A Users' Guide to Interpreting Observational Studies of Pediatric Anesthetic Neurotoxicity

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At a meeting of the Royal Society of Medicine in 1965, Sir Bradford Hill proposed to answer the question he himself posed to the assembled audience: “How do we determine what are physical, chemical and psychologic hazards of occupation and in particular those that are rare and not easily recognized?”1 Although the question Hill proposed was directed at problems of occupational medicine, the article subsequently published from this lecture has become the sentinel guide for the assessment of causation in epidemiologic research. Since the publication of the paper, more than a decade ago, in Science by Ikonomidou,2 there has been a steady stream of work convincingly demonstrating that anesthetic agents and other drugs that act as N-methyl-D-aspartate agonists and γ-aminobutyric acid antagonists can produce widespread apoptotic neurodegeneration, with associated cognitive and behavioral decrements in a variety of animal species, including nonhuman primates. Predictably, these studies have prompted a great deal of concern. They have also generated a series of observational studies seeking evidence for similar effects in children, with varying results.3– 8 The study by Block et al. in this month’s issue of Anesthesiology9 is yet another examination of the association between exposure to anesthesia in young children and outcome, in this case performance on a test of academic achievement. The central concern of those who provide anesthesia to children is that of causation: Does anesthetic exposure at a young age cause neurodevelopmental problems? In the hierarchy of study designs, the randomized control trial reigns as the gold standard. Unfortunately, such studies are expensive, time-consuming, and, in this area, may be ethically impossible. An ongoing randomized clinical trial comparing regional and general anesthesia for infants receiving inguinal herniorraphy will be valuable, but in the meantime, the anesthesia community is left to make judgments regarding the potential applicability of animal findings to children based on a growing number of retrospective observational studies. These studies provide insight, but how should they be interpreted? For example, in studies that find an association between anesthesia and subsequent neurodevelopmental problems, is anesthesia merely a marker for another causative factor (e.g., the stress of a surgical procedure, or the underlying condition which makes surgery necessary)? We here present a “users’ guide” of several questions that should be considered when interpreting observational studies of the association between anesthetic exposure and neurodevelopmental or other outcomes. This discussion is by no means exhaustive, but is meant to alert consumers of literature in this area regarding some of the potential strengths and weaknesses of available and to-be-published studies. This guide should not be seen as criticism of Block et al. or others authors who have contributed to this body of work. Indeed, as nicely typified by Block et al., most authors spend a great deal of time injecting caution into the discourse and highlighting study limitations.