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The editorial discusses the potential of remimazolam as a competitor to propofol in pediatric anesthesia. While a recent study found remimazolam to be well-tolerated and non-inferior to propofol in children, further research is needed to fully understand its pharmacological effects in pediatric patients. The editorial emphasizes the importance of pharmacokinetic-pharmacodynamic modeling and collaboration between pharmaceutical companies and clinicians to advance pediatric anesthesia. Safety concerns, drug interactions, and the need for more informative studies are highlighted as essential considerations for the successful development of remimazolam in pediatric anesthesia. [Extracted from the article]

The protease inhibitor, ritonavir, is a strong inhibitor of CYP 3A. The drug is used for management of the human immunovirus and is currently part of an oral antiviral drug combination (nirmatrelvir–ritonavir) for the early treatment of SARS‐2 COVID‐19‐positive patients aged 12 years and over who have recognized comorbidities. The CYP 3A enzyme system is responsible for clearance of numerous drugs used in anesthesia (e.g., alfentanil, fentanyl, methadone, rocuronium, bupivacaine, midazolam, ketamine). Ritonavir will have an impact on drug clearances that are dependent on ritonavir concentration, anesthesia drug intrinsic hepatic clearance, metabolic pathways, concentration‐response relationship, and route of administration. Drugs with a steep concentration‐response relationship (ketamine, midazolam, rocuronium) are mostly affected because small changes in concentration have major changes in effect response. An increase in midazolam concentration is observed after oral administration because CYP 3A in the gastrointestinal wall is inhibited, causing a large increase in relative bioavailability. Fentanyl infusion may be associated with a modest increase in plasma concentration and effect, but the large between subject variability of pharmacokinetic and pharmacodynamic concentration changes suggests it will have little impact on an individual patient, especially when used with adverse effect monitoring. It has been proposed that drugs that have no or only a small metabolic pathway involving the CYP 3A enzyme be used during anesthesia, for example, propofol, atracurium, remifentanil, and the volatile agents. That anesthesia approach denies children of drugs with considerable value. It is better that the inhibitory changes in clearance of these drugs are understood so that rational drug choices can be made to tailor drug use to the individual patient. Altered drug dose, anticipation of duration of effect, timing of administration, use of reversal agents and perioperative monitoring would better behoove children undergoing anesthesia. [ABSTRACT FROM AUTHOR]

Pharmacokinetic‐pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure‐response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure‐response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6‐monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time‐concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg−1 was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 μg.L−1 can be achieved by a diamorphine intravenous infusion in neonates 14 μg.kg−1.h−1, in a 5‐year‐old child 42 μg.kg−1.h−1 and in an 15 year‐old‐adolescent 33 μg.kg−1.h−1. [ABSTRACT FROM AUTHOR]

Background: Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified. Methods: Pooled oxycodone time‐concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed‐effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory‐based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A maturation function described the increase in clearance in neonates and infants. Results: There were 237 subjects (24 weeks postmenstrual age to 75 years; 0.44–110 kg) providing 1317 plasma concentrations. A three‐compartment model with first‐order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h−1.70 kg−1 (CV 71%); intercompartmental clearances (Q2) 220 L.h−1.70 kg−1 (CV 64%); Q3 1.45 L.h−1.70 kg−1; volume of distribution in the central compartment (V1) 98.2 L.70 kg−1 (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70 kg−1 (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70 kg−1. Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (TABS) were: 1.1 minutes for intramuscular, 70 minutes for epidural, 82 minutes for nasogastric, and 159.6 minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7 minutes. Conclusions: Clearance matured with age; 8% of the typical adult value at 24 weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat‐free mass. [ABSTRACT FROM AUTHOR]

Background: Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals. Methods: We assumed a target concentration of 35 mcg.L−1 (acceptable range ±20%) to be associated with adequate analgesia without increased risk of adverse effects from respiratory depression. Pharmacokinetic simulation was used to estimate dose in neonates through to obese adults given intravenous or parenteral oxycodone. Results: There were 84% of simulated oxycodone concentrations within the acceptable range during maintenance dosing. Variability around the simulated target concentration decreased with age. The maturation of oxycodone clearance is reflected in changes to context‐sensitive halftime where clearance is immature in neonates compared with older children and adults. The intravenous loading and maintenance doses for a typical 5‐year‐old child are 100 mcg.kg−1 and 33 mcg.kg−1.h−1. In a typical adult, the loading dose is 100 mcg.kg−1 and maintenance dose 23 mcg.kg−1.h−1. Conclusion: Simulation was used to suggest loading and maintenance doses to attain an oxycodone concentration of 35 mcg.L−1 predicted in adults. Although the covariates age and weight contribute 92% variability for clearance, there remains variability accounting for 16% of concentrations outside the target range. Duration of analgesic effect after ceasing infusion is anticipated to be longer in neonates where context‐sensitive halftime is greater than older children and adults. [ABSTRACT FROM AUTHOR]

Background: Clonidine is used off‐label in children but only limited pediatric pharmacokinetic data are available for intravenously administered clonidine. Objectives: To determine pharmacokinetic parameter estimates of clonidine in healthy children undergoing surgery and to investigate age‐related differences. Furthermore, to investigate possible pharmacokinetic differences of clonidine between this group of children and a cohort with cardiac diseases. Methods: In a randomized placebo‐controlled trial (The PREVENT AGITATION trial), blood samples for clonidine pharmacokinetic analysis were collected in a proportion of the enrolled patients. Healthy children with ASA score 1‐2 in the age‐groups 1 to <2 years and 2‐5 years were randomized for blood sampling. Clonidine was administered as a single intravenous bolus of 3 µg/kg intraoperatively. Blood samples were drawn at baseline, 5, 10, 15, 30, 60 minutes after dosing and additionally every hour until discharge from the PACU. Clonidine analysis was performed on liquid chromatography‐mass spectrometry. Results: Data form eighteen children were available for pharmacokinetic analysis (ASA I; male/female: 17/1; age: 1‐5 years; weight 8.7‐24 kg). Population parameter estimates for the 2‐compartment model were similar to previous published data for children who underwent cardiac surgery. A pooled analysis including data from 59 children indicated clearance of 14.4 L h−1 70 kg−1 and volume of distribution of 192.6 L 70 kg−1. No age‐related pharmacokinetic differences and no difference in time from administration of study medication to awakening were found. Children 1 to <2 years had a shorter PACU stay than children 2‐5 years (mean difference 17% 95% CI:3%‐34%, P =.02). Conclusion: Pharmacokinetic parameter estimates were similar for children undergoing general surgery and cardiac surgery given a single dose of intravenous clonidine. These results indicated that no dose reduction is needed in children aged 1 to <2 years compared with those 2‐5 years, which was supported by pharmacodynamic observations. [ABSTRACT FROM AUTHOR]

