Abstract
The pharmacokinetics (PK), pharmacodynamics (PD) and side effect profile of most medications used in children differ from those in adults; these differences are most pronounced in neonates. PK are affected by maturation of organ function and body composition, altered protein binding, distinct disease spectrum, diverse behaviour and dissimilar receptor patterns (Kearns et al., N Engl J Med 349(12):1157–67, 2003). The capacity of the end organ, such as the brain, heart or skeletal muscle, to respond to medications may also differ in children compared with adults (PD effects). Dose modification to achieve the desired clinical response and avoid toxicity is required for children. Dose calculations are based on knowledge of PK and PD (Anderson and Holford, Arch Dis Child. 98(9):737–44, 2013).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.
Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98(9):737–44. doi:10.1136/archdischild-2013-303720.
Holford NHG. The target concentration approach to clinical drug development. Clin Pharmacokinet. 1995;29(5):287–91.
Benet LZ. A Holy Grail of clinical pharmacology: prediction of drug pharmacokinetics and pharmacodynamics in the individual patient. Clin Pharmacol Ther. 2009;86(2):133–4. doi:10.1038/clpt.2009.102.
West N, Dumont GA, van Heusden K, Petersen CL, Khosravi S, Soltesz K, Umedaly A, Reimer E, Ansermino JM. Robust closed-loop control of induction and maintenance of propofol anesthesia in children. Paediatr Anaesth. 2013;23(8):712–9. doi:10.1111/pan.12183.
Dumont GA, Ansermino JM. Closed-loop control of anesthesia: a primer for anesthesiologists. Anesth Analg. 2013;117(5):1130–8. doi:10.1213/ANE.0b013e3182973687.
McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical guide. Paediatr Anaesth. 1999;9(3):209–16.
Kataria BK, Ved SA, Nicodemus HF, Hoy GR, Lea D, Dubois MY, Mandema JW, Shafer SL. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology. 1994;80(1):104–22.
van Heusden K, Ansermino JM, Soltesz K, Khosravi S, West N, Dumont GA. Quantification of the variability in response to propofol administration in children. IEEE Trans Biomed Eng. 2013;60(9):2521–9. doi:10.1109/tbme.2013.2259592.
Greenblatt DJ, Koch-Weser J. Clinical pharmacokinetics (second of two parts). N Engl J Med. 1975;293(19):964–70. doi:10.1056/NEJM197511062931905.
Greenblatt DJ, Kock-Weser J. Drug therapy. Clinical Pharmacokinetics (first of two parts). N Engl J Med. 1975;293(14):702–5. doi:10.1056/NEJM197510022931406.
Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991;67(1):41–8.
Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg. 1987;66(12):1256–63.
Absalom A, Amutike D, Lal A, White M, Kenny GN. Accuracy of the ‘Paedfusor’ in children undergoing cardiac surgery or catheterization. Br J Anaesth. 2003;91(4):507–13.
Rigby-Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology. 2002;97(6):1393–400.
Anderson BJ. My child is unique; the pharmacokinetics are universal. Pediatr Anesth. 2012;22:530–8. doi:10.1111/j.1460-9592.2011.03788.x.
Minto C, Schnider T. Expanding clinical applications of population pharmacodynamic modelling. Br J Clin Pharmacol. 1998;46(4):321–33.
Sepulveda P, Cortinez LI, Saez C, Penna A, Solari S, Guerra I, Absalom AR. Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children. Br J Anaesth. 2011;107(4):593–600. doi:10.1093/bja/aer198.
Rigouzzo A, Servin F, Constant I. Pharmacokinetic-pharmacodynamic modeling of propofol in children. Anesthesiology. 2010;113(2):343–52. doi:10.1097/ALN.0b013e3181e4f4ca.
Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KHP, Hermann DJ, Muir KT, Mandema JW, Shafer SL. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. Anesthesiology. 1997;86:10–23.
Marsh DF, Hodkinson B. Remifentanil in paediatric anaesthetic practice. Anaesthesia. 2009;64(3):301–8. doi:10.1111/j.1365-2044.2008.05731.x.
Ross AK, Davis PJ, Dear Gd GL, Ginsberg B, McGowan FX, Stiller RD, Henson LG, Huffman C, Muir KT. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg. 2001;93(6):1393–401.
Rigby-Jones AE, Priston MJ, Sneyd JR, McCabe AP, Davis GI, Tooley MA, Thorne GC, Wolf AR. Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery. Br J Anaesth. 2007;99(2):252–61.
Davis PJ, Wilson AS, Siewers RD, Pigula FA, Landsman IS. The effects of cardiopulmonary bypass on remifentanil kinetics in children undergoing atrial septal defect repair. Anesth Analg. 1999;89(4):904–8.
Egan TD. Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet. 1995;29(2):80–94.
Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011;21(3):222–37. doi:10.1111/j.1460-9592.2011.03536.x.
Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992;76(3):334–41.
Wada DR, Drover DR, Lemmens HJ. Determination of the distribution volume that can be used to calculate the intravenous loading dose. Clin Pharmacokinet. 1998;35(1):1–7.
Anderson BJ, Allegaert K, Holford NH. Population clinical pharmacology of children: general principles. Eur J Pediatr. 2006;165(11):741–6.
Anderson BJ, Allegaert K, Holford NH. Population clinical pharmacology of children: modelling covariate effects. Eur J Pediatr. 2006;165(12):819–29.
Duffull S, Waterhouse T, Eccleston J. Some considerations on the design of population pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2005;32(3–4):441–57.
Peck CC, Sheiner LB, Nichols AI. The problem of choosing weights in nonlinear regression analysis of pharmacokinetic data. Drug Metab Rev. 1984;15(1 & 2):133–48.
Peck CC, Beal SL, Sheiner LB, Nichols AI. Extended least squares nonlinear regression: a possible solution to the “choice of weights” problem in analysis of individual pharmacokinetic parameters. J Pharmacokinet Biopharm. 1984;12(5):545–57.
Roberts FL, Dixon J, Lewis GT, Tackley RM, Prys Roberts C. Induction and maintenance of propofol anaesthesia. A manual infusion scheme. Anaesthesia. 1988;43(Suppl):14–7.
Tod M, Jullien V, Pons G. Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet. 2008;47(4):231–43.
West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276(5309):122–6.
Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.
Holford S, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop BH, Mehvar R, Giorgi M, Holford NH. Parent-metabolite pharmacokinetic models for tramadol—tests of assumptions and predictions. J Pharmacol Clin Toxicol. 2014;2(1):1023.
Welzing L, Ebenfeld S, Dlugay V, Wiesen MH, Roth B, Mueller C. Remifentanil degradation in umbilical cord blood of preterm infants. Anesthesiology. 2011;114(3):570–7. doi:10.1097/ALN.0b013e318204e043.
Johnson TN. The problems in scaling adult drug doses to children. Arch Dis Child. 2008;93(3):207–11.
Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683–704.
Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol. 1910;14:4–7.
Pokela ML, Olkkola KT, Seppala T, Koivisto M. Age-related morphine kinetics in infants. Dev Pharmacol Ther. 1993;20(1–2):26–34.
Peters JW, Anderson BJ, Simons SH, Uges DR, Tibboel D. Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates. Clin Pharmacokinet. 2006;45(7):705–14.
Anand KJ, Anderson BJ, Holford NH, Hall RW, Young T, Shephard B, Desai NS, Barton BA. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth. 2008;101(5):680–9.
Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941–52. doi:10.1002/jps.23574.
Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–56.
Edginton AN, Theil FP, Schmitt W, Willmann S. Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol. 2008;4(9):1143–52.
Encinas E, Calvo R, Lukas JC, Vozmediano V, Rodriguez M, Suarez E. A predictive pharmacokinetic/pharmacodynamic model of fentanyl for analgesia/sedation in neonates based on a semi-physiologic approach. Paediatr Drugs. 2013;15(3):247–57. doi:10.1007/s40272-013-0029-1.
Han PY, Duffull SB, Kirkpatrick CM, Green B. Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther. 2007;82(5):505–8.
Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharmacokinet. 1986;11(3):199–213.
Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Pract Ed. 2010;95(4):112–7. doi:10.1136/adc.2009.163055.
Chidambaran V, Venkatasubramanian R, Sadhasivam S, Esslinger H, Cox S, Diepstraten J, Fukuda T, Inge T, Knibbe CA, Vinks AA. Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents. Paediatr Anaesth. 2015;25(9):911–23. doi:10.1111/pan.12684.
Cortinez LI, Anderson BJ, Penna A, Olivares L, Munoz HR, Holford NH, Struys MM, Sepulveda P. Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model. Br J Anaesth. 2010;105(4):448–56. doi:10.1093/bja/aeq195.
Schuttler J, Ihmsen H. Population pharmacokinetics of propofol: a multicenter study. Anesthesiology. 2000;92(3):727–38.
Diepstraten J, Chidambaran V, Sadhasivam S, Esslinger HR, Cox SL, Inge TH, Knibbe CA, Vinks AA. Propofol clearance in morbidly obese children and adolescents: influence of age and body size. Clin Pharmacokinet. 2012;51(8):543–51. doi:10.2165/11632940-000000000-00000.
Egan TD, Huizinga B, Gupta SK, Jaarsma RL, Sperry RJ, Yee JB, Muir KT. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology. 1998;89(3):562–73.
Duffull SB, Dooley MJ, Green B, Poole SG, Kirkpatrick CM. A standard weight descriptor for dose adjustment in the obese patient. Clin Pharmacokinet. 2004;43(15):1167–78.
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67–76. doi:10.1007/s00467-008-0997-5.
Allegaert K, Olkkola KT, Owens KH, Van de Velde M, de Maat MM, Anderson BJ. Covariates of intravenous paracetamol pharmacokinetics in adults. BMC Anesthesiol. 2014;14:77. doi:10.1186/1471-2253-14-77.
Tham LS, Wang LZ, Soo RA, Lee HS, Lee SC, Goh BC, Holford NH. Does saturable formation of gemcitabine triphosphate occur in patients? Cancer Chemother Pharmacol. 2008;63(1):55–64. doi:10.1007/s00280-008-0707-9.
McCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NHG. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and bayesian dose personalization. Clin Cancer Res. 2014;20(3):754–63. doi:10.1158/1078-0432.ccr-13-1960.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(10):1051–65.
Kokki M, Broms S, Eskelinen M, Rasanen I, Ojanpera I, Kokki H. Analgesic concentrations of oxycodone—a prospective clinical PK/PD study in patients with laparoscopic cholecystectomy. Basic Clin Pharmacol Toxicol. 2012;110(5):469–75. doi:10.1111/j.1742-7843.2011.00839.x.
Jeleazcov C, Ihmsen H, Schmidt J, Ammon C, Schwilden H, Schuttler J, Fechner J. Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children. Br J Anaesth. 2008;100(4):509–16.
Standing JF, Hammer GB, Sam WJ, Drover DR. Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty. Paediatr Anaesth. 2011;20(1):7–18. doi:10.1111/j.1460-9592.2009.03174.x.
Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 1980;20:441–62.
Dixon WJ. Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev. 1991;15(1):47–50.
Dawes J, Myers D, Gorges M, Zhou G, Ansermino JM, Montgomery CJ. Identifying a rapid bolus dose of dexmedetomidine (ED50) with acceptable hemodynamic outcomes in children. Pediatr Anesth. 2014;24(12):1260–7. doi:10.1111/pan.12468.
Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18(1):36–42.
Hull CJ, Van Beem HB, McLeod K, Sibbald A, Watson MJ. A pharmacodynamic model for pancuronium. Br J Anaesth. 1978;50(11):1113–23.
Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to D-tubocurarine. Clin Pharmacol Ther. 1979;25(3):358–71.
Holford NHG, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet. 1981;6(6):429–53.
Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12(3):205–19.
West D, West BJ. Physiologic time: a hypothesis. Phys Life Rev. 2013;10(2):210–24. doi:10.1016/j.plrev.2013.04.006.
Cortinez LI, Troconiz IF, Fuentes R, Gambus P, Hsu YW, Altermatt F, Munoz HR. The influence of age on the dynamic relationship between end-tidal sevoflurane concentrations and bispectral index. Anesth Analg. 2008;107(5):1566–72. doi:10.1213/ane.0b013e318181f013.
Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics. 1961;28:169–81.
Johnson KL, Erickson JP, Holley FO, et al. Fentanyl pharmacokinetics in the paediatric population. Anesthesiology. 1984;61:A441.
Meretoja OA, Wirtavuori K, Neuvonen PJ. Age-dependence of the dose–response curve of vecuronium in pediatric patients during balanced anesthesia. Anesth Analg. 1988;67(1):21–6.
Fisher DM, Canfell PC, Spellman MJ, Miller RD. Pharmacokinetics and pharmacodynamics of atracurium in infants and children. Anesthesiology. 1990;73(1):33–7.
Luz G, Innerhofer P, Bachmann B, Frischhut B, Menardi G, Benzer A. Bupivacaine plasma concentrations during continuous epidural anesthesia in infants and children. Anesth Analg. 1996;82(2):231–4.
Luz G, Wieser C, Innerhofer P, Frischhut B, Ulmer H, Benzer A. Free and total bupivacaine plasma concentrations after continuous epidural anaesthesia in infants and children. Paediatr Anaesth. 1998;8(6):473–8.
Erichsen CJ, Sjovall J, Kehlet H, Hedlund C, Arvidsson T. Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief. Anesthesiology. 1996;84(4):834–42.
Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. 1997;33(5):313–27.
Calder A, Bell GT, Andersson M, Thomson AH, Watson DG, Morton NS. Pharmacokinetic profiles of epidural bupivacaine and ropivacaine following single-shot and continuous epidural use in young infants. Paediatr Anaesth. 2012;22(5):430–7. doi:10.1111/j.1460-9592.2011.03771.x.
Russo H, Bressolle F. Pharmacodynamics and pharmacokinetics of thiopental. Clin Pharmacokinet. 1998;35(2):95–134. doi:10.2165/00003088-199835020-00002.
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(6):691–704.
Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A. Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transpl. 2005;11(12):1481–93.
Schoning M, Hartig B. Age dependence of total cerebral blood flow volume from childhood to adulthood. J Cereb Blood Flow Metab. 1996;16(5):827–33. doi:10.1097/00004647-199609000-00007.
Chiron C, Raynaud C, Maziere B, Zilbovicius M, Laflamme L, Masure MC, Dulac O, Bourguignon M, Syrota A. Changes in regional cerebral blood flow during brain maturation in children and adolescents. J Nucl Med. 1992;33(5):696–703.
Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther. 1965;6:454–61.
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(4):695–701.
Engelhardt B. Development of the blood–brain barrier. Cell Tissue Res. 2003;314(1):119–29. doi:10.1007/s00441-003-0751-z.
Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol. 2006;1(3):223–36. doi:10.1007/s11481-006-9025-3.
Henthorn TK, Liu Y, Mahapatro M, Ng KY. Active transport of fentanyl by the blood–brain barrier. J Pharmacol Exp Ther. 1999;289(2):1084–9.
Hamabe W, Maeda T, Kiguchi N, Yamamoto C, Tokuyama S, Kishioka S. Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain. J Pharm Sci. 2007;105(4):353–60.
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(4):231–59. doi:10.1080/10915810600746023.
Gupta M, Brans Y. Gastric retention in neonates. Pediatrics. 1978;62:26–9.
Grand RJ, Watkins JB, Torti FM. Development of the human intestinal tract: a review. Gastroenterology. 1976;70:790–810.
Liang J, Co E, Zhang M, Pineda J, Chen JD. Development of gastric slow waves in preterm infants measured by electrogastrography. Am J Physiol. 1998;274(3 Pt 1):G503–8.
Carlos MA, Babyn PS, Marcon MA, Moore AM. Changes in gastric emptying in early postnatal life. J Pediatr. 1997;130(6):931–7.
Kearns GL, Robinson PK, Wilson JT, Wilson-Costello D, Knight GR, Ward RM, van den Anker JN. Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther. 2003;74(4):312–25.
Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NH. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002;96(6):1336–45.
Pomeranz ES, Chudnofsky CR, Deegan TJ, Lozon MM, Mitchiner JC, Weber JE. Rectal methohexital sedation for computed tomography imaging of stable pediatric emergency department patients. Pediatrics. 2000;105(5):1110–4.
