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PEDIATRIC ANESTHESIA

Use of Anesthetic Agents in Neonates and Young Children

From the Division of Anesthesia, Analgesia, and Rheumatology Products, Office of Drug Evaluation II, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, Silver Spring, Maryland.

Address correspondence and reprint requests to Bob A. Rappaport, MD, Division of Anesthesia, Analgesia, and Rheumatology Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993.

	Abstract

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BACKGROUND: Some drugs used for sedation and anesthesia produce histopathologic central nervous system changes in juvenile animal models. These observations have raised concerns regarding the use of these drugs in pediatric patients. We summarized the findings in developing animals and describe the steps that the Food and Drug Administration (FDA) and others are taking to assess potential risks in pediatric patients. The FDA views this communication as opening a dialog with the anesthesia community to address this issue.

METHODS: We reviewed the available animal studies literature examining the potential neurotoxic effects of commonly used anesthetic drugs on the developing brain. The search strategy involved crossing the keywords neurotoxic and neuroapoptosis with the following general and specific terms: anesthetic, N-methyl-d-aspartate (NMDA), ketamine, midazolam, lorazepam, fentanyl, methadone, morphine, meperidine, isoflurane, nitrous oxide, sevoflurane, halothane, enflurane, desflurane, propofol, etomidate, barbiturate, methoxyflurane, and chloral hydrate. We summarized several studies sponsored by the FDA in rats and monkeys, initially examining the potential for ketamine, as a prototypical agent, to induce neurodegeneration in the developing brain.

RESULTS: Numerous animal studies in rodents indicate that NMDA receptor antagonists, including ketamine, induce neurodegeneration in the developing brain. The effects of ketamine are dose dependent. The data suggest that limiting exposure limits the potential for neurodegeneration. There is also evidence that other general anesthetics, such as isoflurane, can induce neurodegeneration in rodent models, which may be exacerbated by concurrent administration of midazolam or nitrous oxide. There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models. However, the studies that have been reported suggest subtle, but prolonged, behavioral changes in rodents. Although the doses and durations of ketamine exposure that resulted in neurodegeneration were slightly larger than those used in the clinical setting, those associated with isoflurane were not. There are insufficient human data to either support or refute the clinical applicability of these findings.

CONCLUSIONS: Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long-term risk of anesthetics in neonatal and young pediatric patients. The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate -aminobutyric acid signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems or that can induce more or less neurotoxicity is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components. The lack of information to date precludes the ability to designate any one anesthetic agent or regimen as safer than any other. Ongoing studies in juvenile animals should provide additional information regarding the risks. The FDA anticipates working with the anesthesia community and pharmaceutical industry to develop strategies for further assessing the safety of anesthetics in neonates and young children, and for providing data to guide clinicians in making the most informed decisions possible when choosing anesthetic regimens for their pediatric patients.

	Introduction

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Drugs used for sedation and anesthesia, when given to juvenile rodents, produce histopathologic central nervous system (CNS) changes (1–7) that have been correlated with alterations in behavior (6,8). These observations have raised concerns about whether the findings are relevant to the use of these drugs in pediatric patients. In this article, we summarize the findings noted in developing animals, identify drugs that may produce these results, describe steps that the Food and Drug Administration (FDA) and others have taken to address the potential risks of using these drugs in pediatric patients, discuss the limitations of the nonclinical data obtained to date, outline the Agency’s proposed plan to further delineate the potential clinical significance of the findings, and invite the anesthesia community’s input to provide appropriate guidance for clinical use of these drugs.

Sedation and anesthesia drug products have been used for years in pediatric patients without clinical evidence of their producing CNS sequelae. However, adverse effects related to CNS function in pediatric populations may be difficult, if not impossible, to detect. For example, despite animal evidence suggesting the possibility that the combination of isoflurane, midazolam, and nitrous oxide may adversely affect a child’s neurological function, publication of epidemiological studies evaluating the risk have been conspicuously absent from the literature.

