The Relevance of Anesthetic Drug-Induced Neurotoxicity (original) (raw)

Preclinical studies 1-3 in young animals have demonstrated neurodegeneration and subsequent neurocognitive impairment for virtually all clinically available general anesthetic drugs. However, comparative human studies on this issue are scarce and inconclusive. Several reasons account for this discrepancy. First, preclinical animal studies were never driven by a clinical suspicion of neurocognitive deficits associated with exposure to anesthetic drugs in early life. There is no welldefined and specific longterm phenotype associated with exposure to anesthetic drugs. The first preclinical investigations were extrapolated from findings related to fetal alcohol syndrome and long-term fetal exposure to antiepileptic drugs. 3 An a priori expectation that anesthetic drugs also would be neurodegenerative in comparable experimental settings was based on the putative (but unknown) mechanisms of actions of anesthetics. 3 A large number of studies, reviews, and commentaries have since been published as a result. 4,5 There are many challenges that need to be overcome when translating animal studies into a human context. 3,6 If exposure to anesthetic drugs was indeed as harmful in early human life as hypothesized, 4,5 this effect would most likely have been suspected many years ago. Some observational cohort studies 7-9 have demonstrated an association between negative long-term neurocognitive outcomes in young children exposed to anesthesia (and surgery), perpetuating any anxiety. Most of these observational investigations are from single centers (prone to selection bias) reporting on small sample sizes with large age ranges (and very few neonates and infants) and a multitude of surgical procedures. Inconsistent outcome measures confuse the public and professionals alike, resulting in a failure to demonstrate a human corollary to this animal phenomenon. However, what constitutes a meaningful human outcome measure? What is important for the child, the parent, and the public interest? The most commonly reported neurocognitive outcome measures in humans are IQ, learning disabilities, academic performance, neuropsychiatric disorders (autism and attentiondeficit/hyperactivity disorder), and individual neuropsychological test results (eg, Bayley and Wechsler scores). 3 All of these outcome measures have limitations. A global neurocognitive decline (affecting IQ, learning disabilities, and attention-deficit/ hyperactivity disorder) may be the consequence of an indiscriminate effect of anesthetic drugs. If specific brain areas are damaged during susceptible developmental times, the relevant neurological outcome may be subtle (eg, reading, speak