Brian J. Anderson

Size, Myths and the Clinical Pharmacokinetics of Analgesia in Paediatric Patients

SummaryIn the paediatric population, developmental changes can be predicted by age and are independent of size, which is predicted by body weight. Size is commonly standardised using either the per kilogram or the body surface area models. A great many physiological-, structural- and time-related variables scale predictably within and between species with weight exponents of 0.75, 1 and 0.25, respectively.Use of the per kilogram size model has led to the misconception that children have an enhanced capacity to metabolise drugs because of their relatively large liver size or increased hepatic blood flow. This is not necessarily the case. For example, the clearance of opioids often approaches adult rates within the first few months of life when an allometric ¾ power model is used to scale for size. Age-related changes in physiological processes, such as respiration and cardiac output, disappear with appropriate size models. Size is an important, but little recognised, component in the speed of onset of drugs effects and uptake of inhalational anaesthetic agents. Size models cannot be reliably used to predict dose regimens for children from schedules established for adult patients. Dosage regimens are dependent on clearance and volume of distribution as well as pharmacodynamic factors, which change with age. The age-dependent pharmacodynamic changes described for some opioids in the very young have not yet been completely disentangled from age-related pharmacokinetic changes.When bodyweight is standardised and disentangled from age, developmental changes can be understood more clearly. The future investigation of drugs used in paediatric practice must also include an appropriate size model in order to differentiate age-related factors from size-related factors.

Scaling for size: some implications for paediatric anaesthesia dosing

Children remain therapeutic orphans (3±6) and the lack of well-conducted pharmacokinetic±pharmacodynamic studies is often replaced by extrapolation from adult or animal data. Size models play a signi®cant role in determining drug doses for young children, but it is important to appreciate their limitations. This review examines three size models in an attempt to improve understanding of their role, the pharmacokinetic interpretations they have generated and the pitfalls associated with their use. Boxenbaum (7) claims that, generally speaking, there are two extremes of scienti®c personality types: sharpeners and levellers. Sharpeners, highly attuned to system differences and nuances, and always alert to distinctions, try hard to let nothing slip by them unnoticed. Levellers, on the other hand, attempt to submerge system differences, reveal uniform patterns, and condense disparate elements (7). In this review, we have assumed the role of the leveller. More in depth reviews of these size models are available in the literature (8±11).

Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy.

Abstract.Background: Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40xa0mg/kg. Methods: Children aged 9.0±3.0xa0years (±SD) and weight 37.9±16.6xa0kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40xa0mg/kg (n=12), high dose acetaminophen elixir 100xa0mg/kg (n=20) or placebo (n=30) 0.5–1xa0h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0–10] were measured over a 4–8xa0h 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 9.98xa0mg/l (107%). The equilibration half-life (teq) of the analgesic effect compartment was 53xa0min (217%). A placebo drug model for the effects of placebo response had a teq of 1.96xa0h (40%), an elimination half-life of 2.06xa0h (50%) and a potency of 1.54xa0pain relief units (24%). Conclusions: High dose acetaminophen (100xa0mg/kg) was no more effective than 40xa0mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10xa0mg/l is expected to produce a pain reduction of 2.6xa0units. The placebo model accounted for a maximum pain reduction of 5.6xa0units at 3xa0h. The combination of placebo effect and preoperative acetaminophen 40xa0mg/kg results in pain scores below 4xa0units for 5xa0h postoperatively.

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial

BACKGROUNDnRelationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates.nnnMETHODSnVentilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models.nnnRESULTSnA total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.nnnCONCLUSIONSnA sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

Pharmacokinetics of rectal paracetamol after major surgery in children

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.

Common Errors of Drug Administration in Infants

Drug administration errors are common in infants. Although the infant population has a high exposure to drugs, there are few data concerning pharmacokinetics or pharmacodynamics, or the influence of paediatric diseases on these processes. Children remain therapeutic orphans. Formulations are often suitable only for adults; in addition, the lack of maturation of drug elimination processes, alteration of body composition and influence of size render the calculation of drug doses complex in infants.The commonest drug administration error in infants is one of dose, and the commonest hospital site for this error is the intensive care unit. Drug errors are a consequence of system error, and preventive strategies are possible through system analysis. The goal of a zero drug error rate should be aggressively sought, with systems in place that aim to eliminate the effects of inevitable human error. This involves review of the entire system from drug manufacture to drug administration. The nuclear industry, telecommunications and air traffic control services all practise error reduction policies with zero error as a clear goal, not by finding fault in the individual, but by identifying faults in the system and building into that system mechanisms for picking up faults before they occur. Such policies could be adapted to medicine using interventions both specific (the production of formulations which are for children only and clearly labelled, regular audit by pharmacists, legible prescriptions, standardised dose tables) and general (paediatric drug trials, education programmes, nonpunitive error reporting) to reduce the number of errors made in giving medication to infants.