Background: Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood. Methods: Published clearance estimates from different aged patients determined after administration from time‐concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed‐effects models. A target concentration strategy was used to estimate maintenance dose at different ages. Results: There were three publications reporting an estimate of individual clearance estimates in premature neonates, three reporting population clearances in infants, 11 in children 2‐15 years (1 with individual and 9 with population clearances), and 13 adult studies (1 with individual and 12 with population clearances). Clearance maturation, standardized to a 70 kg person was described using the Hill equation. Mature clearance was 3.81 (CV 15.5%, 95%CI 3.72, 3.92) L/h/70 kg. The maturation half‐time was 36.8 (CV 9.2%, 95%CI 34.7, 40.9) weeks postmenstrual age and the Hill coefficient 11.5 (95%CI 8.1, 15). A target effect of four units (visual analogue scale 0‐10) correlated with an effect site concentration of 6.3 mg/L: a concentration achieved at trough after 400 mg 8 hourly in adults. Conclusion: Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. Maturation of ibuprofen clearance was rapid and was 90% of adult values by the first month of life in term neonates (ie, 44 weeks postmenstrual age) and 98% of standardized adult estimates by 3 months of age (53 weeks postmenstrual age). Clearance informed dosing predictions in all ages (premature neonate to adult) and matched those doses in common use in children older than 3 months. [ABSTRACT FROM AUTHOR]

Summary: Postoperative wound infections represent an important source of morbidity and mortality in children. Perioperative antibiotic prophylaxis has been shown to decrease the risk of developing infections and hospital guidelines surrounding antibiotic use exist to standardize patient care. Despite supporting evidence, rates of compliance with guidelines vary. Quality improvement initiatives have been introduced to improve compliance with intraoperative antibiotic guidelines. Thorough infection surveillance, including antibiotic provision in presurgical checklists, computerized voice antibiotic administration prompts, and national feedback systems are now increasingly common. Few studies have been conducted investigating the effectiveness of prophylactic antibiotics in children. Outcome measures such as morbidity and mortality and return to the operating room can be used to examine the relationship between antibiotic use and patient outcome but these measures are limited in that they occur infrequently or are subjective and difficult to measure. Metrics such as days alive out of hospital and length of hospital stay may be useful alternatives for ongoing monitoring of infections and identifying improvements in patient outcomes. Guidelines on antibiotic prophylaxis have facilitated an increase in the correct provision of perioperative antibiotics and a reduction in the incidence of postoperative infection. Measures of patient outcome such as days alive out of hospital and length of hospital stay are easy to collect and calculate but further work is needed to confirm the utility of these measures for monitoring infection rates. [ABSTRACT FROM AUTHOR]

Background S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. Aims The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18 years during long-term sedation. Twenty-five children (median age: 0.42 years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6 mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4 hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model. Results A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CLS- KETAMINE=112 L/h/70 kg, V1S- KETAMINE=7.7 L/70 kg, V2S- KETAMINE=545L/70 kg, QS- was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. Conclusion Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation. [ABSTRACT FROM AUTHOR]kETAMINE=196 L/h/70 kg, and CLS- NORKETAMINE=53 L/h/70 kg. Interpatient variability of CLS- KETAMINE and CLS- NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. Conclusion Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation. [ABSTRACT FROM AUTHOR]

Background In pediatric patients, invasive procedures such as the insertion of a central venous catheter or gastroscopy require deep sedation. It is unknown whether listening to parental voice during deep sedation in children can reduce sedative doses. Aim The aim of this prospective study was to determine the effect of listening to a parent's voice during deep sedation on consumption of sedatives in children. Methods Fifty children aged 2-14 years undergoing central line placement or gastroscopy under deep sedation with propofol were randomly assigned to two groups: (A) listening or (B) not listening their parents' recorded voice reading a standardized text by the use of earphones. Depth of sedation was monitored by Comfort Score and by Bispectral Index. Results Mean sedative dose of propofol in both groups was equal (A 0.25 mg·kg−1·min−1; B 0.28 mg·kg−1·min−1; Δ −0.03 mg·kg−1·min−1 ( CI 95% −0.08 to 0.01); P = 0.089). Furthermore, complication rate ( P = 1.0) and recovery time (A 14.5 min; B 16.1 min; Δ = −1.6 min ( CI 95% −6.98 to 3.81); P = 0.60) did not differ between the intervention and the control group. Conclusion Listening to parental voice during deep sedation does not result in a reduction of sedative dose in children undergoing short medical procedures. [ABSTRACT FROM AUTHOR]

Background Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia ( TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram ( EEG) during the transition phase. Objective The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). Methods Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg−1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg−1·h−1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 μg·kg−1·min−1. Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. Results Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [ IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [ IQR 0.9-2.5] mg·kg−1 and median NI thereafter was 33 [ IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg−1. Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg−1 after sevoflurane induction. Decrease in mean arterial blood pressure correlated significantly with propofol bolus dose ( P = 0.038). After 25 min of TIVA, children younger than 2 years had a higher NI (median difference 14.0, 95% CI: 6.0-20.0, P = 0.001), higher deviations from the expected Narcotend Index (median difference 4.1, 95% CI: 3.9-4.2, P < 0.001) and lower calculated propofol plasma concentrations (median difference 0.2 μg·ml−1, 95% CI: 0.1-0.3 μg·ml−1, P < 0.001) than older children. Conclusion After sevoflurane induction, a reduced propofol bolus dose of 1 mg·kg−1 followed by TIVA according to McFarlan's regime resulted in a NI within the recommended range in children aged 1-8 years. During the course of TIVA, children younger than 2 years displayed higher NI values and more pronounced interindividual variation. Processed EEG monitoring is recommended to find adequate individual age-dependent doses. [ABSTRACT FROM AUTHOR]

Background In children, only a few studies have compared different modes of propofol infusion during a total intravenous anesthesia ( TIVA) with propofol and remifentanil. The aim of this study was to compare Bispectral Index ( BIS) profiles (percentage of time spent at adequate BIS values) between four modes of propofol infusion: titration of the infusion rate on clinical signs ( TIVA0), titration of the infusion rate on the BIS (TIVABIS), target controlled infusion ( TCI) guided by the BIS either with the Kataria model ( TCI KBIS) or the Schnider model ( TCI SBIS). Methods Sixty-six children (aged from 4 to 14 years) were prospectively randomized into one of the four groups. In the TIVA0 group, the anesthesiologist was blinded to the BIS. In each group, the percentage of time with adequate BIS values (45-55), the bias, and imprecision were calculated. Results The propofol consumption was similar in the four groups. During the maintenance phase, the percentage of time spent in the targeted BIS range was significantly lower in the TIVA0 group compared to the three other groups ( TIVA0: 31% ± 22, TIVABIS: 59% ± 17, TCI KBIS: 53% ± 12, TCI SBIS: 56% ± 17). The bias was not statistically different between the four groups, but the imprecision was larger for the TIVA0 group. Compared to the Kataria model, the Schnider model was associated with shorter time delay to reach the desired BIS, to eyes opening, and to tracheal extubation. Conclusions Propofol administration using manual infusion guided by clinical signs was associated with higher risks of over- or underdosage when compared to BIS-guided administrations. When propofol infusion was guided by the BIS, no major difference was found between TIVA and TCI (either with the Kataria or the Schnider model). This study highlights the need of a pharmacodynamic feedback during propofol anesthesia in children. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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. Results 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. Conclusion Preemptive analgesia using IV- PCA with fentanyl showed no significant advantages for postoperative analgesia after corrective osteotomy in pediatric patients. [ABSTRACT FROM AUTHOR]