Burckart GJ, White 3rd TJ, Siegle RL, Jabbour JT, Ramey DR. Rectal thiopental versus an intramuscular cocktail for sedating children before computerized tomography. Am J Hosp Pharm. 1980;37(2):222–4.
Herd D, Anderson BJ. Lack of pharmacokinetic information in children leads clinicians to use experience and trial-and-error to determine how best to administer ketamine. Ann Emerg Med. 2007;49(6):824.e1. doi:10.1016/j.annemergmed.2006.11.036.
Mason KP, Lubisch N, Robinson F, Roskos R, Epstein MA. Intramuscular dexmedetomidine: an effective route of sedation preserves background activity for pediatric electroencephalograms. J Pediatr. 2012;161(5):927–32. doi:10.1016/j.jpeds.2012.05.011.
Mason KP, Lubisch NB, Robinson F, Roskos R. Intramuscular dexmedetomidine sedation for pediatric MRI and CT. AJR Am J Roentgenol. 2011;197(3):720–5. doi:10.2214/ajr.10.6134.
Grassin-Delyle S, Buenestado A, Naline E, Faisy C, Blouquit-Laye S, Couderc LJ, Le Guen M, Fischler M, Devillier P. Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids. Pharmacol Ther. 2012;134(3):366–79. doi:10.1016/j.pharmthera.2012.03.003.
Hadley G, Maconochie I, Jackson A. A survey of intranasal medication use in the paediatric emergency setting in England and Wales. Emerg Med J. 2010;27(7):553–4. doi:10.1136/emj.2009.072538.
Kendall JM, Latter VS. Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects. Clin Pharmacokinet. 2003;42(6):501–13.
Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ. 2001;322(7281):261–5.
Kidd S, Brennan S, Stephen R, Minns R, Beattie T. Comparison of morphine concentration-time profiles following intravenous and intranasal diamorphine in children. Arch Dis Child. 2009;94(12):974–8. doi:10.1136/adc.2008.140194.
Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007;49(3):335–40. doi:10.1016/j.annemergmed.2006.06.016.
Borland M, Milsom S, Esson A. Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a paediatric emergency department: a randomized controlled trial. Emerg Med Australas. 2011;23(2):202–8. doi:10.1111/j.1742-6723.2011.01391.x.
Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emerg Med Australas. 2009;21(3):203–9. doi:10.1111/j.1742-6723.2009.01183.x.
Scheepers LD, Montgomery CJ, Kinahan AM, Dunn GS, Bourne RA, McCormack JP. Plasma concentration of flumazenil following intranasal administration in children. Can J Anaesth. 2000;47(2):120–4.
Rey E, Delaunay L, Pons G, Murat I, Richard MO, Saint-Maurice C, Olive G. Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol. 1991;41(4):355–7.
Iirola T, Vilo S, Manner T, Aantaa R, Lahtinen M, Scheinin M, Olkkola KT. Bioavailability of dexmedetomidine after intranasal administration. Eur J Clin Pharmacol. 2011;67(8):825–31. doi:10.1007/s00228-011-1002-y.
Larsson P, Eksborg S, Lonnqvist PA. Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial. Pediatr Anesth. 2012;22(9):877–83. doi:10.1111/j.1460-9592.2012.03877.x.
Almenrader N, Larsson P, Passariello M, Haiberger R, Pietropaoli P, Lonnqvist PA, Eksborg S. Absorption pharmacokinetics of clonidine nasal drops in children. Paediatr Anaesth. 2009;19(3):257–61. doi:10.1111/j.1460-9592.2008.02886.x.
Hippard HK, Govindan K, Friedman EM, Sulek M, Giannoni C, Larrier D, Minard CG, Watcha MF. Postoperative analgesic and behavioral effects of intranasal fentanyl, intravenous morphine, and intramuscular morphine in pediatric patients undergoing bilateral myringotomy and placement of ventilating tubes. Anesth Analg. 2012;115(2):356–63. doi:10.1213/ANE.0b013e31825afef3.
Drover DR, Hammer GB, Anderson BJ. The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients. Anesth Analg. 2012;114(6):1270–6. doi:10.1213/ANE.0b013e31824f92c2.
Ginsberg G, Hattis D, Miller R, Sonawane B. Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics. 2004;113(4 Suppl):973–83.
Taddio A, Shennan AT, Stevens B, Leeder JS, Koren G. Safety of lidocaine-prilocaine cream in the treatment of preterm neonates. J Pediatr. 1995;127(6):1002–5.
Taddio A, Stevens B, Craig K, Rastogi P, Ben-David S, Shennan A, Mulligan P, Koren G. Efficacy and safety of lidocaine-prilocaine cream for pain during circumcision. N Engl J Med. 1997;336(17):1197–201.
Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology. 1969;30:388–94.
Lerman J. Pharmacology of inhalational anaesthetics in infants and children. Paediatr Anaesth. 1992;2:191–203.
Lerman J, Schmitt Bantel BI, Gregory GA, Willis MM, Eger EI. Effect of age on the solubility of volatile anesthetics in human tissues. Anesthesiology. 1986;65(3):307–11.
Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentrations in neonates and adults. Anesthesiology. 1990;72(5):793–6.
Albani M, Wernicke I. Oral phenytoin in infancy: dose requirement, absorption, and elimination. Pediatr Pharmacol. 1983;3(3–4):229–36.
Abdel-Rahman SM, Johnson FK, Connor JD, Staiano A, Dupont C, Tolia V, Winter H, Gauthier-Dubois G, Kearns GL. Developmental pharmacokinetics and pharmacodynamics of nizatidine. J Pediatr Gastroenterol Nutr. 2004;38(4):442–51.
de Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN. Pharmacokinetics and metabolism of oral midazolam in preterm infants. Br J Clin Pharmacol. 2002;53(4):390–2.
Allegaert K, Anderson BJ, Vrancken M, Debeer A, Desmet K, Tibboel D, Devlieger H. Impact of a paediatric vial on the magnitude of systematic medication errors in preterm neonates: amikacin as an example. Paediatr Perinat Drug Ther. 2006;7:59–63.
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(5):885–91.
Herd DW, Salehi B. Palatability of two forms of paracetamol (acetaminophen) suspension: a randomised trial. Paed Perinatal Drug Ther. 2006;7:189–93.
Larsson P, Nordlinder A, Bergendahl HT, Lonnqvist PA, Eksborg S, Almenrader N, Anderson BJ. Oral bioavailability of clonidine in children. Pediatr Anesth. 2011;21(3):335–40. doi:10.1111/j.1460-9592.2010.03397.x.
Brunette KE, Anderson BJ, Thomas J, Wiesner L, Herd DW, Schulein S. Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures. Paediatr Anaesth. 2011;21(6):653–62. doi:10.1111/j.1460-9592.2011.03548.x.
Gourlay GK, Boas RA. Fatal outcome with use of rectal morphine for postoperative pain control in an infant. BMJ. 1992;304(6829):766–7.
Pelkonen O. Drug metabolism in the human fetal liver. Relationship to fetal age. Arch Int Pharmacodyn Ther. 1973;202(2):281–7.
Pelkonen O, Kaltiala EH, Larmi TK, Karki NT. Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clin Pharmacol Ther. 1973;14(5):840–6.
Pelkonen O, Karki NT. Drug metabolism in human fetal tissues. Life Sci. 1973;13:1163–80.
Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Pediatr Anesth. 2014;24(6):591–601. doi:10.1111/pan.12385.
Hines RN. Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children. Int J Pharm. 2013;452(1–2):3–7. doi:10.1016/j.ijpharm.2012.05.079.
Nebert DW, Adesnik M, Coon MJ, Estabrook RW, Gonzalez FJ, Guengerich FP, Gunsalus IC, Johnson EF, Kemper B, Levin W, et al. The P450 gene superfamily: recommended nomenclature. DNA. 1987;6(1):1–11.
Nebert DW, Gonzalez FJ. P450 genes: structure, evolution, and regulation. Annu Rev Biochem. 1987;56:945–93. doi:10.1146/annurev.bi.56.070187.004501.
Nebert DW, Jaiswal AK, Meyer UA, Gonzalez FJ. Human P-450 genes: evolution, regulation and possible role in carcinogenesis. Biochem Soc Trans. 1987;15(4):586–9.
Cazeneuve C, Pons G, Rey E, Treluyer JM, Cresteil T, Thiroux G, D’Athis P, Olive G. Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults. Br J Clin Pharmacol. 1994;37(5):405–12.
Aranda JV, Sitar DS, Parsons WD, Loughnan PM, Neims AH. Pharmacokinetic aspects of theophylline in premature newborns. N Engl J Med. 1976;295(8):413–6.
Anderson BJ, Gunn TR, Holford NH, Johnson R. Caffeine overdose in a premature infant: clinical course and pharmacokinetics. Anaesth Intens Care. 1999;27(3):307–11.
Anderson BJ, Holford NH, Woollard GA. Aspects of theophylline clearance in children. Anaesth Intens Care. 1997;25(5):497–501.
Hines RN. Ontogeny of human hepatic cytochromes P450. J Biochem Mol Toxicol. 2007;21(4):169–75.
Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther. 2002;300(2):355–60.
Treluyer JM, Gueret G, Cheron G, Sonnier M, Cresteil T. Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility. Pharmacogenetics. 1997;7(6):441–52.
Treluyer JM, Jacqz-Aigrain E, Alvarez F, Cresteil T. Expression of CYP2D6 in developing human liver. Eur J Biochem. 1991;202(2):583–8.
Allegaert K, Holford N, Anderson BJ, Holford S, Stuber F, Rochette A, Troconiz IF, Beier H, de Hoon JN, Pedersen RS, Stamer U. Tramadol and O-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study. Clin Pharmacokinet. 2014;54(2):167–78. doi:10.1007/s40262-014-0191-9.
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, Hines RN. Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. 2004;308(3):965–74.
Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, Zaya MJ. Developmental expression of the major human hepatic CYP3A enzymes. J Pharm Exp Ther. 2003;307(2):573–82.
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485–505.
Berde C. Convulsions associated with pediatric regional anesthesia. Anesth Analg. 1992;75:164–6.
Sutherland JM. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. Am J Dis Child. 1959;97:761–7.
Burns LE, Hodgman JE. Fatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med. 1959;261:1318.
Holford NH, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Pediatr Anesth. 2012;22(3):209–22. doi:10.1111/j.1460-9592.2011.03782.x.
Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.
Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in children: a population analysis. Paediatr Anaesth. 2008;18(8):722–30.
Allegaert K, Peeters MY, Verbesselt R, Tibboel D, Naulaers G, de Hoon JN, Knibbe CA. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth. 2007;99(6):864–70.
Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286(5439):487–91.
Quiding H, Olsson GL, Boreus LO, Bondesson U. Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration. Br J Clin Pharmacol. 1992;33(1):45–9.
Palmer SN, Giesecke NM, Body SC, Shernan SK, Fox AA, Collard CD. Pharmacogenetics of anesthetic and analgesic agents. Anesthesiology. 2005;102(3):663–71.
Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. Br J Anaesth. 2001;86(3):413–21.
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006;57:119–37.
Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant—an ultra-rapid metabolizer. Paediatr Anaesth. 2007;17(7):684–7. doi:10.1111/j.1460-9592.2006.02182.x.
Kearns GL. Pharmacogenetics and development: are infants and children at increased risk for adverse outcomes? Curr Opin Pediatr. 1995;7(2):220–33.
Fagerlund TH, Braaten O. No pain relief from codeine…? An introduction to pharmacogenomics. Acta Anaesthesiol Scand. 2001;45(2):140–9.
Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999;91(23):2001–8.
Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med. 2009;11(1):21–34. doi:10.1097/GIM.0b013e31818efd77.
Andersson T, Flockhart DA, Goldstein DB, Huang SM, Kroetz DL, Milos PM, Ratain MJ, Thummel K. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther. 2005;78(6):559–81. doi:10.1016/j.clpt.2005.08.013.
Allegaert K, van den Anker JN, de Hoon JN, van Schaik RH, Debeer A, Tibboel D, Naulaers G, Anderson BJ. Covariates of tramadol disposition in the first months of life. Br J Anaesth. 2008;100(4):525–32.
West JR, Smith HW, Chasis H. Glomerular filtration rate, effective renal blood flow, and maximal tubular excretory capacity in infancy. J Pediatr. 1948;32:10–8.
Fawer CL, Torrado A, Guignard JP. Maturation of renal function in full-term and premature neonates. Helv Paediatr Acta. 1979;34(1):11–21.
Eichenwald HF, McCracken Jr GH. Antimicrobial therapy in infants and children. Part I Review of antimicrobial agents. J Pediatr. 1978;93(3):337–56.
Anderson BJ, Allegaert K, Van den Anker JN, Cossey V, Holford NH. Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol. 2007;63(1):75–84.
Fisher DM, O’Keeffe C, Stanski DR, Cronnelly R, Miller RD, Gregory GA. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology. 1982;57(3):203–8.
Sawyer DC, Eger 2nd EI, Bahlman SH, Cullen BF, Impelman D. Concentration dependence of hepatic halothane metabolism. Anesthesiology. 1971;34(3):230–5.
Brandom BW, Stiller RL, Cook DR, Woelfel SK, Chakravorti S, Lai A. Pharmacokinetics of atracurium in anaesthetized infants and children. Br J Anaesth. 1986;58(11):1210–3.
Meakin G, McKiernan EP, Morris P, Baker RD. Dose–response curves for suxamethonium in neonates, infants and children. Br J Anaesth. 1989;62(6):655–8.
Cook DR, Wingard LB, Taylor FH. Pharmacokinetics of succinylcholine in infants, children, and adults. Clin Pharmacol Ther. 1976;20(4):493–8.
Goudsouzian NG, Liu LM. The neuromuscular response of infants to a continuous infusion of succinylcholine. Anesthesiology. 1984;60(2):97–101.
Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol. 2005;59(6):670–3.
LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology. 1987;67(3):301–7.
Chugani HT, Kumar A, Muzik O. GABA(A) receptor imaging with positron emission tomography in the human newborn: a unique binding pattern. Pediatr Neurol. 2013;48(6):459–62. doi:10.1016/j.pediatrneurol.2013.04.008.
Meakin G, Morton RH, Wareham AC. Age-dependent variation in response to tubocurarine in the isolated rat diaphragm. Br J Anaesth. 1992;68(2):161–3.
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(2):205–9.
Arnold PD. Coagulation and the surgical neonate. Paediatr Anaesth. 2014;24(1):89–97. doi:10.1111/pan.12296.
Guzzetta NA, Miller BE. Principles of hemostasis in children: models and maturation. Paediatr Anaesth. 2011;21(1):3–9. doi:10.1111/j.1460-9592.2010.03410.x.
Albisetti M. The fibrinolytic system in children. Semin Thromb Hemost. 2003;29(4):339–48. doi:10.1055/s-2003-42585.
Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood. 1987;70(1):165–72.
Ries M, Easton RL, Longstaff C, Zenker M, Corran PH, Morris HR, Dell A, Gaffney PJ. Differences between neonates and adults in tissue-type-plasminogen activator (t-PA)-catalyzed plasminogen activation with various effectors and in carbohydrate sequences of fibrinogen chains. Thromb Res. 2001;103(3):173–84.
Ries M, Easton RL, Longstaff C, Zenker M, Morris HR, Dell A, Gaffney PJ. Differences between neonates and adults in carbohydrate sequences and reaction kinetics of plasmin and alpha(2)-antiplasmin. Thromb Res. 2002;105(3):247–56.
McNicol G, Fletcher A, Alkjaersig N, Sherry S. The absorption, distribution, and excretion of epsilon-aminocaproic acid following oral or intravenous administration to man. J Lab Clin. 1962;59:15–24.
Nielsen VG, Cankovic L, Steenwyk BL. Epsilon-aminocaproic acid inhibition of fibrinolysis in vitro: should the ‘therapeutic’ concentration be reconsidered? Blood Coagul Fibrinolysis. 2007;18(1):35–9. doi:10.1097/MBC.0b013e328010a359.
Yurka HG, Wissler RN, Zanghi CN, Liu X, Tu X, Eaton MP. The effective concentration of epsilon-aminocaproic Acid for inhibition of fibrinolysis in neonatal plasma in vitro. Anesth Analg. 2010;111(1):180–4. doi:10.1213/ANE.0b013e3181e19cec.
Kirk CR, Gibbs JL, Thomas R, Radley-Smith R, Qureshi SA. Cardiovascular collapse after verapamil in supraventricular tachycardia. Arch Dis Child. 1987;62(12):1265–6.
