Pharmacokinetics (PK) of intravenous acetaminophen has not been assessed in preterm neonates with hemodynamically significant patent ductus arteriosus (PDA). Moreover, there is a lack of data evaluating the association between PK and pharmacodynamics (PD) of acetaminophen in hemodynamically significant PDA. Hence, we performed a population PK-PD modeling of acetaminophen in preterm neonates with hemodynamically significant PDA.

A prospective, observational study was carried out in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen (15 mg/kg six hourly) for maximum of nine days. The diameter of the ductus arteriosus was measured using General Electric Vivid 7® (echocardiography) and was the PD measure. The PK-PD modeling was performed using Monolix 2019R2. We performed Monte Carlo (MC) simulations to determine the probability of ductus arteriosus closure from first to the ninth day of acetaminophen treatment.

Fifty-five neonates were recruited. A one-compartment model with first-order elimination described well the PK of acetaminophen. Clearance (CL) and volume of distribution (Vd) for typical neonate weighing 0.98 kg was 0.0452 L/h and 1.18 L, respectively. A combination of an Imax model with effect compartment and an exponential disease progression model described well the PD of acetaminophen. The average baseline diameter of the ductus arteriosus (E0) was 2.53 mm while IC₅₀ was 0.477 µg/mL. The disease progression rate constant (Kprog) and effect compartment transfer rate constant (ke0) were 0.00425 h^-1 and 0.000103 h^-1, respectively. MC simulations of the current dosing regimen revealed a probability of 73.7% ductus arteriosus closure compared to 83.8% with 20 mg/kg six hourly dose.

The PK-PD model developed can be used for dosing acetaminophen in premature neonates with hemodynamically significant PDA. Intravenous dose of 20 mg/kg intravenously every six hours is likely to provide a better therapeutic effect than the existing dosing regimen.

Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management.

The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant.

The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables.

Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Neonatal intensive care unit (NICU) nurses require knowledge and skill to meet the unique needs of infants and families. Increasingly, principles of palliative care are being integrated into the NICU setting to improve the quality of care.

The purpose of this article is to describe the efforts of the End-of-Life Nursing Education Consortium (ELNEC) project and its Pediatric Curriculum, which began in 2003 to provide this education, and to also describe efforts by nurses to implement the training into their practice settings.

The ELNEC Pediatric Palliative Care (ELNEC-PPC) project is a train-the-trainer educational program and evidence-based curriculum.

Participants attend a course or receive online training and then apply the education to implement improved practices in areas such as symptom management, care at the time of death, and bereavement support for families.

Experiences with ELNEC-PPC have demonstrated that nurses can implement the curriculum to improve care.

Continued attention to palliative care in this setting is needed, and future research is needed to evaluate the outcomes of this education and practice change.

Pain control is an important ethical issue to be considered and constitutes the basis of treatment in premature and term newborns. The inadequacy of pain control in these infants in neonatal intensive care units leads to neurodevelopmental and behavioral problems in the long term. For this reason, it is extremely important to raise awareness of the presence of pain in newborn infants, to reduce invasive procedures applied to infants as much as possible, and to minimize pain with non-pharmacologic or pharmacologic treatments when it is inevitable.

Inadequate pain management but also inappropriate use of analgesics in early infancy has negative effects on neurodevelopmental outcome. As a consequence, neonatal pain management is still in search for the Holy Grail. At best, effective pain management is based on prevention, assessment, and treatment followed by a re-assessment of the pain to determine if additional treatment is still necessary. Unfortunately, epidemiological observations suggest that neonates are undergoing painful procedures very frequently, unveiling the need for effective preventive, non-pharmacological strategies. In addition, assessment is still based on validated, multimodal, but subjective pain assessment tools. Finally, in neonatal intensive care units, there is a shift in clinical practices (e.g., shorter intubation and ventilation), and this necessitates the development and validation of new pharmacological treatment modalities. To illustrate this, a shift in the use of opioids to paracetamol has occurred and short-acting agents (remifentanil, propofol) are more commonly administered to neonates. In addition to these new modalities and as part of a more advanced approach of the developmental pharmacology of analgesics, pharmacogenetics also emerged as a tool for precision medicine in neonates. To assure further improvement of neonatal pain management the integration of pharmacogenetics with the usual covariates like weight, age and/or disease characteristics is needed.

