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Neonatal pharmacology
NEONATAL ANAESTHESIA
Neonatal pharmacology
Learning objectives
Brian J Anderson
After reading this article, you should be able to: C precis the challenges that face clinicians delivering dosing regimens in neonates, including appreciation of the non-linear relationship between metabolic processes and size in children C explain how growth and development in the neonate affects drug disposition (with examples) C provide an overview of the recent developments in neonatal pharmacology (with immediate relevance to the anaesthetist)
Abstract Neonatal anaesthesia dosing needs to be based on physiological characteristics of the newborn, pharmacokinetic knowledge, pharmacodynamic considerations and the adverse effects profile. Disease processes and treatments in this group are distinct from adults. Immaturity of enzyme, anatomical and physiological systems cause extensive variability of drug disposition and drug response in neonates. This is further compounded by pharmacogenomic influences. Postmenstrual age is a reasonable measure for maturation of clearance pathways. The neonatal response to drugs is altered and monitoring of effect that guides adult drug use is limited. While neuromuscular monitoring is robust, few other clinically applicable tools are available to provide pharmacodynamic effect feedback. Tools that assess depth of anaesthesia, sedation and pain in neonates have potential to improve effectiveness and safety.
multiple institutions and better computer programs have enabled greater understanding of PK and PD.
Neonatal pharmacokinetics Absorption Physicochemical and patient factors influence the ability of a drug to translocate from its site of administration to the bloodstream and site of action (Box 1).
Keywords Drugs; neonatal; off-label; paediatric; pharmacodynamics; pharmacokinetics; pharmacology; therapeutic orphan
Some factors affecting drug absorption relating to neonates
Royal College of Anaesthetists CPD Matrix: 1A02
Physicochemical factors Drug formulation C Disintegration of tablets or solid phase C Dissolution of drug in gastric or intestinal fluid C Release from sustained-release preparations Molecular weight pK/Proportion of drug in ionized/un-ionized form Lipid solubility
Not all neonates are the same Neonates are a heterogeneous group of children from birth up to the age of 28 days of life. The word ‘neonate’ also includes former prematurely born neonates. Postmenstrual age (PMA) may range from extreme preterm birth at 22 weeks up to 50 weeks PMA while weight may range from <0.5 kg to >5 kg; an entire order of magnitude. Age, size, comorbidity, co-administration of drugs and genetic polymorphisms contribute to the extensive between-individual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Neonates became ‘therapeutic orphans’ after misuse of drugs such as chloramphenicol and thalidomide in this population. Ethical constraints and medicolegal issues surrounding consent and risk in non-therapeutic research limited drug study participation. Technical issues such as blood sampling and amount for assay made PK studies difficult. Recruitment of adequate numbers of neonates with similar pathology at the same stage of growth and development was difficult. Clinical endpoints were often poorly defined. Adverse drug effects may not become apparent until later life. Further, the market for most drugs in children is small in comparison to that in adults. Many of these research obstacles have been dismantled. Financial incentives and legislative changes have been introduced to encourage drug labelling in children. Micro-sampling, more sensitive analytical methods, pooling of data from
Patient factors General C Surface area available for absorption Gastrointestinal C Gastric content and gastric emptying C Gastric and duodenal pH C Size of bile-salt pool C Bacterial colonization of lower intestine C Disease states (e.g. short-gut syndrome, biliary atresia) Muscle C Increased capillary density in neonatal muscle compared with adults increases absorption from muscles C Reduced cardiac output states reduce absorption Skin C Blood supply C Peripheral vasodilation C Thickness of skin/stratum corneum C Surface area Rectal C Rectal venous drainage site C Neonatal absorption > older children
Brian J Anderson PhD FANZCA FCICM is a Consultant Paediatric Anaesthetist and Intensivist at Starship Children’s Hospital, Auckland, New Zealand. Conflicts of interest: none declared.
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The patient factors are particularly relevant in neonates. Box 1
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NEONATAL ANAESTHESIA
Enteral absorption when drugs are given orally is slower in neonates and infants. Gastric emptying and intestinal motility are delayed and may not mature until 6e8 months. This results in an increased time to peak concentration as well as decreased peak concentration compared to older children. Slow gastric emptying is also associated with type of feed (increased calorie density and long-chain fatty acids); and disease states (e.g. pyloric stenosis, congestive cardiac failure, duodenal atresia). Human milk and low-calorie feed quicken gastric emptying. Co-administration of drugs (e.g. opioids) can slow gastro-oesophageal motility. The volume and pH of gastric secretion after birth is variable; gastric and duodenal content influences the ability of a drug to dissolve and alters the ratio of ionized to un-ionized particles. A low pH environment will render acidic drugs with a low pK more un-ionized and better able to cross lipid membranes. Changes in the bile-salt pool can alter the solubilization and absorption of lipophilic drugs or formulations.
Absorption by other routes (e.g. intramuscular, inhalation) is often faster in infants. Inhalational anaesthetic delivery is determined largely by alveolar ventilation and functional residual capacity (FRC). Neonates have increased alveolar ventilation and a smaller FRC compared to adults because of increased chest wall compliance. Consequently, pulmonary absorption is generally more rapid in neonates. 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. 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 suffering 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 unless cardiac output is decreased and peripheral perfusion is reduced. There will then be less anaesthetic uptake in the lung. Alveolar anaesthetic partial pressure may be observed to rise rapidly, but there will be a slower rise in tissue partial pressure and anaesthetic effect is delayed.
Non-enteral absorption: Transdermal absorption in neonates is variable because of an incompletely formed stratum corneum and immature vasomotor control. Neonates have a tendency to form methaemoglobin because they have reduced methaemoglobin reductase activity and foetal haemoglobin is more readily oxidized compared to adult haemoglobin. This, combined with increased percutaneous absorption resulted in reluctance to use repeat lidocaine-prilocaine cream in this age group. Similarly, cutaneous application of iodine antiseptics can result in transient hypothyroidism. Rectal administration is associated with variable plasma concentrations; factors such as variable lower gastrointestinal motility and depth of insertion may affect bioavailability. Absorption via the upper rectal veins undergoes first-pass metabolism, whereas the inferior and middle rectal veins bypass the hepatic first-pass effect and drain directly into the inferior vena cava. Rectal administration (e.g. thiopentone, methohexitone) is speedier for neonates undergoing cardiac catheter study or radiological sedation. However, the betweenindividual absorption and relative bioavailability variability may be more extensive compared to oral administration, making rectal administration less suitable for repeated administration.