Takahashi H, Ishikawa S, Nomoto S, Nishigaki Y, Ando F, Kashima T, Kimura S, Kanamori M, Echizen H. Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children. Clin Pharmacol Ther. 2000;68(5):541–55.
Kupferberg HJ, Way EL. Pharmacologic basis for the increased sensitivity of the newborn rat to morphine. J Pharmacol Exp Ther. 1963;141:105–12.
Domek NS, Barlow CF, Roth LJ. An ontogenetic study of phenobarbital-C-14 in cat brain. J Pharmacol Exp Ther. 1960;130:285–93.
Arai T, Watanabe T, Nagaro T, Matsuo S. Blood–brain barrier impairment after cardiac resuscitation. Crit Care Med. 1981;9(6):444–8.
Hagberg H, Mallard C. Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol. 2005;18(2):117–23.
Baber NS. Tripartite meeting. Paediatric regulatory guidelines: do they help in optimizing dose selection for children? Brit J Clin Pharmacol. 2005;59(6):660–2.
Davidson AJ. Measuring anesthesia in children using the EEG. Pediatr Anesthesia. 2006;16(4):374–87.
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(5):674–9.
Davidson AJ, Sale SM, Wong C, McKeever S, Sheppard S, Chan Z, Williams C. The electroencephalograph during anesthesia and emergence in infants and children. Paediatr Anaesth. 2008;18(1):60–70.
Jeleazcov C, Schmidt J, Schmitz B, Becke K, Albrecht S. EEG variables as measures of arousal during propofol anaesthesia for general surgery in children: rational selection and age dependence. Br J Anaesth. 2007;99(6):845–54.
Hoffman GM, Nowakowski R, Troshynski TJ, Berens RJ, Weisman SJ. Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model. Pediatrics. 2002;109(2):236–43.
Crellin D, Sullivan TP, Babl FE, O’Sullivan R, Hutchinson A. Analysis of the validation of existing behavioral pain and distress scales for use in the procedural setting. Paediatr Anaesth. 2007;17(8):720–33.
von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years. Pain. 2007;127(1–2):140–50.
Schade JG, Joyce BA, Gerkensmeyer J, Keck JF. Comparison of three preverbal scales for postoperative pain assessment in a diverse pediatric sample. J Pain Symptom Manage. 1996;12(6):348–59.
Connelly MA, Brown JT, Kearns GL, Anderson RA, St Peter SD, Neville KA. Pupillometry: a non-invasive technique for pain assessment in paediatric patients. Arch Dis Child. 2014;99(12):1125–31. doi:10.1136/archdischild-2014-306286.
Howard RF, Liossi C. Pain assessment in children. Arch Dis Child. 2014;99(12):1123–4. doi:10.1136/archdischild-2014-306432.
Holford NHG, Peck CC. Population pharmacodynamics and drug development. In: Boxtel CJ, Holford NHG, Danhof M, editors. The in vivo study of drug action. New York: Elsevier Science Publishers; 1992. p. 401–14.
Anderson BJ, van den Anker J. Why is there no morphine concentration-response curve for acute pain? Paediatr Anaesth. 2014;24(3):233–8. doi:10.1111/pan.12361.
Comer SD, Cooper ZD, Kowalczyk WJ, Sullivan MA, Evans SM, Bisaga AM, Vosburg SK. Evaluation of potential sex differences in the subjective and analgesic effects of morphine in normal, healthy volunteers. Psychopharmacology (Berl). 2010;208(1):45–55. doi:10.1007/s00213-009-1703-4.
Djurendic-Brenesel M, Mimica-Dukic N, Pilija V, Tasic M. Gender-related differences in the pharmacokinetics of opiates. Forensic Sci Int. 2010;194(1–3):28–33. doi:10.1016/j.forsciint.2009.10.003.
Sarton E, Romberg R, Dahan A. Gender differences in morphine pharmacokinetics and dynamics. Adv Exp Med Biol. 2003;523:71–80.
Schmitz AK, Vierhaus M, Lohaus A. Pain tolerance in children and adolescents: sex differences and psychosocial influences on pain threshold and endurance. Eur J Pain. 2013;17(1):124–31. doi:10.1002/j.1532-2149.2012.00169.x.
Rabbitts JA, Groenewald CB, Dietz NM, Morales C, Rasanen J. Perioperative opioid requirements are decreased in hypoxic children living at altitude. Pediatr Anesth. 2010;20(12):1078–83. doi:10.1111/j.1460-9592.2010.03453.x.
Rabbitts JA, Groenewald CB, Rasanen J. Geographic differences in perioperative opioid administration in children. Pediatr Anesth. 2012;22(7):676–81. doi:10.1111/j.1460-9592.2012.03806.x.
Jimenez N, Anderson GD, Shen DD, Nielsen SS, Farin FM, Seidel K, Lynn AM. Is ethnicity associated with morphine’s side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy. Pediatr Anesth. 2012;22(7):669–75. doi:10.1111/j.1460-9592.2012.03844.x.
Sadhasivam S, Chidambaran V, Ngamprasertwong P, Esslinger HR, Prows C, Zhang X, Martin LJ, McAuliffe J. Race and unequal burden of perioperative pain and opioid related adverse effects in children. Pediatrics. 2012;129(5):832–8. doi:10.1542/peds.2011-2607.
Sadhasivam S, Krekels EH, Chidambaran V, Esslinger HR, Ngamprasertwong P, Zhang K, Fukuda T, Vinks AA. Morphine clearance in children: does race or genetics matter? J Opioid Manag. 2012;8(4):217–26. doi:10.5055/jom.2012.0119.
Rigby-Jones A, Sneyd JR. Cardiovascular changes after achieving constant effect site concentration of propofol. Anaesthesia. 2008;63(7):780. doi:10.1111/j.1365-2044.2008.05589_1.x.
Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, Baker EM, Jekich BM, Wieseler JL, Somogyi AA, Martin D, Poole S, Judd CM, Maier SF, Watkins LR. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008;22(8):1178–89. doi:10.1016/j.bbi.2008.05.004.
Candiotti KA, Yang Z, Morris R, Yang J, Crescimone NA, Sanchez GC, Bird V, Leveillee R, Rodriguez Y, Liu H, Zhang YD, Bethea JR, Gitlin MC. Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption. Anesthesiology. 2011;114(5):1162–8. doi:10.1097/ALN.0b013e318216e9cb.
Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J. 2006;6(3):200–10.
Walter C, Lotsch J. Meta-analysis of the relevance of the OPRM1 118A > G genetic variant for pain treatment. Pain. 2009;146(3):270–5. doi:10.1016/j.pain.2009.07.013.
Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU, Du Bois R, Riley J. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5(5):324–36. doi:10.1038/sj.tpj.6500327.
Liem EB, Joiner TV, Tsueda K, Sessler DI. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology. 2005;102(3):509–14.
Lotsch J, Geisslinger G. Pharmacogenetics of new analgesics. Br J Pharmacol. 2011;163(3):447–60. doi:10.1111/j.1476-5381.2010.01074.x.
Tournier N, Decleves X, Saubamea B, Scherrmann JM, Cisternino S. Opioid transport by ATP-binding cassette transporters at the blood–brain barrier: implications for neuropsychopharmacology. Curr Pharm Des. 2011;17(26):2829–42.
Linden G, Henderson BE. Genital-tract cancers in adolescents and young adults. N Engl J Med. 1972;286(14):760–1.
Fredriksson A, Archer T, Alm H, Gordh T, Eriksson P. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav Brain Res. 2004;153(2):367–76.
Wang C, Sadovova N, Fu X, Schmued L, Scallet A, Hanig J, Slikker W. The role of the N-methyl-d-aspartate receptor in ketamine-induced apoptosis in rat forebrain culture. Neuroscience. 2005;132(4):967–77.
Anderson BJ, Ralph CJ, Stewart AW, Barber C, Holford NH. The dose-effect relationship for morphine and vomiting after day-stay tonsillectomy in children. Anaesth Intens Care. 2000;28(2):155–60.
Weinstein MS, Nicolson SC, Schreiner MS. A single dose of morphine sulfate increases the incidence of vomiting after outpatient inguinal surgery in children. Anesthesiology. 1994;81(3):572–7.
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(7):561–73.
Welzing L, Kribs A, Eifinger F, Huenseler C, Oberthuer A, Roth B. Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates. Paediatr Anaesth. 2010;20(7):605–11. doi:10.1111/j.1460-9592.2010.03330.x.
Lerman J, Heard C, Steward DJ. Neonatal tracheal intubation: an imbroglio unresolved. Paediatr Anaesth. 2010;20(7):585–90. doi:10.1111/j.1460-9592.2010.03356.x.
Lichtenbelt BJ, Olofsen E, Dahan A, van Kleef JW, Struys MM, Vuyk J. Propofol reduces the distribution and clearance of midazolam. Anesth Analg. 2010;110(6):1597–606. doi:10.1213/ANE.0b013e3181da91bb.
Vuyk J, Lichtenbelt BJ, Olofsen E, van Kleef JW, Dahan A. Mixed-effects modeling of the influence of midazolam on propofol pharmacokinetics. Anesth Analg. 2009;108(5):1522–30. doi:10.1213/ane.0b013e31819e4058.
Atkinson HC, Stanescu I, Anderson BJ. Increased phenylephrine plasma levels with administration of acetaminophen. N Engl J Med. 2014;370(12):1171–2. doi:10.1056/NEJMc1313942.
Atkinson HC, Stanescu I, Salem II, Potts AL, Anderson BJ. Increased bioavailability of phenylephrine by co-administration of acetaminophen: results of four open-label, crossover pharmacokinetic trials in healthy volunteers. Eur J Clin Pharmacol. 2015;71(2):151–8. doi:10.1007/s00228-014-1788-5.
Strolin Benedetti M, Ruty B, Baltes E. Induction of endogenous pathways by antiepileptics and clinical implications. Fundam Clin Pharmacol. 2005;19(5):511–29. doi:10.1111/j.1472-8206.2005.00341.x.
Eker HE, Yalcin Cok O, Aribogan A, Arslan G. Children on phenobarbital monotherapy requires more sedatives during MRI. Pediatr Anesth. 2011;10(10):998–1002. doi:10.1111/j.1460-9592.2011.03606.x.
Stanski DR, Ham J, Miller RD, Sheiner LB. Pharmacokinetics and pharmacodynamics of d-tubocurarine during nitrous oxide-narcotic and halothane anesthesia in man. Anesthesiology. 1979;51(3):235–41.
Prys-Roberts C, Lloyd JW, Fisher A, et al. Deliberate profound hypotension induced with halothane: studies of haemodynamics and pulmonary gas exchange. Br J Anaesth. 1974;46:105.
Pauca AL, Hopkins AM. Acute effects of halothane, nitrous oxide and thiopentone on upper limb blood flow. Br J Anaesth. 1972;43:326–33.
Taivainen T, Meretoja OA. The neuromuscular blocking effects of vecuronium during sevoflurane, halothane and balanced anaesthesia in children. Anaesthesia. 1995;50(12):1046–9.
Greco WR, Park HS, Rustum YM. Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-d-arabinofuranosylcytosine. Cancer Res. 1990;50(17):5318–27.
Minto C, Vuyk J. Response surface modelling of drug interactions. Adv Exp Med Biol. 2003;523:35–43.
Kern SE, Xie G, White JL, Egan TD. A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology. 2004;100(6):1373–81.
Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL. Response surface model for anesthetic drug interactions. Anesthesiology. 2000;92(6):1603–16.
Bouillon TW, Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, Shafer SL. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100(6):1353–72.
Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth. 1992;69(2):162–7.
Dahan A, Nieuwenhuijs D, Olofsen E, Sarton E, Romberg R, Teppema L. Response surface modeling of alfentanil-sevoflurane interaction on cardiorespiratory control and bispectral index. Anesthesiology. 2001;94(6):982–91.
Nieuwenhuijs DJ, Olofsen E, Romberg RR, Sarton E, Ward D, Engbers F, Vuyk J, Mooren R, Teppema LJ, Dahan A. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology. 2003;98(2):312–22.
Cote CJ, Karl HW, Notterman DA, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics. 2000;106(4):633–44.
Drover DR, Litalien C, Wellis V, Shafer SL, Hammer GB. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children. Anesthesiology. 2004;100(6):1382–6.
Coulter FL, Hannam JA, Anderson BJ. Ketofol dosing simulations for procedural sedation. Pediatr Emerg Care. 2014;30(9):621–30.
Andolfatto G, Abu-Laban RB, Zed PJ, Staniforth SM, Stackhouse S, Moadebi S, Willman E. Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial. Ann Emerg Med. 2012;59(6):504–512.e2. doi:10.1016/j.annemergmed.2012.01.017.
Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J. Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology. 1995;82(3):641–8.
Coulter FL, Hannam JA, Anderson BJ. Ketofol simulations for dosing in pediatric anesthesia. Pediatr Anesth. 2014;24(8):806–12. doi:10.1111/pan.12386.
Dallimore D, Anderson BJ, Short TG, Herd DW. Ketamine anesthesia in children—exploring infusion regimens. Paediatr Anaesth. 2008;18(8):708–14.
Murphy A, Campbell DE, Baines D, Mehr S. Allergic reactions to propofol in egg-allergic children. Anesth Analg. 2011;113(1):140–4. doi:10.1213/ANE.0b013e31821b450f.
Molina-Infante J, Arias A, Vara-Brenes D, Prados-Manzano R, Gonzalez-Cervera J, Alvarado-Arenas M, Lucendo AJ. Propofol administration is safe in adult eosinophilic esophagitis patients sensitized to egg, soy, or peanut. Allergy. 2014;69(3):388–94. doi:10.1111/all.12360.
McKeating K, Bali IM, Dundee JW. The effects of thiopentone and propofol on upper airway integrity. Anaesthesia. 1988;43(8):638–40.
Taha S, Siddik-Sayyid S, Alameddine M, Wakim C, Dahabra C, Moussa A, Khatib M, Baraka A. Propofol is superior to thiopental for intubation without muscle relaxants. Can J Anaes. 2005;52(3):249–53. doi:10.1007/BF03016058.
Koh KF, Chen FG, Cheong KF, Esuvaranathan V. Laryngeal mask insertion using thiopental and low dose atracurium: a comparison with propofol. Can Anaesth Soc J. 1999;46(7):670–4. doi:10.1007/BF03013956.
Lerman J, Johr M. Inhalational anesthesia vs total intravenous anesthesia (TIVA) for pediatric anesthesia. Paediatr Anaesth. 2009;19(5):521–34. doi:10.1111/j.1460-9592.2009.02962.x.
Sharples A, Shaw EA, Meakin G. Recovery times following induction of anaesthesia with propofol, methohexitone, enflurane or thiopentone in children. Paediatr Anaesth. 1994;4:101–4.
Jones RD, Chan K, Andrew LJ. Pharmacokinetics of propofol in children. Br J Anaesth. 1990;65(5):661–7.
Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth. 1988;60(2):146–50.
Westrin P. The induction dose of propofol in infants 1–6 months of age and in children 10–16 years of age. Anesthesiology. 1991;74(3):455–8.
Naguib M, Samarkandi AH, Moniem MA, Mansour Eel D, Alshaer AA, Al-Ayyaf HA, Fadin A, Alharby SW. The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study. Anesth Analg. 2006;103(6):1448–52. doi:10.1213/01.ane.0000244534.24216.3a.
Short TG, Aun CS, Tan P, Wong J, Tam YH, Oh TE. A prospective evaluation of pharmacokinetic model controlled infusion of propofol in paediatric patients. Br J Anaesth. 1994;72(3):302–6.
Murat I, Billard V, Vernois J, Zaouter M, Marsol P, Souron R, Farinotti R. Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns. Comparison of three data analysis approaches. Anesthesiology. 1996;84(3):526–32.
Saint-Maurice C, Cockshott ID, Douglas EJ, Richard MO, Harmey JL. Pharmacokinetics of propofol in young children after a single dose. Br J Anaesth. 1989;63(6):667–70.
Coppens MJ, Eleveld DJ, Proost JH, Marks LA, Van Bocxlaer JF, Vereecke H, Absalom AR, Struys MM. An evaluation of using population pharmacokinetic models to estimate pharmacodynamic parameters for propofol and bispectral index in children. Anesthesiology. 2011;115(1):83–93. doi:10.1097/ALN.0b013e31821a8d80.