Pain from skin penetrating procedures (procedural pain) during infancy in the neonatal intensive care unit (NICU) may result in changes of nociceptive sensitivity in later life. This supports the need for pain management during such vulnerable periods in life. This study, therefore, analyses the short- and long-term consequences of neonatal paracetamol (acetaminophen) treatment on pain behaviour in an experimental rat model of neonatal procedural pain.

A repetitive needle-prick model was used, in which neonatal rats received four needle pricks into the left hind paw per day from postnatal day 0 to day 7 (P0-P7). Paracetamol (50 mg/kg/day s.c.) was administered daily (P0-P7), and sensitivity to mechanical stimuli was compared with a needle-prick/saline-treated group and to a tactile control group. At 8 weeks of age, all animals underwent an ipsilateral paw-incision, modelling postoperative pain, and the duration of hypersensitivity was assessed.

Neonatal paracetamol administration had no effect upon short-term mechanical hypersensitivity during the first postnatal week or upon long-term baseline sensitivity from 3 to 8 weeks. However, neonatal paracetamol administration significantly reduced the postoperative mechanical hypersensitivity in young adults, caused by repetitive needle pricking.

Paracetamol administration during neonatal procedural pain does not alter short-term or long-term effects on mechanical sensitivity, but does reduce the duration of increased postoperative mechanical hypersensitivity in a clinically relevant neonatal procedural pain model.

Paracetamol can be used safely in neonatal rats. Neonatal paracetamol treatment had no effect upon short-term mechanical hypersensitivity during the first postnatal week, nor upon long-term baseline sensitivity from 3 to 8 weeks. Paracetamol treatment during the first postnatal week significantly reduced the postoperative mechanical hypersensitivity in young adult rats.

The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset.

Nonlinear mixed-effects models were constructed from paracetamol concentration-time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors.

The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1-14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1-28.1).

Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.

Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks' gestation, 45 mg/kg/d in preterm infants of 34 weeks' gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted.

As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns.

There remains a need for alternative medical treatments for patent ductus arteriosus (PDA) closure in extreme preterm neonates because of therapeutic failure and adverse effects associated with non-selective cyclo-oxygenase inhibitors. Reports of an association between paracetamol exposure and PDA closure in a limited number of extreme preterm neonates have been published. However, causality cannot be taken for granted because a link between the current knowledge of the clinical pharmacology of paracetamol and (patho)physiology of ductal closure is not known. In contrast to non-selective cyclo-oxygenase inhibitors, paracetamol has limited effects at peripheral sites, is a poor antithrombotic and anti-inflammatory drug and exerts its effects primarily within the central nervous system. Although paracetamol appears an effective and safe analgesic in term and near term neonates, its effectiveness and safety for PDA closure are uncertain because the drug is administered in high doses and there remain a limited number of observations in this specific subpopulation so far. Prospective comparative trials are reasonable and are urgently needed to establish both the effectiveness and safety data of paracetamol when used for this indication.

Inadequate management of pain in early human life contributes to impaired neurodevelopmental outcome and alters pain thresholds, pain or stress-related behavior and physiological responses. However, there are also emerging animal experimental data on the impact of exposure to analgo-sedatives on the incidence and extent of neuro-apoptosis. Since this association has also been suggested in humans, the pharmacological treatment of neonatal pain is in search of a new equipoise since these 'conflicting' observations are the main drivers to further reconsider our current treatment regimens. This review focuses on new data concerning clinical pharmacology of morphine, followed by data on more recently introduced opioids like remifentanil and tramadol, locoregional anesthesia and minimally invasive techniques in neonates, and finally with data on intravenous paracetamol. Since the available data are still incomplete, priorities for both clinical management and future research will be proposed.

To assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief.

Randomized, double-blind placebo-controlled trial in 3 Swiss university hospitals. Term and near-term infants (n = 123) delivered by forceps or vacuum were randomized to receive 2 suppositories with paracetamol (60/80/100 mg in infants <3000 g/3000-4000 g/>4000 g birth weight) or placebo at 2 and 8 hours of life. Pain and discomfort during the first 24 hours was assessed by the échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] score. The response to the subsequent heel prick for metabolic screening at days 2-3 of life was investigated by the Bernese Pain Scale for Neonates (BPSN).

The échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] pain scale ratings after assisted vaginal delivery were low and declined within 4 hours of life (P < .01) irrespective of paracetamol administration. At 2-3 days of life, BPSN scores after heel prick were significantly higher in infants who had received paracetamol, compared with controls, both when BPSN were scored by nurses at the bedside (median [IQR] 4 [2-7] vs 2 [0-5], P = .017) or off-site from videos (4 [2-8] vs 2 [1-7], P = .04). Thirty-five of 62 (57%) infants treated with paracetamol cried after heel prick, compared with 25 of 61 (41%) controls (P = .086).