Distribution Fluid distribution: The greatest change in body water compartments occurs in the first year of life (Figure 1). In premature and term neonates, the volume of distribution for water-soluble drugs is increased compared to older children. To achieve the required plasma concentrations of water soluble drugs (e.g. aminoglycosides, neuromuscular blocking drugs) a higher loading dose per kg needs to be administered in the neonate. CSF contributes a greater proportion of body composition, necessitating increased dose (per kilogram) of spinal local anaesthesia drug. Body tissue composition: Neonates have a smaller proportion of weight in the form of fat and muscle compared with adults (Figure 2). The percentage of body weight contributed by fat is 3% in a 1.5 kg premature neonate, 12% in a term neonate. Drugs
Age-related body water compartments Term neonate
Preterm neonate
Adult man
Infant 1 year
TBW 85%
TBW 80%
TBW 60%
TBW 60%
ECF 60%
ECF 45%
ECF 25%
ECF 20%
ICF 25%
ICF 35%
ICF 35%
ICF 40%
ECF, extracellular fluid; ICF, intracellular fluid; TBW, total body water.
Figure 1
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NEONATAL ANAESTHESIA
brains more readily than they do adult brains. Bloodebrain barrier function improves gradually throughout foetal brain development, possibly reaching maturity at term. Disease states such as sepsis, hypoxia and acidosis further reduce the integrity of the bloodebrain barrier.
Proportion of body composition (%)
Proportion of fat and muscle from premature neonate to adult 50
Muscle Fat
Elimination The main routes by which drugs and their metabolites leave the body are the hepatobiliary system, the kidney and the lung. Microsomal enzyme activity can be classified into three groups: (i) mature at birth but decreasing with age (e.g. CYP3A7 responsible for methadone clearance in neonates); (ii) mature at birth and sustained through to adulthood (e.g. plasma esterases that clear remifentanil); and (iii) immature at birth.1 The latter accounts for the majority and the concentrations and activities of many microsomal enzymes are reduced or absent in the neonate. Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is associated with a small increase in clearance. This increase would not be expected to have any clinically relevant impact on renal function or drug dosing.2
40
30
20
10
0
Preterm
Term
Adult
Figure 2
that rely on redistribution to fat and muscle, such as thiopentone or propofol, will have prolonged and higher plasma concentrations. Fentanyl and remifentanil have an increased volume of distribution in neonates. This may contribute to the reduced degree of respiratory depression seen after fentanyl doses as high as 10 mcg/kg in term neonates. However, high dose fentanyl has prolonged effect in neonates due to reduced clearance.
Hepatic metabolic clearance: The liver is the primary organ for metabolic clearance. Drug-metabolizing enzymes are generally divided into phase I and phase II reactions. Phase I reactions are non-synthetic reactions like oxidation, reduction and hydrolysis. An important group of enzymes involved in phase I processes are the cytochrome P450 (CYP) iso-enzymes. Table 1 gives examples of how different CYP enzymes mature at different rates.
Protein binding: Albumin and alpha-1 acid glycoprotein (AAG) concentrations are reduced in neonates, but are similar to those in adults by 6 months postnatal age. The quality of drugeprotein binding also appears to be reduced. Lower protein binding in premature and term neonates compared to older children results in greater free-drug concentration and hence greater drug effect in highly protein-bound drugs. Examples of acidic drugs binding to albumin include diazepam, thiopental and phenytoin. Basic drugs tend to bind AAG. Neonatal jaundice is common in the premature neonate; bilirubin competes with some drugs (e.g. phenytoin) for protein binding, which can result in either further increased free drug concentration or increased free bilirubin. The latter would increase the risk of kernicterus. AAG is an acute phase reactant that increases after surgical stress. This causes an increase in total plasma concentrations for low to intermediate extraction drugs such as bupivacaine. The unbound concentration, however, will not change because clearance of the unbound drug is affected only by the intrinsic metabolizing capacity of the liver. Total bupivacaine concentrations increase in the first 24 hours after surgery in neonates given analgesia by continuous epidural infusion. This increase is attributable to an increase of AAG and toxicity potential is not increased. Clearance (CYP3A4) 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 individuals with very low clearance.
Examples of variable maturation and expression of different cytochrome p450 enzymes.a Enzyme comments
CYP1A2 Caffeine, theophylline, ropivacaine CYP2C9 Phenytoin, ketamine, ibuprofen
Absent in neonate, adult level 4e6 months
CYP2D6 Codeine, Tramadol, beta-blockers
CYP3A4 Midazolam, levobupivacaine
Bloodebrain barrier: There are specific systems selectively expressed in the barrier endothelial cell membranes that mediate the transport of nutrients into the CNS and of toxic metabolites out of the CNS. Small molecules access foetal and neonatal
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Enzyme Example
Enzyme develops rapidly in the postnatal period; Phenytoin halflife is prolonged at 75 hours in preterm neonates; this decreases to 20 hours at term and 8 hours at 2 weeks Usually present at 1 week PMA but only 20% of adult activity at 1 month. Variable because of genetic polymorphism: up to 47% of 3e12year olds cannot convert codeine to morphine. Activity low at birth but increases 5fold over 3 months of life
a
Enzyme activity does not equate to clearance. Clearance is determined by activity, organ size and blood flow.
Table 1
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NEONATAL ANAESTHESIA
adult
34 =
Dosechild ¼ Weightchild=Weight
Phase II reactions convert lipid-soluble drugs to water soluble compounds. The phase II reactions involve synthetic or conjugation reactions (e.g. glucuronide, sulphate conjugation). They show limited activity during foetal life. Some enzymes, e.g. uridine diphospho-glucuronyltransferase (UGT) include different isoforms that mature at different rates. Figure 3 shows the clearance maturation profiles of drugs predominantly metabolized by UGT. Note how the profiles correlate with glomerular filtration rate (GFR). It is thought that propofol matures faster than the other drugs due to the additional contribution of the P450 enzymes to its overall metabolism.3 Failure to appreciate UGT immaturity led to inappropriate doses of chloramphenicol being given to neonates who then developed fatal circulatory collapse known as the ‘gray baby syndrome’ in the 1960s. Although the metabolism of a given drug frequently results in water soluble inactive compounds, metabolism may also result in transformation to a more potent drug (e.g. codeine to morphine by CYP2D6, morphine to morphine-6-glucuronide by UGT2B7) or into a toxic compound (halothane to trifluoroacetyl chloride by CYP2E1 causing halothane hepatitis) Metabolic processes relate to body mass in a nonlinear manner (the term used to describe this is ‘allometry’); scaling down adult dosages using direct proportionality will often result in under-dosing. Clearance is a metabolic process that determines maintenance dose. Drug dose in a child can often be calculated from adult dose:
Doseadult
However, dosing in neonates is more complex because maturation of the clearance pathway must be considered. Most clearance pathways mature within the first 1e2 years of postnatal life. Renal clearance: GFR is related to postmenstrual age. At 40 weeks PMA the GFR is approximately 30% of adult rates (1.5 ml/ kg/min; 20e40 ml/min/1.73m2), which increases rapidly to 50% of adult rates by 3 months.4 Incomplete glomerular development, low perfusion pressure and inadequate osmotic load (for counter-current effects) contribute to reduced renal efficiency in the neonate. Glomerular and tubular function is fully mature by 2 years of age. Drugs eliminated primarily through the kidney such as aminoglycosides or cephalosporin antibiotics have a prolonged elimination half-life in neonates due to immature clearance. Extrahepatic routes of metabolic clearance: Many drugs undergo metabolic clearance at extrahepatic sites. Remifentanil and atracurium are broken down by non-specific esterase in tissue and erythrocytes. Clearance, expressed per kilogram is increased in younger children, likely attributable to size because clearance is similar when scaled to a 70 kg person using allometry.
