In 2016, a multidisciplinary ESPNIC (The European Society of Pediatric and Neonatal Intensive Care) position statement was published guiding professionals in assessing and re-evaluating treatment interventions for pain, distress, inadequate sedation, withdrawal syndrome, and delirium in the pediatric populations for various pain profiles across ages (1, 2). It is widely accepted that neonates can experience pain, and knowledge of the relevance of pain management has increased significantly over the decades (3–5). However, short-term and long-term consequences of pain management approaches remain sparse in extremely low birth weight (ELBW) infants (6–10).

Unfortunately, the treatment of ELBW neonates is still difficult at present, and setting the key endpoints in neonatal analgesic clinical trials is necessary (11, 12). First, validated pain assessment tools are crucial for targeted analgesia. However, out of 65 scores, only 37% were validated for premature neonates, and only one score (the Pain Assessment Tool) for postoperative pain in extremely premature neonates (13). Second, age-appropriate drugs and dose adjustments of analgesic drugs used to adequately treat pain are also important while a still high percentage of analgesic drugs is used in an unlicensed or off-label manner in the intensive care unit (NICU) settings (14). For postoperative pain, in neonates aged between 36 weeks gestational age (GA) and infants <1-year-old, an intermittent intravenous paracetamol dose of 10 mg/kg per 6 h resulted in a significant reduction in opioid use and exposure following non-cardiac major surgery (15).

This is, even more, the case in the specific setting of pain management in ELBW for necrotizing enterocolitis or abdominal surgery, as recently observed by ten Barge et al. (16). In their dataset on 79 preterm cases with necrotizing enterocolitis, the authors concluded that the majority experienced pain, and in some cases, this pain persisted for several hours. Based on a similar concept of using data collected during clinical care within one neonatal intensive care unit (NICU), we performed a comparative analysis and audit of postoperative pain management in ELBW neonates after abdominal surgery.

Consequently, this study aimed to evaluate the unit protocol for postoperative pain management (≤48 h) to achieve postoperative analgesic efficacy goals (e.g., validated pain scores) after major abdominal surgery in ELBW infants. This standardized local approach included the use of single-dose paracetamol as a rescue drug. We hereby documented drug utilization, effective drug dosing (pain scores within the target zone, with emphasis on rescue intravenous paracetamol) as well as safety parameters (e.g., hypotension and/or bradycardia) related to the use of analgesics and sedatives in ELBW neonates.

The main goal of this retrospective study was to generate additional data on the efficacy of paracetamol (effects to reduce postoperative pain) and its safety in ELBW neonates following major abdominal surgery. In this specific setting, and taking the limitations of the small cohort into account, paracetamol rescue medication was associated with less oversedation, suggesting safe postoperative analgesia in this population. Other quality care indicators, such as length of invasive mechanical ventilation or length of hospital stay and long-term outcome according to Bayley II developmental indexes, IVH, PLV, and CLD were similar in both the paracetamol (P) and non-paracetamol (non-P) groups of patients. Additionally, a detailed multimodal analysis focused on identifying deficiencies in pre-existing local postoperative pain management in the neonatal intensive care unit.

According to COMFORTneo, adequate pain control was only partially achieved in patients treated with paracetamol. On the other hand, the non-paracetamol group showed oversedation together along with more severe hypotension. Interestingly, the non-P group was significantly younger at the time of the surgery (median of PNA 8 vs. 29 days, respectively) and more vulnerable as speculated. Based on a local unit protocol, the rescue dose (RD) of intravenous paracetamol was administered to eleven neonates while in two patients, RD was added to analgesic drugs “routinely.” The median (IQR) COMFORTneo before the RD of paracetamol was 12 (9–13.3) within the target range but the decision to give the RD of paracetamol was based on the current situation when the neonate was considered as “uncomfortable” based on the standardized treatment protocol. The median (IQR) COMFORTneo after the RD was 13.9 (11–15), but the median (IQR) time to COMFORTneo reassessment was 5 (4–6) h after RD instead of 30–60 min as recommended in the literature because neonates were considered as “comfortable.” Moreover, no episode of obvious pain after the giving rescue paracetamol at the time of the COMFORT neo reassessment was reported by nurses. Recently published data on ELBW neonates treated for pain are in line with our results and support the need for improvement of neonatal pain management in ELBW neonates (16).

