Search

Background: The impact of tramadol in children given acetaminophen-ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy., Methods: Children undergoing tonsillectomy were given oral paracetamol and ibuprofen perioperatively. Blood was taken for paracetamol and ibuprofen drug assay on up to six occasions over 6 h after the initial dose. Tramadol was administered by caregivers for unacceptable postoperative pain. Pain was measured using the Parent's Postoperative Pain Measurement rating two hourly on the first postoperative day. A first-order absorption, one-compartment linear model with first-order elimination was used to describe acetaminophen and ibuprofen disposition. Analgesia was described using an E MAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models., Results: Pharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (E MAX ) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C 50, ACET ) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C 50 (C 50, IBU ) 3.95 (95%CI 2.57, 7.53) mg/L. The Hill coefficient was 1.48 (95%CI 0.92, 2.62) and an interaction term was fixed at zero (additivity). The half-time (t 1/2 keo) for equilibration between the plasma and effect site was 0.34 hour (95%CI 0.23, 1.98) for acetaminophen and 1.04 hour (95%CI 0.75, 1.77) for ibuprofen. Tramadol had a C 50, TRAM of 0.07 (95%CI 0.048, 1.07) mg/L with a t 1/2 keo, TRAM 1.78 hour (95%CI 1.06, 1.96)., Conclusion: Ibuprofen has an EC 50 for analgesia in children similar to that of adults (3.95 mg/L; 95%CI 2.57-7.53, vs 5-10 mg/L adults). The maximum effect from combination therapy (ie, 65% reduction in pain score) achieves satisfactory analgesia with commonly used doses but increased dose adds little additional benefit. The addition of tramadol to this analgesic mixture prolongs analgesia duration., (© 2018 John Wiley & Sons Ltd.)

Purpose of Review: Dexmedetomidine is a drug with sedative, anxiolytic, sympatholytic and analgesic properties, which is finding widespread practice in paediatric anaesthesia and related practices. The present review summarizes its pharmacology and current experience with the drug., Recent Findings: Dexmedetomidine is proving useful in many diverse areas in paediatric anaesthesia where its sedative properties are useful for premedication, fibreoptic intubation and radiologic procedures. Its use as an adjunct for balanced anaesthesia where it can decrease the use of other drugs, reduce emergence delirium, postoperative shivering and vomiting. Muted apoptotic neuroprotective effects may realize benefits in neonates. Cardiac conduction delay, an adverse effect, may prove beneficial for arrhythmias after congenital cardiac surgery., Summary: Most of the paediatric published studies concerning dexmedetomidine are observational in nature, with limited control groups or comparators. Adverse effects (e.g. bradycardia) still require greater scrutiny in the paediatric population and particularly with respect to different age groups. Dexmedetomidine currently has a firm position in the armamentarium of anaesthesia pharmacology. It is not the new all-in-one drug, but it is shaping up as a valuable adjunct for diverse indications within paediatric anaesthesia. VIDEO ABSTRACT: http://links.lww.com/COAN/A44.

Background: Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects., Methods: MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol., Results: There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg)., Conclusions: Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.

Background: Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled., Methods: This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models., Results: Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (F(PREG) = 1.14) and decreased during abdominal surgery (F(ABDCL) = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (F(ORTHOV) = 0.649), while those in intensive care had increased V2 (F(ICV) = 1.51)., Conclusions: Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored.

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., (© 2014 John Wiley & Sons Ltd.)

Objectives: We suggested a loading dose (20 mg · kg(-1) ) followed by 10 mg · kg(-1) q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg · l(-1) in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20 mg · kg(-1) ) were used to validate this effect compartment concentration., Methods: Pain scores (Leuven Neonatal Pain Score, LNPS, 0-14) before and 0.5, 1, 2, 3, 4, 5, and 6 h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO, www.clinicaltrials.gov, NCT00969176) were collected. Trends were analyzed using repeated measures anova. An E(max) model with a delayed response compartment was fitted to data using population modeling., Results: Nineteen of 60 neonates included in the PARANEO study received monotherapy with IV paracetamol to treat mild to moderate pain (e.g., alprostadil administration, delivery related trauma). Using repeated measures anova, there was a trend (P = 0.02) for lower pain scores within 30 min after administration, with a slight increase in pain scores from 5 to 6 h. An E(max) model had a maximum effect of 4.15 pain units, an EC(50) of 2.07 mg · l(-1). Equilibration halftime (T(1/2) keo) was 1.58 h., Conclusion: Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10 mg · l(-1) (loading dose of 20 mg · kg(-1) ) is associated with a pain score reduction of 3.4 LNPS units. This analysis suggests a similar paracetamol effect compartment concentration in neonates compared to children., (© 2012 Blackwell Publishing Ltd.)