Iwakiri H, Nishihara N, Nagata O, Matsukawa T, Ozaki M, Sessler DI. Individual effect-site concentrations of propofol are similar at loss of consciousness and at awakening. Anesth Analg. 2005;100(1):107–10. doi:10.1213/01.ANE.0000139358.15909.EA.
McCormack J, Mehta D, Peiris K, Dumont G, Fung P, Lim J, Ansermino JM. The effect of a target controlled infusion of propofol on predictability of recovery from anesthesia in children. Pediatr Anesth. 2010;20(1):56–62. doi:10.1111/j.1460-9592.2009.03196.x.
Rigouzzo A, Girault L, Louvet N, Servin F, De-Smet T, Piat V, Seeman R, Murat I, Constant I. The relationship between bispectral index and propofol during target-controlled infusion anesthesia: a comparative study between children and young adults. Anesth Analg. 2008;106(4):1109–16. doi:10.1213/ane.0b013e318164f388.
Fuentes R, Cortinez I, Ibacache M, Concha M, Munoz H. Propofol concentration to induce general anesthesia in children aged 3–11 years with the Kataria effect-site model. Paediatr Anaesth. 2015;25(6):554–9. doi:10.1111/pan.12657.
Eleveld DJ, Absalom AR. Does it matter how you get from D (drug dose) to E (clinical effect)? Paediatr Anaesth. 2015;25(6):544–5. doi:10.1111/pan.12665.
Steur RJ, Perez RS, De Lange JJ. Dosage scheme for propofol in children under 3 years of age. Paediatr Anaesth. 2004;14(6):462–7. doi:10.1111/j.1460-9592.2004.01238.x.
Valtonen M, Iisalo E, Kanto J, Rosenberg P. Propofol as an induction agent in children: pain on injection and pharmacokinetics. Acta Anaesthesiol Scand. 1989;33(2):152–5.
Cameron E, Johnston G, Crofts S, Morton NS. The minimum effective dose of lignocaine to prevent injection pain due to propofol in children. Anaesthesia. 1992;47(7):604–6.
Aun CS, Sung RY, O’Meara ME, Short TG, Oh TE. Cardiovascular effects of i.v. induction in children: comparison between propofol and thiopentone. Br J Anaesth. 1993;70(6):647–53.
Wodey E, Chonow L, Beneux X, Azzis O, Bansard JY, Ecoffey C. Haemodynamic effects of propofol vs thiopental in infants: an echocardiographic study. Br J Anaesth. 1999;82(4):516–20.
Short SM, Aun CS. Haemodynamic effects of propofol in children. Anaesthesia. 1991;46(9):783–5.
Wolf AR, Potter F. Propofol infusion in children: when does an anesthetic tool become an intensive care liability? Paediatr Anaesth. 2004;14(6):435–8. doi:10.1111/j.1460-9592.2004.01332.x.
Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet. 2001;357(9256):606–7. doi:10.1016/S0140-6736(00)04064-2.
Crean P. Sedation and neuromuscular blockade in paediatric intensive care; practice in the United Kingdom and North America. Paediatr Anaesth. 2004;14(6):439–42. doi:10.1111/j.1460-9592.2004.01259.x.
Kingston HG, Kendrick A, Sommer KM, Olsen GD, Downes H. Binding of thiopental in neonatal serum. Anesthesiology. 1990;72(3):428–31.
Sorbo S, Hudson RJ, Loomis JC. The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology. 1984;61(6):666–70.
Larsson P, Anderson BJ, Norman E, Westrin P, Fellman V. Thiopentone elimination in newborn infants: exploring Michaelis-Menten kinetics. Acta Anaesthesiol Scand. 2011;55(4):444–51. doi:10.1111/j.1399-6576.2010.02380.x.
Lindsay WA, Shepherd J. Plasma levels of thiopentone after premedication with rectal suppositories in young children. Br J Anaesth. 1969;41(11):977–84.
Jonmarker C, Westrin P, Larsson S, Werner O. Thiopental requirements for induction of anesthesia in children. Anesthesiology. 1987;67(1):104–7.
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(3):344–6.
Fouts JR, Adamson RH. Drug metabolism in the newborn rabbit. Science. 1959;129(3353):897–8.
Tibballs J, Malbezin S. Cardiovascular responses to induction of anaesthesia with thiopentone and suxamethonium in infants and children. Anaesth Intens Care. 1988;16(3):278–84.
Russo H, Bressolle F, Duboin MP. Pharmacokinetics of high-dose thiopental in pediatric patients with increased intracranial pressure. Ther Drug Monit. 1997;19(1):63–70.
Turcant A, Delhumeau A, Premel-Cabic A, Granry JC, Cottineau C, Six P, Allain P. Thiopental pharmacokinetics under conditions of long-term infusion. Anesthesiology. 1985;63(1):50–4.
Sakai T, Singh H, Mi WD, Kudo T, Matsuki A. The effect of ketamine on clinical endpoints of hypnosis and EEG variables during propofol infusion. Acta Anaesthesiol Scand. 1999;43(2):212–6.
White PF, Schuttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57(2):197–203.
Grant IS, Nimmo WS, McNicol LR, Clements JA. Ketamine disposition in children and adults. Br J Anaesth. 1983;55(11):1107–11.
Schuttler J, Stanski DR, White PF, Trevor AJ, Horai Y, Verotta D, Sheiner LB. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm. 1987;15(3):241–53.
Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989;36(2):186–97. doi:10.1007/bf03011442.
Herd D, Anderson BJ. Ketamine disposition in children presenting for procedural sedation and analgesia in a children’s emergency department. Paediatr Anaesth. 2007;17(7):622–9.
Ihmsen H, Geisslinger G, Schuttler J. Stereoselective pharmacokinetics of ketamine: R(−)-ketamine inhibits the elimination of S (+)-ketamine. Clin Pharmacol Ther. 2001;70(5):431–8.
Cook RD, Davis PJ. Pediatric anesthesia pharmacology. In: Lake CL, editor. Pediatric cardiac anesthesia. 2nd ed. East Norwalk: Appleton & Lange; 1993. p. 134.
Hartvig P, Larsson E, Joachimsson PO. Postoperative analgesia and sedation following pediatric cardiac surgery using a constant infusion of ketamine. J Cardiothorac Vasc Anesth. 1993;7(2):148–53.
Chang T, Glazko AJ. Biotransformation and disposition of ketamine. Int Anesthesiol Clin. 1974;12(2):157–77.
Lockhart CH, Nelson WL. The relationship of ketamine requirement to age in pediatric patients. Anesthesiology. 1974;40(5):507–8.
Wieber J, Gugler R, Hengstmann JH, Dengler HJ. Pharmacokinetics of ketamine in man. Anaesthesist. 1975;24(6):260–3.
Herd DW, Anderson BJ, Holford NH. Modeling the norketamine metabolite in children and the implications for analgesia. Paediatr Anaesth. 2007;17(9):831–40.
White M, de Graaff P, Renshof B, van Kan E, Dzoljic M. Pharmacokinetics of S(+) ketamine derived from target controlled infusion. Br J Anaesth. 2006;96(3):330–4. doi:10.1093/bja/aei316.
Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71(5):539–42.
Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203–7.
Nielsen BN, Friis SM, Romsing J, Schmiegelow K, Anderson BJ, Ferreiros N, Labocha S, Henneberg SW. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014;24(2):170–80. doi:10.1111/pan.12268.
Hollister GR, Burn JM. Side effects of ketamine in pediatric anesthesia. Anesth Analg. 1974;53(2):264–7.
Gingrich BK. Difficulties encountered in a comparative study of orally administered midazolam and ketamine. Anesthesiology. 1994;80(6):1414–5.
Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449–61. doi:10.1016/j.annemergmed.2010.11.030.
Green SM, Roback MG, Krauss B. Laryngospasm during emergency department ketamine sedation: a case–control study. Pediatr Emerg Care. 2010;26(11):798–802. doi:10.1097/PEC.0b013e3181fa8737.
Brown L, Christian-Kopp S, Sherwin TS, Khan A, Barcega B, Denmark TK, Moynihan JA, Kim GJ, Stewart G, Green SM. Adjunctive atropine is unnecessary during ketamine sedation in children. Acad Emerg Med. 2008;15(4):314–8. doi:10.1111/j.1553-2712.2008.00074.x.
Green SM, Rothrock SG. Transient apnea with intramuscular ketamine. Am J Emerg Med. 1997;15(4):440–1.
Greene CA, Gillette PC, Fyfe DA. Frequency of respiratory compromise after ketamine sedation for cardiac catheterization in patients less than 21 years of age. Am J Cardiol. 1991;68(10):1116–7.
Mitchell RK, Koury SI, Stone CK. Respiratory arrest after intramuscular ketamine in a 2-year-old child. Am J Emerg Med. 1996;14(6):580–1. doi:10.1016/S0735-6757(96)90105-9.
Tweed WA, Minuck M, Mymin D. Circulatory responses to ketamine anesthesia. Anesthesiology. 1972;37(6):613–9.
Hickey PR, Hansen DD, Cramolini GM, Vincent RN, Lang P. Pulmonary and systemic hemodynamic responses to ketamine in infants with normal and elevated pulmonary vascular resistance. Anesthesiology. 1985;62(3):287–93.
Williams GD, Maan H, Ramamoorthy C, Kamra K, Bratton SL, Bair E, Kuan CC, Hammer GB, Feinstein JA. Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine. Pediatr Anesth. 2010;20(1):28–37. doi:10.1111/j.1460-9592.2009.03166.x.
Oklu E, Bulutcu FS, Yalcin Y, Ozbek U, Cakali E, Bayindir O. Which anesthetic agent alters the hemodynamic status during pediatric catheterization? Comparison of propofol versus ketamine. J Cardiothorac Vasc Anesth. 2003;17(6):686–90.
Christ G, Mundigler G, Merhaut C, Zehetgruber M, Kratochwill C, Heinz G, Siostrzonek P. Adverse cardiovascular effects of ketamine infusion in patients with catecholamine-dependent heart failure. Anaesth Intens Care. 1997;25(3):255–9.
Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients with neurological injury? Anesth Analg. 2005;101(2):524–34.
Green SM, Andolfatto G, Krauss BS. Ketamine and intracranial pressure: no contraindication except hydrocephalus. Ann Emerg Med. 2015;65(1):52–4. doi:10.1016/j.annemergmed.2014.08.025.
Bourgoin A, Albanese J, Wereszczynski N, Charbit M, Vialet R, Martin C. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med. 2003;31(3):711–7. doi:10.1097/01.CCM.0000044505.24727.16.
Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM. The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review. Ann Emerg Med. 2015;65(1):43–51.e42. doi:10.1016/j.annemergmed.2014.06.018.
Yoshikawa K, Murai Y. The effect of ketamine on intraocular pressure in children. Anesth Analg. 1971;50(2):199–202.
Davidson A, Flick RP. Neurodevelopmental implications of the use of sedation and analgesia in neonates. Clin Perinatol. 2013;40(3):559–73. doi:10.1016/j.clp.2013.05.009.
Lin EP, Soriano SG, Loepke AW. Anesthetic neurotoxicity. Anesthesiol Clin. 2014;32(1):133–55. doi:10.1016/j.anclin.2013.10.003.
Sinner B, Becke K, Engelhard K. General anaesthetics and the developing brain: an overview. Anaesthesia. 2014;69(9):1009–22. doi:10.1111/anae.12637.
Davidson AJ. Anesthesia and neurotoxicity to the developing brain: the clinical relevance. Paediatr Anaesth. 2011;21(7):716–21. doi:10.1111/j.1460-9592.2010.03506.x.
Lin L, Zhang JW, Huang Y, Bai J, Cai MH, Zhang MZ. Population pharmacokinetics of intravenous bolus etomidate in children over 6 months of age. Pediatr Anesth. 2012;22(4):318–26. doi:10.1111/j.1460-9592.2011.03696.x.
Sfez M, Le Mapihan Y, Levron JC, Gaillard JL, Rosemblatt JM, Le Moing JP. Comparison of the pharmacokinetics of etomidate in children and in adults. Ann Fr Anesth Reanim. 1990;9(2):127–31.
Su F, El-Komy MH, Hammer GB, Frymoyer A, Cohane CA, Drover DR. Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease. Biopharm Drug Dispos. 2015;36(2):104–14. doi:10.1002/bdd.1924.
Wanscher M, Tonnesen E, Huttel M, Larsen K. Etomidate infusion and adrenocortical function. A study in elective surgery. Acta Anaesthesiol Scand. 1985;29(5):483–5.
Sneyd JR. Novel etomidate derivatives. Curr Pharm Des. 2012;18(38):6253–6.
Bramwell KJ, Haizlip J, Pribble C, VanDerHeyden TC, Witte M. The effect of etomidate on intracranial pressure and systemic blood pressure in pediatric patients with severe traumatic brain injury. Pediatr Emerg Care. 2006;22(2):90–3. doi:10.1097/01.pec.0000199563.64264.3a.
Sarkar M, Laussen PC, Zurakowski D, Shukla A, Kussman B, Odegard KC. Hemodynamic responses to etomidate on induction of anesthesia in pediatric patients. Anesth Analg. 2005;101(3):645–50. doi:10.1213/01.ane.0000166764.99863.b4.
Inturrisi CE, Colburn WA. Application of pharmacokinetic-pharmacodynamic modeling to analgesia. In: Foley KM, Inturrisi CE, editors. Advances in pain research and therapy. Opioid analgesics in the management of clinical pain. New York: Raven Press; 1986. p. 441–52.
Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K, Hansen SH, Arendt-Nielsen L, Drewes AM. Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol. 2008;48(5):619–31. doi:10.1177/0091270008314465.
van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A. Morphine-6-glucuronide: morphine’s successor for postoperative pain relief? Anesth Analg. 2006;102(6):1789–97.
Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology. 2004;101(5):1201–9.
Hannam JA, Anderson BJ. Contribution of morphine and morphine-6-glucuronide to respiratory depression in a child. Anaesth Intensive Care. 2012;40(5):867–70.
Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology. 2003;99(4):788–98.
Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth. 2003;90(5):642–52.
Bray RJ, Beeton C, Hinton W, Seviour JA. Plasma morphine levels produced by continuous infusion in children. Anaesthesia. 1986;41(7):753–5.
Lynn AM, Opheim KE, Tyler DC. Morphine infusion after pediatric cardiac surgery. Crit Care Med. 1984;12(10):863–6.
Anderson BJ, Persson M, Anderson M. Rationalising intravenous morphine prescriptions in children. Acute Pain. 1999;2:59–67.
Aubrun F, Mazoit JX, Riou B. Postoperative intravenous morphine titration. Br J Anaesth. 2012;108(2):193–201. doi:10.1093/bja/aer458.
Bernard R, Salvi N, Gall O, Egan M, Treluyer JM, Carli PA, Orliaguet GA. MORPHIT: an observational study on morphine titration in the postanesthetic care unit in children. Paediatr Anaesth. 2014;24(3):303–8. doi:10.1111/pan.12286.
Morton NS, Errera A. APA national audit of pediatric opioid infusions. Paediatr Anaesth. 2010;20(2):119–25. doi:10.1111/j.1460-9592.2009.03187.x.
West N, Nilforushan V, Stinson J, Ansermino JM, Lauder G. Critical incidents related to opioid infusions in children: a five-year review and analysis. Can J Anaesth. 2014;61(4):312–21. doi:10.1007/s12630-013-0097-2.
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(2):208–17.
Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther. 1993;54(2):158–67.
Miners JO, Knights KM, Houston JB, Mackenzie PI. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol. 2006;71(11):1531–9. doi:10.1016/j.bcp.2005.12.019.
Wang J, Evans AM, Knights KM, Miners JO. Differential disposition of intra-renal generated and preformed glucuronides: studies with 4-methylumbelliferone and 4-methylumbelliferyl glucuronide in the filtering and nonfiltering isolated perfused rat kidney. J Pharm Pharmacol. 2011;63(4):507–14. doi:10.1111/j.2042-7158.2010.01244.x.
Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol. 2013;76(4):587–602. doi:10.1111/bcp.12086.
Nahata MC, Miser AW, Miser JS, Reuning RH. Variation in morphine pharmacokinetics in children with cancer. Dev Pharmacol Ther. 1985;8(3):182–8.