Infants born by assisted vaginal delivery have low pain scores in the immediate period after birth. Paracetamol given to newborns soon after birth may aggravate a subsequent stress response.

We suggested a loading dose (20 mg · kg(-1) ) followed by 10 mg · kg(-1) q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg · l(-1) in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20 mg · kg(-1) ) were used to validate this effect compartment concentration.

Pain scores (Leuven Neonatal Pain Score, LNPS, 0-14) before and 0.5, 1, 2, 3, 4, 5, and 6 h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO, www.clinicaltrials.gov, NCT00969176) were collected. Trends were analyzed using repeated measures anova. An E(max) model with a delayed response compartment was fitted to data using population modeling.

Nineteen of 60 neonates included in the PARANEO study received monotherapy with IV paracetamol to treat mild to moderate pain (e.g., alprostadil administration, delivery related trauma). Using repeated measures anova, there was a trend (P = 0.02) for lower pain scores within 30 min after administration, with a slight increase in pain scores from 5 to 6 h. An E(max) model had a maximum effect of 4.15 pain units, an EC(50) of 2.07 mg · l(-1). Equilibration halftime (T(1/2) keo) was 1.58 h.

Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10 mg · l(-1) (loading dose of 20 mg · kg(-1) ) is associated with a pain score reduction of 3.4 LNPS units. This analysis suggests a similar paracetamol effect compartment concentration in neonates compared to children.

This article describes developments in pain assessment in critically ill neonates and infants during the last 5 to 6 years. Pain assessment instruments show a redundancy of items and a lack of profound psychometric background. Although most research focuses primarily on acute pain, in clinical practice there is also the challenge of assessing prolonged and/or persisting pain. The effectiveness of pain assessment is still a matter of debate and has recently been challenged as a primary end point in analgesia-related trials. Integration of observation of behavior with reliable and specific neurobiology-based parameters remains a challenge.

Effective analgesia in neonates is still hampered owing to a lack of data on pharmacokinetics and pharmacodynamics of analgesics. In this article, the consecutive steps taken to document aspects of disposition (pharmacokinetics and metabolism) and safety (hepatic tolerance, hemodynamic stability and effects on body temperature) during exposure to intravenous acetaminophen in neonates are summarized. Based on these data, dosing suggestions were formulated. However, we have to be aware that such dosing suggestions are - at present - without any validated pharmacodynamic correlates since the applicability of a fixed acetaminophen target concentration (10 mg·l(-1)) in neonates of different subpopulations remains to be documented. In addition, the number of observations in extreme preterm neonates is limited. Finally, epidemiological data suggest a link between perinatal acetaminophen exposure and an increased risk to developing asthma. Consequently, well designed and appropriately powered pharmacodynamic studies in neonates are urgently required, with specific emphasis on extreme preterm neonates.

Over the last 25 years, pediatric care has changed dramatically with increased survival after premature birth, more complex care, better outcomes, and reduced mortality. There is a better understanding of how pain pathways and receptor systems develop and also how to assess pain at different stages of development. The myth that children do not feel pain has been comprehensively dispelled. Safe analgesic dose regimens for neonates, infants, and children have been developed based upon a better understanding of developmental pharmacokinetics and pharmacodynamics. It is a myth that pain in children cannot be prevented or treated safely and effectively because of the risks of adverse effects and addiction. Large-scale prospective audits have clarified the safety profile and risk-benefit balance for different techniques. There is now a substantial evidence base supporting many techniques of postoperative and procedural pain management for all age-groups of children. Guidelines based upon systematic review of this evidence have been published and updated, but the real challenge is in implementation of accurate pain assessment and safe, effective pain management comprehensively to all children whatever the procedure, clinical setting, developmental stage of the child, or comorbidities. In developed countries, these are core topics in the education of all doctors and nurses who care for children, and they are integrated into clinical practice by acute pediatric pain teams for most hospitals. However, it is disappointing that many country's healthcare systems do not give pediatric pain management a priority and in many parts of the world there are no analgesics available. So pain-free healthcare is sadly lacking in many hospitals. My hope is that the current knowledge can be used more effectively to relieve the unnecessary suffering of children in the 21st century.