Zeilmaker-Roest G, de Vries-Rink C, van Rosmalen J, van Dijk M, de Wildt SN, Knibbe CAJ, Koomen E, Jansen NJG, Kneyber MCJ, Maebe S, Van den Berghe G, Haghedooren R, Vlasselaers D, Bogers AJJC, Tibboel D, Wildschut ED.
Crit Care. 2024 Apr 30;28(1):143. doi: 10.1186/s13054-024-04905-3. PMID: 38689310 Free PMC article. Clinical Trial.
Take-Home Points
What is already known:
- Opioids as the standard of care: Opioids like morphine have been the standard treatment for managing postoperative pain in children undergoing cardiothoracic surgery, despite known risks of respiratory depression, dependence, and prolonged hospital stays.
- Acetaminophen’s potential: Previous studies have suggested that IV acetaminophen may reduce opioid requirements in various surgical contexts, but evidence in pediatric cardiac surgery has been limited and inconsistent.
What this study adds:
- Significant opioid reduction: This study demonstrates that intermittent IV acetaminophen reduces morphine consumption by 79% in the first 48 hours after surgery without compromising pain relief.
- Comparable safety and efficacy: IV acetaminophen provides similar pain control, safety profiles, and adverse event rates compared to continuous morphine, supporting its use as a primary analgesic in this high-risk patient population.
Commentary by: Dr Lindsey Weidmann, Dr Nick Pratap (Philidelphia, USA)
The Problem: Opioid Dependence in Postoperative Care
Opioids have long been considered the cornerstone of postoperative pain management in the intensive care unit following major pediatric cardiac procedures. Indeed, IV opioids are recommended by a recent clinical practice guideline from the Society for Critical Care Medicine as the primary analgesic for treating moderate to severe pain in critically ill pediatric patients (Smith et al, 2022). However, reliance on opioids comes with significant risks. Common side effects include respiratory depression, gastrointestinal complications like constipation and nausea, and serious concerns about tolerance, dependence, and withdrawal syndromes after medium- to longer-term use. All these issues might be reduced through lower dosing but, on the other hand, inadequately treated pain may have both short-term and long-term harms. Furthermore, a recent study by O’Byrne et al (2024) raises concerns that higher opioid doses administered to infants undergoing cardiac surgery are associated with worse neurodevelopmental outcomes at 2 years of age.
Managing postoperative pain is further complicated by a lack of universally accepted pain management protocols for pediatric patients. Guidelines often default to opioids because of their proven efficacy, but the potential for prolonged ICU stays, delayed recovery, and long-term developmental impacts drives the search for safer alternatives. In recent years, efforts have increasingly focused on multi-modal pain management strategies that reduce opioid exposure while maintaining adequate analgesia.
The Study: Reducing Opioid Use with IV Acetaminophen
Zeilmaker-Roest and colleagues recently published a randomized controlled trial including postoperative ICU patients at four pediatric cardiac units in the Netherlands and Belgium. The research team enrolled 208 infants aged 0–3 years undergoing open heart procedures, ranging from RACHS surgical complexity scores of 1 to 5. The population therefore reflected a wide spectrum of pediatric cardiac surgery patients, including single ventricle palliations and biventricular repairs. Infants were randomized into two groups: one receiving intermittent intravenous acetaminophen (paracetamol in the manuscript, reflecting European nomenclature) and the other receiving continuous morphine infusion for 48 hours following surgery. Each group also received a placebo of the non-study drug to ensure double-blinding. For example, the paracetamol group received an infusion of normal saline to simulate morphine infusion. Both groups received a morphine loading dose of 100 mcg/kg immediately post-surgery to stabilize initial pain. Additional “PRN” doses of morphine could be administered by the blinded healthcare team according to a protocol. IV acetaminophen was dosed according to recommendations in the Netherlands which are slightly lower than the US drug license.
The study was carefully designed as a double-blind, multi-center randomized controlled trial, ensuring high reliability, and minimizing bias. Researchers tracked not only the total morphine consumption but also secondary outcomes such as rescue morphine doses, numeric rating scale (NRS) pain scores, adverse events, and overall ICU length of stay. This comprehensive approach provided a holistic view of postoperative pain management effectiveness.
Key Findings: Effective Pain Relief, Fewer Opioids
The results were striking. Infants in the IV acetaminophen group required five times less morphine than those in the continuous morphine group (median: 145 mcg/kg vs. 692.6 mcg/kg, p < 0.001). Despite this dramatic reduction, the two groups reported similar pain control outcomes, with no statistically significant differences in average pain scores based on the Numeric Rating Scale and COMFORT-B scales.