Background The safety of ketamine in children with pulmonary hypertension has been debated because of conflicting results of prior studies in which changes in mean pulmonary artery pressure ( mPAP) and pulmonary vascular resistance ( PVR) have been widely variable. The goal of this prospective study was to quantitate the effects of ketamine on pulmonary hemodynamics in a cohort of children with pulmonary hypertension under conditions in which variables such as airway/ventilatory management, FiO2, and use of vasodilating anesthetics were controlled. Methods The IRB approved this study of 34 children undergoing cardiac catheterization for pulmonary hypertension studies. Following anesthetic induction with sevoflurane and tracheal intubation facilitated by the administration of rocuronium 0.7-1 mg·kg−1 iv, sevoflurane was discontinued and anesthesia was maintained with midazolam 0.1 mg·kg−1 iv (or 0.5 mg·kg−1 po preoperatively) and remifentanil iv infusion 0.5-0.7 mcg·kg−1·min−1. Ventilation was mechanically controlled to maintain Pa CO2 35-40 mmHg. When endtidal sevoflurane was 0% and FiO2 was 0.21, baseline heart rate ( HR), mean arterial pressure ( MAP), mPAP, right atrial pressure ( RAP), pulmonary artery occlusion pressure ( PAOP), right ventricular end-diastolic pressure ( RVEDP), cardiac output, and arterial blood gases were measured, and indexed systemic vascular resistance ( SVRI), indexed pulmonary vascular resistance ( PVRI), and cardiac index ( CI) were calculated. Each child then received a bolus of ketamine 2 mg·kg−1 infused over 2 min. Measurements and calculations were repeated 2 min after the conclusion of the infusion. Results The mean (95% CI) increase in mPAP following ketamine was 2 mmHg (0.2, 3.7), which was statistically significant but clinically insignificant. PVRI and PVRI/ SVRI did not change significantly. Hemodynamic changes did not differ among subjects with differing severity of pulmonary hypertension or between subjects chronically treated with pulmonary vasodilators or not. Conclusion Ketamine is associated with minimal, clinically insignificant hemodynamic changes in sedated, mechanically ventilated children with pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Demonstrably accurate records facilitate clinical decision making, improve patient safety, provide better defense against frivolous lawsuits, and enable better medical policy decisions. Anesthesia Information Management Systems ( AIMS) have the potential to improve on the accuracy and reliability of handwritten records. Interfaces with electronic recording systems within the hospital or wider community allow correlation of anesthesia relevant data with biochemistry laboratory results, billing sections, radiological units, pharmacy, earlier patient records, and other systems. Electronic storage of large and accurate datasets has lent itself to quality assurance, enhancement of patient safety, research, cost containment, scheduling, anesthesia training initiatives, and has even stimulated organizational change. The time for record making may be increased by AIMS, but in some cases has been reduced. The question of impact on vigilance is not entirely settled, but substantial negative effects seem to be unlikely. The usefulness of these large databases depends on the accuracy of data and they may be incorrect or incomplete. Consequent biases are threats to the validity of research results. Data mining of biomedical databases makes it easier for individuals with political, social, or economic agendas to generate misleading research findings for the purpose of manipulating public opinion and swaying policymakers. There remains a fear that accessibility of data may have undesirable regulatory or legal consequences. Increasing regulation of treatment options during the perioperative period through regulated policies could reduce autonomy for clinicians. These fears are as yet unsubstantiated. [ABSTRACT FROM AUTHOR]

Background Thoracic bioreactance is a noninvasive and continuous method of cardiac output ( CO) measurement that is being developed in adult patients. Very little information is available on thoracic bioreactance use in children. Objective The aim of the study was to evaluate the ability of a bioreactance device ( NICOM®; Cheetah Medical, Tel Aviv, Israel) to estimate CO and to track changes in CO induced by volume expansion (VE) in children. Methods Cardiac output values obtained using the NICOM® device ( CONICOM) and measured by trans-thoracic echocardiography ( COTTE) were compared in pediatric neurosurgical patients during the postoperative period. Results Seventy-three pairs of measurements of CO obtained in 30 children were available for analysis. The bias (lower and upper limits of agreement) between CONICOM and COTTE was −0.11 (−1.4 to 1.2) l·min−1. The percentage error (PE) was 55%. The precision of the NICOM® device was 45%. A significant correlation was observed between the CO values obtained using the two methods ( r = 0.89, <0.001). The concordance percentage between changes in COTTE and CONicom induced by VE was 84% following exclusion of patients with changes in CO <15% ( n = 5). Conclusions The PE observed is too large, and the limits of agreement too wide, to enable us to comment on the equivalence of the two techniques of CO measurements. However, the NICOM® device performs well in tracking changes in CO following VE. [ABSTRACT FROM AUTHOR]

Background Intravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants. Methods Concentration-time data were obtained from 57 children who received 1-1.5 mg·kg−1 of racemic ketamine as an intravenous bolus. A population pharmacokinetic analysis was conducted using nonlinear mixed effects models, and the results were used as inputs to develop a D-optimal sampling schedule. Results The pharmacokinetics of ketamine were described using a two-compartment model. The volume of distribution in the central and peripheral compartments were 20.5 l∙70 kg−1 and 220 l∙70 kg−1, respectively. The intercompartmental clearance and total body clearance were 87.3 and 87.9 l·h−1∙70 kg−1, respectively. Population parameter variability ranged from 34% to 98%. Initially, blood samples were drawn on 3-6 occasions spanning a range of 14-152 min after dosing. Using these data, we determined that four optimal sampling windows occur at 1-5, 5.5-7.5, 10-20, and 90-180 min after dosing. Monte Carlo simulations indicated that these sampling windows produced precise and unbiased ketamine pharmacokinetic parameter estimates. Conclusion An optimal sampling schedule was developed that allowed assessment of the pharmacokinetic parameters of ketamine among children requiring short-term procedural sedation. [ABSTRACT FROM AUTHOR]

Aims Clonidine may be used intraoperatively to decrease emergence delirium in children, but the drug's impact on postoperative sedation is poorly quantified. Methods A prospective audit of children (≤15 years) undergoing (adeno) tonsillectomy or adenoidectomy over a period of 4 months was carried out. All children received sevoflurane for induction and maintenance of anesthesia. The use of clonidine as an adjunct was left to the discretion of the anesthesiologist. Postoperative sedation was assessed using the University of Michigan Sedation Scale ( UMSS) at 30 min intervals until discharge. Arousal was characterized using a zero asymptote model. The impact of clonidine dose on half-time to an awake state after anesthesia was investigated using nonlinear mixed effects models. Survival analysis was used to explore the effect of clonidine dose on discharge time. Results The mean age of children ( n = 177) was 5.4 sd 3.3 years, range 0.8-15.0 years and weight was 23.8 sd 11.4 kg, range 10.0-76.4 kg. There were 73 children given clonidine 0.29-4.80 mcg·kg−1 after induction. The half-time to emergence was 10.8 (95% CI 8.5, 13.2) min. Emergence half-time was increased to 15 min with clonidine 0.5 mcg·kg−1, 20 min with clonidine 1.5 mcg·kg−1, 25 min with clonidine 2 mcg·kg−1 and 65 min with clonidine 4 mcg·kg−1. Clonidine doses 0.5-3 mcg·kg−1 did not affect hospital discharge time. Conclusions Clonidine administered intraoperatively for (adeno) tonsillectomy or adenoidectomy prolonged emergence from anesthesia. Doses of 0.5-3 mcg·kg−1 caused greater sedation in the postanesthesia care unit but did not impact on hospital discharge times. [ABSTRACT FROM AUTHOR]

