Download PDF
Anästhesiol Intensivmed Notfallmed Schmerzther 1999; 34(10): 616-625
DOI: 10.1055/s-1999-216
ÜBERSICHT
Georg Thieme Verlag Stuttgart · New York

Pharmakokinetik bei Neugeborenen und Säuglingen*

Pharmacokinetics in Neonates and Infants.A. Röper, P. M. Lauven
  • Klinik für Anästhesie und operative Intensivmedizin, Städtische Kliniken Bielefeld gem.GmbH
Further Information

Publication History

Publication Date:
31 December 1999 (online)

Also available at
    Permissions and Reprints

Zusammenfassung.

Anatomisch-physiologische Veränderungen von Neugeborenen und Säuglingen können die Pharmakokinetik anästhesierelevanter Medikamente deutlich beeinflussen. Zudem stellt die Neugeborenenphase die Lebensphase mit den schnellsten und ausgeprägtesten Veränderungen bezüglich wichtiger Organfunktionen dar. Änderungen der Körperzusammensetzung und des Proteingehaltes beeinflussen das Verteilungsvolumen, die Distribution zwischen den Kompartimenten und die freie Plasmafraktion einiger Pharmaka wie z. B. Relaxanzien oder Lokalanästhetika. Durch die Unreife hepatischer mikrosomaler Enzymsysteme kommt es zu einer verminderten Metabolisierung v. a. von Substanzen mit einer niedrigen hepatisch-metabolischen Clearance wie beispielsweise Diazepam, Morphin oder einige Lokalanästhetika. Die Entwicklung der Enzymsysteme im ersten Lebensjahr führt zu einer Steigerung der Clearance, die z. T. über das Erwachsenenniveau hinaus geht. Zudem treten Veränderungen der Pharmakodynamik bei diesen Kindern im Sinne einer veränderten Sensibilität gegenüber Pharmaka auf. So nimmt die MAC volatiler Anästhetika mit zunehmendem Alter ab. Da es sich in dieser Altersgruppe um ein sehr heterogenes Patientenklientel mit großen interindividuellen Differenzen handelt, ist eine individuell angepaßte Dosierung erforderlich, um einen optimalen pharmakodynamischen Effekt ohne toxische Nebenwirkungen zu erzielen.

Physiologic changes influence the pharmacokinetics of drugs relevant to anesthesia in neonates and infants. The neonatal phase is the phase of life with the most rapid and dramatic changes of organ-functions responsible for pharmacokinetics of most anesthetics. Changes in body composition and the content of plasma proteins influence volume of distribution, the drug distribution to different compartments and the amount of free fraction in plasma. Due to the immaturity of hepatic microsomal enzyme systems there is a decreased metabolism particular of agents which undergo low hepatic extraction like Diazepam, Morphine or some local anesthetics. In the first year of life capacity of the enzymatic systems increases and also clearance increases. Until puberty the clearance of some drugs is greater than the adult level. There are also pharmacodynamic changes like modified sensitivity to some drugs like volatile anesthetics or neuromuscular blocking agents. In summary neonates and infants are a highly heterogenous group with large interindividual differences. Therefore the dosage of anesthetic agents must be individualized to achieve optimal pharmacodynamic effects without toxicity in this age group.

Schlüsselwörter:

Pharmakokinetik - Neugeborene & - Säuglinge - Pädiatrische Anästhesie - Pharmakodynamik

Key words:

Pharmacokinetics - Neonates - Infants - Pediatric anesthesia - Pharmacodynamics

Literatur

  • 1 van den Anker J N. Pharmacokinetics and renal function in preterm infants.  Acta Paediatr. 1996;  85 1393-1399
    PubMedGoogle Scholar
  • 2 Blumer J L. Clinical pharmacology of midazolam in infants and children.  Clin Pharmacokinet. 1998;  37 37-47
    PubMedGoogle Scholar
  • 3 Bovill J G, Sebel P S, Blackburn C L. The pharmacokinetics of sufentanil in surgical patients.  Anesthesiology. 1984;  61 502-506
    PubMedGoogle Scholar
  • 4 Brandom B W, Stiller R L, Cook D R, Woelfel S K, Lai A. Pharmacokinetics of atracurium in anaesthetized infants and children.  Brit J Anaesth. 1986;  58 1210-1213
    PubMedGoogle Scholar
  • 5 Bricker S R, Telford R J, Booker P D. Pharmacokinetics of bupivacaine following intraoperative intercostal nerve block in neonates and in infants aged less than 6 months.  Anesthesiology. 1989;  70 942-947
    PubMedGoogle Scholar
  • 6 Browne B L, Wolf A R, Prys-Roberts C. Dose requirements for propofol in children during total i. v. anesthesia.  Brit J Anaesth. 1990;  64 396-397
    PubMedGoogle Scholar
  • 7 Burtin P, Jacqz-Aigrain E, Girard P, Lenclen R, Magny J F, Betremieux P, Tehiry C, Desplanques L, Mussat P. Population pharmacokinetics of midazolam in neonates.  Clin Pharmacol Ther. 1994;  56 615-625
    CrossrefPubMedGoogle Scholar
  • 8 Cameron C B, Robinson S, Gregory G A. The minimum anesthetic concentration of isoflurane in children.  Anesth Analg. 1984;  63 418-420
    PubMedGoogle Scholar
  • 9 Choonara I, Lawrence A, Michaelkiewicz A. Morphin metabolism in neonates and infants.  Brit J Clin Pharm. 1992;  34 434-437
    PubMedGoogle Scholar
  • 10 Cook D R. Mivacurium in infants and children.  J Drug Dev. 1993;  5 7-14
    PubMedGoogle Scholar
  • 11 Davis P J, Kilian A, Stiller R L. Pharmacokinetics of alfentanil in newborne premature infants and older children.  Dev Pharmacol Ther. 1990;  13 21-27
    PubMedGoogle Scholar
  • 12 Davis P J, Ross A K, Henson L D, Muir K T, McGowan F X, Gupta S K. Pharmacokinetics of remifentanil in anesthetized children 2 - 12 years of age.  Anesth Analg. 1995;  80 -95
    PubMedGoogle Scholar
  • 13 Davis P J, Ross A K, Henson L D, Muir K T. Remifentanil pharmacokinetics in neonates.  Anesthesiology. 1997;  87 -1064
    PubMedGoogle Scholar
  • 14 Demarquez J L, Galperine R, Billeaud C, Brachet-Liermain A. High-dose thiopental pharmacokinetics in brain-injured children and neonates.  Dev Pharmacol Ther. 1987;  10 292-230
    PubMedGoogle Scholar
  • 15 Ecoffey C, Bahlman S H, Munson E S. Bupivacaine in children: pharmacokinetics following caudal anesthesia.  Anesthesiology. 1985;  63 447-448
    PubMedGoogle Scholar
  • 16 Eger E I, Bahlman S H, Munson E S. The effect of age on the rate in increase of alveolar anesthetic concentration.  Anesthesology. 1971;  35 365-371
    PubMedGoogle Scholar
  • 17 Ekstrand S J, Fomon J, Ziegler E E, Nelson S E. Fluoride pharmacokinetics in infancy.  Pediatr Des. 1994;  35 157-163
    PubMedGoogle Scholar
  • 18 Fisher D M, O'Keeffe C, Stanski D R, Cronelly R, Miller R D. Pharmacokinetics and pharmacodynamics of d-turbocurarine in infants, children, and adults.  Anesthesiology. 1982;  57 203-208
    PubMedGoogle Scholar
  • 19 Fisher D M, Castagnoli K, Miller R D. Vecuronium kinetics and dynamics in anesthetized infants and children.  Clin Pharmacol Ther. 1985;  37 402-406
