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Anesthesia Neurotoxicity in Neonates: The Need for Clinical Research

Section Editor(s): Saidman, LawrenceDavidson, Andrew FANZCA, MBBS, MD; McCann, Mary Ellen MD, MPH; Morton, Neil MBChB, FRCA

doi: 10.1213/01.ane.0000269692.57331.48
Letters to the Editor: Letters & Announcements
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Department of Anaesthesia; Royal Children's Hospital; Melbourne, Australia; andrew.davidson@rch.org.au (Davidson)

Department of Anesthesia; Boston Children's Hospital; Boston, MA (Ellen McCann)

Hospital for Sick Children; Glasgow, UK (Morton)

The FDA does not wish to respond.

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To the Editor:

We agree with the comments in Mellon et al.'s (1) excellent review of the potential toxicity of anesthetic agents in neonates, that evidence is insufficient to recommend substantial changes in clinical practice. Mellon et al. present a thorough and laudable plan for primate experiments. As for clinical research, they comment that epidemiological studies are lacking and future epidemiological studies may be considered. We would like to draw the readers' attention to the several clinical studies already published.

Several human cohort studies have demonstrated an association between surgery in the neonatal period and poor neurodevelopmental outcome (2,3). Premature infants who underwent laparotomy had poorer neurodevelopmental outcome compared with matched controls (4), and children who are born with esophageal atresia have increased long-term learning, emotional and behavioral problems compared with the general population (5). A large cohort study by the Victorian Infant Collaborative Group found a clear association between surgery in preterm babies and poor sensorineural outcome at 5 yr of age (6). There is also a link between surgery for patent ductus arteriosus and outcome (7).

Many of these babies have other reasons for poor outcome apart from anesthesia, including the condition requiring surgery, coexisting malformations, prematurity, sepsis, cardiovascular instability or the inflammatory, and stress effects of major surgery itself. None of these studies provide evidence for an association between anesthesia per se and poor outcome.

While it is questionable if the animal evidence can be extrapolated to humans and existing human cohort data provides no clear link between anesthesia and outcome, the question is of sufficient concern to warrant further clinical investigation. Mellon et al. are correct that in any past or future cohort study confounding influences abound and the specific effect of anesthetic agents will remain very hard to discern. Fortuitously in many pediatric centers there are two established anesthesia techniques for infant hernia surgery: general anesthesia and awake regional anesthesia. Comparing outcome after regional and general anesthesia may be feasible in a large cohort study, or twin registries may be used (as a Scandinavian group are now doing); however, we believe that the choice between technique is sufficiently close to equipoise that a randomized trial is feasible, of no greater difficulty than a cohort study and will provide far stronger evidence than any cohort study. Such a trial has recently commenced. Several hundred infants will be enrolled in hospitals across UK, Australia, North America, and New Zealand. They will be randomized to general anesthesia or awake regional anesthesia and followed for 5 yr. With further animal data and cohort data, we believe this trial will be crucial in addressing the safety of general anesthesia in neonates.

Andrew Davidson, FANZCA, MBBS, MD

Department of Anaesthesia

Royal Children's Hospital

Melbourne, Australia

andrew.davidson@rch.org.au

Mary Ellen McCann, MD, MPH

Department of Anesthesia

Boston Children's Hospital

Boston, MA

Neil Morton, MBChB, FRCA

Hospital for Sick Children

Glasgow, UK

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REFERENCES

1. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007;104:509–20
2. Walker K, Holland AJ, Winlaw D, Sherwood M, Badawi N. Neurodevelopmental outcomes and surgery in neonates. J Paediatr Child Health 2006;42:749–51
3. Ludman L, Spitz L, Wade A. Educational attainments in early adolescence of infants who required major neonatal surgery. J Pediatr Surg 2001;36:858–62
4. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999;15:496–9
5. Bouman NH, Koot HM, Hazebroek FW. Long-term physical, psychological, and social functioning of children with esophageal atresia. J Pediatr Surg 1999;34:399–404
6. Surgery and the tiny baby: sensorineural outcome at 5 years of age. The Victorian Infant Collaborative Study Group. J Paediatr Child Health 1996;32:167–72
7. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A; Trial of Indomethacin Prophylaxis in Preterms Investigators. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr 2007;150:229–34, 234.e1
© 2007 International Anesthesia Research Society