Secondary Logo

Journal Logo

Pharmacology in the very young: anaesthetic implications

Anderson, Brian J.

European Journal of Anaesthesiology: June 2012 - Volume 29 - Issue 6 - p 261–270
doi: 10.1097/EJA.0b013e3283542329
Review
Free

Anaesthesia dosing in infants (0–2 years) should be based on pharmacokinetic–pharmacodynamic considerations and adverse effects profiles. Disease processes and treatments in this group are distinct from those in adults. Absorption, distribution and clearance change dramatically during this period because of maturation of anatomical and physiological processes as well as behavioural changes. Pharmacogenomic expression also matures in this period. Population-based and physiological-based pharmacokinetic modelling has improved the understanding of maturation and subsequent dose approximation. Postmenstrual, rather than postnatal, age is a reasonable measure for maturation. There remains a need for clinically applicable tools to assess pharmacodynamics which can provide response feedback; this has been achieved for neuromuscular monitoring, but not yet fully for depth of anaesthesia, sedation or pain. Morbidity and mortality associated with paediatric anaesthesia have historically been highest in this age group and continue to be so. Some of this morbidity was attributable to a poor understanding of developmental pharmacology; this facet continues to plague the specialty.

From the Department of Anaesthesiology, University of Auckland, Auckland, New Zealand

Correspondence to Professor Brian J. Anderson, Paediatric Intensive Care Unit, Starship Children's Hospital, Park Road, Grafton, Auckland, New Zealand Tel: +64 9 3074903; fax: +64 9 3078986; e-mail: briana@adhb.govt.nz

Published online 25 April 2012

Back to Top | Article Outline

Introduction

Infants and neonates include those from birth up to the age of 2 years of life. Consequently, postmenstrual age may range from extreme preterm birth at 22 weeks up to 780 weeks while weight ranges from 0.5 to 20 kg. Maturation of anatomical and physiological systems distinguishes this group as a specific population with major pharmacological differences compared with their older counterparts. Morbidity and mortality associated with paediatric anaesthesia has historically been highest in this age group1 and continues to be so.2 Some of this increased morbidity and mortality is attributable to poor understanding of maturational changes in the way the body handles a drug (pharmacokinetics),3 drug effects (pharmacodynamics) which change with age4 and adverse effects which are age-specific.5 This review examines each of these aspects of developmental pharmacology in infants and neonates and attempts to show how maturational changes impact on anaesthesia drug dosing. It is hoped that a greater understanding of these concepts may increase pharmacological safety and promote further research in this group of children.

Back to Top | Article Outline

Pharmacokinetic differences

Elimination

The main routes by which drugs and their metabolites leave the body are the hepatobiliary, renal and respiratory systems. Elimination rate is commonly described by clearance. Clearance is the important pharmacokinetic parameter that is used to determine maintenance dose or infusion rate at steady state. The liver is the primary organ for clearance of most drugs, although the lungs have a major role for anaesthetic vapours. Although the metabolism of a drug most frequently results in inactive compounds, metabolism may also result in transformation to a more potent drug (e.g. codeine to morphine by P450 CYP2D6) or into a toxic compound (halothane to trifluoroacetyl chloride by CYP2E1 causing halothane hepatitis).

Two major considerations which influence drug action in children are growth and maturation. How these factors interact is not necessarily transparent from simple clinical observations because they correlate very closely. One approach is to standardise for size before incorporating a factor for maturation and organ function.6

Back to Top | Article Outline

Size and maturation

There is a nonlinear relationship between clearance and size. Clearance in children 1–2 years of age, expressed as l h−1 kg−1, is commonly greater than that observed in older children and adolescents. Consequently, infusion rates of propofol or remifentanil are higher in young children than in adolescents. This ‘artefact of size’ disappears when allometric scaling is used (Fig. 1). Allometry is a term used to describe the nonlinear relationship between size and function. This nonlinear relationship is expressed as

Fig. 1

Fig. 1

where y is the variable of interest (e.g. basal metabolic rate) and PWR is the allometric exponent. The value of the allometric exponent has been the subject of much debate. Basal metabolic rate is the commonest variable investigated and camps advocating for an allometric exponent value of two-thirds (i.e. body surface area) are at odds with those advocating a value of three-quarters. A great many physiological, structural and time-related variables scale predictably within and between species with exponents on weights of three-quarters, 1 and one-quarter, respectively.8 These allometric exponents have applicability to pharmacokinetic parameters such as clearance (exponent of three-quarters), volume (V, exponent of 1) and half-life (T1/2, exponent of one-quarter).9 Use of these allometric models allows prediction of dose in children from the adult dose; such prediction is not possible using the mg kg−1 scaling. Paediatric doses in children out of the neonatal age group are greater than in adults. Allometric scaling has the potential to be used in programmes for target-controlled infusion pumps because scaling from the adult dose is possible. Table 1 shows an example of allometric scaling and per kilogram scaling side by side.

Table 1

Table 1

Remifentanil and atracurium are degraded by nonspecific esterases in tissues and erythrocytes. Clearance, expressed per kilogram, is increased in younger children,10–14 attributable to size because clearance is similar in all age groups when scaled to a 70 kg person using allometry.10 Nonspecific blood esterases which metabolise remifentanil and atracurium are mature at birth.15

The equilibration half-time (T1/2keo) for propofol distribution to the effect compartment increases with age,16 contributing to rapid onset of sedation in infants. Similarly, the observed speed of onset of intermediate duration neuromuscular blocking drugs (e.g. atracurium) is faster as age decreases, but can be scaled using a one-quarter power to approximately 3 min for a standard 70 kg person.17

Unlike remifentanil clearance, allometry alone is insufficient to predict clearance in neonates and infants from adult estimates for most drugs. Most clearance systems are not mature at birth. The addition of a model describing clearance maturation in these early years is required. The sigmoid hyperbolic or Hill model18 (also used to describe the oxygen saturation curve) has been found useful for describing this maturation process (MF).

