, Koomen E, Jansen NJG, Kneyber MCJ, et al. Intravenous morphine versus intravenous paracetamol after cardiac surgery in neonates and infants: a study protocol for a randomized controlled trial. Trials. 2018;19(1):318.\\u003c/li\\u003e\\n\\u003cli\\u003eGiordano V, Edobor J, Deindl P, Wildner B, Goeral K, Steinbauer P, et al. Pain and Sedation Scales for Neonatal and Pediatric Patients in a Preverbal Stage of Development: A Systematic Review. JAMA Pediatr. 2019;173(12):1186-97.\\u003c/li\\u003e\\n\\u003cli\\u003eIsta E, Te Beest H, van Rosmalen J, de Hoog M, Tibboel D, van Beusekom B, et al. Sophia Observation withdrawal Symptoms-Paediatric Delirium scale: A tool for early screening of delirium in the PICU. Aust Crit Care. 2017.\\u003c/li\\u003e\\n\\u003cli\\u003eCavalcanti PE, Sa MP, Santos CA, Esmeraldo IM, Chaves ML, Lins RF, et al. Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for Cardio- Thoracic Surgery (STS-EACTS) mortality score. Rev Bras Cir Cardiovasc. 2015;30(2):148-58.\\u003c/li\\u003e\\n\\u003cli\\u003ePollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med. 1996;24(5):743-52.\\u003c/li\\u003e\\n\\u003cli\\u003eLeteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F, et al. PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013;41(7):1761-73.\\u003c/li\\u003e\\n\\u003cli\\u003eFormulary DP. [Available from: www.kinderformularium.nl.\\u003c/li\\u003e\\n\\u003cli\\u003eKrekels EH, Tibboel D, de Wildt SN, Ceelie I, Dahan A, van Dijk M, et al. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet. 2014;53(6):553-63.\\u003c/li\\u003e\\n\\u003cli\\u003eWang C, Sadhavisvam S, Krekels EH, Dahan A, Tibboel D, Danhof M, et al. Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. Clin Drug Investig. 2013;33(7):523-34.\\u003c/li\\u003e\\n\\u003cli\\u003eKlingenberg B. A new and improved confidence interval for the Mantel-Haenszel risk difference. Stat Med. 2014;33(17):2968-83.\\u003c/li\\u003e\\n\\u003cli\\u003ede Hoogd S, Goulooze SC, Valkenburg AJ, Krekels EHJ, van Dijk M, Tibboel D, et al. Postoperative breakthrough pain in paediatric cardiac surgery not reduced by increased morphine concentrations. Pediatr Res. 2021;90(6):1201-6.\\u003c/li\\u003e\\n\\u003cli\\u003ePenk JS, Lefaiver CA, Brady CM, Steffensen CM, Wittmayer K. Intermittent Versus Continuous and Intermittent Medications for Pain and Sedation After Pediatric Cardiothoracic Surgery; A Randomized Controlled Trial. Crit Care Med. 2018;46(1):123-9.\\u003c/li\\u003e\\n\\u003cli\\u003eHong JY, Kim WO, Koo BN, Cho JS, Suk EH, Kil HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy. Anesthesiology. 2010;113(3):672-7.\\u003c/li\\u003e\\n\\u003cli\\u003eKorpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. ANESTHESIOLOGY. 1999;91(2):442-7.\\u003c/li\\u003e\\n\\u003cli\\u003eAli S, Sofi K, Dar AQ. Comparison of Intravenous Infusion of Tramadol Alone with Combination of Tramadol and Paracetamol for Postoperative Pain after Major Abdominal Surgery in Children. Anesth Essays Res. 2017;11(2):472-6.\\u003c/li\\u003e\\n\\u003cli\\u003ePatel AK, Gai J, Trujillo-Rivera E, Faruqe F, Kim D, Bost JE, et al. Association of Intravenous Acetaminophen Administration With the Duration of Intravenous Opioid Use Among Hospitalized Pediatric Patients. JAMA Netw Open. 2021;4(12):e2138420.\\u003c/li\\u003e\\n\\u003cli\\u003eHartman ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: A systematic review. Pediatric Critical Care Medicine. 2009;10(2):246-55.\\u003c/li\\u003e\\n\\u003cli\\u003eNasr VG, DiNardo JA. Sedation and Analgesia in Pediatric Cardiac Critical Care. Pediatr Crit Care Med. 2016;17(8 Suppl 1):S225-31.\\u003c/li\\u003e\\n\\u003cli\\u003eWolf AR, Jackman L. Analgesia and sedation after pediatric cardiac surgery. Paediatr Anaesth. 2011;21(5):567-76.\\u003c/li\\u003e\\n\\u003cli\\u003eBorenstein-Levin L, Hochwald O, Ben-Ari J, Dinur G, Littner Y, Eytan D, et al. Same baby, different care: variations in practice between neonatologists and pediatric intensivists. Eur J Pediatr. 2022;181(4):1669-77.\\u003c/li\\u003e\\n\\u003cli\\u003eValkenburg AJ, Goulooze SC, Breatnach CV, Mathot RAA, Tibboel D, van Dijk M, et al. Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study. Pediatr Crit Care Med. 2021;22(4):e259-e69.\\u003c/li\\u003e\\n\\u003cli\\u003eAmula V, Vener DF, Pribble CG, Riegger L, Wilson EC, Shekerdemian LS, et al. Changes in Anesthetic and Postoperative Sedation-Analgesia Practice Associated With Early Extubation Following Infant Cardiac Surgery: Experience From the Pediatric Heart Network Collaborative Learning Study. Pediatr Crit Care Med. 2019;20(10):931-9.