Nahata MC, Miser AW, Miser JS, Reuning RH. Analgesic plasma concentrations of morphine in children with terminal malignancy receiving a continuous subcutaneous infusion of morphine sulfate to control severe pain. Pain. 1984;18(2):109–14.
Peters JW, Anderson BJ, Simons SH, Uges DR, Tibboel D. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med. 2005;31(2):257–63.
Bolan EA, Tallarida RJ, Pasternak GW. Synergy between mu opioid ligands: evidence for functional interactions among mu opioid receptor subtypes. J Pharmacol Exp Ther. 2002;303(2):557–62. doi:10.1124/jpet.102.035881.
Pasternak GW. Preclinical pharmacology and opioid combinations. Pain Med. 2012;13 Suppl 1:S4–11. doi:10.1111/j.1526-4637.2012.01335.x.
Lotsch J, Skarke C, Schmidt H, Grosch S, Geisslinger G. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology. 2001;95(6):1329–38.
Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther. 1987;240(1):159–66.
Wynands JE, Townsend GE, Wong P, Whalley DG, Srikant CB, Patel YC. Blood pressure response and plasma fentanyl concentrations during high- and very high-dose fentanyl anesthesia for coronary artery surgery. Anesth Analg. 1983;62(7):661–5.
Kuhls E, Gauntlett IS, Lau M, Brown R, Rudolph CD, Teitel DF, Fisher DM. Effect of increased intra-abdominal pressure on hepatic extraction and clearance of fentanyl in neonatal lambs. J Pharmacol Exp Ther. 1995;274(1):115–9.
Koren G, Goresky G, Crean P, Klein J, MacLeod SM. Pediatric fentanyl dosing based on pharmacokinetics during cardiac surgery. Anesth Analg. 1984;63(6):577–82.
Koren G, Goresky G, Crean P, Klein J, MacLeod SM. Unexpected alterations in fentanyl pharmacokinetics in children undergoing cardiac surgery: age related or disease related? Dev Pharmacol Ther. 1986;9(3):183–91.
Koren G, Barker C, Goresky G, Bohn D, Kent G, Klein J, MacLeod SM, Biggar WD. The influence of hypothermia on the disposition of fentanyl--human and animal studies. Eur J Clin Pharmacol. 1987;32(4):373–6.
Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med. 1993;21(7):995–1000.
Ginsberg B, Howell S, Glass PS, Margolis JO, Ross AK, Dear GL, Shafer SL. Pharmacokinetic model-driven infusion of fentanyl in children. Anesthesiology. 1996;85(6):1268–75.
Katz R, Kelly HW, Hsi A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med. 1994;22(5):763–7.
Suresh S, Anand KJS. Opioid tolerance in neonates: a state of the art review. Paediatr Anaesth. 2001;11:511–21.
Arandia HY, Patil VU. Glottic closure following large doses of fentanyl. Anesthesiology. 1987;66(4):574–5.
Sokoll MD, Hoyt JL, Gergis SD. Studies in muscle rigidity, nitrous oxide, and narcotic analgesic agents. Anesth Analg. 1972;51(1):16–20.
Murat I, Levron JC, Berg A, Saint-Maurice C. Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology. 1988;68(5):717–22.
Mani V, Morton NS. Overview of total intravenous anesthesia in children. Paediatr Anaesth. 2010;20(3):211–22. doi:10.1111/j.1460-9592.2009.03112.x.
Sam WJ, Hammer GB, Drover DR. Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery. BMC Anesthesiol. 2009;9:5. doi:10.1186/1471-2253-9-5.
Michelsen LG, Holford NH, Lu W, Hoke JF, Hug CC, Bailey JM. The pharmacokinetics of remifentanil in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg. 2001;93(5):1100–5.
Barker N, Lim J, Amari E, Malherbe S, Ansermino JM. Relationship between age and spontaneous ventilation during intravenous anesthesia in children. Paediatr Anaesth. 2007;17(10):948–55. doi:10.1111/j.1460-9592.2007.02301.x.
Litman RS. Conscious sedation with remifentanil during painful medical procedures. J Pain Symptom Manage. 2000;19(6):468–71.
Choong K, AlFaleh K, Doucette J, Gray S, Rich B, Verhey L, Paes B. Remifentanil for endotracheal intubation in neonates: a randomised controlled trial. Arch Dis Child. 2010;95(2):F80–4. doi:10.1136/adc.2009.167338.
Penido MG, Garra R, Sammartino M, Pereira e Silva Y. Remifentanil in neonatal intensive care and anaesthesia practice. Acta Paediatr. 2010;99(10):1454–63. doi:10.1111/j.1651-2227.2010.01868.x.
Anderson BJ, Holford NH. Leaving no stone unturned, or extracting blood from stone? Paediatr Anaesth. 2010;20(1):1–6. doi:10.1111/j.1460-9592.2009.03179.x.
Galinkin JL, Davis PJ, McGowan FX, Lynn AM, Rabb MF, Yaster M, Henson LG, Blum R, Hechtman D, Maxwell L, Szmuk P, Orr R, Krane EJ, Edwards S, Kurth CD. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg. 2001;93(6):1387–92.
Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology. 2008;109(2):308–17. doi:10.1097/ALN.0b013e31817f4c5d.
Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clin Pharmacokinet. 1996;31(4):275–92. doi:10.2165/00003088-199631040-00004.
Meuldermans W, Van Peer A, Hendrickx J, Woestenborghs R, Lauwers W, Heykants J, Vanden Bussche G, Van Craeyvelt H, Van der Aa P. Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology. 1988;69(4):527–34.
Davis PJ, Cook DR. Clinical pharmacokinetics of the newer intravenous anaesthetic agents. Clin Pharmacokinet. 1986;11(1):18–35.
Marlow N, Weindling AM, Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Arch Dis Child. 1990;65(4 Spec No):349–51.
Killian A, Davis PJ, Stiller RL, Cicco R, Cook DR, Guthrie RD. Influence of gestational age on pharmacokinetics of alfentanil in neonates. Dev Pharmacol Ther. 1990;15(2):82–5.
Meistelman C, Saint-Maurice C, Lepaul M, Levron JC, Loose JP, MacGee K. A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology. 1987;66(1):13–6.
Roure P, Jean N, Leclerc AC, Cabanel N, Levron JC, Duvaldestin P. Pharmacokinetics of alfentanil in children undergoing surgery. Br J Anaesth. 1987;59(11):1437–40.
Goresky GV, Koren G, Sabourin MA, Sale JP, Strunin L. The pharmacokinetics of alfentanil in children. Anesthesiology. 1987;67(5):654–9.
Persson MP, Nilsson A, Hartvig P. Pharmacokinetics of alfentanil in total i.v. anaesthesia. Br J Anaesth. 1988;60(7):755–61.
Shafer A, Sung ML, White PF. Pharmacokinetics and pharmacodynamics of alfentanil infusions during general anesthesia. Anesth Analg. 1986;65(10):1021–8.
Chauvin M, Bonnet F, Montembault C, Levron JC, Viars P. The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient. Anesth Analg. 1986;65(10):999–1003.
Wilson AS, Stiller RL, Davis PJ, Fedel G, Chakravorti S, Israel BA, McGowan Jr FX. Fentanyl and alfentanil plasma protein binding in preterm and term neonates. Anesth Analg. 1997;84(2):315–8.
Demirbilek S, Ganidagli S, Aksoy N, Becerik C, Baysal Z. The effects of remifentanil and alfentanil-based total intravenous anesthesia (TIVA) on the endocrine response to abdominal hysterectomy. J Clin Anesth. 2004;16(5):358–63. doi:10.1016/j.jclinane.2003.10.002.
Ganidagli S, Cengiz M, Baysal Z. Remifentanil vs alfentanil in the total intravenous anaesthesia for paediatric abdominal surgery. Paediatr Anaesth. 2003;13(8):695–700.
Saarenmaa E, Huttunen P, Leppaluoto J, Fellman V. Alfentanil as procedural pain relief in newborn infants. Arch Dis Child Fetal Neonatal Ed. 1996;75(2):F103–7.
Pokela ML, Olkkola KT, Koivisto M, Ryhanen P. Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants. Clin Pharmacol Ther. 1992;52(4):342–9.
Hilberman M, Hyer D. Potency of sufentanil. Anesthesiology. 1986;64(5):665–8.
Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg. 1987;66(11):1067–72.
Guay J, Gaudreault P, Tang A, Goulet B, Varin F. Pharmacokinetics of sufentanil in normal children. Can J Anaesth. 1992;39(1):14–20.
Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M. Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg. 1996;82(1):167–72.
Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247(2):625–34.
Davis PJ, Cook DR, Stiller RL, Davin-Robinson KA. Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery. Anesth Analg. 1987;66(3):203–8.
Chauvin M, Ferrier C, Haberer JP, Spielvogel C, Lebrault C, Levron JC, Duvaldestin P. Sufentanil pharmacokinetics in patients with cirrhosis. Anesth Analg. 1989;68(1):1–4.
Helmers JH, Noorduin H, Van Peer A, Van Leeuwen L, Zuurmond WW. Comparison of intravenous and intranasal sufentanil absorption and sedation. Can J Anaesth. 1989;36(5):494–7. doi:10.1007/bf03005373.
Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE. Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil. Anesthesiology. 1988;68(5):671–5.
Roelofse JA, Shipton EA, de la Harpe CJ, Blignaut RJ. Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog. 2004;51(4):114–21.
Zedie N, Amory DW, Wagner BK, O’Hara DA. Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther. 1996;59(3):341–8.
Koren G, Maurice L. Pediatric uses of opioids. Pediatr Clin North Am. 1989;36(5):1141–56.
Jaffe JH, Martine WR. Opioid analgesics and antagonists. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, editors. The pharmacological basis of therapeutics. New York: Pergamon Press; 1990. p. 485–531.
Hamunen K, Maunuksela EL, Seppala T, Olkkola KT. Pharmacokinetics of i.v. and rectal pethidine in children undergoing ophthalmic surgery. Br J Anaesth. 1993;71(6):823–6.
Caldwell J, Wakile LA, Notarianni LJ, Smith RL, Correy GJ, Lieberman BA, Beard RW, Finnie MD, Snedden W. Maternal and neonatal disposition of pethidine in childbirth--a study using quantitative gas chromatography–mass spectrometry. Life Sci. 1978;22(7):589–96.
Hagmeyer KO, Mauro LS, Mauro VF. Meperidine-related seizures associated with patient-controlled analgesia pumps. Ann Pharmacother. 1993;27(1):29–32.
Flacke JW, Flacke WE, Bloor BC, Van Etten AP, Kripke BJ. Histamine release by four narcotics: a double-blind study in humans. Anesth Analg. 1987;66(8):723–30.
Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther. 2002;9(1):53–68.
Ngan Kee WD. Intrathecal pethidine: pharmacology and clinical applications. Anaesth Intens Care. 1998;26(2):137–46.
Collins JJ, Geake J, Grier HE, Houck CS, Thaler HT, Weinstein HJ, Twum-Danso NY, Berde CB. Patient-controlled analgesia for mucositis pain in children: a three-period crossover study comparing morphine and hydromorphone. J Pediatr. 1996;129(5):722–8.
Hagen N, Thirlwell MP, Dhaliwal HS, Babul N, Harsanyi Z, Darke AC. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. J Clin Pharmacol. 1995;35(1):37–44.
Parab PV, Ritschel WA, Coyle DE, Gregg RV, Denson DD. Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos. 1988;9(2):187–99.
Ritschel WA, Parab PV, Denson DD, Coyle DE, Gregg RV. Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects. J Clin Pharmacol. 1987;27(9):647–53.
Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL. Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol. 1981;21(4):152–6.
Volles DF, McGory R. Perspectives in pain management: pharmacokinetic considerations: pharmacokinetic considerations. Crit Care Clin. 1999;15(1):55–75.
Babul N, Darke AC, Hain R. Hydromorphone and metabolite pharmacokinetics in children. J Pain Symptom Manage. 1995;10(5):335–7.
Wermeling DP, Clinch T, Rudy AC, Dreitlein D, Suner S, Lacouture PG. A multicenter, open-label, exploratory dose-ranging trial of intranasal hydromorphone for managing acute pain from traumatic injury. J Pain. 2010;11(1):24–31. doi:10.1016/j.jpain.2009.05.002.
Coda BA, Rudy AC, Archer SM, Wermeling DP. Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg. 2003;97(1):117–23.
Kokki M, Broms S, Eskelinen M, Neuvonen PJ, Halonen T, Kokki H. The analgesic concentration of oxycodone with co-administration of paracetamol—a dose-finding study in adult patients undergoing laparoscopic cholecystectomy. Basic Clin Pharmacol Toxicol. 2012;111(6):391–5. doi:10.1111/j.1742-7843.2012.00916.x.
Czarnecki ML, Jandrisevits MD, Theiler SC, Huth MM, Weisman SJ. Controlled-release oxycodone for the management of pediatric postoperative pain. J Pain Symptom Manage. 2004;27(4):379–86.
Kokki H, Rasanen I, Lasalmi M, Lehtola S, Ranta VP, Vanamo K, Ojanpera I. Comparison of oxycodone pharmacokinetics after buccal and sublingual administration in children. Clin Pharmacokinet. 2006;45(7):745–54. doi:10.2165/00003088-200645070-00009.
Kokki H, Tuomilehto H, Karvinen M. Pharmacokinetics of ketoprofen following oral and intramuscular administration in young children. Eur J Clin Pharmacol. 2001;57(9):643–7.
Leow KP, Cramond T, Smith MT. Pharmacokinetics and pharmacodynamics of oxycodone when given intravenously and rectally to adult patients with cancer pain. Anesth Analg. 1995;80(2):296–302.
Kokki H, Kokki M, Sjovall S. Oxycodone for the treatment of postoperative pain. Exp Opin Pharmacother. 2012;13(7):1045–58. doi:10.1517/14656566.2012.677823.
Olkkola KT, Hamunen K, Seppala T, Maunuksela EL. Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children. Br J Clin Pharmacol. 1994;38(1):71–6.
Lam J, Kelly L, Ciszkowski C, Landsmeer ML, Nauta M, Carleton BC, Hayden MR, Madadi P, Koren G. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr. 2012;160(1):33–7.e32. doi:10.1016/j.jpeds.2011.06.050.
Pokela ML, Anttila E, Seppala T, Olkkola KT. Marked variation in oxycodone pharmacokinetics in infants. Paediatr Anaesth. 2005;15(7):560–5.
El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 6 months to 7 years old. J Clin Pharmacol. 2006;46(4):433–42.
Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanpera I. Pharmacokinetics of oxycodone after intravenous, buccal, intramuscular and gastric administration in children. Clin Pharmacokinet. 2004;43(9):613–22. doi:10.2165/00003088-200443090-00004.
Korjamo T, Tolonen A, Ranta VP, Turpeinen M, Kokki H. Metabolism of oxycodone in human hepatocytes from different age groups and prediction of hepatic plasma clearance. Front Pharmacol. 2011;2:87. doi:10.3389/fphar.2011.00087.
Sabatowski R, Kasper SM, Radbruch L. Patient-controlled analgesia with intravenous l-methadone in a child with cancer pain refractory to high-dose morphine. J Pain Sympt Manag. 2002;23(1):3–5.
Suresh S, Anand KJ. Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management. Semin Perinatol. 1998;22(5):425–33.
Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122–32.
Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19(4):13–24.
Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med. 2000;1(2):119–23.
Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna NF. Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr. 1991;119(1 Pt 1):136–41.
Shir Y, Shenkman Z, Shavelson V, Davidson EM, Rosen G. Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases. Clin J Pain. 1998;14(4):350–3.
Davies D, DeVlaming D, Haines C. Methadone analgesia for children with advanced cancer. Pediatr Blood Cancer. 2008;51(3):393–7. doi:10.1002/pbc.21584.
Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration--response relationships. Anesthesiology. 1984;61(1):19–26.
Rosen TS, Pippenger CE. Pharmacologic observations on the neonatal withdrawal syndrome. J Pediatr. 1976;88(6):1044–8.
Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet. 1976;1(3):219–30.
Kaufmann JJ, Koski WS, Benson DN, Semo NM. Narcotic and narcotic antagonist pKa’s and partition coefficients and their significance in clinical practice. Drug Alcohol Depend. 1975;1(2):103–14.
Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982;57(6):458–67.
