Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. 692-693 (doi:10.1542/peds.2007-1937)

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LETTER TO THE EDITOR

Timing of Dose-Finding Studies: Before or After Completion of a Randomized Clinical Trial?: In Reply

Mohamed E. Abdel-Latif, MBBS, MRCPCH, MPH, MscEpi¹
Kei Lui, MBBS, FRACP, MD^1
1 Department of Newborn Care
Royal Hospital for Women
Randwick, New South Wales 2031, Australia
School of Women's and Children's Health
University of New South Wales
Kensington, New South Wales 2032, Australia

John Awad, MBBS, FANZCA, FJFICM^2
2 Department of Paediatric Intensive Care
Sydney Children Hospital
Randwick, New South Wales 2031, Australia

Satish Ghanta, MBBS, MD^3
3 Department of Newborn Care
Royal Hospital for Women
Randwick, New South Wales 2031, Australia

Julee Oei, MBBS, FRACP^4
4 Department of Newborn Care
Royal Hospital for Women
Randwick, New South Wales 2031, Australia
School of Women's and Children's Health
University of New South Wales
Kensington, New South Wales 2032, Australia

We acknowledge the comments by van den Anker concerning our clinical trial on propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation,¹ and we are grateful for the opportunity to respond to his questions. van den Anker questions the rationale behind our dose of 2.5 mg/kg and how a clinical trial was conducted without previous information on the pharmacokinetics of propofol in neonates. We agree that there is a need for more neonatal pharmacokinetics studies on propofol, but we think that there is a reasonable existing body of evidence on propofol pharmacokinetics on pregnant women and their newborns^2–4 and children⁵ to warrant conduction of randomized, controlled trials. Dailland et al,² Gin et al,⁶ and others^3,4 have reported on placental transfer, breast milk concentrations, and early neonatal effects of propofol, and these studies suggested that propofol seems to be safe for the newborn infant.

We agree that glucuronidation plays a major role in the metabolism of propofol, but this mechanism is more important when repeated doses (eg, in the case of chloramphenicol mentioned by van den Anker) or infusions are considered. The dose of 2 to 3 mg/kg has been used in children in other studies,⁷ and in our trial, in which we evaluated the clinical efficacy of propofol as a single-dose induction agent in endotracheal intubation, we found that 24% (8 of 33) of our study infants required a second dose to achieve hypnosis. This first "fail" rate was not different from that of the control regimen (23% [7 of 30]). We, however, did not encounter any major complications, although our trial was not powered to detect adverse effects. The recovery phase from propofol was relatively short and, indeed, shorter than that of the suxamethonium regimen. We emphasize that our experience should not be extrapolated to repeated courses or infusion of propofol, for which detailed drug-elimination kinetic studies are most important.

van den Anker also raises the very important point that clinical researchers and pediatric clinical pharmacologists should join forces to establish multidisciplinary teams to design and conduct safe and effective studies with medicines in the neonatal population. We agree and believe that such partnerships, indeed, will advance evidence-based practices in neonatal intensive care.

Finally, we believe that premedication for endotracheal intubation is a major advance in neonatology but, like other steps forward, is inevitably accompanied by a steep learning curve underwritten by patient safety.

REFERENCES

1. Ghanta S, Abdel-Latif ME, Lui K, Ravindranathan H, Awad J, Oei J. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Pediatrics. 2007;119(6) . Available at: www.pediatrics.org/cgi/content/full/119/6/e1248
2. Dailland P, Cockshott ID, Lirzin JD, et al. Intravenous propofol during cesarean section: placental transfer, concentrations in breast milk, and neonatal effects—a preliminary study. Anesthesiology. 1989;71 :827 –834[CrossRef][Web of Science][Medline]
3. 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 :1393 –1400[CrossRef][Web of Science][Medline]
4. Cortambert F, Marti-Flich J, Dasset MP, Mullet C. The pharmacokinetics of propofol used in cesarean section: a preliminary study in the newborn infant [in French]. Cah Anesthesiol. 1989;37 :33 –37[Medline]
5. Rigby-Jones A, Priston M, Wolf A, Sneyd J. Paediatric propofol pharmacokinetics: a multicentre study. Paediatr Anaesth. 2007;17 :610
6. Gin T, Gregory MA, Chan K, Oh TE. Maternal and fetal levels of propofol at caesarean section. Anaesth Intensive Care. 1990;18 :180 –184[Web of Science][Medline]
7. 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 :667 –670[Abstract/Free Full Text]

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Abdel-Latif, M. E. Articles by Oei, J. Search for Related Content PubMed Articles by Abdel-Latif, M. E. Articles by Oei, J. Related Collections Respiratory Tract Social Bookmarking                         What's this?