Background Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg−1 is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. Methods Children ( n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg−1 before surgery and 20 mg·kg−1 rectally at the end of surgery with diclofenac suspension 0.1 mg·kg−1, 0.5 mg·kg−1, or 2.0 mg·kg−1 before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg−1, 0.5 mg·kg−1, or 2.0 mg·kg−1 only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. Results Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect ( EMAX) was 4.9. The concentration resulting in 50% of EMAX (C50) was 1.23 mg·l−1 for diclofenac and 13.3 mg·l−1 for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg−1 with acetaminophen 15 mg·kg−1 achieves equivalent analgesia to acetaminophen 30 mg·kg−1. Conclusions Combination therapy can be used to achieve similar analgesia with lower doses of both drugs. [ABSTRACT FROM AUTHOR]

Background The use of isotonic electrolytic solutions for the intraoperative fluid management in children is largely recognized, but the exact composition still needs to be defined. Objectives The primary objective of this randomized controlled open trial was to compare the changes in chloride plasma concentration using two intraoperative isotonic fluid regimens (Sterofundin vs normal saline, both added with 1% of glucose) in children undergoing major surgery. Secondary objectives were to compare changes in other electrolytes, renal function, and the occurrence of hypoglycemia. Methods Children aged between 1 and 36 months, scheduled for major surgery, were randomized to receive Sterofundin or saline during the intraoperative time. Children with preoperative electrolyte abnormalities, hemodynamic instability, and severe renal or hepatic dysfunction were excluded. The primary outcome was the Δ of Cl− (Δ = change in plasma concentration between post- and pre-infusion), and secondary outcomes included Δ of other electrolytes and intraoperative hypoglycemia. Results A total of 240 patients were included in the two study sites and randomized to receive Sterofundin plus 1% glucose or normal saline plus 1% glucose, in a open fashion (229 were finally analyzed). Δ of Cl− and Mg++ was statistically less relevant in patients who received intraoperative Sterofundin, and Δ of the other electrolytes was comparable between the two study groups. Relative risk of hyperchloremia was significantly higher when large volumes were infused (over than 46.7 ml·kg−1), regardless of type of crystalloid infused. Hypoglycemia occurred in two of 229 patients. Conclusions Sterofundin is safer than normal saline in protecting young children undergoing major surgery against the risk of increasing plasma chlorides and the subsequent metabolic acidosis. [ABSTRACT FROM AUTHOR]

Background The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking. Objectives To investigate a pediatric formulation of intranasal sufentanil 0.5 mcg·kg−1 and ketamine 0.5 mg·kg−1 for procedural pain and to characterize the pharmacokinetic ( PK) profile. Methods Fifty children (≥10 kg) scheduled for a painful procedure were included in this prospective nonrandomized open-label clinical trial. Thirteen of these children had central venous access for drug assay sampling; enabling a compartmental PK analysis using nonlinear mixed-effects models. Pain intensity before and during the procedure was measured using age-appropriate pain scales. Heart rate, oxygen saturation and sedation were recorded. Results Children had a mean age of 8.8 ( sd 4.9) years and weight 35.2 ( sd 20.1) kg. Sufentanil/ketamine nasal spray was effective (procedural pain intensity scores ≤5 (0-10)) in 78% of the painful procedures. The spray was well accepted by 94% of the children. Oxygen saturation and heart rate remained stable, and sedation was minimal. The bioavailability of sufentanil and ketamine was 24.6% and 35.8%, respectively. Maximum plasma concentration ( Cmax) of sufentanil was 0.042 mcg·l−1 (coefficient of variation ( CV) 12.9%) at 13.8 min ( CV 12.4%) ( Tmax). Cmax for ketamine was 0.102 mg·l−1 ( CV 10.8%), and Tmax was 8.5 min ( CV 17.3%). Conclusion Sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures with few adverse effects and has promising features for use in pediatric procedural pain management. [ABSTRACT FROM AUTHOR]

Introduction Plethysmographic Variability Index ( PVI) has been shown to accurately predict responsiveness to fluid loads in adults. The goal of this study was to evaluate PVI accuracy when predicting fluid responsiveness during noncardiac surgery in children. Material and Methods Children aged 2-10 years scheduled for noncardiac surgery under general anesthesia were included. PVI was assessed concomitantly with stroke volume index ( SVI). A response to fluid load was defined by an SVI increase of more than 15%. A 10 ml·kg−1 normal saline intravenous fluid challenge was administered before surgical incision and after anesthetic induction. After incision, fluid challenges were administered when SVI values decreased by more than 15% or where judged necessary by the anesthesiologist. Statistical analyses include receiving operator characteristics ( ROC) analysis and the determination of gray zone method with an error tolerance of 10%. Results Fifty-four patients were included, 97 fluid challenges administered and 45 responses recorded. Area under the curve of ROC curves was 0.85 [0.77-0.93] and 0.8 [0.7-0.89] for baseline PVI and SVI values, respectively. Corresponding gray zone limits were [10-17%] and [22-31 ml·m−2], respectively. PVI values exhibited different gray zone limits for pre-incision and postincision fluid challenges, whereas SVI values were comparable. PVI value percentages in the gray zone were 34% overall and 44% for challenges performed after surgical incision. Discussion This study found both PVI and prechallenge SVI to be accurate when used to predict fluid load response during anesthetized noncardiac surgery in children. However, a third of recorded PVI values were inconclusive. [ABSTRACT FROM AUTHOR]

Background Conventional endotracheal pediatric tubes offer high resistance due to their small diameters and relatively high flow during ventilation. Any increase of the diameter of the tube lumen decreases the airway resistance and subsequently, the work of breathing ( WOB). We compared ventilation mechanics using a new, cone-shaped endotracheal tube of our design to the Cole and standard tubes. Methods The study has been divided into three parts: (i) preliminary laboratory tests, (ii) in vitro study with infant lung model, and (iii) clinical study in infants. Flow resistance and WOB were compared, using standard, Cole (in experimental phase only) and cone tubes. Results We proved that inspiratory ( Ri) and expiratory ( Re) resistance, and WOB, were significantly lower in patients ventilated via a cone tube. Mean Ri decreased by 37%, compared with the baseline values, Re - by 35%, and total WOB - by 12%. Conclusion The cone tube offers lower resistance to gas flow than the standard, used nowadays in clinical practice. It can be especially beneficial to spontaneously breathing patients reducing WOB and improving gas exchange. [ABSTRACT FROM AUTHOR]

