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ARTICLES: Satish Ghanta, Mohamed E. Abdel-Latif, Kei Lui, Hari Ravindranathan, John Awad, and Julee Oei Propofol Compared With the Morphine, Atropine, and Suxamethonium Regimen as Induction Agents for Neonatal Endotracheal Intubation: A Randomized, Controlled Trial Pediatrics 2007; 119: e1248-e1255 [Abstract] [Full text] [PDF]

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Further studies needed to establish safety profile

Santanu Sen   (17 June 2007)

propofol disposition in neonates: interindividual variability is to be anticipated

karel allegaert   (5 July 2007)

Further studies needed to establish safety profile 17 June 2007
Santanu Sen, Specialist Registrar in Paediatrics Mayday University Hospital, Croydon, London, UK. Send letter to journal: Re: Further studies needed to establish safety profile Santanu.Sen{at}gmail.com Santanu Sen	It was fascinating to read Ghanta etal's (1) article on the use of propofol in premedication before neonatal intubation. Propofol is being increasingly used in the paediatric age group especially for short anaesthetic procedures such as endoscopy. Its’ use has already been established in paediatric intensive care units where it is routinely used for premedication before elective intubations. With its pharmacological properties of short half life preservation of spontaneous respiration, it is interesting to see an extension of its role on the neonatal intensive care units. This is even more relevant as use of premedication in the neonatal units is still not universal. The French data (2) suggests that premedication is used in 74% of cases in their neonatal units but only in 21% in the delivery rooms. Current data from USA (3) suggest that only 43% of units use premedication with a written policy in place in only 24% of units. The ideal premedication for neonatal intubation is yet not established and the current paper makes a valuable addition to the drug combinations that are currently used. Aranda etal (4) published their efforts at a systematic analysis of trials looking at analgesia and sedation during intubation in neonates. Trials comparing fentanyl with morphine were inconclusive because of small sample sizes, though meta- analyses indicated that both morphine and fentanyl can reduces stress responses as expected. Midazolam compared with placebo has significant adverse effects (P < 0.05) with no apparent clinical benefit. Though morphine is at present widely used for premedication in neonatal units, probably is not drug of first choice and this is also the conclusion of Bryne et al (5) in their review due to the variable pharmacokinetics and pharmacodynamics of the drug in neonates. In fact one randomised trial (6) showed that it had no benefit in reducing the physiological instability or time needed to perform elective intubations and suggested that alternatives with more rapid onset of action should be considered. Fentanyl certainly is widely used (7) in this regard and also use of mivacurium in place of suxamethonium also seems to be increasing in popularity. Use of multiple drugs including controlled drugs such as morphine is cumbersome needing added ursing time for preparation and documentation. In a busy neonatal unit the ideal premedication should be one that is readily available, quick to prepare, easy to administer with a good safety profile. We agree with the authors that as a single agent propofol seems to be a good candidate for this role. However there is a need for further larger studies to establish its safety profile in a neonatal age group before using it widely in this fragile population subgroup. References 1 Satish Ghanta, Mohamed E. Abdel-Latif, Kei Lui, Hari Ravindranathan, John Awad, and Julee Oei. Propofol Compared With the Morphine, Atropine, and Suxamethonium Regimen as Induction Agents for Neonatal Endotracheal Intubation: A Randomized, Controlled Trial. Pediatrics 2007; 119: e1248-e1255 2 Walter-Nicolet E, Flamant C, Negrea M, Parat S, Hubert P, Mitanchez D. Premedication before tracheal intubation in French neonatal intensive care units and delivery rooms Arch Pediatr. 2007 Feb;14(2):144-9. Epub 2006 Dec 18. 3 Sarkar S, Schumacher RE, Baumgart S, Donn SM.Are newborns receiving premedication before elective intubation? J Perinatol. 2006 May;26(5):286- 9. 4 Aranda JV, Carlo W, Hummel P, Thomas R, Lehr VT, Anand KJ. Analgesia and sedation during mechanical ventilation in neonates. Clin Ther. 2005 Jun;27(6):877-99. 5 E Byrne, R MacKinnon. Should premedication be used for semi-urgent or elective intubation in neonates? Arch Dis Child. 2006 Jan;91(1):79-83. 6 Lemyre B, Doucette J, Kalyn A, Gray S, Marrin ML. Morphine for elective endotracheal intubation in neonates: a randomized trial BMC Pediatr. 2004 Oct 5;4:20. 7 Whyte S, Birrell G, Wyllie J. Premedication before intubation in UK neonatal units Arch Dis Child Fetal Neonatal Ed 2000;82:F38-F41 ( January ) Conflict of Interest: None declared
