Miscellaneous Articles

Defining Safe Use of Anesthesia in Children

Anesthetic agents are commonly used for a variety of medical procedures in infants and children, but little is known about their effects on the developing brain. A growing body of data from studies in animals suggests that under certain circumstances, such as prolonged anesthesia, these drugs could adversely affect neurologic, cognitive, and social development of neonates and young children. We believe that these findings should be of concern to the scientific and medical communities.

Over the past decade, studies in rodents have found that exposure to anesthetic agents during sensitive periods of brain development (i.e., the brain growth spurt) results in widespread neuronal apoptosis and functional deficits later in development. So far, agents that either antagonize N -methyl-D-aspartate (NMDA) receptors or potentiate the neurotransmission of γ-aminobutyric acid (GABAergic agents) have been implicated, and no safe doses of these agents or safe durations of administration have been defined.

More recent investigations in nonhuman primates have extended these findings. Studies conducted by the National Center for Toxicology Research (NCTR) of the Food and Drug Administration (FDA) have demonstrated that exposure to ketamine - the prototypical NMDA-receptor antagonist - resulted in increased neuronal cell death in nonhuman primates. Specifically, a dose of ketamine sufficient to produce a light surgical plane of anesthesia for either 9 or 24 hours resulted in neuroapoptosis in 5-day-old rhesus monkeys. No similar effect was seen when ketamine was administered for only 3 hours. Neuroapoptosis in the brain of the fetus was also evident when pregnant rhesus monkeys were exposed to ketamine for 24 hours on day 122 of gestation (equivalent to the third trimester of human pregnancy), but no neuroapoptosis was noted following administration of ketamine on postnatal day 35.1 Neuroapoptosis has also been demonstrated in primates who were given isoflurane (predominantly a GABAergic agent) on postnatal day 6.2

Although the functional consequences of these histopathologic changes can only be inferred at this time, the FDA and others are currently conducting studies in animals to address the neurocognitive and neurobehavioral effects of anesthetic-induced apoptosis. At the NCTR, the FDA is using a so-called operant test battery to evaluate the cognitive function of rhesus monkeys exposed to a dose of ketamine sufficient to produce a light surgical plane of anesthesia for 24 hours on postnatal day 5 or 6. This battery consists of a number of tasks that evaluate short-term memory and attention, learning, time perception, motivation, and color and position discrimination. The results to date indicate that, as compared with controls, ketamine-treated animals have lower training scores - and continue to score lower than controls for at least 10 months after the administration of ketamine.3 Similar studies of isoflurane in primates are ongoing.

Nonhuman primates are believed to offer the most appropriate model for assessing neurodevelopmental risk to humans; however, such cognitive testing in primates is expensive and requires many years to complete. Therefore, limited data exist to date. More rapid progress can be made using rodent models. Additional data from animal studies may help to define the window of vulnerability and the extent of anesthesia-induced neuronal alterations and provide insights both into the functional end points that should be assessed in clinical studies and into ways of blocking or ameliorating potential adverse effects. It is not known how the data from rodents or primates translate to humans, but such findings raise questions that require further scientific investigation.

Studies in children have attempted to assess the effects of anesthetics on the developing human brain. For instance, a retrospective cohort analysis followed a birth cohort of 383 children who underwent inguinal hernia repair during the first 3 years of life and compared them with 5050 children in a control sample who had undergone no hernia repair before the age of 3.4 The children who underwent hernia repair were twice as likely as those who did not to be given a diagnosis of a developmental or behavioral disorder (adjusted hazard ratio, 2.3; 95% confidence interval [CI], 1.3 to 4.1). A population-based, retrospective, birth-cohort study examined the educational and medical records of children who were exposed to a single anesthetic (n=449), two anesthetics (n=100), or more (n=44). In contrast to the hernia-repair study, this study reported no increased risk of learning disabilities with a single anesthetic (hazard ratio, 1.0; 95% CI, 0.79 to 1.27). However, an increasing risk of learning disabilities was associated with two or more anesthetics (hazard ratio, 1.59; 95% CI, 1.06 to 2.37; and hazard ratio, 2.60; 95% CI, 1.60 to 4.24, respectively). The risk of learning disabilities also increased with greater cumulative exposure to anesthesia.5