The TM50 describes the maturation half-time, whereas the Hill coefficient relates to the slope of this maturation profile. Maturation of clearance begins before birth in utero, suggesting that postmenstrual age would be a better predictor of drug elimination than postnatal age.

Back to Top | Article Outline

Hepatic metabolic clearance

Phase 1 reactions are typified by the cytochrome P450 (CYP, so named because these enzymes absorb light at wavelengths near 450 nm) iso-enzymes. These, with the exception of CYP3A7, have a low phenotypic activity until birth. CYP2E1 activity surges after birth,19 CYP2D6 becomes detectable soon thereafter, CYP3A4 and CYP2C appear during the first week and CYP1A2 is the last to appear.20,21 Neonates depend on the immature CYP3A4 for levobupivacaine clearance and on CYP1A2 for ropivacaine clearance, dictating reduced epidural infusion rates in this age group.3,22,23 Formation of the major (M1) metabolite of tramadol, reflecting CYP2D6 activity,24 appears rapidly around term and reaches 84% of mature values by 44 weeks’ postmenstrual age. This enzyme has genetic polymorphisms altering phenotypic expression, which have different maturation rates in the very young.21,25 Genetic polymorphism,26,27 influencing plasma cholinesterase activity and its influence on succinylcholine, is another well known example of pharmacogenetic effects.

Some phase II iso-enzymes are mature in full-term neonates (e.g. sulphate conjugation), whereas others are not (acetylation, glycination, glucuronidation).28,29 A failure to appreciate immaturity of uridine diphosphate-glucuronosyltransferase (UGT) resulted in cardiovascular collapse of neonates given chloramphenicol in the late 1950s.30 UGT is also important for the metabolic clearance of drugs such as paracetamol, morphine, propofol and dexmedetomidine. Allometric body-size scaling complimented by maturation models9,31 have been used to describe clearance maturation of these drugs.32–36 Clearance is immature in the preterm 24-week postmenstrual age neonate and matures to reach adult rates by the end of the first year of life (Fig. 2). These maturation profiles closely match that of glomerular filtration rate; the elimination pathway of the water-soluble metabolites matches their production by UGT. Although UGT is the major metabolic pathway for propofol, multiple CYP iso-enzymes (CYP2B6, CYP2C9, CYP2A6) also contribute to its metabolism and cause a faster maturation profile than expected from UGT alone.38

Fig. 2

Fig. 2

This maturation process can be difficult to discern because other factors such as illness impact on observed clearance. The influence of illness is exemplified by morphine clearance, which is reduced in very sick neonates who are candidates for extracorporeal membrane oxygenation (ECMO); clearance increases dramatically a few days after ECMO is started.39 Similarly, clearance of propofol is reduced after cardiac surgery in children.40 The use of concomitant drugs may alter clearance. Phenobarbital induces CYP3A4,41 an enzyme responsible for ketamine clearance; ketamine, which is metabolised by CYP3A4, has a reduced sedative effect in children on long-term phenobarbital therapy.42,43

Back to Top | Article Outline

Pulmonary elimination

The factors determining anaesthetic absorption through the lung (alveolar ventilation, functional residual capacity, cardiac output, blood/gas solubility) also contribute to elimination kinetics. We might anticipate more rapid wash-out in neonates for any given duration of anaesthesia because there is less distribution to fat and muscle content. Halothane, and to a far lesser extent isoflurane and sevoflurane, undergo hepatic metabolism, but at typical anaesthetising concentrations, hepatic elimination is extremely small.44

Back to Top | Article Outline

Renal elimination

Renal elimination of drugs and their metabolites is determined by three processes: glomerular filtration, tubular secretion and tubular reabsorption. Glomerular filtration rate is only 10% of the mature value at 25 weeks, 35% at term and 90% of the adult glomerular filtration rate at 1 year of age (Fig. 2).45

Aminoglycosides are almost exclusively cleared by glomerular filtration rate and the reduced maintenance dose is predicted by postmenstrual age because it predicts the time course of renal maturation.46 Similarly, the clearance of the neuromuscular blocking drug D-tubocurarine can be directly correlated with glomerular filtration rate.47

Immaturity of the clearance pathways can be used to our advantage when managing apnoea after anaesthesia in the preterm neonate. N7-Methylation of theophylline to produce caffeine is well developed in the neonate, whereas oxidative demethylation (CYP1A2) responsible for caffeine metabolism is deficient. Theophylline is effective for the management of postoperative apnoea in the preterm neonate, in part because it is a prodrug of caffeine, which is effective in controlling apnoea in this age group and can only be cleared slowly by the immature kidney.48

Back to Top | Article Outline

Absorption

Anaesthetic drugs are mainly delivered intravenously or through inhalation, but premedication and postoperative pain relief are commonly administered enterally. Absorption characteristics impact on the amount of drug available, the maximum concentration, the speed of onset of effect, the duration of effect and the time to offset of effect.

