Worldwide, > 380 million children and adolescents are overweight or obese, including 41 million children aged < 5 years. Obesity can change the pharmacokinetic properties of drugs by altering their distribution, metabolism, and elimination. Thus, children who are overweight or obese are at increased risk for receiving inappropriate doses of commonly used drugs, which can result in treatment failure, adverse events, and/or drug toxicity. This review analyzes available data on paracetamol dosing for pain and fever in children and adolescents who are overweight or obese to identify gaps and challenges in optimal dosing strategies. Literature searches using Medline, Embase, and ClinicalTrials.gov were conducted to identify English-language articles reporting paracetamol pharmacokinetics, dosing practices, and guidelines in children and adolescents who are overweight or obese. Of 24 relevant studies identified, 20 were specific to overweight/obese individuals and 15 were specific to children and/or adolescents. Data on paracetamol pharmacokinetics in children and adolescents who are overweight or obese are lacking, and there is no high-quality evidence to guide paracetamol prescribing practices in these patients. Adult data have been extrapolated to pediatric populations; however, extrapolation does not address differences in paracetamol metabolism in adults versus children; the efficacy and safety effects of such differences are unknown. Given the growing worldwide prevalence of obesity in children and adolescents and the likelihood that paracetamol use in this population will increase accordingly, obesity-specific pediatric dosing guidelines for paracetamol are urgently needed. High-quality research is necessary to inform such guidelines.

While postoperative pain management was shown to reduce unwanted physiological and emotional outcomes, pediatric postoperative pain management remains suboptimal. Medical-clowns were shown to be beneficial in many medical contexts including reduction of stress, anxiety and pain. This study was set to assess the effectiveness of medical-clowns on pediatric postoperative pain reduction. Children age 4 or above, planned for elective hernia repair surgery were recruited. Children were randomly divided to a control or medicalclown escorted groups. Demographical and clinical data were collected using questionnaires and electronic sheets. Children escorted by clowns reported lower levels of pain upon admittance, discharge and 12- hours post-surgery. Statistically significant reduction of parental distress and significantly higher serum cortisol levels were observed in the clown-therapy group. Although small, our study supports the possibility that preoperative medical-clown therapy might be a cheap, safe and yet beneficial method for postoperative pain reduction.

Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post-cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement.

This is a prospective, multi-center, randomized controlled trial at four level-3 pediatric intensive care units (ICUs) in the Netherlands and Belgium. Children who are 0-36 months old will be randomly assigned to receive either intermittent IV paracetamol or continuous IV morphine up to 48 h post-operatively. Morphine will be available as rescue medication for both groups. Validated pain and sedation assessment tools will be used to monitor patients. The sample size (n = 208, 104 per arm) was calculated in order to detect a 30% reduction in morphine dose; two-sided significance level was 5% and power was 95%.

This study will focus on the reduction, or replacement, of morphine by IV paracetamol in children (0-36 months old) after cardiac surgery. The results of this study will form the basis of a new pain management algorithm and will be implemented at the participating ICUs, resulting in an evidence-based guideline on post-operative pain after cardiac surgery in infants who are 0-36 months old.

Dutch Trial Registry ( www.trialregister.nl ): NTR5448 on September 1, 2015. Institutional review board approval (MEC2015-646), current protocol version: July 3, 2017.

Postoperative pain can cause physiological distress, postoperative complications, and extended lengths of hospitalized stay. In children, management of postoperative pain is still recognized as being inadequate.

The aim of this trial was to investigate the effects of intraperitoneal ropivacaine on postoperative pain, and recovery of bowel function and emetic events after laparoscopic herniorrhaphy in toddlers.

Seventy-six children aged from 9 months to 3 years were recruited between August 2013 and June 2014 at Tongji Hospital and randomly assigned into two groups. One group received intraperitoneal ropivacaine right before surgery and the control group received intraperitoneal saline. A standard combined general anesthesia procedure was performed under regular monitoring. Postoperative pain was assessed by the FLACC scale. Postoperative analgesic consumption, time to flatus, time to first stool, and postoperative emetic events were also recorded.