Drugs cleared by UGT have maturation similar to GFR. GFR, glomerular filtration rate. TM50, maturation half time. Hill, Hill coefficient relating to slope of the maturation profile. From Anderson BJ, Holford NHG. Tips and traps analyzing paediatric PK data. Pediatr Anaesth 2011; 21(3): 222-237, with permission. Figure 3
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Pulmonary elimination: The factors determining anaesthetic absorption through the lung (alveolar ventilation, FRC, cardiac output, 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 some hepatic metabolism.
that required in adults (130 mg/l); consistent with the immaturity of the fibrinolytic system at birth.5 Neonatal dose is driven by an understanding of both PK and PD. While PK continues to be explored, PD remains the poor cousin and neonatal PD understanding remains an area for greater investigation. Measures of effect (e.g. bispectral index) cannot be used in neonates, contributing to less enthusiasm to use total intravenous anaesthesia in this cohort.
Neonatal pharmacodynamics Individual drugs
Neonates and infants have altered pharmacodynamics compared to children and adults. The minimum alveolar concentration (MAC) for almost all vapours is less in neonates than in infancy. Changes in regional blood flow may influence the amount of drug going to the brain. Gamma-aminobutyric acid (GABAA) receptor numbers or developmental shifts in the regulation of chloride transporters in the brain may change with age, altering response (e.g. midazolam). Neonates have an increased sensitivity to the effects of neuromuscular blocking drugs. The combination of increased volume of distribution and increased sensitivity dictates similar dose to adults (although effect is longer in neonates due to decreased clearance). Amide local anaesthetic agents induce shorter block duration and require a larger weight scaled dose to achieve similar dermatomal levels when given by subarachnoid block to infants. This may in part be due to myelination, spacing of nodes of Ranvier, and length of nerve exposed. There is an age-dependent expression of intestinal motilin receptors and the modulation of antral contractions in neonates. Prokinetic agents may not be useful in very preterm infants, partially useful in older preterm infants, and useful in full-term infants. Similarly, bronchodilators are ineffective because of the paucity of bronchial smooth muscle that can cause bronchospasm. 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. Catecholamine release and response to vasoactive drugs vary with age. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Systemic vasoconstriction is greater than pulmonary vasoconstriction in neonates given dopamine. b-Receptor maturation lags behind a-receptor maturation during the development of the adrenergic system. The preterm neonate has immature clearance leading to an increased dopamine concentration with prolonged infusion in neonates. These maturation changes in PK and PD may contribute to dopamine’s continued popularity in the neonatal nursery while its popularity wanes in the adult population. Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. The concentration of EACA required to inhibit fibrinolysis in neonates (50 mg/l) is less than
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Analgesics Morphine e The neonatal increased sensitivity to morphine can be attributable to pharmacokinetic rather than pharmacodynamic differences in those born at term, although functional expression of mu opioid receptors on sensory neurons is developmentally regulated in neonates. Morphine clearance increases rapidly in the neonatal period (Figure 3). Clearance reaches 80% of adult values by 6 months of age, although clearance reduced in the critically ill. There was no relationship found between morphine plasma concentrations (0e440 mcg/l) and the pain response (premature infant pain profile or heart rate) to endotracheal suctioning.6 Respiratory depression relates to plasma concentration rather than dose.7 Fentanyl e Several factors are important in the clearance of fentanyl: hepatic blood flow, hepatic function and age-dependent changes in the volume of distribution. It is known that fentanyl clearance is markedly reduced when there is an increase in intraabdominal pressure (e.g. omphalocele repair). Animal data suggests that the reduction in clearance is not due to reduced hepatic blood flow but a combination of immature hepatic enzymes and a maldistribution of hepatic blood away from regions of cytochrome p450 activity. Tramadol e has multiple modes of action; in addition to mu eopioid activity of the parent compound and (stronger) mueffects of the M1 metabolite, it also acts via 5HT and noradrenaline uptake inhibition. It is metabolized by CYP2D6, which exhibits genetic polymorphism. These enzymes can be given an activity score; the higher the score, the faster the clearance maturation (Figure 4). Tramadol provides analgesia both from both the parent compound (target concentration 100 ng/ml) and from its M1 metabolite (target concentration 15 ng/ml). Identification of slow metabolizers using genotype may not be predictive of M1 concentrations; genotype may not always equate with phenotype.8 Apnoea is associated with a tenfold dosing error in children (>9 mg/kg). One formulation is prescribed as drops rather than as ml and this can confuse caregivers, resulting in accidental overdose.9 Tramadol ingested by mothers does not reach worrisome concentrations in breast-fed babies.10 Paracetamol e As the absorption of rectal paracetamol has been shown to be variable and slow, intravenous paracetamol reduces the morphine requirement in neonates. An effect site target concentration of 10 mg/L is associated with similar analgesia to that described in children.11 It is thought that reduced activity of CYP2E1 (responsible for forming the toxic metabolite NAPQI) is reduced in the neonate, so reports of hepatotoxicity are rare. High doses (e.g. PMA 28e32 weeks, 10 mg/kg; 32e36 weeks, 12.5 mg/kg; and >36 weeks,
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haemodynamic response to an age-adjusted MAC of volatile agents is no different from older children.