Drug absorption after oral administration is slower in neonates than in children due to delayed gastric emptying.49,50 Slow gastric emptying and reduced clearance may dictate reduced doses and frequency of administration (Fig. 3) of analgesic drugs such as paracetamol. Chloral hydrate used as a sedative has delayed onset in those less than 6 months of age. This slow absorption combined with reduced clearance causes a prolonged effect which contributes to respiratory depression and death in this age group.52

Fig. 3

Fig. 3

The larger relative skin surface area, increased cutaneous perfusion and thinner stratum corneum in neonates increase systemic exposure of topical drugs (e.g. corticosteroids, local anaesthetic creams, antiseptics). Neonates have a tendency to form methaemoglobin because they have reduced methaemoglobin reductase activity and fetal haemoglobin is more readily oxidised compared with adult haemoglobin. This, combined with increased percutaneous absorption, has resulted in reluctance to use repeat lidocaine-prilocaine cream in this age group.53

The nature of the epidural space in infants is different from the adult, with increased vascularity and a smaller absorptive surface for local anaesthetics. Anatomical studies have shown that the epidural fat is spongy and gelatinous in appearance with distinct spaces between individual fat globules.54 With increasing age, fat becomes more tightly packed and fibrous. The absorption half-time of epidural levobupivacaine decreases from birth until 6 months’ postnatal age. This, combined with reduced clearance (the cytochrome P450, CYP3A4), causes the time to maximum plasma concentration (Tmax) to be delayed in neonates (Fig. 4).23 This slower absorption may contribute to increased rostral spread of local anaesthetic and the consequent longer duration of caudal analgesia observed in infants.55

Fig. 4

Fig. 4

Neonates and infants have an increased alveolar ventilation : functional residual capacity ratio compared with adults, primarily as a result of an increased metabolic demand for oxygen, which drives an increase in alveolar ventilation. Consequently, the alveolar : inspired fractions and therefore the blood : inspired partial pressure of anaesthetics reach equilibration more rapidly in neonates than in children and adults.56 The higher cardiac output and greater fraction of the cardiac output distributed to vessel-rich tissues (i.e. a clearance factor) and the lower tissue : blood solubility (i.e. a volume factor) further contribute to the more rapid wash-in of inhalational anaesthetics in early life.57–59

Disease characteristics further contribute to the variability in inhalational absorption. Induction of anaesthesia may be slowed by right-to-left shunting of blood in neonates who have cyanotic congenital cardiac disease or intrapulmonary conditions. This slowing is greatest with the least soluble anaesthetics (e.g. nitrous oxide, sevoflurane). Left-to-right shunts usually have minimal impact on uptake because cardiac output is increased so that systemic tissue perfusion is maintained at normal levels.

Analgesic medications and delivery systems commonly used in adults may not be possible or practicable in children because they do not have behavioural maturity. Infants are unable to use patient-controlled analgesia devices. Dose accuracy is lost when buccal and sublingual administration is attempted because those routes require prolonged exposure to the mucosal surface. Infants find it difficult to hold drug in their mouth for the requisite retention time (particularly if taste is unfavourable) and this results in more swallowed drug or drug spat out than in adults.60 If the drug has a high first pass effect, then the lower relative bioavailability results in lower plasma concentrations. Although many analgesics are available in an oral liquid formulation, taste is a strong determinant of compliance and unpalatable preparations may be refused.61 Taste changes with age.

Back to Top | Article Outline

Distribution

At its simplest, volume of distribution determines the initial dose of a drug. The bigger the volume of distribution, the bigger the dose required to achieve a target concentration. However, many drugs used in anaesthesia distribute to more than one compartment and do not have one simple volume of distribution. Larger doses may cause greater adverse effects, for example, hypotension with propofol. Distribution is influenced by body composition, protein binding, haemodynamics (e.g. regional blood flow) and membrane permeability.

Back to Top | Article Outline

Body composition

Total body water and extracellular fluid62 are increased in neonates and their reduction tends to follow postnatal age. The percentage of body weight contributed by fat is 3% in a 1.5 kg premature neonate and 12% in a term neonate. This proportion doubles by 4–5 months of age. These body component changes affect volumes of distribution of drugs. Polar drugs such as aminoglycosides distribute rapidly into the extracellular fluid, but enter cells more slowly. The initial dose of such drugs which can be described by one simple compartment is consequently higher in the neonate compared with those in a child or adult. In contrast, morphine is a hydrophilic drug and has a reduced volume of distribution in neonates32; the initial dose of morphine given to a neonate, expressed as mg per kg, should be less than that given to an adult. Respiratory depression is more likely if the direct proportional adult dose is given to a neonate.

Reduction in blood propofol concentration after induction of anaesthesia is attributable to redistribution rather than rapid clearance because its pharmacokinetics are described using more than one compartment. Neonates have low body fat and muscle content and so less propofol is apportioned to the ‘deep’ compartments. Delayed awakening occurs because the concentration in the brain remains higher than that observed in older children as a consequence of this reduced redistribution.