Berde CB, Sethna NF, Holzman RS, Reidy RN, Gondek EJ. Pharmacokinetics of methadone in children and adolescents in the perioperative period. Anesthesiology. 1987;67(3A):A519.
Chana SK, Anand KJ. Can we use methadone for analgesia in neonates? Arch Dis Child Fetal Neonatal Ed. 2001;85(2):F79–81.
Stemland CJ, Witte J, Colquhoun DA, Durieux ME, Langman LJ, Balireddy R, Thammishetti S, Abel MF, Anderson BJ. The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion. Paediatr Anaesth. 2013;23(1):51–7. doi:10.1111/pan.12021.
Foster DJ, Somogyi AA, White JM, Bochner F. Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2004;57(6):742–55. doi:10.1111/j.1365-2125.2004.02079.x.
Inturrisi CE, Portenoy RK, Max MB, Colburn WA, Foley KM. Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther. 1990;47(5):565–77.
Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23(6):802–5.
Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95(7):915–8. doi:10.1016/j.amjcard.2004.11.055.
Tremlett M, Anderson BJ, Wolf A. Pro-con debate: is codeine a drug that still has a useful role in pediatric practice? Paediatr Anaesth. 2010;20(2):183–94. doi:10.1111/j.1460-9592.2009.03234.x.
Cox RG. Hypoxaemia and hypotension after intravenous codeine phosphate. Can J Anaes. 1994;41(12):1211–3. doi:10.1007/BF03020664.
Parke TJ, Nandi PR, Bird KJ, Jewkes DA. Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations. Anaesthesia. 1992;47(10):852–4.
Shanahan EC, Marshall AG, Garrett CP. Adverse reactions to intravenous codeine phosphate in children. A report of three cases. Anaesthesia. 1983;38(1):40–3.
Zolezzi M, Al Mohaimeed SA. Seizures with intravenous codeine phosphate. Ann Pharmacother. 2001;35(10):1211–3.
Anderson BJ. Is it farewell to codeine? Arch Dis Child. 2013;98(12):986–8. doi:10.1136/archdischild-2013-304974.
Tremlett MR. Wither codeine? Paediatr Anaesth. 2013;23(8):677–83. doi:10.1111/pan.12190.
Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, Carleton B, Hayden MR, Madadi P, Koren G. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129(5):e1343–7. doi:10.1542/peds.2011-2538.
Racoosin JA, Roberson DW, Pacanowski MA, Nielsen DR. New evidence about an old drug—risk with codeine after adenotonsillectomy. N Engl J Med. 2013;368(23):2155–7. doi:10.1056/NEJMp1302454.
Voelker R. Children’s deaths linked with postsurgical codeine. JAMA. 2012;308(10):963. doi:10.1001/2012.jama.11525.
Waters KA, McBrien F, Stewart P, Hinder M, Wharton S. Effects of OSA, inhalational anesthesia, and fentanyl on the airway and ventilation of children. J Appl Physiol. 2002;92(5):1987–94. doi:10.1152/japplphysiol.00619.2001.
Semple D, Russell S, Doyle E, Aldridge LM. Comparison of morphine sulphate and codeine phosphate in children undergoing adenotonsillectomy. Paediatr Anaesth. 1999;9(2):135–8.
Tobias JD, Lowe S, Hersey S, Rasmussen GE, Werkhaven J. Analgesia after bilateral myringotomy and placement of pressure equalization tubes in children: acetaminophen versus acetaminophen with codeine. Anesth Analg. 1995;81(3):496–500.
St Charles CS, Matt BH, Hamilton MM, Katz BP. A comparison of ibuprofen versus acetaminophen with codeine in the young tonsillectomy patient. Otolaryngol Head Neck Surg. 1997;117(1):76–82.
Persson K, Hammarlund-Udenaes M, Mortimer O, Rane A. The postoperative pharmacokinetics of codeine. Eur J Clin Pharmacol. 1992;42(6):663–6.
Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain. 1998;76(1–2):27–33.
Magnani B, Evans R. Codeine intoxication in the neonate. Pediatrics. 1999;104(6), e75.
Moreland TA, Brice JE, Walker CH, Parija AC. Naloxone pharmacokinetics in the newborn. Br J Clin Pharmacol. 1980;9(6):609–12.
American Academy of Pediatrics Committee on Drugs: Naloxone dosage and route of administration for infants and children: addendum to emergency drug doses for infants and children. Pediatrics 1990;86(3):484–485.
Tenenbein M. Continuous naloxone infusion for opiate poisoning in infancy. J Pediatr. 1984;105(4):645–8.
Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paed Anaesth. 2008;18(10):915–21.
Gibb IA, Anderson BJ. Paracetamol (acetaminophen) pharmacodynamics; interpreting the plasma concentration. Arch Dis Child. 2008;93:241–7.
Murat I, Baujard C, Foussat C, Guyot E, Petel H, Rod B, Ricard C. Tolerance and analgesic efficacy of a new i.v. paracetamol solution in children after inguinal hernia repair. Paediatr Anaesth. 2005;15(8):663–70.
Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pharmacol. 2001;57(8):559–69.
Shinoda S, Aoyama T, Aoyama Y, Tomioka S, Matsumoto Y, Ohe Y. Pharmacokinetics/pharmacodynamics of acetaminophen analgesia in Japanese patients with chronic pain. Biol Pharm Bull. 2007;30(1):157–61.
Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ. The paracetamol concentration-effect relation in neonates. Paediatr Anaesth. 2013;23(1):45–50. doi:10.1111/pan.12076.
Allegaert K, Murat I, Anderson BJ. Not all intravenous paracetamol formulations are created equal. Paediatr Anaesth. 2007;17(8):811–2.
Anderson BJ, Pons G, Autret-Leca E, Allegaert K, Boccard E. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Anaesth. 2005;15(4):282–92.
Anderson BJ, Pearce S, McGann JE, Newson AJ, Holford NH. Investigations using logistic regression models on the effect of the LMA on morphine induced vomiting after tonsillectomy. Paediatr Anaesth. 2000;10(6):633–8.
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(2):125–34.
Allegaert K, Anderson BJ, Naulaers G, De Hoon J, Verbesselt R, Debeer A, Devlieger H, Tibboel D. Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol. 2004;60(3):191–7.
Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, Perkins EJ, Chalkiadis GA, Hunt RW. I.V. acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth. 2008;101(4):523–30.
Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child. 2011;96(6):575–80. doi:10.1136/adc.2010.204552.
Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther. 2003;307(1):402–7.
Anderson BJ, Holford NHG, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatrics. 1999;135:290–5.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871–6.
Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with therapeutic intent. J Pediatr. 1998;132(1):5–8.
Li H, Mandema J, Wada R, Jayawardena S, Desjardins P, Doyle G, Kellstein D. Modeling the onset and offset of dental pain relief by ibuprofen. J Clin Pharmacol. 2012;52(1):89–101. doi:10.1177/0091270010389470.
Hannam JA, Anderson BJ, Mahadevan M, Holford NH. Postoperative analgesia using diclofenac and acetaminophen in children. Paediatr Anaesth. 2014;24(9):953–61. doi:10.1111/pan.12422.
Aranda JV, Varvarigou A, Beharry K, Bansal R, Bardin C, Modanlou H, Papageorgiou A, Chemtob S. Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. Acta Paediatr. 1997;86(3):289–93.
Van Overmeire B, Touw D, Schepens PJ, Kearns GL, van den Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001;70(4):336–43.
Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71(3):115–21.
Hamman MA, Thompson GA, Hall SD. Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol. 1997;54(1):33–41.
Tanaka E. Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clin Pharm Ther. 1998;23(6):403–16.
Scott CS, Retsch-Bogart GZ, Kustra RP, Graham KM, Glasscock BJ, Smith PC. The pharmacokinetics of ibuprofen suspension, chewable tablets, and tablets in children with cystic fibrosis. J Pediatr. 1999;134(1):58–63.
Wiest DB, Pinson JB, Gal PS, Brundage RC, Schall S, Ransom JL, Weaver RL, Purohit D, Brown Y. Population pharmacokinetics of intravenous indomethacin in neonates with symptomatic patent ductus arteriosus. Clin Pharmacol Ther. 1991;49(5):550–7.
Smyth JM, Collier PS, Darwish M, Millership JS, Halliday HL, Petersen S, McElnay JC. Intravenous indomethacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study. Br J Clin Pharmacol. 2004;58(3):249–58.
Olkkola KT, Maunuksela EL, Korpela R. Pharmacokinetics of postoperative intravenous indomethacin in children. Pharmacol Toxicol. 1989;65(2):157–60.
Allegaert K, Cossey V, Debeer A, Langhendries JP, Van Overmeire B, de Hoon J, Devlieger H. The impact of ibuprofen on renal clearance in preterm infants is independent of the gestational age. Pediatr Nephrol. 2005;20(6):740–3.
Naulaers G, Delanghe G, Allegaert K, Debeer A, Cossey V, Vanhole C, Casaer P, Devlieger H, Van Overmeire B. Ibuprofen and cerebral oxygenation and circulation. Arch Dis Child Fetal Neonatal Ed. 2005;90(1):F75–6.
Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA. 1995;273(12):929–33.
Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics. 1999;104(4), e39.
Keenan GF, Giannini EH, Athreya BH. Clinically significant gastropathy associated with nonsteroidal antiinflammatory drug use in children with juvenile rheumatoid arthritis. J Rheumatol. 1995;22(6):1149–51.
Dowd JE, Cimaz R, Fink CW. Nonsteroidal antiinflammatory drug-induced gastroduodenal injury in children. Arthritis Rheum. 1995;38(9):1225–31.
Ameratunga R, Randall N, Dalziel S, Anderson BJ. Samter’s triad in childhood: a warning for those prescribing NSAIDs. Paediatr Anaesth. 2013;23(8):757–9. doi:10.1111/pan.12216.
Palmer GM. A teenager with severe asthma exacerbation following ibuprofen. Anaesth Intensive Care. 2005;33(2):261–5.
Cardwell M, Siviter G, Smith A. Non-steroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2005;2, CD003591.
Ment LR, Vohr BR, Makuch RW, Westerveld M, Katz KH, Schneider KC, Duncan CC, Ehrenkranz R, Oh W, Philip AG, Scott DT, Allan WC. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6):832–4.
Dodwell ER, Latorre JG, Parisini E, Zwettler E, Chandra D, Mulpuri K, Snyder B. NSAID exposure and risk of nonunion: a meta-analysis of case–control and cohort studies. Calcif Tissue Int. 2010;87(3):193–202. doi:10.1007/s00223-010-9379-7.
Kokki H. Nonsteroidal anti-inflammatory drugs for postoperative pain: a focus on children. Paediatr Drugs. 2003;5(2):103–23.
Watcha MF, Jones MB, Lagueruela RG, Schweiger C, White PF. Comparison of ketorolac and morphine as adjuvants during pediatric surgery. Anesthesiology. 1992;76(3):368–72.
Mandema JW, Stanski DR. Population pharmacodynamic model for ketorolac analgesia. Clin Pharmacol Ther. 1996;60(6):619–35.
Olkkola KT, Maunuksela EL. The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children. Br J Clin Pharmacol. 1991;31(2):182–4.
Potts AL, Cheeseman JF, Warman GR. Circadian rhythms and their development in children: implications for pharmacokinetics and pharmacodynamics in anesthesia. Pediatr Anesth. 2011;21(3):238–46. doi:10.1111/j.1460-9592.2010.03343.x.
Lynn AM, Bradford H, Kantor ED, Seng KY, Salinger DH, Chen J, Ellenbogen RG, Vicini P, Anderson GD. Postoperative ketorolac tromethamine use in infants aged 6–18 months: the effect on morphine usage, safety assessment, and stereo-specific pharmacokinetics. Anesth Analg. 2007;104(5):1040–51. doi:10.1213/01.ane.0000260320.60867.6c.
Gregoire N, Gualano V, Geneteau A, Millerioux L, Brault M, Mignot A, Roze JC. Population pharmacokinetics of ibuprofen enantiomers in very premature neonates. J Clin Pharmacol. 2004;44(10):1114–24.
Lynn AM, Bradford H, Kantor ED, Andrew M, Vicini P, Anderson GD. Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2–6 months. Paediatr Anaesth. 2011;21(3):325–34. doi:10.1111/j.1460-9592.2010.03484.x.
Kauffman RE, Lieh-Lai MW, Uy HG, Aravind MK. Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther. 1999;65(4):382–8.
Strom BL, Berlin JA, Kinman JL, Spitz PW, Hennessy S, Feldman H, Kimmel S, Carson JL. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA. 1996;275(5):376–82.
Gupta A, Daggett C, Drant S, Rivero N, Lewis A. Prospective randomized trial of ketorolac after congenital heart surgery. J Cardiothorac Vasc Anesth. 2004;18(4):454–7.
Giannantonio C, Papacci P, Purcaro V, Cota F, Tesfagabir MG, Molle F, Lepore D, Baldascino A, Romagnoli C. Effectiveness of ketorolac tromethamine in prevention of severe retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2011;48(4):247–51. doi:10.3928/01913913-20100920-01.
Papacci P, De Francisci G, Iacobucci T, Giannantonio C, De Carolis MP, Zecca E, Romagnoli C. Use of intravenous ketorolac in the neonate and premature babies. Paediatr Anaesth. 2004;14(6):487–92. doi:10.1111/j.1460-9592.2004.01250.x.
Zuppa AF, Mondick JT, Davis L, Cohen D. Population pharmacokinetics of ketorolac in neonates and young infants. Am J Ther. 2009;16(2):143–6. doi:10.1097/MJT.0b013e31818071df.
Brocks DR, Jamali F. Clinical pharmacokinetics of ketorolac tromethamine. Clin Pharmacokinet. 1992;23(6):415–27.
Foster PN, Williams JG. Bradycardia following intravenous ketorolac in children. Eur J Anaesthesiol. 1997;14(3):307–9.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.
Allegaert K, Anderson BJ, Verbesselt R, Debeer A, de Hoon J, Devlieger H, Van Den Anker JN, Tibboel D. Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity. Br J Anaesth. 2005;95(2):231–9.
Engelhardt T, Steel E, Johnston G. Tramadol for pain relief in children undergoing tonsillectomy. A comparison with morphine. Paediatr Anaesth. 2002;12(9):834–5.
Umuroglu T, Eti Z, Ciftci H, Yilmaz Gogus F. Analgesia for adenotonsillectomy in children: a comparison of morphine, ketamine and tramadol. Paediatr Anaesth. 2004;14(7):568–73.
Hullett BJ, Chambers NA, Pascoe EM, Johnson C. Tramadol vs morphine during adenotonsillectomy for obstructive sleep apnea in children. Pediatr Anesth. 2006;16(6):648–53.
Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth. 2011;21(3):266–73. doi:10.1111/j.1460-9592.2010.03389.x.
Mandema JW, Tuk B, van Steveninck AL, Breimer DD, Cohen AF, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharm Ther. 1992;51(6):715–28.
Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, Harmatz JS, Shader RI. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharm Ther. 1989;45(4):356–65.
Buhrer M, Maitre PO, Crevoisier C, Stanski DR. Electroencephalographic effects of benzodiazepines. II Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol Ther. 1990;48(5):555–67.
Johnson TN, Rostami-Hodjegan A, Goddard JM, Tanner MS, Tucker GT. Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis. Br J Anaesth. 2002;89(3):428–37.
de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med. 2003;31(7):1952–858.
Hartwig S, Roth B, Theisohn M. Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit. Eur J Pediatr. 1991;150(11):784–8.
Lloyd-Thomas AR, Booker PD. Infusion of midazolam in paediatric patients after cardiac surgery. Br J Anaesth. 1986;58(10):1109–15.
Booker PD, Beechey A, Lloyd-Thomas AR. Sedation of children requiring artificial ventilation using an infusion of midazolam. Br J Anaesth. 1986;58(10):1104–8.
Persson P, Nilsson A, Hartvig P, Tamsen A. Pharmacokinetics of midazolam in total i.v. anaesthesia. Br J Anaesth. 1987;59(5):548–56.
Nilsson A, Tamsen A, Persson P. Midazolam-fentanyl anesthesia for major surgery. Plasma levels of midazolam during prolonged total intravenous anesthesia. Acta Anaesthiol Scand. 1986;30(1):66–9.
Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharm Ther. 1981;30(5):653–61.
Lee TC, Charles BG, Harte GJ, Gray PH, Steer PA, Flenady VJ. Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation: midazolam neonatal pharmacokinetics. Anesthesiology. 1999;90(2):451–7.