Background: The value of acetaminophen-ibuprofen combination therapy over single therapy is uncertain in acute pediatric pain management. A model describing the interaction between these two drugs would be useful both for understanding current literature and for future study design., Methods: Published pooled time-effect profiles in adults given combination or single therapy after dental extraction were used to construct an interaction model. Pain was measured using pain intensity differences (PRID, 0-10) from zero to eight hours postoperatively. Pharmacodynamic parameter estimates were assumed the same in adults as children. Pediatric pharmacokinetic estimates were scaled using allometric theory. Curve fitting was performed using nonlinear mixed effects models., Results: Pooled data were available in adults given eight single and multiple dose combinations as well as placebo. The ibuprofen dose range was 100-400 mg, and acetaminophen dose range was 500-1000 mg. Pharmacodynamic parameter estimates, expressed using the Hill equation, were maximum effect (E(MAX) ) 4.06 (95% CI: 3.24, 5.51), the concentration of acetaminophen associated with 50% of the maximal drug effect (EC(50,ACET) ) 11.9 (95% CI: 6.0, 49.5) mg·l(-1) , the ibuprofen EC(50) (EC(50,IBU) ) 5.07 (95% CI: 3.50, 8.26) mg·l(-1), and Hill coefficient 2 (95% CI: 1.3, 2.8). An interaction term was fixed at zero (additive interaction). Simulation showed that the addition of acetaminophen to ibuprofen when less than 5 mg·kg(-1) was effective; acetaminophen had minimal effect when given with ibuprofen at doses greater than 5 mg·kg(-1) in the immediate postoperative period. A more sustained analgesic effect was noted at 4-8 h after combination dosing., Conclusions: This drug interaction modeling example is useful to explain combination therapy nuances and impacts on study design. Differences in effect between single drug therapy and combination therapy should be sought at lower doses and beyond the immediate postoperative period. Combination therapy may prolong the duration of analgesia. The maximum effect (E(MAX) ) limits the early additional analgesic gain from combination therapy beyond commonly used doses., (© 2011 Blackwell Publishing Ltd.)

Background: The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates., Methods: A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27-45 weeks' postmenstrual age (PMA)) was undertaken using non-linear mixed effects models. Data from three published studies were pooled with newly collected time-concentration points during repeated intravenous paracetamol administration., Results: A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%., Conclusions: Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32-44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential.

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 Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) 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 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.

Background: Acetaminophen is often used with a non-steriodal anti-inflammatory drug for acute pain. Hitherto, these drugs have had to be given separately, typically at different time intervals. Maxigesic tablets combine acetaminophen and ibuprofen in clinically appropriate doses to simplify administration and dosage regimen. We compared this combination with each of the constituent drugs for the relief of pain after extraction of third molar teeth., Methods: Adults (more than 16 yr) having one or more wisdom teeth removed under general or local anaesthesia were instructed to take two tablets before operation, then two tablets every 6 h for up to 48 h of: (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg per tablet (Maxigesic); (ii) acetaminophen 500 mg per tablet alone; or (iii) ibuprofen 150 mg per tablet alone. The primary outcome measure was the area under the curve (AUC) of the 100 mm visual analogue scale pain measurements taken for up to 48 h after surgery, divided by time, at rest and on activity. Pharmacokinetic data were collected in a subset of patients., Results: The mean (sem) time-corrected AUC on rest and activity, respectively, were: combination group 22.3 (3.2) and 28.4 (3.4); acetaminophen group 33.0 (3.1) and 40.4 (3.3); and ibuprofen group 34.8 (3.2) and 40.2 (3.4); P<0.01 for each of the four comparisons of combination vs constituent drug. There was no pharmacokinetic interaction between acetaminophen and ibuprofen administered together., Conclusions: Maxigesic tablets provide superior pain relief after oral surgery to acetaminophen or ibuprofen alone.

Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H(2) synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH(2). The two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG(2) is dependent on a tyrosine-385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe(3+) at the POX site is essential for conversion of tyrosine-385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide-generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG(2). Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti-inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p-aminophenol). p-Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.

Background: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation., Methods: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM)., Results: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled., Conclusions: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The effect compartment does not have real measurable concentrations, but concentrations equate approximately to those observed in the cerebrospinal fluid. A time delay exists before drug reaches the effect compartment, and the equilibration half-time between the central and effect compartment is described by a single first-order parameter (Teq or T(1/2)keo), reported to be approximately 1 h for paracetamol. Paediatric analgesic studies are limited because they have only explored postoperative pain after tonsillectomy or day-stay surgery. Other pain types and pain confounders have not been investigated. Adult studies are also similarly limited. Studies investigating antipyresis have not explored the maximum response, limiting the precision of any EC(50) estimate. The influence of the cyclical nature of fever or initial temperature is seldom accounted for in antipyretic studies. Target effect compartment concentrations of 5 mg/l for fever and 10 mg/l for pain do not seem unreasonable on the basis of current literature. Speed of onset may be shortened by giving a larger initial dose or improving absorption characteristics. Consequent plasma concentration achieved, differences in effect compartment equilibration times, and the shape of the effect compartment concentration-response curve help to explain differences between common analgesic/antipyretic drugs.

Background: 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 x kg(-1) (15 mg x kg(-1) paracetamol) 6 h., Methods: 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., Results: 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/F(oral)) 24 (55%) l x 70 kg(-1), peripheral volume of distribution (V3/F(oral)) 30 (32%) l x 70 kg(-1), clearance (CL/F(oral)) 16 (40%) l x h(-1) x 70 kg(-1) and intercompartment clearance (Q/F(oral)) 55 (116%) l x h(-1) x 70 kg(-1). Clearance increased from 27 weeks PCA (1.87 l x 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 '1/4 power' models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l x 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/F(oral)) and clearance (CL/F(oral)) 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., Conclusions: A mean paracetamol serum concentration of 10 mg x l(-1) is achieved in children 2-15 years given a standard dose of propacetamol 30 mg x 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 x l(-1) may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.

Background: There are few studies describing acetaminophen (APAP) cerebrospinal fluid (CSF) concentrations in children. This current study was undertaken in children--from neonates to adolescents--in order to investigate age-related changes in the plasma to CSF equilibration half-time (Teq) of APAP., Methods: Children (n=41) 1 week to 18 years of age undergoing (semi) elective surgery for placement or revision of a ventriculo-peritoneal shunt or insertion of a temporary external ventricular drain received a loading dose of 30-40 mg/kg APAP 1 h before scheduled surgery. Blood and CSF samples for APAP concentration analysis were collected during surgery. In those children with a temporary external drain, blood and CSF sampling were extended into the postoperative period. APAP and CSF pharmacokinetics were estimated using non-linear mixed-effects models. Size was standardized to a 70-kg person using allometric "1/4 power models"., Results: Median (25-75th percentile) age and weight of the patients included in this study were 12 months (3-62 months) and 10.0 kg (5.8-20.0 kg). Median (25-75th percentile) time between APAP loading dose administration and collection of blood samples and median time (25-75th percentile) between APAP loading dose and collection of CSF were, respectively, 125 min (95-210 min) and 133 min (33-202 min). The population mean Teq, standardized to a 70-kg person, was 1.93 h (CV 43%), an estimate similar to that described in adults (2.1 h). There was no relationship between age and Teq other than that predicted by size. APAP plasma concentrations ranged from 0.0 mg/l to 33.0 mg/l, APAP CSF concentrations ranged from 0.0 mg/l to 21.0 mg/l., Conclusion: Size rather than blood-brain-barrier maturation determines Teq changes with age in children. We predict a neonate (3.5 kg), 1-year-old child (10 kg), 5-year-old child (20 kg), 10-year-old child (30 kg) and adult (70 kg) to have Teq values of 0.9, 1, 1.4, 1.6, and 1.93 h, respectively.

Background: Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (<6 weeks) or children (3-9 years). There are no studies investigating infants., Methods: Infants ( n=47) undergoing major craniofacial surgery were given paracetamol 19-45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33-59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models., Results: Mean (+/-SD) age and weight of the patients were 11.8+/-2.5 months and 9.1+/-1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric "1/4 power" models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance., Conclusion: Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.