Aim To determine if the addition of adrenaline, clonidine, or their combination altered the pharmacokinetic profile of levobupivacaine administered via the caudal epidural route in children. Methods Children aged <18 years old scheduled to undergo sub-umbilical surgery were administered caudal levobupivacaine plain 2.5 mg·ml−1 or with adjuvants adrenaline 5 mcg·ml−1 or clonidine 2 mcg·ml−1 or their combination. Covariate analysis included weight and postnatal age (PNA). Time-concentration profile analysis was undertaken using nonlinear mixed effects models. A one-compartment linear disposition model with first-order input and first-order elimination was used to describe the data. The effect of either clonidine or adrenaline on absorption was investigated using a scaling parameter ( Fabs CLON, Fabs ADR) applied to the absorption half-life (Tabs). Results There were 240 children (median weight 11.0, range 1.9-56.1 kg; median postnatal age 16.7, range 0.6-167.6 months). Absorption of levobupivacaine was faster when mixed with clonidine (Fabs CLON 0.60; 95% CI 0.44, 0.83) but slower when mixed with adrenaline (Fabs ADR 2.12; 95% CI 1.45, 3.08). The addition of adrenaline to levobupivacaine resulted in a bifid absorption pattern. While initial absorption was unchanged (Tabs 0.15 h 95% CI 0.12, 0.18 h), there was a late absorption peak characterized by a Tabs LATE 2.34 h (95% CI 1.44, 4.97 h). The additional use of clonidine with adrenaline had minimal effect on the bifid absorption profile observed with adrenaline alone. Neither clonidine nor adrenaline had any effect on clearance. The population parameter estimate for volume of distribution was 157 l 70 kg−1. Clearance was 6.5 l·h−1 70 kg−1 at 1-month PNA and increased with a maturation half-time of 1.6 months to reach 90% of the mature value (18.5 l·h−1 70 kg−1) by 5 months PNA. Conclusions The addition of adrenaline decreases the rate of levobupivacaine systemic absorption, reducing peak concentration by half. Levobupivacaine concentrations with adrenaline adjuvant were reduced compared to plain levobupivacaine for up to 3.5 hours. Clonidine as an adjuvant results in faster systemic absorption of levobupivacaine and similar concentration time profile to levobupivacaine alone. Adding adrenaline with clonidine does not alter the concentration profile observed with adrenaline alone. [ABSTRACT FROM AUTHOR]

Aim: We performed a retrospective audit of intravenous morphine infusion administered to children in an effort to characterize the relationship between dose and age. Methods: A retrospective audit of morphine infusions was reviewed for a 24-months period and included all children who received continuous intravenous nurse-controlled morphine infusions and patient-controlled analgesia; a population undergoing acute and elective surgical procedures, as well as medical and oncological treatments. The relationship between age and infusion rate was investigated using nonlinear mixed effects models. Results: There were 886 children whose data were acceptable for review. Morphine dose increased with age from 9.97 (CV 28%) μg·kg−1 per h in neonates. The Hill equation with an exponential of 1.5 best described these changes. Morphine rate reached 90% of its mean final rate of 22.5 (CV 167%) μg·kg−1 per h, observed in teenagers, at approximately 5 years of age. There was considerable uncertainty of this age-morphine rate profile, and the maturation half-life of this profile was 20 months of age (CV 632%). An increase in dosing variability was observed with increasing age. Conclusions: Morphine infusions at steady-state did not mirror clearance maturation in children nursed in our hospital. We suggest that initial infusion rates in children are started at 10 μg·kg−1 per h in neonates, 15 μg·kg−1 per h in toddlers and 25 μg·kg−1 per h in children above the age of 5 years. The large variability associated with infusion rates means that subsequent infusion rates will depend on feedback from pain scores, adjuvant medications and adverse effects. [ABSTRACT FROM AUTHOR]

Background The optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1. Methods Adolescents aged 12-19 years undergoing idiopathic scoliosis correction were administered 0.25 mg·kg−1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70-kg person using allometric models. Results A three-compartment linear disposition model best described observed time-concentration profiles. Population parameter estimates (between-subjects variability) were central volume (V1) 19.1 (126%) L 70 kg−1, peripheral volumes of distribution V2 65.5 (60%) L 70 kg−1, V3 485 (23%) L 70 kg−1, clearance ( CL) 9.3 (11%) L·h−1·70 kg−1, and inter-compartment clearances Q2 282 (95%) L·h−1 70 kg−1, Q3 139 (42%) L·h−1 70 kg−1. The terminal elimination half-life was 44.4 h. The mean observed methadone concentration was <58 mcg·L−1 by the first hour after administration. Conclusions Current pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg-1) with an infusion (0.1-0.15 mg·kg−1·h−1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h. [ABSTRACT FROM AUTHOR]

The pharmacokinetic (PK) parameters that are important for dosing (e.g., clearance and volume) are well known. They are used in universal mathematical formulae that describe the time course of drug concentration. Additional formulae can be used to describe major covariate effects in children, such as size and maturation. PK parameters describing the time-concentration profile of a drug after administration are those for a typical individual in a population. These parameters are associated with variability. Further, any one individual may not be typical of the population studied. While size and maturation are two important considerations in children and assist with dosing estimation, there are also a number of additional PK covariates (e.g., organ function, disease, drug interactions, pharmacogenetics), and identifying these sources of variability allows us to individualize drug dose. Pharmacology is not simply an application of PK, and determinants of drug dose also require an understanding of the variability associated with pharmacodynamic response and a balancing of beneficial effects against unwanted effects. Each child is unique in this respect. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area. Children ( n = 20) were given ketamine 5 or 10 mg·kg orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5-1 mg·kg) to nine children during the procedure while a further nine children were given an infusion (0.1 mg·kg·h) continued for 4-19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8-24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time-concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed-effects models. The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 2.1 years, range 1-8 years; weight 14.7 4.9 kg, range 7.9-25 kg), and these children contributed 214 ketamine and norketamine observations. A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half-time was 59 (90% CI 29.4, 109.2) min and had high between-subject variability (BSV 148%). Population parameter estimates, standardized to a 70-kg person, were central volume 21.1 (BSV 47.1%) l·70 kg, peripheral volume of distribution 109 (27.5%) l·70 kg, clearance 81.3 (46.1%) l·h·70 kg, and inter-compartment clearance 259 (50.1%) l·h·70 kg. Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l·70 kg with an elimination clearance of 64.4 (BSV 63.4%) l·h·70 kg and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h·70 kg. The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (<0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg·kg followed by intravenous ketamine 1 mg·kg i.v. with the advent of short-duration surgical dressing change at 45 min. [ABSTRACT FROM AUTHOR]

Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75-100% but is unknown in children. Children (3-10 years) undergoing adenotonsillectomy were administered oral clonidine 4 mcg·kg mixed with apple fruit drink as premedication. Intravenous plasma was assayed for clonidine concentration at 5, 15, 30, 45 min and 1, 2, 4, 6, 12, 18 h after administration. Clonidine plasma concentrations were determined by liquid chromatography-mass spectroscopy, and pharmacokinetic parameters were calculated using nonlinear effects mixed-effects models. Current data were pooled with published time-concentration profiles from children ( n = 49) administered intravenous clonidine to determine oral bioavailability. There were eight children studied (age 3-10 years, weight 10.5-36 kg). A two-compartment model with first-order absorption and elimination was used to describe time-concentration profiles. Population parameter estimates (CV%; 95% CI), standardized to a 70-kg person, were absorption half-life (Tabs), 0.45 (85.1; 0.221-0.884) h, absorption lag time (Tlag), 0.148 (91.2; 0.002-0.316) h, Clearance (CL) 17.9 (30.3; 16-20.3) l·h per 70 kg, between compartment clearance (Q) 121 (44.3; 80.1-165) l·h per 70 kg, central volume (V1) 81.2 (71.5; 60.7-105) l·70 kg, peripheral volume of distribution (V2) 113 (33.9; 91-131) l·70 kg. The oral bioavailability was 55.4% (CV 6.4%; 95% CI 0.469, 0.654). Clonidine administered with an apple fruit drink displays a variable and relatively slow absorption after oral administration ( T 1.04 h, C 0.77 mcg·l). The oral bioavailability was 55.4%, which is less than reported in adults. Consequently, higher oral doses of clonidine (per kg) are required when this formulation is used to achieve concentrations similar to those reported in adults. [ABSTRACT FROM AUTHOR]

Background: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration–response profile for these hemodynamic effects in children after cardiac surgery. Methods: A simultaneous pharmacokinetic–pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1–4 mcg·kg−1 following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. Results: Children had a mean age of 2.67 years (range 4 days–14 years) and a mean weight of 12.34 (range 3.4–48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emaxpos of 50.3 (CV 44.50%) mmHg, EC50pos 1.1 (48.27%) μg·l−1 and a Hillpos coefficient of 1.65. The delayed central sympatholytic response was described with an Emaxneg of −12.30 (CV 37.01%) mmHg, EC50neg 0.10 (104.40%) μg·l−1 and a Hillneg coefficient of 2.35. The equilibration half-time ( T1/2keo) was 9.66 (165.23%) min. Conclusions: Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 μg·l−1 was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 μg·kg−1) followed by a continuous infusion should be used to avoid initial increases in MAP. [ABSTRACT FROM AUTHOR]

Background: Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects. Methods: Data from four studies investigating dexmedetomidine pharmacokinetics after i.v. administration ( n = 95) were combined to undertake a population pharmacokinetic analysis of dexmedetomidine time–concentration profiles (730 observations) using nonlinear mixed effects modeling (NONMEM). Estimates were standardized to a 70-kg adult using allometric size models. Results: Children had a mean age of 3.8 (median 3 years, range 1 week–14 years) and weight of 16.0 kg (median 13.3 kg, range 3.1–58.9 kg). Population parameter estimates (between subject variability) for a two-compartment model were clearance (CL) 42.1 (CV 30.9%) l·h−1·70 kg−1, central volume of distribution (V1) 56.3 (61.3%) l·70 kg−1, inter-compartment clearance (Q) 78.3 (37.0%) l·h−1·70 kg−1 and peripheral volume of distribution (V2) 69.0 (47.0%) l·70 kg−1. Clearance maturation with age was described using the Hill equation. Clearance increases from 18.2 l·h−1·70 kg−1 at birth in a term neonate to reach 84.5% of the mature value by 1 year of age. Children given infusion after cardiac surgery had 27% reduced clearance compared to a population given bolus dose. Simulation of published infusion rates that provide adequate sedation for intensive care patients found a target therapeutic concentration of between 0.4 and 0.8 μg·l−1. Conclusions: The sedation target concentration is similar to that described for adults. Immature clearance in the first year of life and a higher clearance (when expressed as l·h−1·kg−1) in small children dictate infusion rates that change with age. Extrapolation of dose from children given infusion in intensive care after cardiac surgery may not be applicable to those sedated for noninvasive procedures out of intensive care. [ABSTRACT FROM AUTHOR]

Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry-sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures. [ABSTRACT FROM AUTHOR]

Background: There are few data describing dexmedetomidine population pharmacokinetics (PK) in children (0–15 years) despite increasing use. Methods: An open-label study was undertaken to examine the PK of i.v. dexmedetomidine 1–4 μg·kg−1 bolus in children after cardiac surgery ( n = 45). A population PK analysis of dexmedetomidine time–concentration profiles (148 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70-kg adult using allometric size models. Results: Children had a mean age of 3.38 years (range 4 days to 14 years) and weight 15.1 kg (range 3.1–58.9 kg). A two-compartment disposition model with first order elimination was superior to a one-compartment model. Population parameter estimates (between subject variability) were clearance (CL) 39.2 (CV 30.36%) l·h−1 per 70 kg, central volume of distribution (V1) 36.9 (69.49%) l per 70 kg, inter-compartment clearance (Q) 68.2 (37.6%) l·h−1 per 70 kg and peripheral volume of distribution (V2) 69.9 (48.6%) l per 70 kg. Clearance at birth was 15.55 l·h−1 per 70 kg and matured with a half-time of 46.5 weeks to reach 87% adult rate by 1 year of age. Simulation of an infusion of 1 μg·kg−1 over 10 min followed by an infusion of 0.7 μg·kg−1·h−1 for 50 min suggested that children arouse from sedation at a plasma concentration of 0.304 μg·l−1. Conclusions: Clearance in neonates is approximately one-third of that described in adults, consistent with immature elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [ABSTRACT FROM AUTHOR]

Background: The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. Methods: During surgery all infants (6 months–2 years) received a rectal loading dose of 40 mg·kg−1 paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg·kg−1 propacetamol, a prodrug of paracetamol, or 20 mg·kg−1 paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0–10 cm) and COMFORT Behavior scale (score 6–30) were used to monitor analgesia in the 24-h period following surgery. Results: Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric ‘1/4 power’ models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l·h−1·70 kg−1, intercompartmental clearance 116 l·h−1·70 kg−1, central and peripheral volume of distribution 7.9 and 44 l·70 kg−1, respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score ≥4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 ( P < 0.05). Conclusions: Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to describe ketamine pharmacodynamics (PD) in children. Adult ketamine concentrations during recovery are reported as 0.74 mg·l−1 (sd 0.24 mg·l−1) with an EC50 for anesthesia of 2 mg·l−1 (sd 0.5 mg·l−1), but pediatric data are few. Methods: Children presenting for painful procedures in an Emergency Department were given ketamine 1–1.5 mg·kg−1 i.v. Blood was assayed for ketamine on three to six occasions (median 3) over the subsequent 14–152 min (median 28.5). Procedures were videotaped. Level of sedation (0–5; unresponsive – spontaneously awake without stimulus) and a test of memory were recorded. PD was investigated using a variable slope Emax model (sedation) or logistic regression (arousal time, memory) with nonlinear mixed effects models. Results: In total 60 children were enrolled. Pharmacokinetic data were collected in 54 of these children and there were 43 children available for PD study. The mean age was 8.15 years (sd 3.5 years) and weight was 34.9 kg (sd 15.8 kg). The half-time describing equilibration between the effect compartment and central compartment was 11 s (95% CI 0.07–20 s). The EC50 for arousal was 0.52 (90% CI 0.22–1.17) mg·l−1. The Emax model with a baseline (E0) of five (spontaneously awake without stimulus) yielded a fractional Emax 0.939 [coefficient of variability (CV) 24%], an EC50 0.56 (CV 136%) mg·l−1 and a Hill coefficient 3.71. The EC50 for recall memory was 0.44 (90% CI 0.09–1.70) mg·l−1. The EC50 for remembering was 0.38 (90% CI 0.12–1.75) mg·l−1. Conclusions: Concentrations associated with arousal in children are analogous to adults. The ability to recall and remember occurs at similar concentrations to those associated with arousal. A concentration of 1 mg·l−1 was associated with a sedation level of three or less (arouses to consciousness with moderate tactile or loud verbal stimulus) in 95% of children while 1.5 mg·l−1 was associated with a sedation level of two or less (rouses slowly to consciousness with sustained painful stimulus) in 95% of children. These concentrations can be attained for 3–4 min after 1 mg·kg−1 and 1.5 mg·kg−1 ketamine IV bolus, respectively. The mean arousal time can be anticipated at approximately 10 min (1 mg·kg−1) and 15 min (1.5 mg·kg−1). [ABSTRACT FROM AUTHOR]