No conclusions about causality can be drawn on the basis of these nonrandomized studies in humans because of the substantial potential for confounding. Indeed, there are conflicting findings between the two cited studies regarding a single exposure to anesthetics. It is not possible to discern from the published study reports whether or how differences in surgical procedures, anesthetic drugs, patient monitoring, or anesthesia techniques affected the outcomes. It is possible that the children undergoing surgery also differed from the non-exposed children in ways that were not discernible. At present, there is not enough information to draw any firm conclusions regarding an association between anesthetic exposure and subsequent learning disabilities, and additional studies such as those that are ongoing (see box) are warranted.

Ongoing Clinical Trials Assessing the Effects of Anesthetics on Neurocognitive Development.

Generating definitive data about the effects of anesthetics on the developing brain will most likely take numerous animal and human studies spanning many years. Planning, conducting, and interpreting these studies will pose enormous challenges to the medical and scientific community. It seems unlikely that any single individual or organization will be able to muster the resources to take on this project.

The FDA is continuing efforts to address the pediatric safety of anesthetics. On March 29, 2007, the FDA's Anesthetic and Life Support Drugs Advisory Committee met to discuss the data from animal studies suggesting that exposure to anesthetic agents during the period of rapid brain growth produces widespread neuronal apoptosis with possible long-term functional consequences. The committee members agreed that additional research was essential to understanding the implications of the animal data for children who must be exposed to anesthetic and sedative drugs for necessary medical procedures. They also concluded that there was insufficient information to warrant changing the practice of pediatric anesthesia, other than to forgo elective procedures in children less than 3 years of age. Since that time, numerous nonclinical and clinical studies have been undertaken (and published) in an attempt to further understand this challenging issue; therefore, a second advisory committee meeting on this issue is scheduled for March 10, 2011. The committee will evaluate the weight of existing scientific evidence and discuss the research agenda and potential risk-communication issues.

As part of its Critical Path Initiative, the FDA has entered into a public-private partnership with the International Anesthesia Research Society (IARS) called SmartTots (Strategies for Mitigating Anesthesia-Related Neuro-Toxicity in Tots). This partnership will seek to mobilize the scientific community, stimulate dialogue among thought leaders in the anesthesia community, and work to raise funding for the necessary research.

But these activities are just the first step. We need to definitively answer the questions of whether anesthetic use in children poses a risk to their development and, if so, under what circumstances. Although withholding anesthesia from children who need surgery is unreasonable, obtaining more information about safe use is imperative. If anesthetic agents are found, in certain cases, to affect the developing brain, strategies for mitigating and managing such risks can be implemented. The FDA is committed to pursuing these answers with the medical and scientific communities and will take the steps necessary to ensure that the benefits of anesthetic use in children continue to outweigh any potential risks.

NEJM | March 9, 2011 | Topics: Drugs, Devices, and the FDA

Bob Rappaport, M.D., R. Daniel Mellon, Ph.D., Arthur Simone, M.D., Ph.D., and Janet Woodcock, M.D.

This article (10.1056/NEJMp1102155) was published on March 9, 2011, at NEJM.org.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the Division of Anesthesia and Analgesia Products, Office of New Drugs (B.R., R.D.M., A.S.) and the Center for Drug Evaluation and Research (J.W.), Food and Drug Administration, Silver Spring, MD.

References

1. Slikker W, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007;98:145-158
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2. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010;112:834-841
CrossRef | Web of Science | Medline

3. Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011 January 15 (Epub ahead of print).

4. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol 2009;21:286-291
CrossRef | Web of Science | Medline

5. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009;110:796-804
CrossRef | Web of Science | Medline