Importantly, adverse events like respiratory depression, gastrointestinal issues, and hemodynamic instability occurred at comparable rates in both groups, suggesting that IV acetaminophen did not increase safety risks.
Looking Ahead: Shifting the Postoperative Pain Paradigm
The findings suggest that IV acetaminophen could serve as a safe, effective primary analgesic for infants undergoing heart surgery, significantly reducing reliance on opioids. By achieving comparable pain control with far less morphine, IV acetaminophen offers a promising alternative for minimizing opioid exposure in critically ill children.
While the study was limited to a 48-hour postoperative window and conducted in Europe, its implications are well worth considering on the western side of the Atlantic. The potential benefits extend beyond pain relief, possibly reducing ICU length of stay, improving recovery times, and lowering the risk of opioid-related complications. The results could prompt a re-evaluation of pediatric analgesia guidelines, further supporting shifts of clinical practice toward evidence-based, opioid-sparing strategies.
In applying this study’s findings to our patients, additional questions come to mind. First, it is unclear from the manuscript if any children were extubated in the OR prior to ICU admission which is a practice that is common in some US centers. Intubated children typically need more sedation to tolerate an endotracheal tube. We note however similar durations of postoperative mechanical ventilation and reintubation between the control and study arms.
In addition, we note that many trial participants received co-medication with sedative drugs. Again, this additional sedation was balanced between the arms, but included substantial proportions receiving benzodiazepines, also propofol, and ketamine. Dexmedetomidine and clonidine were uncommonly administered in this study, in comparison to preferences for alpha-2 agonists in many North American programs. The fact that both groups received similar amounts of additional post-op sedation is notable since morphine itself has sedating properties. One could hypothesize that those in the morphine infusion group would receive less additional sedation, however this was not the case. This speaks to the non-inferiority of adding acetaminophen to the post-operative pain management regimen.
The findings of the trial’s primary outcome of median weight-adjusted cumulative morphine dose in the first forty-eight postoperative hours deserve further attention. Although this outcome was a sum of both continuous and intermittent morphine dosing, the equivalent infusion rates would be 0.003 and 0.014 mcg/kg/h if infusions were at a constant rate for 48 h in the intermittent acetaminophen and continuous opioid arms which, even for the opioid “heavy” group seems low compared to US practices. This could be related to earlier extubation postoperatively since median durations of mechanical ventilation were 11.8 and 15.4 h, respectively. We note that morphine dosing was guided by a prior pharmacokinetic study from the group (Krekels et al, 2014). Details of the morphine administration protocol are given in the manuscript’s supplementary material online. We point out that a previous quality improvement project, led by one of the current writers, was also able to reduce morphine infusion rates in a US pediatric cardiac ICU through the application of pharmacokinetic principles (Donnellan et al, 2019).
Of note, around a quarter of patients in each study arm were withdrawn during the study period. Most commonly unblinding was for sustained fever, according to a priori criteria designed to ensure that morphine-group patients would not be denied the antipyretic benefits of acetaminophen.
What’s Next?
The next steps for research could involve extending follow-up periods to assess long-term neurodevelopmental outcomes of using IV acetaminophen to spare opioids in pediatric cardiac patients.
Future studies could also explore combinations of IV acetaminophen with other non-opioid analgesics, such as NSAIDs or alpha-2 agonists like dexmedetomidine, to enhance pain control further while minimizing opioid requirements. As hospitals worldwide seek safer, more effective pain management protocols, the adoption of IV acetaminophen as a routine practice could transform postoperative care for the youngest and most vulnerable patients.
References
Donnellan A, Sawyer J, Peach A, Staveski S, Nelson DP, Pratap JN. Reducing exposure to sedative medication for patients in the pediatric cardiac intensive care unit: a quality improvement project. Pediatr Crit Care Med. 2019;20(4), 340-349. DOI: 10.1097/PCC.0000000000001870
Krekels EH, Tibboel D, de Wildt SN, Ceelie I, Dahan A, van Dijk M, Danhof M, Knibbe CA. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet. 2014;53(6):553-63. doi: 10.1007/s40262-014-0135-4.
O’Byrne ML, Baxelbaum K, Tam V, et al. Association of postnatal opioid exposure and 2-year neurodevelopmental outcomes in infants undergoing cardiac surgery. J Am Coll Cardiol. 2024; 84(11):1010-1021. doi:10.1016/j.jacc.2024.06.033
Smith HA, 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):e74-110.