It seems the use of paracetamol in the “rescue” regimen was not significant in its effects to reduce the dose of opiates or the number of other analgesic boluses administered during the study period. The possible explanations may be (1) lack of consistency of caregivers in reassessing pain scores after interventions, as the daily number of assessments was the same between groups; (2) age-related differences in opiate pharmacokinetics; and (3) possible differences in interindividual disease characteristics and developmental changes in pain perception (23). Krekels et al. presented relevant data on a population pharmacokinetic (PK) model for morphine in (pre)term neonates. In their analysis, a similar difference in rescue medication and likely morphine over-exposure was observed in neonates with PNA<10 days. By reducing 50–75% of the routine 10 μg/kg/h infusion rate, steady-state concentrations of morphine and its metabolites were achieved. On contrary, in neonates ≥10 days of postnatal age (PNA), the infusion rate derived from PK modeling was higher than at the traditional dose (24, 25). Age-related changes in PK (e.g., greater distribution volume, lower clearance, higher free fraction of the drug in neonates) have also been known for synthetic opioids such as sufentanil (18, 26, 27). Drug clearance is generally not only driven by maturation but also by non-maturational covariates (e.g., disease-related differences in distribution and drug elimination) (28).

Opiates have been widely used analgesic agents in neonatal intensive care units in the past few decades despite negative short-term side effects and possible long-term neurobehavioral consequences for premature individuals (29–32). In contrast, the information on paracetamol is still more limited, for example, intravenous paracetamol is effective in reducing opioid consumption in term neonates and infants (15, 33, 34). However, there is limited evidence in ELBW neonates, in whom paracetamol is still off-label, for pain, or to treat patent ductus arteriosus (35). Recent studies show that the introduction of intravenous paracetamol as part of a postoperative pain management protocol along with the education of care providers leads to improved quality of care indicators even in premature infants. (e.g., reduction of analgesic and sedative consumption, shortening of mechanical ventilation, and parenteral nutrition) (36–39). Although these studies did not mention the usage of a loading dose of paracetamol. In our limited study population, the use of paracetamol to reduce the opioid dose was ineffective. This was probably due to inappropriate dosing and rescue analgesic medication adjustment which are unlikely to reach steady-state paracetamol concentration (40).

This study was performed to evaluate a standardized approach to postoperative pain (≤48 h) to achieve postoperative analgesic efficacy and safety objectives in ELBW neonates and meant as a baseline study for internal prospective validation of postoperative analgesia conducted in this population. The limitations of this study were, for example, the design of a retrospective observational study, the small sample size, and the initial phase of scoring implementation without an adequate reliability score among the caregivers' evidence. Another limiting factor of a designed postoperative follow-up period could be the amount of medication taken before and during surgery and the possible tolerance to opiates, especially in postnatally older patients. However, the median days of continuous opiate use preoperatively and their dosing did not statistically differ between the two study groups.

Therefore, implementing appropriate age-related dosing of opioids co-administered with intravenous paracetamol, including a loading dose, and setting up an educational program to achieve the best consistency and inter-rater reliability of healthcare professionals in pain assessment methods are the main goals of the prospective study. In addition, supporting parental contributions should be part of daily clinical practice. These interventions are the future direction of our project.

The introduction of intravenous paracetamol as a rescue medication in ELBW neonates after abdominal surgery was safe analgesia, although it did not reduce opiate consumption in the rescue regimen. Prospective validation is needed to optimize postoperative analgesia according to analgesic efficacy and safety goals in this population.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of General University Hospital in Prague (available at https://www.vfn.cz › odbornici › eticka-komise › informace). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

HC contributed to conceptualization, data curation, investigation, methodology, and writing—original draft. LB contributed to formal analysis and visualization. BZ contributed to investigation and resources. KA contributed to supervision and writing—original draft. PP contributed to conceptualization, methodology, project administration, supervision, and writing—original draft. All authors contributed to the article and approved the submitted version.

This work was supported by the Ministry of Health of the Czech Republic [RVO VFN 64165]; and Charles University [UNCE 204064]. PP was supported by an unrestricted research grant of the Intensive Care of the Erasmus MC-Sophia Children's Hospital and Progress Q25.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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