M1 formation clearance (litres/hour/70 kg)
Tramadol clearance maturation; comparing groups with different cytochrome P450 enzyme activity 40
30
CYP0 CYP0.5 CYP1 CYP1.5 CYP2 CYP3
Local anaesthetic agents The toxic plasma concentration of bupivacaine is unknown in neonates. However, many infusion regimens aim for a plasma concentration of less than 1 mcg/ml. The recommended dose is neonates is 1.5 mg/kg (c.f. 2.5 mg/kg in children) because bupivacaine has high binding to AAG and that is reduced in neonates. Failure to appreciate reduced clearance in neonates has resulted in convulsions during continuous epidural infusion. Safe continuous epidural bupivacaine infusion rates 0.2e0.25 mg/kg/h in neonates and 0.4e0.5 mg/kg/h in children were empirically derived. Similar considerations apply to ropivacaine (CYP1A2) and levobupivacaine (CYP3A4) where clearance is also reduced in neonates.
Population trend CYP0.5 Population trend CYP2 Population trend CYP3
20
10
0 25
30
35
40
45
50
55
Sedatives Diazepam e has capacity-limited clearance. Immature clearance in neonates can prolong the elimination half-life of diazepam to up to 100 hours in the neonate (18 h in young adults). The active metabolite N-desmethyldiazepam is similar in potency and half-life to diazepam. The prolonged action in neonates renders the drug less suitable for many applications than the shorter acting sedating agents. Diazepam has respiratory depressant effects that are quite variable, especially when combined with opioids.
Postmenstrual age (weeks)
Figure 4
15 mg/kg) have been used over 4 days without hepatotoxicity, although most advocate more modest doses.12 Liver function changes during therapy are commonly transitory and may not reflect hepatotoxicity.13 Remifentanil e Although the T1/2 is similar in all age groups, the volume of distribution of remifentanil in neonates is greater than in older children. Neonatal clearance is very high at 90.5 ml/ min/kg compared to adolescents at 57.2 ml/min/kg. The adult estimated clearance is 40 ml/min/kg. Neonates require a higher initial infusion rate (e.g. 0.4 mcg/kg/min) with subsequent titration. Ibuprofen e NSAIDs are used to close the ductus arteriosus in premature neonates, but their use for analgesia remains infrequent because of an unexplored adverse effect profile in this age group. Analgesic dosing, based on clearance maturation data, is likely considerably less than that required for ductus arteriosus closure.14
Midazolam e Unlike diazepam, the active metabolite of midazolam has minimal activity; it is therefore more suited for use in neonates. The clearance is prolonged (T1/2 6e12 hours) compared with older children (T1/2 1.4e4.0 hours). This T1/2 is increased by factors that reduce hepatic blood flow, vasopressors or hypovolaemic states. Intravenous bolus of midazolam in
Minimum alveolar concentration (MAC) of isoflurane with increasing age 2. 0 1–6 months
MAC (% isoflurance)
Intravenous anaesthetic agents Propofol e Clearance is reduced in neonates (Figure 3). Reports of profound hypotension lasting 20 min or so in neonates given propofol 3 mg/kg are disturbing and reflect the paucity of PKPD investigations in this cohort. Current infusion rates for anaesthesia in children less than 3 years of age are based on clinical experience from children undergoing anaesthesia with mechanical ventilation. However, assessment of anaesthesia depth is difficult in neonates and pharmacokinetic-pharmacodynamic modelling suggests regimens that require less drug.15
1. 8
1. 6
Neonates 32–37 weeks’ gestation
1.4
32 weeks’ gestation 1. 2
1. 0 0.5
1.0
5
10
50
100
Postconception age (years)
Inhalational anaesthetic agents The MAC of halothane, isoflurane and desflurane is low in premature neonates, peaks at 1e6 months and then falls gradually as age increases (Figure 5). Sevoflurane differs, in that the MAC in neonates (3.3%) does not change through to 3 months (3.2%). Older infants and children have a MAC of approximately 2.5%. The reason for this different pattern is unclear. The
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This pattern of the MAC throughout childhood is similar for desflurane and halothane Reproduced with permission from LeDez KM, Lerman J. The minimum alveolar concentration of isoflurane in preterm neonates. Anesthesiol 1987; 67: 301–7.
Figure 5
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neonates has been associated with hypotension; particularly if administered with fentanyl. When an EEG signal is used as an effect measure, an EC50 of 0.035e0.077 mg/l, with a T1/2 keo of 0.9e1.6 minutes has been described in adults. Sedation in children is more difficult to quantify. No PKPD relationship was established in children 2 days to 17 years who were given a midazolam infusion in intensive care. Midazolam dosing can be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Desirable sedation in children after cardiac surgery is achieved at mean serum concentrations between 0.1 and 0.5 mg/L.
6
7
8
Inotropes Milrinone, an inodilator, is used increasingly in children after congenital cardiac surgery. Renal clearance is the primary route of elimination, and we might anticipate that maturation of milrinone clearance closely follows that of GFR. Clearance in adults is 9 L/ h/70 kg is reported in adults with congestive heart failure, whereas 26-week PMA infants (expected to have 10% of adult GFR) have a clearance of 0.96 L/h/70 kg.3 A
9 10
11
12
REFERENCES 1 Hines RN. Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children. Int J Pharm 2013; 452: 3e7. 2 Anderson BJ, Holford NHG. Negligible impact of birth on renal function and drug metabolism. Pediatr Anesth 2018; 28: 1015e21. 3 Sumpter A, Anderson BJ. Pediatric pharmacology in the first year of life. Curr Opin Anaesthesiol 2009; 22: 469e75. 4 Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24: 67e76. 5 Eaton MP, Alfieris GM, Sweeney DM, et al. Pharmacokinetics of epsilon-aminocaproic acid in neonates undergoing cardiac
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13
14
15
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surgery with cardiopulmonary bypass. Anesthesiology 2015; 122: 1002e9. 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: 680e9. Lynn AM, Nespeca MK, Opheim KE, et al. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77: 695e701. Allegaert K, Holford N, Anderson BJ, et al. Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study. Clin Pharmacokinet 2015; 54: 167e78. Anderson BJ, Thomas J, Ottaway K, et al. Tramadol: keep calm and carry on. Pediatr Anesth 2017; 27: 785e8. Palmer GM, Anderson BJ, Linscott DK, et al. Tramadol, breast feeding and safety in the newborn. Arch Dis Child 2018; 103: 1110e3. Allegaert K, Naulaers G, Vanhaesebrouck S, et al. The paracetamol concentration-effect relation in neonates. Pediatr Anesth 2013; 23: 45e50. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 2011; 96: 575e80. Hayward KL, Powell EE, Irvine KM, et al. Can paracetamol (acetaminophen) be administered to patients with liver impairment? Br J Clin Pharmacol 2016; 81: 210e22. Anderson BJ, Hannam JA. A target concentration strategy to determine ibuprofen dosing in children. Pediatr Anesth 2019; 29: 1107e13. Morse J, Hannam JA, Cortinez LI, et al. A manual propofol infusion regimen for neonates and infants. Pediatr Anesth 2019; 29: 907e14.