Background: The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens., Methods: A population pharmacokinetic analysis of acetaminophen time-concentration profiles in 283 children (124 aged < or = 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28-64 weeks), and median weight was 3.1 kg (range, 1.2-9.0 kg)., Results: Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric "1/4 power" models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l x h(-1) x 70 kg(-1)) with a maturation half-life of 11.3 weeks to reach 10.8 l x h(-1) x 70 kg(-1) by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66., Conclusions: A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg x kg(-1) x d(-1) in premature neonates at 30 weeks' postconception, 45 mg x kg(-1) x d(-1) at 34 weeks' gestation, 60 mg x kg(-1) x d(-1) at term, and 90 mg x kg(-1) x d(-1) at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg. kg-1. d-1 in premature neonates at 30 weeks' gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg x kg(-1) x d(-1) at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2-3 days.

Background: Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40 mg/kg., Methods: Children aged 9.0 +/- 3.0 years (+/- SD) and weight 37.9+/- 16.6 kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40 mg/kg (n = 12). high dose acetaminophen elixir 100 mg/kg (n =20) or placebo (n=30) 0.5 -1 h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0-10] were measured over a 4-8 h postoperative period. These data were pooled with data from a previous study investigating acetaminophen pharmacodynamics (n = 120) and analysed using a non-linear mixed effect model. Placebo effects and drug effects were modelled using effect-site concentration models., Results: A one-compartment model with first-order input, lag time and first-order elimination was used to describe the population pharmacokinetics of acetaminophen. Pharmacokinetic parameter estimates were similar to those previously described. Pharmacodynamic population parameter estimates [population variability coefficient of variation (CV)] for a maximum analgesic effect (Emax) model, in which the greatest possible pain relief (VAS 0-10) equates to an Emax of 10, were Emax 5.17 (64%) and 50% effective concentration 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic effect compartment was 53 min (217%). A placebo drug model for the effects of placebo response had a t(eq) of 1.96 h (40%), an elimination half-life of 2.06 h (50%) and a potency of 1.54 pain relief units (24%)., Conclusions: High dose acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10 mg/l is expected to produce a pain reduction of 2.6 units. The placebo model accounted for a maximum pain reduction of 5.6 units at 3 h. The combination of placebo effect and preoperative acetaminophen 40 mg/kg results in pain scores below 4 units for 5 h postoperatively.

Aims: The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants., Methods: Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated., Results: Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively., Conclusions: Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (Tabs 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Objective: To predict serum concentrations to evaluate and improve guidelines for the treatment of children (1 to 5 years) with accidental ingestion of acetaminophen elixir., Methods: Acetaminophen concentrations for 1000 children were simulated with pharmacokinetic parameters and their expected variability. The distribution of concentrations arising from a 300 mg/kg dose at different age groups was predicted. These predictions were validated by comparison with concentrations obtained at 4 hours from 121 children with accidental ingestion of acetaminophen elixir., Results: No child who presented with overdose had a concentration in the probable risk area of the Rumack-Matthew toxicity nomogram. Enteral charcoal administered 98 minutes (SD 44) after ingestion had no effect on serum concentrations. The simulation predicted that an acetaminophen dose of 300 mg/kg would result in concentrations of 32 to 208 mg/L (95% CI) at 4 hours after ingestion. The maximum concentration occurred before 2 hours in 95% of simulated children., Conclusion: Children (1 to 5 years) with reported ingestion of >250 mg/kg acetaminophen elixir should have serum concentrations measured at 2 hours after ingestion rather than at the 4-hour time point recommended in adults. This can be expected to speed discharge and reduce anxiety. The use of enteral charcoal is unlikely to enhance acetaminophen elimination, unless it is given within an hour of acetaminophen ingestion.