Harte GJ, Gray PH, Lee TC, Steer PA, Charles BG. Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates. J Paediatr Child Health. 1997;33(4):335–8.
de Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN. Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharm Ther. 2001;70(6):525–31.
Burtin P, Jacqz-Aigrain E, Girard P, Lenclen R, Magny JF, Betremieux P, Tehiry C, Desplanques L, Mussat P. Population pharmacokinetics of midazolam in neonates. Clin Pharm Ther. 1994;56(6 Pt 1):615–25.
Jacqz-Aigrain E, Daoud P, Burtin P, Maherzi S, Beaufils F. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol. 1992;42(3):329–32.
Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol. 1990;39(2):191–2.
Anderson BJ, Larsson P. A maturation model for midazolam clearance. Paediatr Anaesth. 2011;21(3):302–8. doi:10.1111/j.1460-9592.2010.03364.x.
Mulla H, McCormack P, Lawson G, Firmin RK, Upton DR. Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Anesthesiology. 2003;99(2):275–82.
Mathews HM, Carson IW, Lyons SM, Orr IA, Collier PS, Howard PJ, Dundee JW. A pharmacokinetic study of midazolam in paediatric patients undergoing cardiac surgery. Br J Anaesth. 1988;61(3):302–7.
Hiller A, Olkkola KT, Isohanni P, Saarnivaara L. Unconsciousness associated with midazolam and erythromycin. Br J Anaesth. 1990;65(6):826–8.
Payne KA, Coetzee AR, Mattheyse FJ. Midazolam and amnesia in pediatric premedication. Acta Anaesthesiol Belg. 1991;42(2):101–5.
Twersky RS, Hartung J, Berger BJ, McClain J, Beaton C. Midazolam enhances anterograde but not retrograde amnesia in pediatric patients. Anesthesiology. 1993;78(1):51–5.
Tobias JD. Sedation and analgesia in the pediatric intensive care unit. Pediatr Ann. 2005;34(8):636–45.
Alexander CM, Gross JB. Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesth Analg. 1988;67(4):377–82.
Yaster M, Nichols DG, Deshpande JK, Wetzel RC. Midazolam-fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics. 1990;86(3):463–7.
Dhonneur G, Combes X, Leroux B, Duvaldestin P. Postoperative obstructive apnea. Anesth Analg. 1999;89(3):762–7.
Kensche M, Sander JW, Sisodiya SM. Significant hypotension following buccal midazolam administration. BMJ Case Rep. 2010. doi:10.1136/bcr.09.2010.3371
Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet. 1978;3(1):72–91.
Visudtibhan A, Chiemchanya S, Visudhiphan P, Kanjanarungsichai A, Kaojarern S, Pichaipat V. Serum diazepam levels after oral administration in children. J Med Assoc Thai. 2002;85 Suppl 4:S1065–70.
Buhrer M, Maitre PO, Hung O, Stanski DR. Electroencephalographic effects of benzodiazepines. I Choosing an electroencephalographic parameter to measure the effect of midazolam on the central nervous system. Clin Pharmacol Ther. 1990;48(5):544–54.
Mould DR, DeFeo TM, Reele S, Milla G, Limjuco R, Crews T, Choma N, Patel IH. Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam. Clin Pharmacol Ther. 1995;58(1):35–43. doi:10.1016/0009-9236(95)90070-5.
Arendt RM, Greenblatt DJ, Liebisch DC, Luu MD, Paul SM. Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity. Psychopharmacology (Berl). 1987;93(1):72–6.
Gamble JA, Dundee JW, Assaf RA. Plasma diazepam levels after single dose oral and intramuscular administration. Anaesthesia. 1975;30(2):164–9.
Hillestad L, Hansen T, Melsom H. Diazepam metabolism in normal man. II Serum concentration and clinical effect after oral administration and cumulation. Clin Pharmacol Ther. 1974;16(3):485–9.
Hillestad L, Hansen T, Melsom H, Drivenes A. Diazepam metabolism in normal man. I. Serum concentrations and clinical effects after intravenous, intramuscular, and oral administration. Clin Pharmacol Ther. 1974;16(3):479–84.
Meberg A, Langslet A, Bredesen JE, Lunde PK. Plasma concentration of diazepam and N-desmethyldiazepam in children after a single rectal or intramuscular dose of diazepam. Eur J Clin Pharmacol. 1978;14(4):273–6.
Kanto J. Plasma concentrations of diazepam and its metabolites after peroral, intramuscular, and rectal administration. Correlation between plasma concentration and sedatory effect of diazepam. Int J Clin Pharmacol Biopharm. 1975;12(4):427–32.
Fell D, Gough MB, Northan AA, Henderson CU. Diazepam premedication in children. Plasma levels and clinical effects. Anaesthesia. 1985;40(1):12–7.
Morselli PL, Principi N, Tognoni G, Reali E, Belvedere G, Standen SM, Sereni F. Diazepam elimination in premature and full term infants, and children. J Perinat Med. 1973;1(2):133–41.
Peinemann F, Daldrup T. Severe and prolonged sedation in five neonates due to persistence of active diazepam metabolites. Eur J Pediatr. 2001;160(6):378–81.
Klotz U, Avant GR, Hoyumpa A, Schenker S, Wilkinson GR. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55(2):347–59. doi:10.1172/JCI107938.
Klotz U, Ziegler G, Reimann IW. Pharmacokinetics of the selective benzodiazepine antagonist Ro 15–1788 in man. Eur J Clin Pharmacol. 1984;27(1):115–7.
Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15–1788). Clin Pharmacokinet. 1988;14(1):1–12. doi:10.2165/00003088-198814010-00001.
Janssen U, Walker S, Maier K, von Gaisberg U, Klotz U. Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther. 1989;46(3):317–23.
Jones RD, Chan K, Roulson CJ, Brown AG, Smith ID, Mya GH. Pharmacokinetics of flumazenil and midazolam. Br J Anaesth. 1993;70(3):286–92.
Roncari G, Ziegler WH, Guentert TW. Pharmacokinetics of the new benzodiazepine antagonist Ro 15–1788 in man following intravenous and oral administration. Br J Clin Pharmacol. 1986;22(4):421–8.
Tobias JD. Controlled hypotension in children: a critical review of available agents. Paediatr Drugs. 2002;4(7):439–53.
Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J. 2004;97(5):451–5.
Nichols DP, Berkenbosch JW, Tobias JD. Rescue sedation with dexmedetomidine for diagnostic imaging: a preliminary report. Paediatr Anaesth. 2005;15(3):199–203.
Hammer GB, Philip BM, Schroeder AR, Rosen FS, Koltai PJ. Prolonged infusion of dexmedetomidine for sedation following tracheal resection. Paediatr Anaesth. 2005;15(7):616–20.
Tobias JD. Dexmedetomidine to treat opioid withdrawal in infants following prolonged sedation in the pediatric ICU. J Opioid Manag. 2006;2(4):201–5.
Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg. 2004;98(1):60–3.
Walker J, Maccallum M, Fischer C, Kopcha R, Saylors R, McCall J. Sedation using dexmedetomidine in pediatric burn patients. J Burn Care Res. 2006;27(2):206–10. doi:10.1097/01.BCR.0000200910.76019.CF.
Tobias JD. Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology. Pediatr Crit Care Med. 2007;8(2):115–31. doi:10.1097/01.PCC.0000257100.31779.41.
Koroglu A, Teksan H, Sagir O, Yucel A, Toprak HI, Ersoy OM. A comparison of the sedative, hemodynamic, and respiratory effects of dexmedetomidine and propofol in children undergoing magnetic resonance imaging. Anesth Analg. 2006;103(1):63–7. doi:10.1213/01.ANE.0000219592.82598.AA.
Potts AL, Anderson BJ, Holford NH, Vu TC, Warman GR. Dexmedetomidine hemodynamics in children after cardiac surgery. Paediatr Anaesth. 2010;20(5):425–33. doi:10.1111/j.1460-9592.2010.03285.x.
Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology. 2000;93(2):382–94.
Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology. 2000;93(5):1345–9.
Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs. 2000;59(2):263–8.
Hsu YW, Cortinez LI, Robertson KM, Keifer JC, Sum-Ping ST, Moretti EW, Young CC, Wright DR, Macleod DB, Somma J. Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 2004;101(5):1066–76.
Potts AL, Anderson BJ, Warman GR, Lerman J, Diaz SM, Vilo S. Dexmedetomidine pharmacokinetics in pediatric intensive care--a pooled analysis. Pediatr Anaesth. 2009;19(11):1119–29. doi:10.1111/j.1460-9592.2009.03133.x.
Mason KP, Zurakowski D, Zgleszewski S, Prescilla R, Fontaine PJ, Dinardo JA. Incidence and predictors of hypertension during high-dose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth. 2010;20(6):516–23. doi:10.1111/j.1460-9592.2010.03299.x.
Mason KP, Lerman J. Review article: dexmedetomidine in children: current knowledge and future applications. Anesth Analg. 2011;113(5):1129–42. doi:10.1213/ANE.0b013e31822b8629.
Hammer GB, Drover DR, Cao H, Jackson E, Williams GD, Ramamoorthy C, Van Hare GF, Niksch A, Dubin AM. The effects of dexmedetomidine on cardiac electrophysiology in children. Anesth Analg. 2008;106(1):79–83.
Tobias JD, Chrysostomou C. Dexmedetomidine: antiarrhythmic effects in the pediatric cardiac patient. Pediatr Cardiol. 2013;34(4):779–85. doi:10.1007/s00246-013-0659-7.
Parent BA, Munoz R, Shiderly D, Chrysostomou C. Use of dexmedetomidine in sustained ventricular tachycardia. Anaesth Intensive Care. 2010;38(4):781.
Chrysostomou C, Morell VO, Wearden P, Sanchez-de-Toledo J, Jooste EH, Beerman L. Dexmedetomidine: therapeutic use for the termination of reentrant supraventricular tachycardia. Congenit Heart Dis. 2013;8(1):48–56. doi:10.1111/j.1747-0803.2012.00669.x.
Char D, Drover DR, Motonaga KS, Gupta S, Miyake CY, Dubin AM, Hammer GB. The effects of ketamine on dexmedetomidine-induced electrophysiologic changes in children. Paediatr Anaesth. 2013;23(10):898–905. doi:10.1111/pan.12143.
Su F, Nicolson SC, Gastonguay MR, Barrett JS, Adamson PC, Kang DS, Godinez RI, Zuppa AF. Population pharmacokinetics of dexmedetomidine in infants after open heart surgery. Anesth Analg. 2010;110(5):1383–92. doi:10.1213/ANE.0b013e3181d783c8.
Chrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, da Rocha MG, Wisemandle WA, Gramlich L. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J Pediatr. 2014;164(2):276–282.e3. doi:10.1016/j.jpeds.2013.10.002.
Mahmoud M, Radhakrishman R, Gunter J, Sadhasivam S, Schapiro A, McAuliffe J, Kurth D, Wang Y, Nick TG, Donnelly LF. Effect of increasing depth of dexmedetomidine anesthesia on upper airway morphology in children. Paediatr Anaesth. 2010;20(6):506–15. doi:10.1111/j.1460-9592.2010.03311.x.
Mahmoud M, Jung D, Salisbury S, McAuliffe J, Gunter J, Patio M, Donnelly LF, Fleck R. Effect of increasing depth of dexmedetomidine and propofol anesthesia on upper airway morphology in children and adolescents with obstructive sleep apnea. J Clin Anesth. 2013;25(7):529–41. doi:10.1016/j.jclinane.2013.04.011.
Olutoye OA, Glover CD, Diefenderfer JW, McGilberry M, Wyatt MM, Larrier DR, Friedman EM, Watcha MF. The effect of intraoperative dexmedetomidine on postoperative analgesia and sedation in pediatric patients undergoing tonsillectomy and adenoidectomy. Anesth Analg. 2010;111(2):490–5. doi:10.1213/ANE.0b013e3181e33429.
Tobias JD, Goble TJ, Bates G, Anderson JT, Hoernschemeyer DG. Effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescents. Paediatr Anaesth. 2008;18(11):1082–8. doi:10.1111/j.1460-9592.2008.02733.x.
Bala E, Sessler DI, Nair DR, McLain R, Dalton JE, Farag E. Motor and somatosensory evoked potentials are well maintained in patients given dexmedetomidine during spine surgery. Anesthesiology. 2008;109(3):417–25. doi:10.1097/ALN.0b013e318182a467.
Mahmoud M, Sadhasivam S, Salisbury S, Nick TG, Schnell B, Sestokas AK, Wiggins C, Samuels P, Kabalin T, McAuliffe J. Susceptibility of transcranial electric motor-evoked potentials to varying targeted blood levels of dexmedetomidine during spine surgery. Anesthesiology. 2010;112(6):1364–73. doi:10.1097/ALN.0b013e3181d74f55.
Anschel DJ, Aherne A, Soto RG, Carrion W, Hoegerl C, Nori P, Seidman PA. Successful intraoperative spinal cord monitoring during scoliosis surgery using a total intravenous anesthetic regimen including dexmedetomidine. J Clin Neurophysiol. 2008;25(1):56–61. doi:10.1097/WNP.0b013e318163cca6.
Pickard A, Davies P, Birnie K, Beringer R. Systematic review and meta-analysis of the effect of intraoperative alpha(2)-adrenergic agonists on postoperative behaviour in children. Br J Anaesth. 2014;112(6):982–90. doi:10.1093/bja/aeu093.
Bergendahl H, Lonnqvist PA, Eksborg S. Clonidine in paediatric anaesthesia: review of the literature and comparison with benzodiazepines for premedication. Acta Anaesthesiol Scand. 2006;50(2):135–43.
Blackburn L, Almenrader N, Larsson P, Anderson BJ. Intranasal clonidine pharmacokinetics. Paediatr Anaesth. 2014;24(3):340–2. doi:10.1111/pan.12297.
Potts AL, Larsson P, Eksborg S, Warman G, Lonnqvist PA, Anderson BJ. Clonidine disposition in children; a population analysis. Pediatr Anesth. 2007;17(10):924–33. doi:10.1111/j.1460-9592.2007.02251.x.
Sumiya K, Homma M, Watanabe M, Baba Y, Inomata S, Kihara S, Toyooka H, Kohda Y. Sedation and plasma concentration of clonidine hydrochloride for pre-anesthetic medication in pediatric surgery. Biol Pharm Bull. 2003;26(4):421–3.
Klein RH, Alvarez-Jimenez R, Sukhai RN, Oostdijk W, Bakker B, Reeser HM, Ballieux BE, Hu P, Klaassen ES, Freijer J, Burggraaf J, Cohen AF, Wit JM. Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach. Horm Res Paediatr. 2013;79(5):300–9. doi:10.1159/000350819.
Hall JE, Uhrich TD, Ebert TJ. Sedative, analgesic and cognitive effects of clonidine infusions in humans. Br J Anaesth. 2001;86(1):5–11.
De Kock MF, Pichon G, Scholtes JL. Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth. 1992;39(6):537–44.
Bernard JM, Hommeril JL, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology. 1991;75(4):577–82.
Marinangeli F, Ciccozzi A, Donatelli F, Di Pietro A, Iovinelli G, Rawal N, Paladini A, Varrassi G. Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain. 2002;6(1):35–42.
Davies DS, Wing AM, Reid JL, Neill DM, Tippett P, Dollery CT. Pharmacokinetics and concentration-effect relationships of intervenous and oral clonidine. Clin Pharm Ther. 1977;21(5):593–601.
Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet. 1988;14(5):287–310.
Arndts D. New aspects of the clinical pharmacology of clonidine. Chest. 1983;83(2 Suppl):397–400.
Arndts D, Doevendans J, Kirsten R, Heintz B. New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol. 1983;24(1):21–30.
Hesselmans LF, Jennekens FG, Van den Oord CJ, Veldman H, Vincent A. Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors. Anat Rec. 1993;236(3):553–62. doi:10.1002/ar.1092360315.
Jaramillo F, Schuetze SM. Kinetic difference between embryonic- and adult-type acetylcholine receptors in rat myotubes. J Physiol. 1988;396:267–96.
Goudsouzian NG. Maturation of neuromuscular transmission in the infant. Br J Anaesth. 1980;52(2):205–14.