Back to Top | Article Outline

Plasma proteins

Albumin and α1-acid glycoprotein concentrations are reduced in neonates, albeit with a broad range of scatter (0.32–0.92 g l−1), but are similar to those in adults by 6 months’ postnatal age.63,64 Bupivacaine is bound to α1-acid glycoprotein. The recommended bolus epidural dose of bupivacaine in neonates is lower than in children (1.5–2 vs. 2.5 mg kg−1) because a greater proportion is unbound drug and it is unbound drug which exerts its effect.3

α1-Acid glycoprotein is an acute phase reactant which increases after surgical stress. This causes an increase in total plasma concentrations of low-extraction to intermediate-extraction drugs such as bupivacaine.65 However, the unbound concentration does not change because clearance of the unbound drug is affected only by the intrinsic metabolising capacity of the liver. Any increase in unbound concentrations observed during long-term epidural infusion is attributable to reduced clearance rather than the concentration of α1-acid glycoprotein.17 Total bupivacaine concentration increases in the first 24 h after surgery in neonates given analgesia by continuous epidural infusion. This increase is attributable to an increase of α1-acid glycoprotein. This knowledge, combined with reports of seizures in infants given an epidural infusion of bupivacaine, has led to recommendations to stop epidural infusion at 24 h. However, it is the unbound bupivacaine which is responsible for effect and this unbound concentration may not change, implying that the infusion could be run for a longer duration.66 Clearance is the key parameter and this is reduced in neonates. Unfortunately, clearance is associated with large between-subject variability and this means that unbound bupivacaine concentrations may continue to rise in some infants with very low clearance. Consequently, continuous epidural bupivacaine infusion rates in neonates (0.2 mg kg−1 h−1) are less than those in children (0.4 mg kg−1 h−1) and there is a reluctance to continue these infusions beyond 48 h.67

Plasma albumin concentrations approximate to adult values by 5 months’ postnatal age and are lowest in preterm neonates. Binding capacity approaches adult values by 1 year of age. In addition, free fatty acids and unconjugated bilirubin compete with acidic drugs (e.g. ibuprofen, ceftriaxone) for albumin binding. Neonates also have a tendency to manifest a metabolic acidosis which alters ionisation and binding properties of plasma proteins. The induction dose of thiopental is lower in neonates than in children, possibly due to decreased binding of thiopental to plasma albumin; 13% of the drug is unbound in newborns compared with 7% in adults.68

Back to Top | Article Outline

Regional blood flows

The initial phase of distribution after intravenous administration of drugs reflects regional blood flow. The brain, heart and liver are exposed first. The drug is then redistributed to other relatively well perfused tissues, such as skeletal muscle. There is a much slower tertiary distribution to relatively underperfused tissues of the body, noted particularly with long-term drug infusions. These changes contribute to a lower context sensitive half-time in infants, with quicker ‘awakening’ after sedative drugs; infants have less fat and muscle bulk to which drug can redistribute and later leach out from. However, clearance is typically reduced in neonates and causes a longer context sensitive half-time.

Perinatal circulatory changes (e.g. ductus venosus, ductus arteriosus) alter drug disposition.69 Relative to cardiac output, blood flows to kidney and brain increase with age, whereas that to the liver decreases through neonatal life.70 Cerebral and hepatic masses as a proportion of body weight are much higher in the infant than in the adult.71 Reduced cardiac output and cerebral perfusion in neonates means that onset time after intravenous induction is slower in neonates, although reduced protein binding may counter this observation for some drugs. Offset time is also delayed because redistribution to well perfused and deep underperfused tissues is more limited.

Back to Top | Article Outline

Blood–brain barrier

The blood–brain barrier is a network of tight junctions to restrict paracellular diffusion of compounds between blood and brain. The ‘leaky blood–brain barrier theory’ was initially proposed to explain the reduced respiratory depression observed with pethidine compared with morphine in neonates.72 However, respiratory depression could have been due to higher morphine concentrations caused by a smaller volume of distribution in neonates when given the same dose (in mg per kg) as adults. The respiratory depressant effects of morphine are similar from 2 to 570 days of age at the same blood morphine concentration.73

The blood–brain barrier may have an impact in other ways. Small molecules access fetal and neonatal brains more readily.74 Blood–brain barrier function improves gradually, possibly reaching maturity at term.74 For example, kernicterus is more common in premature neonates. Drugs bound to plasma proteins do not normally cross the blood–brain barrier. However, unbound lipophilic drugs diffuse passively across the blood–brain barrier to achieve equilibrium very quickly. This may contribute to the propensity of bupivacaine to cause seizures in neonates. Decreased protein binding in neonates results in a greater proportion of unbound drug.

In addition to passive diffusion, there are also specific active transport systems. Pathological conditions affecting the central nervous system (CNS) can cause blood–brain barrier breakdown and alterations in these transport systems. Fentanyl is actively transported across the blood–brain barrier by a saturable ATP-dependent process, whereas ATP-binding cassette proteins such as P-glycoprotein actively pump out opioids such as fentanyl and morphine.75 P-glycoprotein modulation significantly influences brain distribution and onset time of opioids, and the magnitude and duration of the analgesic response.76 Modulation may occur with disease processes, fever or drugs (e.g. verapamil).75 Genetic polymorphisms affecting P-glycoprotein-related genes may explain differences in CNS-active drug sensitivity.77

Back to Top | Article Outline

Pharmacodynamics

Altered pharmacodynamics in infants

Children's responses to drugs have much in common with the responses in adults once developmental pharmacokinetic aspects are considered.78 The perception that drug effects differ in children arises because these drugs have not been adequately studied in paediatric populations with size-related and age-related effects as well as different diseases. However, neonates and infants do have altered pharmacodynamics. A common example is bronchodilators; these are ineffective in infants aged less than 1 year because of the paucity of bronchial smooth muscle that can cause bronchospasm.

