Paediatric Pharmacology: anaesthetic implications Brian Anderson PhD, FANZCA, FCICM Professor Anaesthesiology University of Auckland New Zealand Duccio di Buoninsegna 1308
A Lack of Knowledge of Pharmacology Leads To Bad Outcomes in Children Paediatric anaesthesia morbidity and mortality has historically been highest in 0-1 year age group Some of this increased morbidity and mortality is attributable to poor understanding of - drug effects (pharmacodynamics) that change with age - maturational changes in the way the body handles a drug (pharmacokinetics), - adverse effects that are age specific
Cytochrome P450 maturation (Phase 1) Immature at birth Different CYPs mature at different rates Practical Implication Reduce Infusion rates in neonates Concentration = infusion rate/cl Bupivacaine (CYP3A4) continuous epidural infusion rates in neonates (0.2 mg/kg/h) are less than children (0.4 mg/kg/h) Berde C. Anesth Analg 1992
Pain Score What do we want to know to determine dose? Concentration-response relationship (PD) Target effect Target concentration Dose to achieve concentration (PK) Covariate effects - age, weight, disease Toxicity data 10 9 8 7 6 5 4 3 2 1 0 concentration 2.5 mcg/l concentration 10 mcg/l therapeutic effect adverse effect A adverse effect B 0 5 10 15 20 Concentration (mcg/l)
Size models to calculate dose Per kilogram Body surface area Allometry
Per kilogram model Under predicts dose if weight < 47 kg Error increases as size decreases Explanations for under prediction fallacious Morphine - relative big liver Fentanyl - increased hepatic blood flow Remifentanil -??? % difference in clearance 20 10 0-10 -20-30 -40-50 -60 per kilogram model 0 20 40 60 80 100 Weight (kg) per kilogram Holford N. Clin Pharmacokinet 1996;30:329
West LJ. Science 1962;138:1100
Body Surface Area Model Nomogram required BSA = W(kg) 0.425 * H(cm) 0.725 * 0.007184 Original model from only 10 individuals - Du Bois D. Arch Intern Med 1916;17:863 Works reasonably well 7-100 kg BSA = k x Height 0 x Weight 2 3 % difference in clearance surface area model 30 25 20 15 10 Weight (kg) 5 0 0 10 20 30 40 50 60 70 80 90 100-5 surface area Holford N. Clin Pharmacokinet 1996;30:329
Predictions Match Observations 18 Orders of Magnitude Peters R. The ecological implications of body size. Cambridge: Cambridge University Press; 1983.
Tramadol Clearance Holford S et al. J Clin Pharm Tox 2014
The Size Problem: allometric theory CL = CL std * (WT / WT std ) 3/4 V = V std * (WT / WT std ) 4/4 T = T std * (WT / WT std ) ¼ West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science. 1999;284(5420):1677-9. NOTE Surface area model can be approximated by exponent of 2/3
Clearance Clearance changes with weight 40 35 30 25 20 15 10 5 0 Allometric 3/4 power BSA (allometric 2/3 power) Per kilogram 0 50 100 150 200 250 300 Weight
Allometric Examples Estimated Coefficient 0.74 Booth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D, et al. Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients. J Clin Pharmacol. 2007;47(1):101-11. Drover D, Hammer G, Anderson BJ. The pharmacokinetics of ketorolac after single postoperative intrnasal administration is adolescent patients. Analg Anesth 2011: 114 (6): 1270-6
Initial Dose or Infusion Bolus Dose Dose = V x Target Concentration Infusion At steady-state Rate in = Rate out Infusion rate = CL x Target Concentration
Clinical Considerations Propofol Infusion Adult bolus 1 mg/kg then 10-8-6 mg/kg/h Child bolus 1 mg/kg then 15-13-10 mg/kg/h Adult 10-8-6 Child 10-8-6
Maintenance Dose in Child CL CHILD = CL ADULT weight CHILD weight ADULT 3 4 Age Weight Dose 6 months 7.5 1/5 1 year 10 1/4 3 years 14 1/3 7 years 22 1/2 12 years 35 2/3
Clearance Clearance changes with weight 40 35 30 Maturation 25 20 15 10 5 0 Allometric 3/4 power BSA (allometric 2/3 power) Per kilogram 0 50 100 150 200 250 300 Weight
Clearance Pathway Maturation Class 1: mature at birth but decrease with age high CYP3A7 at birth decreases, CYP3A4 increases Methadone Ward R. Pediatr Anesth 2014 Class 2: mature at birth Esterases (remifentanil), Welzing L. Anesthesiol 2011 Sulphate Van der Marel CD. Eur J Clin Pharmacol 2003 Class 3: Most mature in first few years of life Hines RN. Int J Pharmaceutics 2012
Median and 90% Intervals GFR Growth Curves Rhodin MM. Human renal function maturation; a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76 100 CL CL TM max Hill 50 Age Age Hill Hill CLmax=6.84 L/h/70kg TM 50 =46.4 weeks PCA Hill=3.43 928 patients 22 weeks PCA to 32 y % Adult 75 50 25 0-26 0 26 52 78 Age (PNA) Weeks
Renal and Metabolic Maturation 100 Propofol 80 TM 50 38.5 weeks Hill 4.6 Dexmedetomidine TM 50 46.5 weeks GFR Hill 2.78 % Adult 60 40 20 TM 50 47.6 weeks Hill 3.4 Morphine TM 50 54.2 weeks Hill 3.92 Paracetamol TM 50 52.2 weeks Hill 3.4 Propofol Metabolism Glucuronide CYP2B6, CYP2C9 or CYP2A6 0 0 30 60 90 120 150 Postmenstrual age (weeks) Allegaert 2007, Rhodin 2009, Potts 2008, Anand 2008, Anderson 2009
Infusion rate (mg/kg/h) Morphine Infusion - target concentration 10 mg/l 20 16 12 8 predicted infusion rate practical infusion rate 4 0 5 10 15 20 25 Postnatal age (years)
Maturation of hepatic enzyme activity (Phase I) Kearns G. N Eng J Med 2003; 349: 1157-67.