Background: There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current pediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods: Published data from four studies investigating clonidine PK after intravenous (i.v.), rectal and epidural administration ( n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of i.v. clonidine 1–2 μg·kg−1 bolus in children after cardiac surgery ( n = 41). A population pharmacokinetic analysis of clonidine time–concentration profiles (380 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70-kg adult using allometric size models. Results: Children had a mean age of 4 (sd 3.6 years, range 1 week–14 years) years and weight 17.8 (sd 12.6, range 2.8–60) kg. A two compartment disposition model with first-order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14.6 (CV 35.1%) l·h−1 70 kg−1, central volume of distribution (V1) 62.5 (71.1%) l 70 kg−1, intercompartment clearance (Q) 157 (77.3%) l·h−1 70 kg−1 and peripheral volume of distribution (V2) 119 (22.9%) l 70 kg−1. Clearance at birth was 3.8 l·h−1 70 kg−1 and matured with a half-time of 25.7 weeks to reach 82% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 123%, V2 126%). There was a lag time of 2.3 (CV 73.2%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum (0.98 CV 24.5% h vs 0.26 CV 32.3% h). The relative bioavailability of epidural and rectal clonidine was unity ( F = 1). Conclusions: Clearance in neonates is approximately one-third that described in adults, consistent with immature elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [ABSTRACT FROM AUTHOR]

Background: Norketamine, a metabolite of ketamine, is an analgesic with a potency one-third that of ketamine. The aim of this study was to describe norketamine pharmacokinetics in children in order to predict time–concentration profiles for this metabolite after racemic ketamine single dose and infusion administration. The possible analgesic potential resulting from norketamine concentration may then be predicted using simulation. Methods: Ketamine and norketamine data were available from two sources: (i) children presenting for procedural sedation in an emergency department given ketamine 1–1.5 mg·kg−1 IV as a bolus dose; and (ii) a literature search of those studies describing ketamine and norketamine time–concentration profiles after either IV or IM single-dose ketamine in adults and children. A population pharmacokinetic analysis was undertaken using nonlinear mixed effects models (NONMEM). A two-compartment (central, peripheral) linear disposition model was used to fit the parent drug. An additional metabolite compartment was linked to the central compartment by series of intermediate compartments to account for norketamine delayed formation. Norketamine volume of distribution was fixed equivalent to central volume. Simulation was used to predict norketamine time–concentration profiles in children given either ketamine as an i.v. bolus 2 mg·kg−1 or as an analgesic infusion 0.2 mg·kg−1·h−1 for 24 h. Results: The analysis comprised 621 observations from 70 subjects. There were 57 children (age 8.3,sd: 3.5 years, range: 1.5–14; weight 32.5,sd: 15.6 kg, range: 10.8–74.8) and 13 adults. Population parameter estimates for the parent drug, standardized to a 70 kg person using allometric models were central volume (V1) 22 (BSV 89.6%) l.70 kg−1, peripheral volume of distribution (V2) 129 (30.9%) l.70 kg−1, clearance other than that metabolized to norketamine (CLother) 47.8 (37.7%) l·h−1·70 kg−1 and intercompartment clearance (Q) 216 (54.5%) l·h−1·70 kg−1. The norketamine formation clearance (CL2M) was 12.4 (127%) l·h−1·70 kg−1, elimination clearance (CLM) was 13.5 (145%) l·h−1·70 kg−1, and the rate constant for intermediate compartments was 26.5 (59.1%) h−1. Conclusions: Ketamine has a longer elimination half-life (2.1 h) than norketamine (1.13 h). Simulation suggested that norketamine contributes to analgesia for 4 h after 2 mg·kg−1 i.v. bolus, provided the assumption that a norketamine concentration above 0.1 mg·l−1 contributes analgesia is true. Similarly, the norketamine metabolite may contribute to analgesia for 1.5 h after low-dose infusion (0.2 mg·kg−1·h−1) cessation. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to describe ketamine pharmacokinetics in children to simulate time–concentration profiles to predict duration of concentrations associated with anesthesia, arousal and analgesia. Methods: Children presenting for painful procedures in the Emergency Dept were given ketamine 1–1.5 mg·kg−1 i.v. Blood was assayed for ketamine on 3–6 occasions (median 3) over the subsequent 14–152 min (median 28.5). A population pharmacokinetic analysis was undertaken by using nonlinear mixed effects models (NONMEM). Simulation was used to predict time–concentration profiles in this cohort Results: There were 188 observations from 54 children (age 8.3sd 3.5 years, weight 32.5sd 15.6 kg). A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Population parameter estimates and their between subject variability (BSV), standardized to a 70-kg person using allometric models, were central volume (V1) 38.7 (BSV 64%) l.70 kg−1, peripheral volume of distribution (V2) 102 (51.7%) l.70 kg−1, clearance (CL) 90 (38.1%) l·h−1 70 kg−1 and intercompartment clearance (Q) 215 (19%) l·h−1 70 kg−1. At 10 min half of the children given 1 mg·kg−1 will have a serum concentration below 0.75 mg·l−1. This is a concentration associated with ‘awakening’ in adults. However, almost all the children will still have a serum concentration above 0.1 mg·l−1, a level associated with analgesia in adults. Conclusions: Ketamine 1 mg·kg−1 i.v. provides satisfactory serum concentrations for children undergoing sedation for painful procedures of <5-min duration and produces concentrations associated with analgesic effect for more than 10 min. Clearance increases with decreasing age in children. The relationship between serum concentration and effect is poorly defined in children. [ABSTRACT FROM AUTHOR]