Goudsouzian NG, Standaert FG. The infant and the myoneural junction. Anesth Analg. 1986;65(11):1208–17.
Meretoja OA, Brandom BW, Taivainen T, Jalkanen L. Synergism between atracurium and vecuronium in children. Br J Anaesth. 1993;71(3):440–2.
Meretoja OA, Taivainen T, Jalkanen L, Wirtavuori K. Synergism between atracurium and vecuronium in infants and children during nitrous oxide-oxygen-alfentanil anaesthesia. Br J Anaesth. 1994;73(5):605–7.
Keens TG, Bryan AC, Levison H, Ianuzzo CD. Developmental pattern of muscle fiber types in human ventilatory muscles. J Appl Physiol. 1978;44(6):909–13.
Meretoja OA. Neuromuscular blocking agents in paediatric patients: influence of age on the response. Anaesth Intens Care. 1990;18(4):440–8.
Donati F, Antzaka C, Bevan DR. Potency of pancuronium at the diaphragm and the adductor pollicis muscle in humans. Anesthesiology. 1986;65(1):1–5.
Laycock JR, Baxter MK, Bevan JC, Sangwan S, Donati F, Bevan DR. The potency of pancuronium at the adductor pollicis and diaphragm in infants and children. Anesthesiology. 1988;68(6):908–11.
Laycock JR, Donati F, Smith CE, Bevan DR. Potency of atracurium and vecuronium at the diaphragm and the adductor pollicis muscle. Br J Anaesth. 1988;61(3):286–91.
Meakin G, Shaw EA, Baker RD, Morris P. Comparison of atracurium-induced neuromuscular blockade in neonates, infants and children. Br J Anaesth. 1988;60(2):171–5.
Basta SJ, Ali HH, Savarese JJ, Sunder N, Gionfriddo M, Cloutier G, Lineberry C, Cato AE. Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant. Anesth Analg. 1982;61(9):723–9.
Woelfel SK, Brandom BW, McGowan Jr FX, Cook DR. Clinical pharmacology of mivacurium in pediatric patients less than off years old during nitrous oxide-halothane anesthesia. Anesth Analg. 1993;77(4):713–20.
Goudsouzian NG, Denman W, Schwartz A, Shorten G, Foster V, Samara B. Pharmacodynamic and hemodynamic effects of mivacurium in infants anesthetized with halothane and nitrous oxide. Anesthesiology. 1993;79(5):919–25.
Saldien V, Vermeyen KM, Wuyts FL. Target-controlled infusion of rocuronium in infants, children, and adults: a comparison of the pharmacokinetic and pharmacodynamic relationship. Anesth Analg. 2003;97(1):44–9.
Fisher DM, Miller RD. Neuromuscular effects of vecuronium (ORG NC45) in infants and children during N2O, halothane anesthesia. Anesthesiology. 1983;58(6):519–23.
Fisher DM, Castagnoli K, Miller RD. Vecuronium kinetics and dynamics in anesthetized infants and children. Clin Pharm Ther. 1985;37(4):402–6.
Wierda JM, Meretoja OA, Taivainen T, Proost JH. Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children. Br J Anaesth. 1997;78(6):690–5.
Kalli I, Meretoja OA. Infusion of atracurium in neonates, infants and children. A study of dose requirements. Br J Anaesth. 1988;60(6):651–4.
Alifimoff JK, Goudsouzian NG. Continuous infusion of mivacurium in children. Br J Anaesth. 1989;63(5):520–4.
Woelfel SK, Dong ML, Brandom BW, Sarner JB, Cook DR. Vecuronium infusion requirements in children during halothane-narcotic-nitrous oxide, isoflurane-narcotic-nitrous oxide, and narcotic-nitrous oxide anesthesia. Anesth Analg. 1991;73(1):33–8.
Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia. Anesth Analg. 1985;64(5):471–6.
Woloszczuk-Gebicka B, Lapczynski T, Wierzejski W. The influence of halothane, isoflurane and sevoflurane on rocuronium infusion in children. Acta Anaesthesiol Scand. 2001;45(1):73–7.
Woloszczuk-Gebicka B, Wyska E, Grabowski T, Swierczewska A, Sawicka R. Pharmacokinetic-pharmacodynamic relationship of rocuronium under stable nitrous oxide-fentanyl or nitrous oxide-sevoflurane anesthesia in children. Paediatr Anaesth. 2006;16(7):761–8. doi:10.1111/j.1460-9592.2005.01840.x.
Meakin G, Walker RW, Dearlove OR. Myotonic and neuromuscular blocking effects of increased doses of suxamethonium in infants and children. Br J Anaesth. 1990;65(6):816–8.
Cook DR, Gronert BJ, Woelfel SK. Comparison of the neuromuscular effects of mivacurium and suxamethonium in infants and children. Acta Anaesthesiol Scand. 1995;106:S35–40.
DeCook TH, Goudsouzian NG. Tachyphylaxis and phase II block development during infusion of succinylcholine in children. Anesth Analg. 1980;59(9):639–43.
Gronert BJ, Brandom BW. Neuromuscular blocking drugs in infants and children. Pediatr Clin N Am. 1994;41(1):73–91.
Sutherland GA, Bevan JC, Bevan DR. Neuromuscular blockade in infants following intramuscular succinylcholine in two or five per cent concentration. Can Anaesth Soc J. 1983;30(4):342–6.
Matteo RS, Lieberman IG, Salanitre E, McDaniel DD, Diaz J. Distribution, elimination, and action of d-tubocurarine in neonates, infants, children, and adults. Anesth Analg. 1984;63(9):799–804.
Tassonyi E, Pittet JF, Schopfer CN, Rouge JC, Gemperle G, Wilder-Smith OH, Morel DR. Pharmacokinetics of pipecuronium in infants, children and adults. Eur J Drug Metab Pharmacokinet. 1995;20(3):203–8.
Meretoja OA, Erkola O. Pipecuronium revisited: dose–response and maintenance requirement in infants, children, and adults. J Clin Anesth. 1997;9(2):125–9. doi:10.1016/S0952-8180(96)00235-8.
Fisher DM, Canfell PC, Fahey MR, Rosen JI, Rupp SM, Sheiner LB, Miller RD. Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology. 1986;65(1):6–12.
Imbeault K, Withington DE, Varin F. Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children during N2O/O2/propofol anesthesia. Anesth Analg. 2006;102(3):738–43. doi:10.1213/01.ane.0000195342.29133.ce.
Reich DL, Hollinger I, Harrington DJ, Seiden HS, Chakravorti S, Cook DR. Comparison of cisatracurium and vecuronium by infusion in neonates and small infants after congenital heart surgery. Anesthesiology. 2004;101(5):1122–7.
Kirkegaard-Nielsen H, Meretoja OA, Wirtavuori K. Reversal of atracurium-induced neuromuscular block in paediatric patients. Acta Anaesth Scand. 1995;39(7):906–11.
Meakin G, Sweet PT, Bevan JC, Bevan DR. Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology. 1983;59(4):316–21.
Fisher DM, Cronnelly R, Miller RD, Sharma M. The neuromuscular pharmacology of neostigmine in infants and children. Anesthesiology. 1983;59(3):220–5.
Meretoja OA, Taivainen T, Wirtavuori K. Cisatracurium during halothane and balanced anaesthesia in children. Paediatr Anaesth. 1996;6(5):373–8.
Meistelman C, Debaene B, D’Hollander A, Donati F, Saint-Maurice C. Importance of the level of paralysis recovery for a rapid antagonism of vecuronium with neostigmine in children during halothane anesthesia. Anesthesiology. 1988;69(1):97–9.
Debaene B, Meistelman C, d’Hollander A. Recovery from vecuronium neuromuscular blockade following neostigmine administration in infants, children, and adults during halothane anesthesia. Anesthesiology. 1989;71(6):840–4.
Bevan JC, Purday JP, Reimer EJ, Bevan DR. Reversal of doxacurium and pancuronium neuromuscular blockade with neostigmine in children. Can Anaesth Soc J. 1994;41(11):1074–80. doi:10.1007/BF03015657.
Hinderling PH, Gundert-Remy U, Schmidlin O. Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics. J Pharm Sci. 1985;74(7):703–10.
Virtanen R, Kanto J, Iisalo E, Iisalo EU, Salo M, Sjovall S. Pharmacokinetic studies on atropine with special reference to age. Acta Anaesthesiol Scand. 1982;26(4):297–300.
Pihlajamaki K, Kanto J, Aaltonen L, Iisalo E, Jaakkola P. Pharmacokinetics of atropine in children. Int J Clin Pharmacol Ther Toxicol. 1986;24(5):236–9.
Barrington KJ. The myth of a minimum dose for atropine. Pediatrics. 2011;127(4):783–4. doi:10.1542/peds.2010-1475.
Eisa L, Passi Y, Lerman J, Raczka M, Heard C. Do small doses of atropine (<0.1 mg) cause bradycardia in young children? Arch Dis Child. 2015;100(7):684–8. doi:10.1136/archdischild-2014-307868.
Palmisano BW, Setlock MA, Brown MP, Siker D, Tripuraneni R. Dose–response for atropine and heart rate in infants and children anesthetized with halothane and nitrous oxide. Anesthesiology. 1991;75(2):238–42.
Rautakorpi P, Ali-Melkkila T, Kaila T, Olkkola KT, Iisalo E, Kanto J. Pharmacokinetics of glycopyrrolate in children. J Clin Anesth. 1994;6(3):217–20.
Ali-Melkkila T, Kaila T, Kanto J. Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings. Acta Anaesthesiol Scand. 1989;33(6):513–7.
Mirakhur RK, Dundee JW. Glycopyrrolate: pharmacology and clinical use. Anaesthesia. 1983;38(12):1195–204.
Mirakhur RK, Jones CJ. Atropine and glycopyrrolate: changes in cardiac rate and rhythm in conscious and anaesthetised children. Anaesth Intens Care. 1982;10(4):328–32.
Salem MR, Wong AY, Mani M, Bennett EJ, Toyama T. Premedicant drugs and gastric juice pH and volume in pediatric patients. Anesthesiology. 1976;44(3):216–9.
Meyers EF, Tomeldan SA. Glycopyrrolate compared with atropine in prevention of the oculocardiac reflex during eye-muscle surgery. Anesthesiology. 1979;51(4):350–2.
Rautakorpi P, Manner T, Ali-Melkkila T, Kaila T, Olkkola K, Kanto J. Pharmacokinetics and oral bioavailability of glycopyrrolate in children. Pharmacol Toxicol. 1998;83(3):132–4.
Plaud B, Meretoja O, Hofmockel R, Raft J, Stoddart PA, van Kuijk JH, Hermens Y, Mirakhur RK. Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients. Anesthesiology. 2009;110(2):284–94. doi:10.1097/ALN.0b013e318194caaa.
Robertson EN, Driessen JJ, Vogt M, De Boer H, Scheffer GJ. Pharmacodynamics of rocuronium 0.3 mg kg−1 in adult patients with and without renal failure. Eur J Anaesthesiol. 2005;22(12):929–32. doi:10.1017/S0265021505001584.
Staals LM, Snoeck MM, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function. Br J Anaesth. 2008;101(4):492–7. doi:10.1093/bja/aen216.
Staals LM, Snoeck MM, Driessen JJ, van Hamersvelt HW, Flockton EA, van den Heuvel MW, Hunter JM. Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study. Br J Anaesth. 2010;104(1):31–9. doi:10.1093/bja/aep340.
Morell RC, Berman JM, Royster RI, Petrozza PH, Kelly JS, Colonna DM. Revised label regarding use of succinylcholine in children and adolescents. Anesthesiology. 1994;80(1):242–5.
Badgwell JM, Hall SC, Lockhart C. Revised label regarding use of succinylcholine in children and adolescents. Anesthesiology. 1994;80(1):243–5.
Goudsouzian NG. Recent changes in the package insert for succinylcholine chloride: should this drug be contraindicated for routine use in children and adolescents? (Summary of the discussions of the anesthetic and life support drug advisory meeting of the Food and Drug Administration, FDA building, Rockville, MD, June 9, 1994). Anesth Analg. 1995;80(1):207–8.
Anderson BJ, Brown TC. Anaesthesia for a child with congenital myotonic dystrophy. Anaesth Intens Care. 1989;17(3):351–4.
Galley HF, Mahdy A, Lowes DA. Pharmacogenetics and anesthesiologists. Pharmacogenomics. 2005;6(8):849–56. doi:10.2217/14622416.6.8.849.
Neitlich HW. Increased plasma cholinesterase activity and succinylcholine resistance: a genetic variant. J Clin Invest. 1966;45(3):380–7. doi:10.1172/JCI105353.
Lockridge O. Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine. Pharmacol Ther. 1990;47(1):35–60.
Olsson GL, Hallen B. Pharmacological evacuation of the stomach with metoclopramide. Acta Anaesthesiol Scand. 1982;26(5):417–20.
Albibi R, McCallum RW. Metoclopramide: pharmacology and clinical application. Ann Intern Med. 1983;98(1):86–95.
Kan KK, Rudd JA, Wai MK. Differential action of anti-emetic drugs on defecation and emesis induced by prostaglandin E2 in the ferret. Eur J Pharmacol. 2006;544(1–3):153–9. doi:10.1016/j.ejphar.2006.06.034.
Kearns GL, Butler HL, Lane JK, Carchman SH, Wright GJ. Metoclopramide pharmacokinetics and pharmacodynamics in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 1988;7(6):823–9.
Kearns GL, van den Anker JN, Reed MD, Blumer JL. Pharmacokinetics of metoclopramide in neonates. J Clin Pharmacol. 1998;38(2):122–8.
Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006;19(6):606–11. doi:10.1097/01.aco.0000247340.61815.38.
Khalil SN, Roth AG, Cohen IT, Simhi E, Ansermino JM, Bolos ME, Cote CJ, Hannallah RS, Davis PJ, Brooks PB, Russo MW, Anschuetz GC, Blackburn LM. A double-blind comparison of intravenous ondansetron and placebo for preventing postoperative emesis in 1- to 24-month-old pediatric patients after surgery under general anesthesia. Anesth Analg. 2005;101(2):356–61. doi:10.1213/01.ANE.0000155261.27335.29.
Mondick JT, Johnson BM, Haberer LJ, Sale ME, Adamson PC, Cote CJ, Croop JM, Russo MW, Barrett JS, Hoke JF. Population pharmacokinetics of intravenous ondansetron in oncology and surgical patients aged 1–48 months. Eur J Clin Pharmacol. 2010;66(1):77–86. doi:10.1007/s00228-009-0730-8.
Anderson BJ. Pharmacology of paediatric TIVA. Rev Colomb Anestesiol. 2013;41:205–14.
Leeder JS, Kearns GL. Pharmacogenetics in pediatrics. Implications for practice. Pediatr Clin North Am. 1997;44(1):55–77.
Lotsch J, Kettenmann B, Renner B, Drover D, Brune K, Geisslinger G, Kobal G. Population pharmacokinetics of fast release oral diclofenac in healthy volunteers: relation to pharmacodynamics in an experimental pain model. Pharm Res. 2000;17(1):77–84.
Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth. 2007;17(11):1028–34.
Allegaert K, Holford N, Anderson BJ, Holford S, Stuber F, Rochette A, Troconiz IF, Beier H, de Hoon JN, Pedersen RS, Stamer U. Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study. Clin Pharmacokinet. 2015;54(2):167–78. doi:10.1007/s40262-014-0191-9.
Anderson BJ. Pediatric models for adult target-controlled infusion pumps. Paed Anaesth. 2010;20(3):223–32. doi:10.1111/j.1460-9592.2009.03072.x.
Sumpter A, Anderson BJ. Phenobarbital and some anesthesia implications. Pediatr Anesth. 2011;21:995–7.
Hannam JA, Anderson BJ. Pharmacodynamic interaction models in pediatric anesthesia. Paediatr Anaesth. 2015;25:970–80. doi:10.1111/pan.12735.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Anderson, B.J. (2017). Pharmacokinetics and Pharmacodynamics in the Pediatric Patient. In: Absalom, A., Mason, K. (eds) Total Intravenous Anesthesia and Target Controlled Infusions. Springer, Cham. https://doi.org/10.1007/978-3-319-47609-4_25
Download citation
DOI: https://doi.org/10.1007/978-3-319-47609-4_25
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-47607-0
Online ISBN: 978-3-319-47609-4
eBook Packages: MedicineMedicine (R0)