When compared with the control group, children who received intraperitoneal ropivacaine experienced less pain 0-4 h after surgery [P < 0.001, difference in median FLACC (95% CI) for 2 h time point is 2.00 (0.87-3.13), for 4 h time point is 1.00 (0.55-1.45)]. In addition, the number of toddlers who received analgesia 0-24 h after surgery in the ropivacaine group was lower than that in the control group [P < 0.001, difference in proportions (95% CI) is 0.575 (0.3865-0.7638)]. Compared with the control group, time to flatus in ropivacaine group was also much shorter [21.1 h vs 16.7 h, P = 0.04, difference in mean (95% CI) is 4.4 (1.49-7.28)], and the time to first stool after surgery was earlier in the ropivacaine group [30.7 h vs 25.6 h, P = 0.003, difference in mean (95% CI) is 5.1 (1.78-8.45)]. Furthermore, the incidence of emetic events in the ropivacaine group was significantly lower than the control group [32.4% vs 11.1%, P = 0.03, difference in proportions (95% CI) is 0.212 (0.0246-0.4002)].

The present results indicate that intraperitoneal ropivacaine reduces early postoperative pain and improves recovery after laparoscopic herniorrhaphy in toddlers. Therefore, IPLA is a good stratagem for postoperative pain management after laparoscopic surgery in toddlers.

Preemptive analgesia is an anti-nociceptive treatment that starts before surgery and prevents the establishment of central sensitization. Whether preemptive analgesia is more effective than conventional regimens for managing postoperative pain remains controversial. This study evaluated the efficacy of intravenous preemptive analgesia for acute postoperative pain control in pediatric patients.

In this prospective randomized controlled trial, 51 children aged 3-7 years, scheduled for corrective osteotomy were randomized into control (group C) or preemptive (group P) group. Both groups received standardized general anesthesia, including intravenous patient-controlled analgesia (IV-PCA) with fentanyl, which was started before skin incision in group P or 5 min thereafter in group C. IV-PCA data, pain scores using verbal rating scale (VRS) and Wong-Baker FACES(®) pain rating scale (WBFS), emergence agitation score (EAS) using the Pediatric Anesthesia Emergence Delirium (PAED) scale, analgesic requirements, and complications were recorded.

The primary outcome, pain score at postoperative 1 h, showed no difference between the groups. Both groups did not demonstrate emergence agitation (PAED cutoff value ≥ 12), although the EAS at admission to the postanesthetic care unit (PACU) was lower in group P than in group C (P = 0.002; mean difference 4.85, 95% CI 1.97-7.73). There were no differences in the delivered volume of IV-PCA, frequency of pushing the IV-PCA button, effective push attempts, VRS, WBFS, EAS at discharge from the PACU, additional analgesic requirements, and complications.

Preemptive analgesia using IV-PCA with fentanyl showed no significant advantages for postoperative analgesia after corrective osteotomy in pediatric patients.

The effect of a single-dose systemic acetaminophen to treat postoperative pain has been previously quantified, but the effect of systemic acetaminophen to prevent postoperative pain is currently not well defined. The preventive analgesic effect of acetaminophen has yet to be quantified in a meta-analysis. The objective of the current investigation was to evaluate the effect of a single preventive dose of systemic acetaminophen on postoperative pain outcomes.

A wide search was performed to identify randomized controlled trials that evaluated the effects of a single dose of systemic acetaminophen on pain outcomes in a large variety of surgical procedures. Meta-analysis was performed using a random-effect model.

Eleven randomized clinical trials evaluating 740 patients were included in the analysis. The weighted mean difference (95% confidence interval [CI]) of the combined effects favored acetaminophen over control for early pain at rest (≤4 h, -1.1 (-2.0 to -0.2)) and early pain at movement (24 h, -1.9 (-2.8 to -1.0)) Postoperative opioid consumption was decreased in the systemic acetaminophen group compared with control. Weighted mean difference (95% CI) of -9.7 (-13.0 to -6.4) mg morphine intravenous equivalents systemic acetaminophen also reduced postoperative nausea and vomiting compared with control, odds ratio (95% CI) of 0.25 (0.13 to 0.47), numbers needed to treat (95% CI)=3.3 (2.3 to 5.9).