Abstract: The recently introduced fentanyl transdermal therapeutic system (TTS) with a drug release rate of 12.5 μg/h matches the lower dosing requirements of cancer pain control in children. It is likely that fentanyl TTS will be used in pediatrics with increasing frequency. We compiled the published evidence on pediatric applications of this drug formulation to help physicians get the most benefit from its use. Within this systematic review, a total of 11 observational clinical or pharmacokinetic studies were identified. There are no pediatric randomized or controlled cohort studies. Pharmacokinetic studies poorly described time-concentration profiles after application. The time to reach steady-state serum drug concentrations seems to be longer, clearance (expressed as liters per kilogram per hour) higher, and elimination half-life shorter in children than in adults. There are no fundamental differences in effect or profile of adverse effects compared with adults. Fentanyl TTS may be associated with less constipation compared with morphine use. Frequently, pediatric patients need supplemental mechanical fixation of the fentanyl TTS by means of medical tape. Younger patients tend to have a higher fentanyl requirement when referenced to body weight. Both parents and medical professionals are satisfied with fentanyl TTS to a higher degree than with individual analgesic pretreatment regimens. Fentanyl TTS is a promising option for chronic pain control in children. An approximate conversion factor of 45 mg/day oral morphine to 12.5 μg/h fentanyl TTS is used for initial therapy dose estimation in children receiving long-term morphine therapy. This is conservatively low to avoid respiratory depression. Daily oral morphine equivalent dose should be at least 30 mg/d before fentanyl TTS therapy is started with 12.5 μg/h. Evidence for superiority of fentanyl TTS treatment above conventional opioid administration is both scarce and of low quality. Perspective: The article gives a comprehensive overview of all pediatric data concerning the fentanyl TTS. Children may take longer to reach steady-state fentanyl serum concentrations than adults, and younger children may require higher doses referenced to body weight than older children or adults. Consequently, there is a need to provide sufficient medication in the phase of therapy initiation to prevent breakthrough pain. The 72-hour dosing schedule recommended by the manufacturers may not be applicable to children because of poor patch adhesiveness. The authors suggest to ensure firm fixation of the fentanyl TTS with additional medical tape if necessary and to change the fentanyl TTS after 48 hours. Transdermal fentanyl in children may exhibit fewer side effects when compared with other opioids, especially constipation. Randomized studies are urgently needed to definitively answer this question. [Copyright &y& Elsevier]

The aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg·kg−1 (15 mg·kg−1 paracetamol) 6 h.A population pharmacokinetic analysis of paracetamol time–concentration profiles (846 observations) from 144 children [postconception age (PCA) 27 weeks–14 years] was undertaken using nonlinear mixed effects models (nonmem). These data were taken from seven separate studies involving children given intravenous propacetamol. Time–concentration profiles (503 observations) from a further 86 children (PCA: 37 weeks–14 years) given paracetamol elixir orally were included in the analysis to assess relative bioavailability of intravenous propacetamol.A three-compartment (depot, central and peripheral) linear disposition model fitted data better than a two-compartment (depot and central) model. Population parameter estimates (between subject variability, %) were central volume (V2/Foral) 24 (55%) l · 70 kg−1, peripheral volume of distribution (V3/Foral) 30 (32%) l · 70 kg−1, clearance (CL/Foral) 16 (40%) l · h−1 · 70 kg−1 and intercompartment clearance (Q/Foral) 55 (116%) l · h−1 · 70 kg−1. Clearance increased from 27 weeks PCA (1.87 l·h−1 70 kg−1) to reach 84% of the mature value by 1 year of age (standardized to a 70 kg person using allometric‘power’ models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l·70 kg−1) to reach 110% of its mature value by 6 months of age. Central volume of distribution and intercompartment clearance did not change with age. Between occasions variability for the peripheral volume of distribution (V3/Foral) and clearance (CL/Foral) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (K a 96 h−1) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5.A mean paracetamol serum concentration of 10 mg·l−1 is achieved in children 2–15 years given a standard dose of propacetamol 30 mg·kg−1 6 h. This concentration in the effect compartment is associated with a pain reduction of 2.6/10 after tonsillectomy and provides satisfactory analgesia for mild to moderate pain. Clearance is reduced in children less than 1 year of age and the target concentration of 10 mg·l−1 may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group. [ABSTRACT FROM AUTHOR]

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population. [ABSTRACT FROM AUTHOR]

Physiological-based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages. Published CL estimates after intravenous administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed effects models. There were 16 publications reporting an estimate of CL after intravenous administration in children, although few estimates were available from 44-80 weeks postmenstrual age (PMA). CL maturation, standardized to a 70 -kg person was described using the Hill equation. Mature CL was 523 (CV 32%, 95%CI 469, 597) ml·min·70 kg. The maturation half-time was 73.6 (95%CI 59.4, 80.0) weeks PMA and the Hill coefficient 3 (95%CI 2.2, 4.1). Predicted CL changes with age based on this model were in close agreement with physiologically based pharmacokinetic (PBPK) models. A comparison with a published PBPK model predictions revealed a root mean squared prediction error (precision) of 4.0% (95%CI 1.1, 5.8) and bias was −0.9% (95%CI −4.3, 2.6). Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. If a midazolam sedation target concentration of 0.1 mg·l, similar to that given to adults, is assumed, then we might anticipate steady-state infusion rates of 0.014 mg·kg·h in neonates, 0.05 mg·kg·h in a 1-year-old, 0.06 mg·kg·h in a 5-year-old and 0.05 mg·kg·h in a 12-year-old child. Age-related pharmacodynamic differences that will affect dose and the impact of active metabolites on response are not yet quantified. [ABSTRACT FROM AUTHOR]

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900. [ABSTRACT FROM AUTHOR]

Summary: Objective: To compare the differences in pain, analgesic use and bleeding in children after tonsillectomy using either a harmonic scalpel or a bipolar diathermy surgical technique. Methods: Children 6–15 years presenting for tonsillectomy were randomised to either a harmonic scalpel or bipolar diathermy surgical technique. Post-operative pain scores (VAS, 0–10) were recorded within 30min of surgery and again at the 4h hospital discharge. A subsequent telephone interview daily for 7 days and then every second day until day 13 was used to monitor pain scores, analgesic use and tonsil bed bleeding. Results: There were 204 children studied. The response rate over the first 7 days was 93% for the children in the harmonic scalpel group and 87% for the bipolar group. Children experienced moderate post-operative pain for the first 6 days, after which pain declined from 4–7 to reach a score of 1–2 by day 11. Children undergoing harmonic scalpel tonsillectomy (n =103) reported higher mean pain scores than those who underwent bipolar diathermy (n =101) for current pain (4.7 versus 4.2, p =0.002), worst pain of the day (6.9 versus 6.2, p <0.001) and pain on swallowing (5.9 versus 5.2, p <0.001) over the first 6 post-operative days. Analgesic use (acetaminophen, ibuprofen) was similar in both groups. Hospital readmission for bleeding in children who underwent harmonic scalpel was similar to those who underwent bipolar diathermy tonsillectomy (9% versus 11%) as was bleeding requiring surgical re-exploration (4% versus 2%). Conclusions: Tonsillectomy was associated with considerable pain for the first 6 post-operative days. Children undergoing harmonic scalpel tonsillectomy had a slight increase in pain compared to the bipolar diathermy group during this time. Both methods of tonsillectomy are effective and safe. [Copyright &y& Elsevier]