    PubMedGoogle Scholar
  • 20 Fisher D M, Canfell P C, Spellmann M J, Miller R D. Pharmacokinetics and pharmacodynamics of atracurium in infants and children.  Anesthesiology. 1990;  73 33-37
    PubMedGoogle Scholar
  • 21 Fisher D M, Zwass M S. MAC of desflurane in 60 % nitrous oxide in infants and children.  Anesthesiology. 1992;  76 354-356
    PubMedGoogle Scholar
  • 22 Friis-Hansen B. Body composition during growth: biochemical data and in vivo measurements.  Pediatrics. 1971;  47 264-274
    PubMedGoogle Scholar
  • 23 Gauntlett J S, Fisher D M, Hertzka R E, Kuhle E, Spellmann M J, Rudolph C. Pharmacokinetics of fentanyl in neonatal humans and lambs: Effects of age.  Anesthesiology. 1988;  69 683-687
    PubMedGoogle Scholar
  • 24 Glass P S, Hardmann H D, Kamiyama Y, Quil T J, Morton G, Donn K H. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid remifentanil (GI 807084B).  Anesth Analg. 1993;  77 1031-1040
    PubMedGoogle Scholar
  • 25 Goresky G V, Koren G, Sabourin M A. The pharmacokinetics of alfentanil in children.  Anesthesiology. 1987;  67 654-659
    PubMedGoogle Scholar
  • 26 Goudsouzian N G. Atracurium in infants and children.  Brit J Anaesth. 1986;  58 23
    PubMedGoogle Scholar
  • 27 Grant I S, Nimmo W S, McNicol L R, Clements J A. Ketamine disposition in children and adults.  Brit J Anaesth. 1983;  55 1107-1110
    PubMedGoogle Scholar
  • 28 Greeley W J, Brujn N P, Davis D P. Sufentanil pharmacokinetics in pediatric cardiovascular patients.  Anesth Analg. 1987;  66 1067-1072
    PubMedGoogle Scholar
  • 29 Greeley W J, Brujn N P. Changes in sufentanil pharmacokinetics within the neonatal period.  Anesth Analg. 1988;  67 86-90
    PubMedGoogle Scholar
  • 30 Gregory G A, Eger F I, Munson E S. The relationship between age and halothan requirements in man.  Anesthesiology. 1969;  30 488-491
    PubMedGoogle Scholar
  • 31 Hartel R, Quinn M, Green M. Morphin glucuronidation in premature infants.  Brit J Clin Pharm. 1993;  35 314-317
    PubMedGoogle Scholar
  • 32 Jacqz-Aigran E, Wood C, Robieux I. Pharmacokinetics of midazolam in neonates.  Eur J Clin Pharmacol. 1990;  39 191-192
    CrossrefPubMedGoogle Scholar
  • 33 Jacqz-Aigran E, Daoud P, Burtin P, Meherzi S, Beaufils F. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates.  Eur J Clin Pharmacol. 1992;  42 329-332
    PubMedGoogle Scholar
  • 34 Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates.  Clin Pharmacokinet. 1996;  3 423-443
    PubMedGoogle Scholar
  • 35 Johnson K L, Erickson J P, Holley D F, Scott J C. Fentanyl pharmacokinetics in the pediatric population.  Anesthesiology. 1984;  3 -441
    PubMedGoogle Scholar
  • 36 Jones R DM, Chan K, Andrew L J. Pharmacokinetics of propofol in children.  Brit J Anaesth. 1990;  65 661-667
    PubMedGoogle Scholar
  • 37 Kalli I, Meretoja O A. Infusion of atracurium in neonates, infants, and children.  Brit J Anaesth. 1998;  60 651-654
    PubMedGoogle Scholar
  • 38 Kart T, Christrup L L, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: Part 1 - Pharmacokinetics.  Paed Anaesth. 1997;  7 5-11
    PubMedGoogle Scholar
  • 39 Kingston H G, Kendrick A, Sommer K M, Olsen G D, Downes H. Binding of thiopental in neonatal serum.  Anesthesiology. 1990;  72 428-431
    PubMedGoogle Scholar