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Neonatal pharmacology
Learning objectives
Brian J Anderson
After reading this article, you should be able to: C precis the challenges that face clinicians delivering dosing regimens in neonates, including appreciation of the non-linear relationship between metabolic processes and size in children C explain how growth and development in the neonate affects drug disposition (with examples) C provide an overview of the recent developments in neonatal pharmacology (with immediate relevance to the anaesthetist)
Abstract Neonatal anaesthesia dosing needs to be based on physiological characteristics of the newborn, pharmacokinetic knowledge, pharmacodynamic considerations and the adverse effects profile. Disease processes and treatments in this group are distinct from adults. Immaturity of enzyme, anatomical and physiological systems cause extensive variability of drug disposition and drug response in neonates. This is further compounded by pharmacogenomic influences. Postmenstrual age is a reasonable measure for maturation of clearance pathways. The neonatal response to drugs is altered and monitoring of effect that guides adult drug use is limited. While neuromuscular monitoring is robust, few other clinically applicable tools are available to provide pharmacodynamic effect feedback. Tools that assess depth of anaesthesia, sedation and pain in neonates have potential to improve effectiveness and safety.
multiple institutions and better computer programs have enabled greater understanding of PK and PD.
Neonatal pharmacokinetics Absorption Physicochemical and patient factors influence the ability of a drug to translocate from its site of administration to the bloodstream and site of action (Box 1).
Keywords Drugs; neonatal; off-label; paediatric; pharmacodynamics; pharmacokinetics; pharmacology; therapeutic orphan
Some factors affecting drug absorption relating to neonates
Royal College of Anaesthetists CPD Matrix: 1A02
Physicochemical factors Drug formulation C Disintegration of tablets or solid phase C Dissolution of drug in gastric or intestinal fluid C Release from sustained-release preparations Molecular weight pK/Proportion of drug in ionized/un-ionized form Lipid solubility
Not all neonates are the same Neonates are a heterogeneous group of children from birth up to the age of 28 days of life. The word ‘neonate’ also includes former prematurely born neonates. Postmenstrual age (PMA) may range from extreme preterm birth at 22 weeks up to 50 weeks PMA while weight may range from <0.5 kg to >5 kg; an entire order of magnitude. Age, size, comorbidity, co-administration of drugs and genetic polymorphisms contribute to the extensive between-individual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Neonates became ‘therapeutic orphans’ after misuse of drugs such as chloramphenicol and thalidomide in this population. Ethical constraints and medicolegal issues surrounding consent and risk in non-therapeutic research limited drug study participation. Technical issues such as blood sampling and amount for assay made PK studies difficult. Recruitment of adequate numbers of neonates with similar pathology at the same stage of growth and development was difficult. Clinical endpoints were often poorly defined. Adverse drug effects may not become apparent until later life. Further, the market for most drugs in children is small in comparison to that in adults. Many of these research obstacles have been dismantled. Financial incentives and legislative changes have been introduced to encourage drug labelling in children. Micro-sampling, more sensitive analytical methods, pooling of data from
Patient factors General C Surface area available for absorption Gastrointestinal C Gastric content and gastric emptying C Gastric and duodenal pH C Size of bile-salt pool C Bacterial colonization of lower intestine C Disease states (e.g. short-gut syndrome, biliary atresia) Muscle C Increased capillary density in neonatal muscle compared with adults increases absorption from muscles C Reduced cardiac output states reduce absorption Skin C Blood supply C Peripheral vasodilation C Thickness of skin/stratum corneum C Surface area Rectal C Rectal venous drainage site C Neonatal absorption > older children
Brian J Anderson PhD FANZCA FCICM is a Consultant Paediatric Anaesthetist and Intensivist at Starship Children’s Hospital, Auckland, New Zealand. Conflicts of interest: none declared.
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The patient factors are particularly relevant in neonates. Box 1
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Enteral absorption when drugs are given orally is slower in neonates and infants. Gastric emptying and intestinal motility are delayed and may not mature until 6e8 months. This results in an increased time to peak concentration as well as decreased peak concentration compared to older children. Slow gastric emptying is also associated with type of feed (increased calorie density and long-chain fatty acids); and disease states (e.g. pyloric stenosis, congestive cardiac failure, duodenal atresia). Human milk and low-calorie feed quicken gastric emptying. Co-administration of drugs (e.g. opioids) can slow gastro-oesophageal motility. The volume and pH of gastric secretion after birth is variable; gastric and duodenal content influences the ability of a drug to dissolve and alters the ratio of ionized to un-ionized particles. A low pH environment will render acidic drugs with a low pK more un-ionized and better able to cross lipid membranes. Changes in the bile-salt pool can alter the solubilization and absorption of lipophilic drugs or formulations.
Absorption by other routes (e.g. intramuscular, inhalation) is often faster in infants. Inhalational anaesthetic delivery is determined largely by alveolar ventilation and functional residual capacity (FRC). Neonates have increased alveolar ventilation and a smaller FRC compared to adults because of increased chest wall compliance. Consequently, pulmonary absorption is generally more rapid in neonates. 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. 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 suffering 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 unless cardiac output is decreased and peripheral perfusion is reduced. There will then be less anaesthetic uptake in the lung. Alveolar anaesthetic partial pressure may be observed to rise rapidly, but there will be a slower rise in tissue partial pressure and anaesthetic effect is delayed.
Non-enteral absorption: Transdermal absorption in neonates is variable because of an incompletely formed stratum corneum and immature vasomotor control. Neonates have a tendency to form methaemoglobin because they have reduced methaemoglobin reductase activity and foetal haemoglobin is more readily oxidized compared to adult haemoglobin. This, combined with increased percutaneous absorption resulted in reluctance to use repeat lidocaine-prilocaine cream in this age group. Similarly, cutaneous application of iodine antiseptics can result in transient hypothyroidism. Rectal administration is associated with variable plasma concentrations; factors such as variable lower gastrointestinal motility and depth of insertion may affect bioavailability. Absorption via the upper rectal veins undergoes first-pass metabolism, whereas the inferior and middle rectal veins bypass the hepatic first-pass effect and drain directly into the inferior vena cava. Rectal administration (e.g. thiopentone, methohexitone) is speedier for neonates undergoing cardiac catheter study or radiological sedation. However, the betweenindividual absorption and relative bioavailability variability may be more extensive compared to oral administration, making rectal administration less suitable for repeated administration.