Background: There are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia., Methods: Children undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100). No other analgesic agents were administered. Individual concentrations of acetaminophen in serum and pain scores (0-10) measured over a 4-h postoperative period were analyzed using a nonlinear mixed-effects model (NONMEM)., Results: Mean (% CV) estimates of population pharmacokinetic parameters with percent coefficient of variation, standardized to a 70-kg person, for a one-compartment model with first-order input, lag time, and first order-elimination were a volume of distribution of 60 (21) 1 and a clearance of 13.5 (46) 1/h. Rectally administered acetaminophen had an absorption half-life of 35 (63) min with a lag time of 40 min. The absorption half-life for the oral preparation was 4.5 (63) min without a detectable lag time. The relative bioavailability of the rectal compared with the oral formulation was 0.54. The equilibration half-time of an effect compartment was 1.6 (131) h. Pharmacodynamic population parameter estimates (percent coefficient of variation) for a fractional sigmoidal Emax model, in which the greatest possible pain relief equates to an Emax of 1, were Emax = 1, EC50 (the concentration producing 50% of Emax) = 3.4 (94) mg/l, and Hill coefficient = 0.54 (42)., Conclusions: The pharmacodynamics of acetaminophen can be described using a sigmoidal Emax model with a low Hill coefficient. To achieve a mean posttonsillectomy pain score of 3.6 of 10, an effect compartment concentration of 10 mg/l is necessary.

The effect preoperative paracetamol elixir has on gastric contents is unknown. Children presenting for elective adenotonsillectomy were randomized to receive either paracetamol elixir (40 mg x kg(-1)) 90 min before surgery or paracetamol suppositories (40 mg x kg(-1)) intraoperatively. Following induction of anaesthesia a 16 Fr multiple-oriface orogastric tube was passed into the stomach and measure taken of the residual gastric volume and pH. The children had a mean age of 8.5 years (SD 3.2) with a weight of 35 kg (SD 16.5). Children given elixir (n=41) had a mean residual gastric volume of 0.083 ml x kg(-1) (95% CI; 0.006, 1.24) and a pH of 1.83 (95% CI; 0.75, 4.49), while those given suppositories (n=40) had a mean residual gastric volume of 0.083 ml x kg(-1)(95% CI; 0.008, 0.9) and a pH of 2.07 (95% CI; 0.84, 5.12). There was no significant difference between these two groups. Paracetamol elixir is rapidly absorbed in the gastrointestinal system of children and preoperative administration has no effect on gastric contents. Given paracetamol's slow equilibration rate constant from the central to the effect compartment, children may be given this medication preoperatively for routine surgical procedures.

Aims: Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children., Methods: Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model., Results: Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%)., Conclusions: Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.

A pharmacokinetic dynamic simulation model was used to predict rectal paracetamol dosing schedules which would maintain steady state plasma concentrations of 10-20 mg.l-1. These plasma concentrations of paracetamol are known to reduce fever. The conventional dosing schedule of 15 mg.kg-1 four hourly was unsatisfactory. Steady state concentrations of 8-12 mg.l-1 were only reached after 16 h. A loading dose of 50 mg.kg-1 followed by 30 mg.kg-1 six hourly achieved plasma concentrations of 9-18 mg.l-1. Paracetamol is a mild analgesic. A higher plasma paracetamol concentration of 25 mg.l-1 is known to give satisfactory analgesia to 60% of children after tonsillectomy. This concentration can be reached after a loading dose of 70 mg.kg-1 and a maintenance dose of 50 mg.kg-1 8 hourly. Doses above 150 mg.kg-1.day-1 have been reported to cause reversible liver toxicity after 2-8 days and should not be sustained.

Glycogelatin capsular suppositories containing a paracetamol slurry 40 mg.kg-1 were given PR to 20 children (12 months-17 yrs) after major orthopaedic surgery and plasma concentrations of paracetamol measured for up to 18 h. The mean maximum concentration (Cmax) was 0.115 (SD 0.049) mmol.l-1. Peak concentration occurred (Tmax) at 2.3 (SD 1.2) h. Mean concentration was 0.07 (SD 0.03) mmol.l-1 at six h. Apparent paracetamol clearance was 5.8 ml.min-1.kg-1. The plasma concentration of paracetamol associated with analgesic effectiveness in children is unknown, but antipyretic effects are seen in the range 0.066-0.130 mmol.l-1. Paracetamol suppositories 40 mg.kg-1 given perioperatively achieve effective therapeutic antipyretic plasma concentrations within 1-2 h. The timing is coincident with the recovery phase of short duration paediatric surgery. The coefficient of variance of Cmax was 43%. Some individual patients may not achieve a Cmax which is therapeutic.