Growth - organ size - organ blood flow brain liver kidney heart
Caffeine - a long acting stimulant in neonates Good central respiratory stimulant Poor hepatic clearance Immature P450 CYP1A2 Immature renal clearance T1/2 days in neonate, hours in adults
Caffeine half-life changes with age Data from DeCarolis MP, Romagnoli C, Muzil U, et al. Pharmacokinetic aspects of caffeine in premature infants. Dev Pharmacol Ther 1991;16:117-22.
Body Composition & Physiology Total body water, ECF Fat Protein binding Muscle mass Spinal column Skin Gastric emptying
Absorption & Delivery Neonates & EMLA cream Epidermis thin greater absorption HbF Methaemoglobinaemia
Oral Absorption of Paracetamol in Neonates Slow gastric emptying Reduced clearance Reduce dose Reduce dosing interval Concentration (mg/l) 18 16 14 12 10 8 6 4 2 0 Neonate Child 0 2 4 6 8 10 12 Time (hours) Anderson BJ. Anesthesiology 2002
Body Water Friis-Hansen Acta Paediatrica 1954
Neuromuscular Blocking Drugs Sensitivity neuromuscular junction Fetal neonatal postjunctional acetylcholine receptors differ from adults receptors (γ-subunit instead of an -subunit ) Quantal release acetylcholine Vd adults initial dose is same in neonates and Duration of effect longer in neonates Clearance reduced
Estimated AAG (mcmol/l) Protein binding - AAG 25 20 Alpha-1 acid glycoprotein reduced in neonates Bupivacaine is bound to AAG 15 10 5 0 0 50 100 150 200 250 300 350 400 Bolus epidural dose of bupivacaine in neonates is lower than in children (1.5-2 mg/kg vs. 2.5 mg/kg) because a greater proportion will be unbound drug and it is unbound drug that exerts effect Postnatal age (weeks) Booker P. Br J Anaesth 1996
Spinal Column Preterm and full-term infants have a much greater CSF volume relative to weight than a child (4 ml/kg in children < 15 kg) or adult (2 mg/kg) this may account in part for the increased dose (mg/kg) of local anesthetic required in infants to produce a successful subarachnoid block. Duration of blockade is shorter in neonates and this may be due to a higher CSF turnover rate than adults.
Acetaminophen Taste Frequency of Key Phrases unpublished (David Herd) Loved it Yummy Nice Liked Sweet OK Sour Did not like Yuk Horrible/Terrible Gross/Disgusting Tastes Like Poo Formulation A Formulation B 0 1 2 3 4 5 6 7 8 9 10 11 Number of children
Is It Just Pharmacokinetics? Drug in Peripheral V2 (L) Q (L.min -1 ) K21 (min -1 ) Central V1 (L) K1e (min -1 ) Effect Compartment Keo (min -1 ) K12 (min -1 ) CL (L.min -1 ) K10 (min -1 ) Effect E max C EC N 50 C EFFECT (Pharmacodynamics) N N
Pharmacology Pharmacokinetics Pharmacodynamics What the body does to the drug What the drug does to the body
Age & Altered Pharmacodynamics Bronchodilators smooth muscle Warfarin sensitivity Cyclosporin (immunosuppresion ) Midazolam GABBA A receptor, Blood flow Calcium and neonatal heart Gastric prokinetics sensitivity
Age and Isoflurane MAC Reason uncertain cerebral blood flow GABBA A receptor numbers Shifts in the regulation of chloride transporters LeDez K. Anesthesiology 1987
Pain Score What do we want to know to determine dose? Pharmacokinetics 10 9 concentration 2.5 mcg/l concentration 10 mcg/l 8 Pharmacodynamic 7 6 5 Adverse Effects 4 3 therapeutic effect adverse effect A 2 1 adverse effect B 0 0 5 10 15 20 Concentration (mcg/l)
Adverse Effects
Propofol Toxicity in Neonates - an immediate effect Neonatal data from neonatologists Papoff P. Pediatrics 2008; 121:448-9 Ghanta S. Pediatrics 2007; 119:e1248-e1255 Concerns BP Allegaert K. Curr Clin Pharmacol 2009;4:84-6 Vanderhaegen J. Neonatology 2010;98:57 63 Welzing L. Pediatr Anesth 2010;20:605-11 Editorial Lerman J. Neonatal tracheal intubation: an imbroglio unresolved. Pediatr Anesth 2011;20: 585-90
Neonatal Hypotension With Propofol 3 mg/kg Vanderhaegen J. Neonatology 2010; 98: 57 63
Ketamine (and other anaesthetic drugs) and the neonate - a long term effect Concerns about widespread neuronal apoptosis and long-term memory deficits Other long term effects due to impact at critical time: Thalidomide - phocomelia Stilboesterol - vaginal carcinoma Tetracycline - teeth staining