Distribution Fluid distribution: The greatest change in body water compartments occurs in the first year of life (Figure 1). In premature and term neonates, the volume of distribution for water-soluble drugs is increased compared to older children. To achieve the required plasma concentrations of water soluble drugs (e.g. aminoglycosides, neuromuscular blocking drugs) a higher loading dose per kg needs to be administered in the neonate. CSF contributes a greater proportion of body composition, necessitating increased dose (per kilogram) of spinal local anaesthesia drug. Body tissue composition: Neonates have a smaller proportion of weight in the form of fat and muscle compared with adults (Figure 2). The percentage of body weight contributed by fat is 3% in a 1.5 kg premature neonate, 12% in a term neonate. Drugs
Age-related body water compartments Term neonate
Preterm neonate
Adult man
Infant 1 year
TBW 85%
TBW 80%
TBW 60%
TBW 60%
ECF 60%
ECF 45%
ECF 25%
ECF 20%
ICF 25%
ICF 35%
ICF 35%
ICF 40%
ECF, extracellular fluid; ICF, intracellular fluid; TBW, total body water.
Figure 1
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brains more readily than they do adult brains. Bloodebrain barrier function improves gradually throughout foetal brain development, possibly reaching maturity at term. Disease states such as sepsis, hypoxia and acidosis further reduce the integrity of the bloodebrain barrier.
Proportion of body composition (%)
Proportion of fat and muscle from premature neonate to adult 50
Muscle Fat
Elimination The main routes by which drugs and their metabolites leave the body are the hepatobiliary system, the kidney and the lung. Microsomal enzyme activity can be classified into three groups: (i) mature at birth but decreasing with age (e.g. CYP3A7 responsible for methadone clearance in neonates); (ii) mature at birth and sustained through to adulthood (e.g. plasma esterases that clear remifentanil); and (iii) immature at birth.1 The latter accounts for the majority and the concentrations and activities of many microsomal enzymes are reduced or absent in the neonate. Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is associated with a small increase in clearance. This increase would not be expected to have any clinically relevant impact on renal function or drug dosing.2
40
30
20
10
0
Preterm
Term
Adult
Figure 2
that rely on redistribution to fat and muscle, such as thiopentone or propofol, will have prolonged and higher plasma concentrations. Fentanyl and remifentanil have an increased volume of distribution in neonates. This may contribute to the reduced degree of respiratory depression seen after fentanyl doses as high as 10 mcg/kg in term neonates. However, high dose fentanyl has prolonged effect in neonates due to reduced clearance.
Hepatic metabolic clearance: The liver is the primary organ for metabolic clearance. Drug-metabolizing enzymes are generally divided into phase I and phase II reactions. Phase I reactions are non-synthetic reactions like oxidation, reduction and hydrolysis. An important group of enzymes involved in phase I processes are the cytochrome P450 (CYP) iso-enzymes. Table 1 gives examples of how different CYP enzymes mature at different rates.
Protein binding: Albumin and alpha-1 acid glycoprotein (AAG) concentrations are reduced in neonates, but are similar to those in adults by 6 months postnatal age. The quality of drugeprotein binding also appears to be reduced. Lower protein binding in premature and term neonates compared to older children results in greater free-drug concentration and hence greater drug effect in highly protein-bound drugs. Examples of acidic drugs binding to albumin include diazepam, thiopental and phenytoin. Basic drugs tend to bind AAG. Neonatal jaundice is common in the premature neonate; bilirubin competes with some drugs (e.g. phenytoin) for protein binding, which can result in either further increased free drug concentration or increased free bilirubin. The latter would increase the risk of kernicterus. AAG is an acute phase reactant that increases after surgical stress. This causes an increase in total plasma concentrations for low to intermediate extraction drugs such as bupivacaine. The unbound concentration, however, will not change because clearance of the unbound drug is affected only by the intrinsic metabolizing capacity of the liver. Total bupivacaine concentrations increase in the first 24 hours after surgery in neonates given analgesia by continuous epidural infusion. This increase is attributable to an increase of AAG and toxicity potential is not increased. Clearance (CYP3A4) 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 individuals with very low clearance.
Examples of variable maturation and expression of different cytochrome p450 enzymes.a Enzyme comments
CYP1A2 Caffeine, theophylline, ropivacaine CYP2C9 Phenytoin, ketamine, ibuprofen
Absent in neonate, adult level 4e6 months
CYP2D6 Codeine, Tramadol, beta-blockers
CYP3A4 Midazolam, levobupivacaine
Bloodebrain barrier: There are specific systems selectively expressed in the barrier endothelial cell membranes that mediate the transport of nutrients into the CNS and of toxic metabolites out of the CNS. Small molecules access foetal and neonatal
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Enzyme Example
Enzyme develops rapidly in the postnatal period; Phenytoin halflife is prolonged at 75 hours in preterm neonates; this decreases to 20 hours at term and 8 hours at 2 weeks Usually present at 1 week PMA but only 20% of adult activity at 1 month. Variable because of genetic polymorphism: up to 47% of 3e12year olds cannot convert codeine to morphine. Activity low at birth but increases 5fold over 3 months of life
a
Enzyme activity does not equate to clearance. Clearance is determined by activity, organ size and blood flow.
Table 1
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adult
34 =
Dosechild ¼ Weightchild=Weight
Phase II reactions convert lipid-soluble drugs to water soluble compounds. The phase II reactions involve synthetic or conjugation reactions (e.g. glucuronide, sulphate conjugation). They show limited activity during foetal life. Some enzymes, e.g. uridine diphospho-glucuronyltransferase (UGT) include different isoforms that mature at different rates. Figure 3 shows the clearance maturation profiles of drugs predominantly metabolized by UGT. Note how the profiles correlate with glomerular filtration rate (GFR). It is thought that propofol matures faster than the other drugs due to the additional contribution of the P450 enzymes to its overall metabolism.3 Failure to appreciate UGT immaturity led to inappropriate doses of chloramphenicol being given to neonates who then developed fatal circulatory collapse known as the ‘gray baby syndrome’ in the 1960s. Although the metabolism of a given drug frequently results in water soluble inactive compounds, metabolism may also result in transformation to a more potent drug (e.g. codeine to morphine by CYP2D6, morphine to morphine-6-glucuronide by UGT2B7) or into a toxic compound (halothane to trifluoroacetyl chloride by CYP2E1 causing halothane hepatitis) Metabolic processes relate to body mass in a nonlinear manner (the term used to describe this is ‘allometry’); scaling down adult dosages using direct proportionality will often result in under-dosing. Clearance is a metabolic process that determines maintenance dose. Drug dose in a child can often be calculated from adult dose:
Doseadult
However, dosing in neonates is more complex because maturation of the clearance pathway must be considered. Most clearance pathways mature within the first 1e2 years of postnatal life. Renal clearance: GFR is related to postmenstrual age. At 40 weeks PMA the GFR is approximately 30% of adult rates (1.5 ml/ kg/min; 20e40 ml/min/1.73m2), which increases rapidly to 50% of adult rates by 3 months.4 Incomplete glomerular development, low perfusion pressure and inadequate osmotic load (for counter-current effects) contribute to reduced renal efficiency in the neonate. Glomerular and tubular function is fully mature by 2 years of age. Drugs eliminated primarily through the kidney such as aminoglycosides or cephalosporin antibiotics have a prolonged elimination half-life in neonates due to immature clearance. Extrahepatic routes of metabolic clearance: Many drugs undergo metabolic clearance at extrahepatic sites. Remifentanil and atracurium are broken down by non-specific esterase in tissue and erythrocytes. Clearance, expressed per kilogram is increased in younger children, likely attributable to size because clearance is similar when scaled to a 70 kg person using allometry.