The minimal alveolar concentration (MAC) is commonly used to express anaesthetic vapour potency. The MAC for almost all these vapours is less in neonates than in infants.55,57,59,79,80 MAC typically peaks at 1–6 months of age before decreasing to adult values in adolescence.57 Changes in regional blood flow may influence the amount of anaesthetic going to the brain. Changes in the number of γ-aminobutyric acidA (GABAA) receptors or developmental shifts in the regulation of chloride transporters in the brain also occur with age and contribute to altered responses (e.g. to midazolam).81 Delivery of halothane to neonates at a MAC suitable for adults can contribute to bradycardia and increased mortality in neonates.4

The dose of thiopental varies with age, for example 3.4 mg kg−1 in neonates, 6.3 mg kg−1 in infants and 4.5 mg kg−1 in children aged 4–7 years.82,83 It remains uncertain whether altered pharmacokinetics or pharmacodynamic responses explain the reduced dose requirements in neonates. The effect site concentration of thiopental for induction of anaesthesia in neonates may be less than that in infants because the neonates have relatively immature cerebral cortical function, rudimentary dendritic arborisations and relatively few synapses,84 but there are no studies to support or refute this premise.85

Neonates have an increased sensitivity to the effects of neuromuscular blocking drugs.47 The reason for this is unknown, but it is consistent with the observation that there is a three-fold reduction in the release of acetylcholine from the infant rat phrenic nerve.86,87 Cardiac calcium stores in the endoplasmic reticulum are reduced in the neonatal heart because of immaturity. Exogenous calcium has greater impact on contractility in this age group than in older children or adults. Conversely, calcium channel blocking drugs (e.g. verapamil) can cause life-threatening bradycardia and hypotension.88

Catecholamine release and responses to vasoactive drugs vary with age. Dopaminergic receptors are fewer in the pulmonary than in the systemic vasculature and this enables the use of dopamine in neonates with known pulmonary hypertension after cardiac surgery. Signs of cardiovascular α-receptor stimulation may occur at lower doses than β-receptor stimulation because β-receptor maturation lags behind α-receptor maturation during the development of the adrenergic system.89 Maturation changes in pharmacokinetics (e.g. reduced elimination89–92) and pharmacodynamics may contribute to the continued popularity of dopamine in the neonatal nursery while its popularity wanes in the adult population.

Back to Top | Article Outline

Measurement of pharmacodynamics in infants

Outcome measures are commonly more difficult to assess in neonates and infants than in children or adults. The common effects measured in anaesthesia are neuromuscular blockade, depth of anaesthesia and sedation or pain. A common effect measure used to assess depth of anaesthesia is the electroencephalogram (EEG) or a modification of detected EEG signals (e.g. spectral edge frequency, bispectral index, entropy). Physiological studies in adults and children indicate that EEG-derived anaesthesia depth monitors can provide an imprecise and drug-dependent measure of arousal. In infants, their use cannot yet be supported.93,94 The EEG in infants is fundamentally different from the EEG in older children; there remains a need for specific neonatal algorithms if EEG-derived anaesthesia depth monitors are to be used in neonates.95,96

There is an extensive number of sedation or pain scales. Most scores are validated for the acute, procedural setting and perform less well for subacute or chronic pain. Future research may provide us with objective tools to quantify pain and sedation, but will have to take maturational aspects of the infant into account97–99 Similarly, postoperative nausea is difficult to quantify in neonates and infants who cannot verbalise; this makes comparison with adult postoperative nausea and vomiting scales tenuous.

Back to Top | Article Outline

Adverse drug effects

Neonates and young children may suffer permanent effects resulting from a stimulus applied at a sensitive point in development. For example, tetracyclines cause staining of developing teeth.100 The incidence of vaginal carcinoma is high in children of mothers treated with stilboesterol during pregnancy.101 There are concerns that neonatal exposure to some anaesthetic agents (e.g. ketamine, midazolam) may cause widespread neuronal apoptosis and long-term memory deficits.102–104

Therapeutic use of drugs balances beneficial effects against adverse effects. However, adverse effects may simply be a consequence of a poor understanding of pharmacokinetics. An infusion of propofol in neonates based on the adult dose in mg kg−1 h−1 results in an overdose and causes hypotension; an infusion of propofol in 1–2-year-olds (where clearance is increased, expressed as mg kg−1 h−1) may result in an underdose and result in awareness. Doses of morphine in the very young have been traditionally limited by fears of respiratory compromise105 and postoperative arterial oxygen desaturation continues to be reported with sedative drugs in neonates.106 These are a result of poor pharmacokinetic understanding. However, there are also pharmacodynamic differences. Premature neonates are more prone to apnoea. Sympathetic–parasympathetic tone is immature in neonates and the use of propofol in neonates has recently been associated with profound hypotension,107,108 questioning our understanding of the dose–effect relationships of this common drug.5 Such information allows informed dosing.