  • 40 Koehntop D, Rogman J, Brundage D, Heglan M, Buckley J. Pharmacokinetics of fentanyl in neonates.  Anesthesiology. 1984;  61 -439
    PubMedGoogle Scholar
  • 41 Koehntop D, Rogman J, Brundage D, Heglan M, Buckley J. Pharmacokinetics of fentanyl in neonates.  Anesth Analg. 1986;  65 227-232
    PubMedGoogle Scholar
  • 42 LeDez K M, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates.  Anesthesiology. 1987;  67 301-307
    PubMedGoogle Scholar
  • 43 Lee T C, Charles B G, Harte G J, Gray P H, Steer P A, Flenady V J. Population pharmacokinetic modelling in very premature infants receiving midazolam during mechanical ventilation.  Anesthesiology. 1999;  90 451-457
    PubMedGoogle Scholar
  • 44 Lerman J, Robinson S, Willis M M, Gregory G A. Anesthetic requirement for halothane in young children 0 - 1 month and 1 - 6 months of age.  Anesthesiology. 1983;  59 421-424
    PubMedGoogle Scholar
  • 45 Lerman J, Gregory G A, Willis M M, Eger E I. Age and solubility of volatile anesthetics in blood.  Anesthesiology. 1984;  61 139-143
    PubMedGoogle Scholar
  • 46 Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children.  Anesthesiology. 1998;  80 814-824
    PubMedGoogle Scholar
  • 47 Lerman J, Strong H A, Ledez K M. Effects of age on the serum concentration of AAG and the binding of lidocaine in pediatric patients.  Clin Pharmacol Ther. 1989;  46 219-225
    PubMedGoogle Scholar
  • 48 Luz G, Innerhofer P, Bachmann B, Frischhut B, Menardi G, Benzer A. Bupivacaine plasma concentration during continuous epidural anesthesia in infants and children.  Anesth Analg. 1996;  82 231-234
    PubMedGoogle Scholar
  • 49 Lynn A M, Slattery J T. Morphine pharmacokinetics in early infancy.  Anesthesiology. 1987;  66 136-139
    PubMedGoogle Scholar
  • 50 Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentration in neonates and adults.  Anesthesiology. 1990;  72 793-796
    PubMedGoogle Scholar
  • 51 Mazoit J X, Denson D D, Samil K. Pharmacokinetics of bupivacain following caudal anesthesia in infants.  Anesthesiology. 1988;  68 387-391
    PubMedGoogle Scholar
  • 52 McDermott C A, Kowalczyk A L, Schnitzler E R. Pharmacokinetics of lorazepam in critically ill neonates with seizures.  J Paediatr. 1992;  120 479-483
    PubMedGoogle Scholar
  • 53 Meistelmann C, Saint-Maurice C, Loose J P, Levron J C. Pharmacokinetics of alfentanil in children.  Anesthesiology. 1984;  61 -443
    PubMedGoogle Scholar
  • 54 Meistelmann C, Saint-Maurice C, Lepaul M. A comparison of alfentanil in children and adults.  Anesthesiology. 1987;  66 13-16
    PubMedGoogle Scholar
  • 55 Meretoja O A, Taivainen T, Wirtavuori K. Pharmacodynamics of mivacurium in infants.  Brit J Anaesth. 1994;  73 490-493
    PubMedGoogle Scholar
  • 56 Mihaly G W, Veilberg V L, Christensen C B, Lundstrom K E. The pharmacokinetics and metabolism of anilide local anaesthetics in neonates.  Eur J Clin Pharmacol. 1978;  13 143-151
    CrossrefPubMedGoogle Scholar
  • 57 Mikkelsen S, Feilberg V L, Christensen C B, Lundstrom K E. Morphine pharmacokinetics in premature and mature infants.  Acta Pediatr. 1994;  83 1025-1028
    PubMedGoogle Scholar
  • 58 Milsap R L, Jusko W J. Pharmacokinetics in infants.  Environ Health Perspect. 1994;  102 107-110
    PubMedGoogle Scholar
  • 59 Monrigal C, Premel-Cabic A, Turcant A, Bourgeonneau M C, Cavellat M, Allain P. Pharmacokinetics of tiopental in women and newborn infants.  Ann Fr Anesth Reanim. 1986;  5 565-569