Drugs cleared by UGT have maturation similar to GFR. GFR, glomerular filtration rate. TM50, maturation half time. Hill, Hill coefficient relating to slope of the maturation profile. From Anderson BJ, Holford NHG. Tips and traps analyzing paediatric PK data. Pediatr Anaesth 2011; 21(3): 222-237, with permission. Figure 3
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Pulmonary elimination: The factors determining anaesthetic absorption through the lung (alveolar ventilation, FRC, cardiac output, 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 some hepatic metabolism.
that required in adults (130 mg/l); consistent with the immaturity of the fibrinolytic system at birth.5 Neonatal dose is driven by an understanding of both PK and PD. While PK continues to be explored, PD remains the poor cousin and neonatal PD understanding remains an area for greater investigation. Measures of effect (e.g. bispectral index) cannot be used in neonates, contributing to less enthusiasm to use total intravenous anaesthesia in this cohort.
Neonatal pharmacodynamics Individual drugs
Neonates and infants have altered pharmacodynamics compared to children and adults. The minimum alveolar concentration (MAC) for almost all vapours is less in neonates than in infancy. Changes in regional blood flow may influence the amount of drug going to the brain. Gamma-aminobutyric acid (GABAA) receptor numbers or developmental shifts in the regulation of chloride transporters in the brain may change with age, altering response (e.g. midazolam). Neonates have an increased sensitivity to the effects of neuromuscular blocking drugs. The combination of increased volume of distribution and increased sensitivity dictates similar dose to adults (although effect is longer in neonates due to decreased clearance). Amide local anaesthetic agents induce shorter block duration and require a larger weight scaled dose to achieve similar dermatomal levels when given by subarachnoid block to infants. This may in part be due to myelination, spacing of nodes of Ranvier, and length of nerve exposed. There is an age-dependent expression of intestinal motilin receptors and the modulation of antral contractions in neonates. Prokinetic agents may not be useful in very preterm infants, partially useful in older preterm infants, and useful in full-term infants. Similarly, bronchodilators are ineffective because of the paucity of bronchial smooth muscle that can cause bronchospasm. 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. Catecholamine release and response to vasoactive drugs vary with age. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Systemic vasoconstriction is greater than pulmonary vasoconstriction in neonates given dopamine. b-Receptor maturation lags behind a-receptor maturation during the development of the adrenergic system. The preterm neonate has immature clearance leading to an increased dopamine concentration with prolonged infusion in neonates. These maturation changes in PK and PD may contribute to dopamine’s continued popularity in the neonatal nursery while its popularity wanes in the adult population. Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. The concentration of EACA required to inhibit fibrinolysis in neonates (50 mg/l) is less than
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Analgesics Morphine e The neonatal increased sensitivity to morphine can be attributable to pharmacokinetic rather than pharmacodynamic differences in those born at term, although functional expression of mu opioid receptors on sensory neurons is developmentally regulated in neonates. Morphine clearance increases rapidly in the neonatal period (Figure 3). Clearance reaches 80% of adult values by 6 months of age, although clearance reduced in the critically ill. There was no relationship found between morphine plasma concentrations (0e440 mcg/l) and the pain response (premature infant pain profile or heart rate) to endotracheal suctioning.6 Respiratory depression relates to plasma concentration rather than dose.7 Fentanyl e Several factors are important in the clearance of fentanyl: hepatic blood flow, hepatic function and age-dependent changes in the volume of distribution. It is known that fentanyl clearance is markedly reduced when there is an increase in intraabdominal pressure (e.g. omphalocele repair). Animal data suggests that the reduction in clearance is not due to reduced hepatic blood flow but a combination of immature hepatic enzymes and a maldistribution of hepatic blood away from regions of cytochrome p450 activity. Tramadol e has multiple modes of action; in addition to mu eopioid activity of the parent compound and (stronger) mueffects of the M1 metabolite, it also acts via 5HT and noradrenaline uptake inhibition. It is metabolized by CYP2D6, which exhibits genetic polymorphism. These enzymes can be given an activity score; the higher the score, the faster the clearance maturation (Figure 4). Tramadol provides analgesia both from both the parent compound (target concentration 100 ng/ml) and from its M1 metabolite (target concentration 15 ng/ml). Identification of slow metabolizers using genotype may not be predictive of M1 concentrations; genotype may not always equate with phenotype.8 Apnoea is associated with a tenfold dosing error in children (>9 mg/kg). One formulation is prescribed as drops rather than as ml and this can confuse caregivers, resulting in accidental overdose.9 Tramadol ingested by mothers does not reach worrisome concentrations in breast-fed babies.10 Paracetamol e As the absorption of rectal paracetamol has been shown to be variable and slow, intravenous paracetamol reduces the morphine requirement in neonates. An effect site target concentration of 10 mg/L is associated with similar analgesia to that described in children.11 It is thought that reduced activity of CYP2E1 (responsible for forming the toxic metabolite NAPQI) is reduced in the neonate, so reports of hepatotoxicity are rare. High doses (e.g. PMA 28e32 weeks, 10 mg/kg; 32e36 weeks, 12.5 mg/kg; and >36 weeks,
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haemodynamic response to an age-adjusted MAC of volatile agents is no different from older children.
M1 formation clearance (litres/hour/70 kg)
Tramadol clearance maturation; comparing groups with different cytochrome P450 enzyme activity 40
30
CYP0 CYP0.5 CYP1 CYP1.5 CYP2 CYP3
Local anaesthetic agents The toxic plasma concentration of bupivacaine is unknown in neonates. However, many infusion regimens aim for a plasma concentration of less than 1 mcg/ml. The recommended dose is neonates is 1.5 mg/kg (c.f. 2.5 mg/kg in children) because bupivacaine has high binding to AAG and that is reduced in neonates. Failure to appreciate reduced clearance in neonates has resulted in convulsions during continuous epidural infusion. Safe continuous epidural bupivacaine infusion rates 0.2e0.25 mg/kg/h in neonates and 0.4e0.5 mg/kg/h in children were empirically derived. Similar considerations apply to ropivacaine (CYP1A2) and levobupivacaine (CYP3A4) where clearance is also reduced in neonates.