Pro–con debate: is codeine a drug that still has a useful role in pediatric practice?

Background: The widespread use of codeine in children has been questioned in recent years because of concerns about unpredictable analgesia and side effects compared to other agents. Objective: To debate the advantages and disadvantages of the use of codeine as an analgesic for children. Design/Participants: 2 debaters (a pediatrician from the United Kingdom and a pharmacist from New Zealand) present arguments for and against the use of codeine. The pharmacist lays out his objections against codeine, which has been used for its analgesic, anti-tussive, and anti-diarrheal properties. Codeines analgesic action is mediated through its metabolite, morphine. Clinicians have long noted variability and lack of analgesia in the response to codeine among certain patients, which is likely due to variations in a particular gene—CYP 2D6—that governs the metabolism of codeine to morphine. Metabolizers can be poor, intermediate, or extensive; 7% to 10% of whites are slow metabolizers, so codeines conversion to morphine is limited, and this would partly explain the lack of efficacy. Only 2% of Asians are slow metabolizers. Neonates have enzymatic immaturity, and codeine is an impractical drug in this age group. Codeine has 1/10 the potency of morphine, so 60 mg of codeine has a morphine equivalence of 6 mg. The pharmacist makes a pitch for the use of oral morphine, compared to codeine, in hospital settings. This is not common in the United States, in part because of its taste as well as greater familiarity with intravenous use. The pediatrician argues that codeine has a long history of clinical usage with effective dose regimens and is available in liquid formulations for children. He concedes, however, that there are no large randomized trials involving codeine in discrete age-specific clinical situations. He argues that it should not be the drug of choice for acute severe pain in cases in which morphine, in particular, is a drug of choice. Until medications such as Tramadol, hydromorphone, or oxycodone are better studied in children, he believes codeine remains the main oral medication if acetaminophen and nonsteroidal anti-inflammatory medications are ineffective. Regarding safety, he notes that the use of codeine for many years and in many patients suggests a good safety record. Conclusions: Both discussants note that experience with codeine is extensive and that alternatives for moderate pain currently are limited. They agree that codeine is likely to remain a popular drug in pediatric medicine for the foreseeable future. Reviewers Comments: The fact of slow versus fast metabolizers of codeine is likely under-appreciated by clinicians. It is something to consider if you have a patient on codeine who is not responding to standard dosing. Also, be sure to think about adding acetaminophen in some combination for the synergistic effects. (Reviewer-Mark F. Ditmar, MD).

Airway management during an EXIT procedure for a fetus with dysgnathia complex.

Nonsyndromal dysgnathia is a rare disorder with a probable genetic basis characterized by a hypoplastic or absent mandible (agnathia), microstomia, microglossia, and ear anomalies secondary to a defect in the ventral portion of the first branchial arch caused by defective neural crest migration or proliferation. Dysgnathic newborn infants often suffer fatal respiratory failure from airway obstruction. Nineteen children with isolated dysgnathia complex are described in the literature – six were stillborn, eight died shortly after birth, and only five survived infancy. All survivors required tracheostomy to maintain an airway. It is difficult to intubate the trachea of these children and early airway management planning is important. We report a neonate who presented with a prenatal ultrasound diagnosis of severe micrognathia, polyhydramnios and a family history of severe micrognathia. Airway management was achieved with fiberoptic intubation through a laryngeal mask airway (LMATM) during an ex utero intrapartum treatment procedure. Fiberoptic intubation was hampered by copious amounts of amniotic fluid. This child and her sibling are the first two siblings with isolated dysgnathia complex to have survived infancy and provide further support for a genetic basis to this condition.

Acetaminophen in cerebrospinal fluid in children

BackgroundThere 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.MethodsChildren (n=41) 1xa0week to 18xa0years 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 30–40xa0mg/kg APAP 1xa0h 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.ResultsMedian (25–75th percentile) age and weight of the patients included in this study were 12xa0months (3–62xa0months) and 10.0xa0kg (5.8–20.0xa0kg). 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, 125xa0min (95–210xa0min) and 133xa0min (33–202xa0min). The population mean Teq, standardized to a 70-kg person, was 1.93xa0h (CV 43%), an estimate similar to that described in adults (2.1xa0h). There was no relationship between age and Teq other than that predicted by size. APAP plasma concentrations ranged from 0.0xa0mg/l to 33.0xa0mg/l, APAP CSF concentrations ranged from 0.0xa0mg/l to 21.0xa0mg/l.ConclusionSize rather than blood–brain-barrier maturation determines Teq changes with age in children. We predict a neonate (3.5xa0kg), 1-year-old child (10xa0kg), 5-year-old child (20xa0kg), 10-year-old child (30xa0kg) and adult (70xa0kg) to have Teq values of 0.9, 1, 1.4, 1.6, and 1.93xa0h, respectively.

My child is unique; the pharmacokinetics are universal

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.