Back to Top | Article Outline

Key learning points

  1. Neonates and infants are a quite diverse group of children. They range from the extremely premature neonate through to 2 years of age, and encompass diverse pathologies, maturation states and weight ranges.
  2. The main routes of elimination are the hepatobiliary system, kidneys and lungs. Size and maturation are the major covariates influencing clearance. The liver and kidneys are immature at birth, maturing over the first 2 years of life. Clearance is generally reduced in the neonate. Postmentrual age rather than postnatal age is a better marker of maturation.
  3. Absorption through skin and lungs is increased in neonates, orally it is slowed by reduced gastric emptying times and rectally it is extremely variable.
  4. Distribution volumes may be increased or decreased depending on body factors (e.g. composition, protein binding, regional blood flow and membrane permeability) and drug physical factors (e.g. lipophilicity).
  5. Neonates display altered responses to drugs compared with older children. Our ability to monitor many of these altered responses remains poor.
Back to Top | Article Outline

Conclusion

An understanding of pharmacology in the very young is important in order to achieve appropriate effects of drugs used by anaesthetists. Many facets of this knowledge in young children remain unknown, even for common drugs (e.g. propofol), hindering the use of target-controlled infusion pumps in that population.109,110 A better understanding of pharmacokinetic and pharmacodynamic maturation in the very young is needed for dose approximation.

Back to Top | Article Outline

Acknowledgements

This review is a selected refresher course lecture at the 2012 Euroanaesthesia meeting in Paris. It extends on an earlier paper ‘Anderson BJ, Allegaert K. The pharmacology of general anaesthetics in the neonate. Best Practice & Research Clinical Anaesthesiology 2010; 24 : 419–431’. Brian Anderson has received honoraria for talks, consultancies and support for travel costs to conferences from Neuren Pharmaceuticals, Bristol-Myer Squibb, Reckitt Benckiser, SmithKline Beecham, ATF and McNiell Pharmaceuticals.

Conflicts of interest: none.