Population trend CYP0.5 Population trend CYP2 Population trend CYP3
20
10
0 25
30
35
40
45
50
55
Sedatives Diazepam e has capacity-limited clearance. Immature clearance in neonates can prolong the elimination half-life of diazepam to up to 100 hours in the neonate (18 h in young adults). The active metabolite N-desmethyldiazepam is similar in potency and half-life to diazepam. The prolonged action in neonates renders the drug less suitable for many applications than the shorter acting sedating agents. Diazepam has respiratory depressant effects that are quite variable, especially when combined with opioids.
Postmenstrual age (weeks)
Figure 4
15 mg/kg) have been used over 4 days without hepatotoxicity, although most advocate more modest doses.12 Liver function changes during therapy are commonly transitory and may not reflect hepatotoxicity.13 Remifentanil e Although the T1/2 is similar in all age groups, the volume of distribution of remifentanil in neonates is greater than in older children. Neonatal clearance is very high at 90.5 ml/ min/kg compared to adolescents at 57.2 ml/min/kg. The adult estimated clearance is 40 ml/min/kg. Neonates require a higher initial infusion rate (e.g. 0.4 mcg/kg/min) with subsequent titration. Ibuprofen e NSAIDs are used to close the ductus arteriosus in premature neonates, but their use for analgesia remains infrequent because of an unexplored adverse effect profile in this age group. Analgesic dosing, based on clearance maturation data, is likely considerably less than that required for ductus arteriosus closure.14
Midazolam e Unlike diazepam, the active metabolite of midazolam has minimal activity; it is therefore more suited for use in neonates. The clearance is prolonged (T1/2 6e12 hours) compared with older children (T1/2 1.4e4.0 hours). This T1/2 is increased by factors that reduce hepatic blood flow, vasopressors or hypovolaemic states. Intravenous bolus of midazolam in
Minimum alveolar concentration (MAC) of isoflurane with increasing age 2. 0 1–6 months
MAC (% isoflurance)
Intravenous anaesthetic agents Propofol e Clearance is reduced in neonates (Figure 3). Reports of profound hypotension lasting 20 min or so in neonates given propofol 3 mg/kg are disturbing and reflect the paucity of PKPD investigations in this cohort. Current infusion rates for anaesthesia in children less than 3 years of age are based on clinical experience from children undergoing anaesthesia with mechanical ventilation. However, assessment of anaesthesia depth is difficult in neonates and pharmacokinetic-pharmacodynamic modelling suggests regimens that require less drug.15
1. 8
1. 6
Neonates 32–37 weeks’ gestation
1.4
32 weeks’ gestation 1. 2
1. 0 0.5
1.0
5
10
50
100
Postconception age (years)
Inhalational anaesthetic agents The MAC of halothane, isoflurane and desflurane is low in premature neonates, peaks at 1e6 months and then falls gradually as age increases (Figure 5). Sevoflurane differs, in that the MAC in neonates (3.3%) does not change through to 3 months (3.2%). Older infants and children have a MAC of approximately 2.5%. The reason for this different pattern is unclear. The
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This pattern of the MAC throughout childhood is similar for desflurane and halothane Reproduced with permission from LeDez KM, Lerman J. The minimum alveolar concentration of isoflurane in preterm neonates. Anesthesiol 1987; 67: 301–7.
Figure 5
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neonates has been associated with hypotension; particularly if administered with fentanyl. When an EEG signal is used as an effect measure, an EC50 of 0.035e0.077 mg/l, with a T1/2 keo of 0.9e1.6 minutes has been described in adults. Sedation in children is more difficult to quantify. No PKPD relationship was established in children 2 days to 17 years who were given a midazolam infusion in intensive care. Midazolam dosing can be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Desirable sedation in children after cardiac surgery is achieved at mean serum concentrations between 0.1 and 0.5 mg/L.
6
7
8
Inotropes Milrinone, an inodilator, is used increasingly in children after congenital cardiac surgery. Renal clearance is the primary route of elimination, and we might anticipate that maturation of milrinone clearance closely follows that of GFR. Clearance in adults is 9 L/ h/70 kg is reported in adults with congestive heart failure, whereas 26-week PMA infants (expected to have 10% of adult GFR) have a clearance of 0.96 L/h/70 kg.3 A
9 10
11
12
REFERENCES 1 Hines RN. Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children. Int J Pharm 2013; 452: 3e7. 2 Anderson BJ, Holford NHG. Negligible impact of birth on renal function and drug metabolism. Pediatr Anesth 2018; 28: 1015e21. 3 Sumpter A, Anderson BJ. Pediatric pharmacology in the first year of life. Curr Opin Anaesthesiol 2009; 22: 469e75. 4 Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24: 67e76. 5 Eaton MP, Alfieris GM, Sweeney DM, et al. Pharmacokinetics of epsilon-aminocaproic acid in neonates undergoing cardiac
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surgery with cardiopulmonary bypass. Anesthesiology 2015; 122: 1002e9. 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: 680e9. Lynn AM, Nespeca MK, Opheim KE, et al. Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77: 695e701. Allegaert K, Holford N, Anderson BJ, et al. Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study. Clin Pharmacokinet 2015; 54: 167e78. Anderson BJ, Thomas J, Ottaway K, et al. Tramadol: keep calm and carry on. Pediatr Anesth 2017; 27: 785e8. Palmer GM, Anderson BJ, Linscott DK, et al. Tramadol, breast feeding and safety in the newborn. Arch Dis Child 2018; 103: 1110e3. Allegaert K, Naulaers G, Vanhaesebrouck S, et al. The paracetamol concentration-effect relation in neonates. Pediatr Anesth 2013; 23: 45e50. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 2011; 96: 575e80. Hayward KL, Powell EE, Irvine KM, et al. Can paracetamol (acetaminophen) be administered to patients with liver impairment? Br J Clin Pharmacol 2016; 81: 210e22. Anderson BJ, Hannam JA. A target concentration strategy to determine ibuprofen dosing in children. Pediatr Anesth 2019; 29: 1107e13. Morse J, Hannam JA, Cortinez LI, et al. A manual propofol infusion regimen for neonates and infants. Pediatr Anesth 2019; 29: 907e14.
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