propofol disposition in neonates: interindividual variability is to be anticipated 5 July 2007
karel allegaert, MD, PhD NICU Gasthuisberg, University Hospitals, Leuven, Belgium Send letter to journal: Re: propofol disposition in neonates: interindividual variability is to be anticipated karel.allegaert{at}uz.kuleuven.ac.be karel allegaert	We would like to congratulate Ghanta et al. with the recently published randomized controlled trial on propofol versus morphine/atropine/suxamethonium as induction agents for endotracheal intubation in neonates. There are indeed various papers and guidelines on different combinations of premedication regimes used in the neonatal intensive care units to facilitate endotracheal intubation in neonates. Short acting agents like propofol, remifentanil or inhalational agents hereby might have the additional advantage that the balance between sedation during endotracheal intubation and subsequent recovery rate might be more appropriated, especially if the trend towards intubation - surfactant administration – extubation is taken into account. Propofol might therefore become an important tool for short term sedation in neonates. However, we would like to drawn the attention of the authors and readers to some specific aspects of propofol disposition in early neonatal life. We only very recently reported on time-concentrations profiles of propofol in 9 neonates following intravenous bolus administration (3 mg/kg, Diprivan) and compared these findings with earlier reported observations in toddlers and children. In its essence, two important observations were made. Firstly, median propofol clearance in neonates (13.6 ml/kg/min) was significantly lower compared to toddlers (43 ml/kg/min) or children (28 ml/kg/min). Secondly, there was a large interindividual variability in propofol clearance in neonates (median 13.6, range 3.7 – 78 ml/kg/min) (3). The first observation is in line with most of the drugs administered in neonates and merely reflects the general principles of developmental pharmacology. The second observation is more difficult to implement in dose-suggestions for propofol in neonates (4,5). The marked interindividual variability of propofol clearance might in part reflect the maturation of metabolic clearance (cytochrome and glucuronidation). One has to be aware that a lipophylic compound needs metabolic clearance before renal elimination and while cytochrome ontogeny in most studies depends on postmenstrual age, ontogeny of glucuronidation mainly depends on postnatal age (4,5). More studies to unveil the covariates of propofol clearance in neonates are therefore needed before dose suggestions and/or recommendations can be formulated. We therefore - in addition to the advice of the authors to assess the short- and long term safety of propofol in neonates (pharmacodynamics) - would strongly recommend to collect observations on both pharmacokinetics and –dynamics of this drug. Until this additional information is available, we recommend to use this drug cautiously in neonates. References 1.Ghanta S, Abdel-Latif ME, Lui K, Ravindranathan H, Awas 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: e1248-55. 2.Silva YP, Renato Santiago Gomez RS , Marcatto J, et al. Morphine versus remifentanil for intubating preterm neonates. Arch Dis Child Fetal Neonatal Ed 2007; 92: F293-F294 3.Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I. Maturational pharmacokinetics of single intravenous bolus administration of propofol. Pediatr Anesth (in press). 4.Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology -- drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157-1167. 5.Rakhmanina NY, van den Anker JN. Pharmacological research in pediatrics: from neonates to adolescents. Adv Drug Deliv Rev 2006; 58: 4-14. Conflict of Interest: None declared

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