Back to Top | Article Outline

References

1. Maund E, McDaid C, Rice S, et al. Paracetamol and selective and nonselective nonsteroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth 2011; 106:292–297.
2. van der Griend BF, Lister NA, McKenzie IM, et al. Postoperative mortality in children after 101 885 anesthetics at a tertiary pediatric hospital. Anesth Analg 2011; 112:1440–1447.
3. Berde C. Convulsions associated with pediatric regional anesthesia. Anesth Analg 1992; 75:164–166.
4. Keenan RL, Shapiro JH, Kane FR, Simpson PM. Bradycardia during anesthesia in infants. An epidemiologic study. Anesthesiology 1994; 80:976–982.
5. Lerman J, Heard C, Steward DJ. Neonatal tracheal intubation: an imbroglio unresolved. Paediatr Anaesth 2010; 20:585–590.
6. Tod M, Jullien V, Pons G. Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet 2008; 47:231–243.
7. Potts AL, Anderson BJ, Warman GR, et al. Dexmedetomidine pharmacokinetics in pediatric intensive care: a pooled analysis. Paediatr Anaesth 2009; 19:1119–1129.
    8. West GB, Brown JH. The origin of allometric scaling laws in biology from genomes to ecosystems: towards a quantitative unifying theory of biological structure and organization. J Exp Biol 2005; 208:1575–1592.
    9. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48:303–332.
    10. Rigby-Jones AE, Priston MJ, Sneyd JR, et al. Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery. Br J Anaesth 2007; 99:252–261.
    11. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I: Model development. Anesthesiology 1997; 86:10–23.
    12. Ross AK, Davis PJ, Dear Gd GL, et al. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg 2001; 93:1393–1401.
    13. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 1998; 88:1467–1474.
    14. Egan TD. Pharmacokinetics and pharmacodynamics of remifentanil: an update in the year 2000. Curr Opin Anaesthesiol 2000; 13:449–455.
    15. Welzing L, Ebenfeld S, Dlugay V, et al. Remifentanil degradation in umbilical cord blood of preterm infants. Anesthesiology 2011; 114:570–577.
    16. Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children. Br J Anaesth 2008; 100:509–516.
    17. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33:313–327.
    18. Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 1910; 14: iv–vii.
    19. Johnsrud EK, Koukouritaki SB, Divakaran K, et al. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther 2003; 307:402–407.
    20. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349:1157–1167.
    21. Ogasawara K, Tanaka M, Nishikawa T. Choice of electrocardiography lead does not affect the usefulness of the T-wave criterion for detecting intravascular injection of an epinephrine test dose in anesthetized children. Anesth Analg 2003; 97:372–376.
    22. Anderson BJ, Hansen TG. Getting the best from pediatric pharmacokinetic data. Paediatr Anaesth 2004; 14:713–715.
    23. Chalkiadis GA, Anderson BJ. Age and size are the major covariates for prediction of levobupivacaine clearance in children. Paediatr Anaesth 2006; 16:275–282.
    24. Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity. Br J Anaesth 2005; 95:231–239.
    25. Allegaert K, van den Anker JN, de Hoon JN, et al. Covariates of tramadol disposition in the first months of life. Br J Anaesth 2008; 100:525–532.
    26. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37:485–505.
    27. Fagerlund TH, Braaten O. No pain relief from codeine...? An introduction to pharmacogenomics. Acta Anaesthesiol Scand 2001; 45:140–149.
    28. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 2002; 300:361–366.
    29. Miyagi SJ, Collier AC. The development of UDP-glucuronosyltransferases 1A1 and 1A6 in the pediatric liver. Drug Metab Dispos 2011; 39:912–919.
    30. Burns LE, Hodgman JE. Fatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med 1959; 261:1318–1321.
    31. Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009; 24:25–36.
    32. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92:208–217.
    33. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth 2008; 101:680–689.
    34. Anderson BJ, Woollard GA, Holford NH. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br J Clin Pharmacol 2000; 50:125–134.
    35. Anderson BJ, Pons G, Autret-Leca E, et al. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Anaesth 2005; 15:282–292.
    36. Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in children: a population analysis. Paediatr Anaesth 2008; 18:722–730.
    37. Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth 2011; 21:222–237.
      38. Allegaert K, Peeters MY, Verbesselt R, et al. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth 2007; 99:864–870.
      39. Peters JW, Anderson BJ, Simons SH, et al. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med 2005; 31:257–263.
      40. Rigby-Jones AE, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97:1393–1400.
      41. Corcos L, Lagadic-Gossmann D. Gene induction by phenobarbital: an update on an old question that receives key novel answers. Pharmacol Toxicol 2001; 89:113–122.
      42. Eker HE, Yalcin Cok O, Aribogan A, Arslan G. Children on phenobarbital monotherapy requires more sedatives during MRI. Paediatr Anaesth 2011; 21:998–1002.
      43. Sumpter A, Anderson BJ. Phenobarbital and some anesthesia implications. Pediatr Anaesth 2011; 21:995–997.
      44. Sawyer DC, Eger EI, Bahlman SH, et al. Concentration dependence of hepatic halothane metabolism. Anesthesiology 1971; 34:230–235.
      45. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24:67–76.
      46. Langhendries JP, Battisti O, Bertrand JM, et al. Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit. Biol Neonate 1998; 74:351–362.
      47. Fisher DM, O’Keeffe C, Stanski DR, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982; 57:203–208.
      48. McNamara DG, Nixon GM, Anderson BJ. Methylxanthines for the treatment of apnea associated with bronchiolitis and anesthesia. Paediatr Anaesth 2004; 14:541–550.
      49. Grand RJ, Watkins JB, Torti FM. Development of the human intestinal tract: a review. Gastroenterology 1976; 70:790–810.
      50. Liang J, Co E, Zhang M, et al. Development of gastric slow waves in preterm infants measured by electrogastrography. Am J Physiol 1998; 274:G503–G508.
      51. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 2002; 96:1336–1345.
        52. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics 2000; 106:633–644.
        53. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine-prilocaine cream for pain during circumcision. N Engl J Med 1997; 336:1197–1201.
        54. Bosenberg AT, Bland BA, Schulte Steinberg O, Downing JW. Thoracic epidural anesthesia via caudal route in infants. Anesthesiology 1988; 69:265–269.
        55. Warner MA, Kunkel SE, Offord KO, et al. The effects of age, epinephrine, and operative site on duration of caudal analgesia in pediatric patients. Anesth Analg 1987; 66:995–998.
        56. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969; 30:388–394.
        57. Lerman J. Pharmacology of inhalational anaesthetics in infants and children. Paediatr Anaesth 1992; 2:191–203.
        58. Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentrations in neonates and adults. Anesthesiology 1990; 72:793–796.
        59. Molin JC, Bendhack LM. Clonidine induces rat aorta relaxation by nitric oxide-dependent and -independent mechanisms. Vascul Pharmacol 2004; 42:1–6.
        60. Karl HW, Rosenberger JL, Larach MG, Ruffle JM. Transmucosal administration of midazolam for premedication of pediatric patients. Comparison of the nasal and sublingual routes. Anesthesiology 1993; 78:885–891.