    PubMedGoogle Scholar
  • 60 Morselli P L, Principi N, Tognoni T, Reali E, Belvedere G, Standen S M, Sereni F. Diazepam elimination in premature and full term infants and children.  J Perinat Med. 1973;  1 133-141
    PubMedGoogle Scholar
  • 61 Morselli P L, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants.  Clin Pharmacokinet. 1980;  5 485-427
    PubMedGoogle Scholar
  • 62 Morselli P L. Clinical pharmacology of the perinatal period and early infancy.  Clin Pharmacokinet. 1989;  17 13-18
    PubMedGoogle Scholar
  • 63 Murat I, Billard V, Vernois J, Zaouter M, Marsol P, Souron R, Farinotti R. Pharmacokinetics of propofol after single dose in children aged 1 - 3 years with minor burns.  Anesthesiology. 1996;  84 526-532
    PubMedGoogle Scholar
  • 64 Murray D J, Mehesh P M, Forbes R B, Dull D. Additive contribution of nitrous oxide to halothane MAC in infants and children.  Anesth Analg. 1990;  71 120-124
    PubMedGoogle Scholar
  • 65 Murray D J, Mehesh P M, Forbes R B. The additive contribution of nitrous oxide to isoflurane MAC in infants and children.  Anesthesiology. 1991;  75 186-190
    PubMedGoogle Scholar
  • 66 Nightingale D A. Use of atracurium in neonatal anaesthesia.  Brit J Anaesth. 1986;  58 32
    PubMedGoogle Scholar
  • 67 O'Kelley B, Fiset P, Meistelman C, Fossard J, Blaud B. Pharmacokinetics of rocuronium in pediatric patients during N2O-Halothane anesthesia.  Anesthesiology. 1992;  77 -907
    PubMedGoogle Scholar
  • 68 O'Kelley B, Fiset P, Meistelman C, Ecoffey C. Pharmacokinetics of rocuronium bromide in paediatric patients.  Eur J Anesth. 1994;  11 57-58
    PubMedGoogle Scholar
  • 69 Olkkola K T, Hamunen K, Maunuksela E L. Clinical pharmacokinetics and pharmacodynamics of opioid analgetics in infants and children.  Clin Pharmacokinet. 1995;  28 385-404
    CrossrefPubMedGoogle Scholar
  • 70 Payne A K, Morgan E S, Gandolfi A J, Brendel K. Biotransformation of sevoflurane by rat neonate liver slices.  Drug Metabol Dispos. 1995;  23 497-500
    PubMedGoogle Scholar
  • 71 Piat V, Dubois M C, Johanet S, Murat I. Induction and recovery characteristics and hemodynamic responses to sevoflurane and halothane in children.  Anaest. 1995;  74 46-49
    PubMedGoogle Scholar
  • 72 Raoof A A, van Obbergh L J, Verbecke R K. Propofol pharmacokinetics in children with biliary atresia.  Br J Anaesth. 1995;  74 46-49
    PubMedGoogle Scholar
  • 73 Sakai T, Mi W D, Ebina T, Kudo T, Kudo M, Matsuki A. Pharmacokinetics of propofol and ketamine during and after total intravenous anesthesia with propofol, fentanyl, and ketamine for pediatric patients.  Masui. 1998;  47 277-280
    PubMedGoogle Scholar
  • 74 Santeiro M L, Chistie J, Stromquist C, Torres B A, Markowsky S J. Pharmacokinetics of continuous infusion fentanyl in newborns.  J Perinatol. 1997;  17 135-139
    PubMedGoogle Scholar
  • 75 Sarner J B, Levine M, Davis P J, Lerman J. Clinical characteristics of sevoflurane in children.  Anesthesiology. 1995;  82 38-42
    PubMedGoogle Scholar
  • 76 Satas S, Johannessen S, Hoern N O, Haaland K, Sorensen D, Thoresen M. Lidocaine pharmacokinetics and toxicity in newborne pigs.  Anaesth Analg. 1997;  85 306-312
    PubMedGoogle Scholar
  • 77 Scheller M S, Saidman L J, Pardrige B L. MAC of sevoflurane in humans and new zealand rabbit.  Can J Anaesth. 1988;  35 153-156