\\u003c/li\\u003e\\n\\u003cli\\u003eAchuff BJ, Moffett BS, Acosta S, Lasa JJ, Checchia PA, Rusin CG. Hypotensive Response to IV Acetaminophen in Pediatric Cardiac Patients. Pediatr Crit Care Med. 2019;20(6):527-33.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"critical-care\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"cric\",\"sideBox\":\"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)\",\"snPcode\":\"13054\",\"submissionUrl\":\"https://submission.nature.com/new-submission/13054/3\",\"title\":\"Critical Care\",\"twitterHandle\":\"@Crit_Care\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Morphine, Intravenous Paracetamol, Randomized controlled trial, Analgesia, Child, Congenital heart defects, Congenital cardiac surgery\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3899589/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3899589/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cb\\u003eBackground\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eTo determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0\\u0026ndash;3 years after cardiac surgery with cardiopulmonary bypass.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eMethods\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016 - July 2020. Children aged 0\\u0026ndash;3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if Numeric Rating Scale (NRS) scores for pain exceeded predetermined cutoff values. Primary outcome was weight-adjusted cumulative morphine dose in mcg/kg in the first 48 hours post-operative. For the comparison of the primary outcome between groups, the non-parametric Van Elteren test with stratification by center was used.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eResults\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eIn total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median cumulative morphine consumption in the first 48 hours postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7- 856.1) mcg/kg ; \\u003cem\\u003eP\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.00001\\u003c/em\\u003e). The rescue morphine consumption was similar between the groups (p\\u0026thinsp;=\\u0026thinsp;0.38). Non-inferiority analysis of IV paracetamol showed no differences between groups in number of NRS scores indicating pain (p\\u0026thinsp;=\\u0026thinsp;0.61).\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eConclusions\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eIn children aged 0\\u0026ndash;3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the weight-adjusted cumulative morphine consumption in the first 48 hours after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eTrial Registration\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eClinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-01-31 20:09:06\",\"doi\":\"10.21203/rs.3.rs-3899589/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-02-22T08:52:31+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-02-21T11:25:05+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-02-09T16:42:26+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"03ccb7ce-ef16-4d03-a25b-dbde9b1a9143\",\"date\":\"2024-02-01T20:17:11+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-02-01T17:49:07+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-01-29T01:56:06+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-01-29T01:56:06+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Critical Care\",\"date\":\"2024-01-26T09:43:14+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"critical-care\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"cric\",\"sideBox\":\"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)\",\"snPcode\":\"13054\",\"submissionUrl\":\"https://submission.nature.com/new-submission/13054/3\",\"title\":\"Critical Care\",\"twitterHandle\":\"@Crit_Care\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"2c58a630-d9fa-4778-991f-d4d0a9fc9924\",\"owner\":[],\"postedDate\":\"January 31st, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-05-01T23:57:34+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-3899589\",\"link\":\"https://doi.org/10.1186/s13054-024-04905-3\",\"journal\":{\"identity\":\"critical-care\",\"isVorOnly\":false,\"title\":\"Critical Care\"},\"publishedOn\":\"2024-04-30 23:57:34\",\"publishedOnDateReadable\":\"April 30th, 2024\"},\"versionCreatedAt\":\"2024-01-31 20:09:06\",\"video\":\"\",\"vorDoi\":\"10.1186/s13054-024-04905-3\",\"vorDoiUrl\":\"https://doi.org/10.1186/s13054-024-04905-3\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3899589\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3899589\",\"identity\":\"rs-3899589\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}