Systemic acetaminophen, when used as a single-dose preventive regimen, is an effective intervention to reduce postoperative pain. It also reduces postoperative nausea and/or vomiting. Doses >1 g were not associated with greater reduction in pain outcomes.

To estimate the valnemulin pharmacokinetic profile in a swine population and to assess a dosage regimen for increasing the likelihood of optimization. This study was, respectively, performed in 22 sows culled by p.o. administration and in 80 growing-finishing pigs by i.v. administration at a single dose of 10 mg/kg to develop a population pharmacokinetic model and Monte Carlo simulation. The relationships among the plasma concentration, dose, and time of valnemulin in pigs were illustrated as C(i,v) = X(0 )(8.4191 × 10(-4) × e(-0.2371t) + 1.2788 × 10(-5) × e(-0.0069t)) after i.v. and C(p.o) = X(0) (-8.4964 × 10(-4) × e(-0.5840t) + 8.4195 × e(-0.2371t) + 7.6869 × 10(-6) × e(-0.0069t)) after p.o. Monte Carlo simulation showed that T(>MIC) was more than 24 h when a single daily dosage at 13.5 mg/kg BW in pigs was administrated by p.o., and MIC was 0.031 mg/L. It was concluded that the current dosage regimen at 10-12 mg/kg BW led to valnemulin underexposure if the MIC was more than 0.031 mg/L and could increase the risk of treatment failure and/or drug resistance.

Many factors contribute to suboptimal pain management in children. Current evidence suggests that severe pain in children has significant long-lasting effects, even more so than in adults. In particular, recent evidence suggests a lack of optimal postoperative pain management in children, especially following ambulatory surgery. This review provides simple guidelines for the management of postoperative pain in children. It discusses the long-term effects of severe pain and how to evaluate pain in both healthy and neurologically impaired children, including neonates. Currently available treatment options are discussed with reference to the efficacy and side effects of opioid and non-opioid and regional analgesic techniques. The impact of preoperative anxiety on postoperative pain, and the efficacy of some nonpharmacological techniques such as hypnosis or distraction, are also discussed. Finally, basic organizational strategies are described, aiming to promote safer and more efficient postoperative pain management in children.

In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific focus on clearance. Concentration-time data obtained in 220 neonates (post-natal age 1-76 days, gestational age 27-42 weeks), infants (0.11-1.33 yrs), children (2-7 yrs) and adults (19-34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent were tested. Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight-dependent exponent k was identified (CLi  = CLp  × (BW/70)(k) ). The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2 kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age-range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges.

The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults.

Extracorporeal membrane oxygenation (ECMO) is a life support system used as a bridge to transplantation in critically ill patients who suffer from acute respiratory or cardiac failure with resultant hypoxemia and tissue hypoxia. This is not amendable to conventional support intervention. Previous studies have shown significant drug losses in the components of an ECMO circuit, leading to decreased plasma drug levels. An in vitro study was conducted to determine: (1) changes in intravenous acetaminophen levels over time and (2) changes in concentration observed between different sites of the ECMO circuit. A single bolus dose of intravenous (IV) acetaminophen was injected into a standard blood-primed ECMO circuit. Plasma drug concentrations in the circuit were then measured at specific time points at three different locations to determine concentrations of the drug at time 0, 15, 30, 60, 240 and 360 minutes. The three samples were drawn pre- and post-membrane oxygenator and the polyvinyl chloride (PVC) tubing. A second bolus dose was administered 24 hours after the first in order to compare "new" and "old" circuits. This entire process was repeated a total of three times. The results show that acetaminophen concentrations do not change significantly over time, with consistent levels seen in both new and old circuits (N=9). Average old circuit concentrations were approximately two times greater than the average new circuit concentrations after the circuit was re-dosed at 24 hours. Drug sequestration in the circuit was not significant in any of the three sites measured. It appears that, while acetaminophen levels remain relatively constant over a six hour period, dosing adjustments may be required for use in a circuit beyond the initial 24 hour period, depending on physiologic clearance of the drug. Assuming a six-hour dosing interval, levels should remain constant.