        61. Herd DW, Salehi B. Palatability of two forms of paracetamol (acetaminophen) suspension: a randomised trial. Paediatr Perinat Drug Ther 2006; 7:189–193.
        62. Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 1961; 28:169–181.
        63. Luz G, Innerhofer P, Bachmann B, et al. Bupivacaine plasma concentrations during continuous epidural anesthesia in infants and children. Anesth Analg 1996; 82:231–234.
        64. Luz G, Wieser C, Innerhofer P, et al. Free and total bupivacaine plasma concentrations after continuous epidural anaesthesia in infants and children. Paediatr Anaesth 1998; 8:473–478.
        65. Erichsen CJ, Sjovall J, Kehlet H, et al. Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief. Anesthesiology 1996; 84:834–842.
        66. Bosenberg AT, Thomas J, Cronje L, et al. Pharmacokinetics and efficacy of ropivacaine for continuous epidural infusion in neonates and infants. Paediatr Anaesth 2005; 15:739–749.
        67. Larsson BA, Lonnqvist PA, Olsson GL. Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg 1997; 84:501–505.
        68. Russo H, Bressolle F. Pharmacodynamics and pharmacokinetics of thiopental. Clin Pharmacokinet 1998; 35:95–134.
        69. Gal P, Gilman JT. Drug disposition in neonates with patent ductus arteriosus. Ann Pharmacother 1993; 27:1383–1388.
        70. Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 2005; 59:691–704.
        71. Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A. Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transpl 2005; 11:1481–1493.
        72. Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6:454–461.
        73. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77:695–701.
        74. Engelhardt B. Development of the blood-brain barrier. Cell Tissue Res 2003; 314:119–129.
        75. Henthorn TK, Liu Y, Mahapatro M, Ng KY. Active transport of fentanyl by the blood-brain barrier. J Pharmacol Exp Ther 1999; 289:1084–1089.
        76. Hamabe W, Maeda T, Kiguchi N, et al. Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain. J Pharmacol Sci 2007; 105:353–360.
        77. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 2006; 25:231–259.
        78. Stephenson T. How children's responses to drugs differ from adults. Br J Clin Pharmacol 2005; 59:670–673.
        79. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67:301–307.
        80. Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements for halothane in young children 0-1 month and 1-6 months of age. Anesthesiology 1983; 59:421–424.
        81. Koch SC, Fitzgerald M, Hathway GJ. Midazolam potentiates nociceptive behavior, sensitizes cutaneous reflexes, and is devoid of sedative action in neonatal rats. Anesthesiology 2008; 108:122–129.
        82. Westrin P, Jonmarker C, Werner O. Thiopental requirements for induction of anesthesia in neonates and in infants one to six months of age. Anesthesiology 1989; 71:344–346.
        83. Jonmarker C, Westrin P, Larsson S, Werner O. Thiopental requirements for induction of anesthesia in children. Anesthesiology 1987; 67:104–107.
        84. Glantz LA, Gilmore JH, Hamer RM, et al. Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood. Neuroscience 2007; 149:582–591.
        85. Norman E, Malmqvist U, Westrin P, Fellman V. Thiopental pharmacokinetics in newborn infants: a case report of overdose. Acta Paediatr 2009; 98:1680–1682.
        86. Meakin G, Morton RH, Wareham AC. Age-dependent variation in response to tubocurarine in the isolated rat diaphragm. Br J Anaesth 1992; 68:161–163.
        87. Wareham AC, Morton RH, Meakin GH. Low quantal content of the endplate potential reduces safety factor for neuromuscular transmission in the diaphragm of the newborn rat. Br J Anaesth 1994; 72:205–209.
        88. Radford D. Side effects of verapamil in infants. Arch Dis Child 1983; 58:465–466.
        89. Seri I, Tulassay T, Kiszel J, et al. Cardiovascular response to dopamine in hypotensive preterm neonates with severe hyaline membrane disease. Eur J Pediatr 1984; 142:3–9.
        90. Cuevas L, Yeh TF, John EG, et al. The effect of low-dose dopamine infusion on cardiopulmonary and renal status in premature newborns with respiratory distress syndrome. Am J Dis Child 1991; 145:799–803.
        91. Seri I. Dopamine and natriuresis. Mechanism of action and developmental aspects. Am J Hypertens 1990; 3:82S–86S.
        92. Seri I, Tulassay T, Kiszel J, et al. Effect of low-dose dopamine infusion on prolactin and thyrotropin secretion in preterm infants with hyaline membrane disease. Biol Neonate 1985; 47:317–322.
        93. Davidson AJ. Measuring anesthesia in children using the EEG. Pediatr Anesthesia 2006; 16:374–387.
        94. Davidson AJ, Huang GH, Rebmann CS, Ellery C. Performance of entropy and Bispectral Index as measures of anaesthesia effect in children of different ages. Br J Anaesth 2005; 95:674–679.
        95. Davidson AJ, Sale SM, Wong C, et al. The electroencephalograph during anesthesia and emergence in infants and children. Paediatr Anaesth 2008; 18:60–70.
        96. Jeleazcov C, Schmidt J, Schmitz B, et al. EEG variables as measures of arousal during propofol anaesthesia for general surgery in children: rational selection and age dependence. Br J Anaesth 2007; 99:845–854.
        97. Thewissen L, Allegaert K. Analgosedation in neonates: do we still need additional tools after 30 years of clinical research? Arch Dis Child Educ Pract Ed 2011; 96:112–118.
        98. Bruguerolle B, Attolini L, Lorec AM, Gantenbein M. Kinetics of bupivacaine after clonidine pretreatment in mice. Can J Anaesth 1995; 42:434–437.
        99. Inomata S, Tanaka E, Miyabe M, et al. Plasma lidocaine concentrations during continuous thoracic epidural anesthesia after clonidine premedication in children. Anesth Analg 2001; 93:1147–1151.
        100. Sanchez AR, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol 2004; 43:709–715.
        101. Linden G, Henderson BE. Genital-tract cancers in adolescents and young adults. N Engl J Med 1972; 286:760–761.
        102. Fredriksson A, Archer T, Alm H, et al. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav. Brain Res 2004; 153:367–376.
        103. Wang C, Sadovova N, Fu X, et al. The role of the N-methyl-D-aspartate receptor in ketamine-induced apoptosis in rat forebrain culture. Neuroscience 2005; 132:967–977.
        104. Davidson AJ. Anesthesia and neurotoxicity to the developing brain: the clinical relevance. Paediatr Anaesth 2011; 21:716–721.
        105. Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: a comparison of hospital analgesic usage in children and adults. Pediatrics 1986; 77:11–15.
        106. Ansermino M, Basu R, Vandebeek C, Montgomery C. Nonopioid additives to local anaesthetics for caudal blockade in children: a systematic review. Paediatr Anaesth 2003; 13:561–573.
        107. Welzing L, Kribs A, Eifinger F, et al. Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates. Paediatr Anaesth 2010; 20:605–611.
        108. Vanderhaegen J, Naulaers G, Van Huffel S, et al. Cerebral and systemic hemodynamic effects of intravenous bolus administration of propofol in neonates. Neonatology 2010; 98:57–63.
        109. Anderson BJ, Hodkinson B. Are there still limitations for the use of target-controlled infusion in children? Curr Opin Anaesthesiol 2010; 23:356–362.
        110. Binning AR, Przesmycki K, Sowinski P, et al. A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/sedation) of morphine-6-glucuronide versus morphine for postoperative pain relief after major abdominal surgery. Eur J Pain 2011; 15:402–408.
        Keywords:

        anaesthesia; developmental pharmacology; neonate; paediatrics; pharmacodynamics; pharmacokinetics

        © 2012 European Society of Anaesthesiology