    PubMedGoogle Scholar
  • 78 Schuetz R L, Beach D L, Guzelian P S. Selective expression of cytochrom P450 CYP3A mRNA in embryonic and adult human liver.  Pharmacogenetics. 1994;  4 11-20
    PubMedGoogle Scholar
  • 79 Shafer S L. Advances in propofol pharmacokinetics and pharmacodynamics.  J Clin Anesth. 1995;  5 145-215
    PubMedGoogle Scholar
  • 80 Singleton M A, Rosen J I, Fisher D M. Pharmacokinetics of fentanyl for infants and adults.  Anesthesiology. 1984;  61 -440
    PubMedGoogle Scholar
  • 81 Sorbo S, Hudson R J, Loomis J C. The pharmacokinetics of thiopental in pediatric surgical patients.  Anesthesiology. 1984;  61 666-670
    PubMedGoogle Scholar
  • 82 Stevens W C, Dolan W M, Gibbons R T. Minimum alveolar concentrations (MAC) of isofluran with and without nitrous oxide in patients of various ages.  Anesthesiology. 1975;  42 197-200
    PubMedGoogle Scholar
  • 83 Taivainen T, Tiainen P, Meretoja O A, Rosenberg P H. Comparison of the effects of sevoflurane and halothane on the quality of anesthesia and fluoride in pediatric patients.  Brit J Anaesth. 1994;  73 590-595
    PubMedGoogle Scholar
  • 84 Taivainen T, Meretoja O A, Erkola O, Rautoma P, Juvakoski M. Rocuronium in infants, children, and adults during belanced anaesthesia.  Paedr Anaest. 1996;  6 271-275
    PubMedGoogle Scholar
  • 85 Tassonyi E, Pittet J F, Schopfer C N, Rouge J C, Gemperle G. Pharmacokinetics of pipecuronium in infants, children and adults.  Eur J Drug Metab Pharmacokinet. 1995;  20 203-208
    PubMedGoogle Scholar
  • 86 Taylor R H, Lerman J. Minimal alveolar concentration of desflurane and hemodynamic responses in neonates, infants, and children.  Anesthesiology. 1991;  75 975-979
    PubMedGoogle Scholar
  • 87 Tucker G T. Pharmacokinetics of local anaesthetics.  Brit J Anaesth. 1986;  58 717-731
    PubMedGoogle Scholar
  • 88 Veroli P, O'Kelly B, Bertrand F, Trouvin J H, Farinotti R, Ecoffey C. Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation.  Brit J Anaesth. 1992;  68 183-186
    PubMedGoogle Scholar
  • 89 Weston P J, Bourchier D. The pharmacokinetics of bupivacaine following interpleural nerve block in infants of very low birthweight.  Paediatr Anaesth. 1995;  5 219-222
    PubMedGoogle Scholar
  • 90 Westrin P. The induction dose of propofol in infants 1 - 6 months of age and in children 10 - 16 years of age.   Anesthesiology. 1991;  74 455-458
    PubMedGoogle Scholar
  • 91 Wierda J M, Kleef U W, Lambalk L M, Kloppenburg W D, Agston S. The pharmacodynamics and pharmacokinetis of Org 9482, a new nondepolarizing neuromuscular blocking agent, in patients anesthetized with nitrous oxide, halothane and fentanyl.  Can J Anaesth. 1991;  75 140-145
    PubMedGoogle Scholar
  • 92 Wierda J M, Meretoja O A, Taivainen T, Proost J H. Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children.  Brit J Anaesth. 1997;  78 690-695
    PubMedGoogle Scholar
  • 93 Woelfel S K, Brandom B, McGowan F X, Cook D R. Clinical pharmacology of mivacurium in pediatric patients less than two years old during nitrous oxide-halothan anesthesia.  Anesth Analg. 1993;  77 713-720
    PubMedGoogle Scholar

Dr. A. Röper

Klinik für Anästhesie und operative Intensivmedizin Städtische Kliniken Bielefeld gem.GmbH

Teutoburger Straße 50

33604 Bielefeld

Email: roeper@sk-bielefeld.de

      >