Drugs that act as N-methyl-d-aspartate (NMDA) receptor antagonists, exemplified by ketamine, and those that act in an agonistic manner at the -aminobutyric acid (GABA) receptor (a.k.a. GABA-mimetics), such as benzodiazepines, induce neuronal injury and death in the brains of juvenile rodents. Drugs that exert their effects at one or both of these receptors include the entire classes of barbiturates, benzodiazepines, and inhaled anesthetics, as well as chloral hydrate, etomidate, propofol, ketamine, and nitrous oxide. Not all of these drugs have been approved for pediatric use, but they are widely used in this patient population. Indeed, ketamine, the most studied of these drugs, is not approved in the United States for patients <16 yr of age. Chloral hydrate has not been approved for anesthetic use in the United States in patients of any age. Table 1 identifies the activity at these receptors for commonly used anesthetics in pediatric practice. Although activity at these receptors does not necessarily imply mechanism of anesthetic action, it does imply a possible risk of neuronal injury or death. In addition, for some drugs, data in the published literature report contradictory receptor activity that may be explained by differences among species, the age of development, or the brain tissue studied. Finally, the inhaled anesthetics can differ significantly in their ability to inhibit the NMDA receptor (11). Likewise, the concentrations at which opioids have been shown to inhibit the NMDA receptors in vitro are relatively high, and also vary among opioids. Methadone blocks NMDA receptors at clinically relevant concentrations (12–14). Anesthetic drugs are also capable of interacting with a variety of other neuronal systems, including GABAergic systems, or interact with a variety of other receptors, including glycine receptors, nicotinic-acetylcholine receptors, serotonergic receptors, and other glutamatergic receptors (9,10,15). The potential clinical significance of these interactions remains to be determined.

The potential effect of NMDA-receptor antagonists on the developing brain was initially focused on the potential use of these compounds to prevent hypoxic/ ischemic brain damage. MK-801, a potent NMDA-receptor antagonist, was shown to prevent neuronal degeneration, presumably by blocking glutamate-induced excitotoxicity (16–21). Subsequent studies, however, suggested that NMDA-receptor antagonists can also have direct neurotoxic effects on the developing brain.

In this paper, we describe what is known about neuronal injury related to NMDA-receptor antagonism and use of GABA-mimetic drugs, provide information on the studies being conducted by the FDA to further investigate this issue, and outline tentative plans for future studies. This paper serves an additional purpose to updating the anesthesia community on the FDA’s concerns about this issue. It is an invitation to dialogue with the FDA, including a solicitation for input from the anesthesia community on the types of information that will be most clinically relevant and the design of future studies. We also hope the anesthesia community will assist in the conduct of clinical studies to help understand the risk of neurotoxicity from sedatives and anesthetics in neonates and young children.

	WHAT IS CURRENTLY KNOWN

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This section provides a detailed summary of the animal studies conducted that evaluated the effects of NMDA-receptor antagonism and use of GABA-mimetic drugs on the developing brain. It should be noted that, frequently, the dosing paradigms used do not correlate directly with those used for pediatric patients. Often the doses and durations of exposure used in the animal studies exceed those used clinically, sometimes substantially. This is an important observation and a key component to preclinical research. Once a toxic dose and effect have been identified, it is possible to evaluate lower doses and durations to determine an exposure level associated with no adverse events (NOAEL), which can than be compared to clinically used dosing paradigms to establish the existence, or lack thereof, of a safety margin. This approach is used for drug development and is an important component of the approval process at the FDA.

Much of the discussion that follows is based on experimentation done with ketamine. This is due, in part, to the use of ketamine in the early studies and to the volume of preclinical experimental work performed with this drug. Our focus on ketamine should not be construed as implying that the risk of neurodegeneration with ketamine is greater, or less, than with other anesthetics. We are simply starting where we have the most preclinical data.

The first reported nonclinical study to indicate that NMDA-receptor antagonist administration during the early stages of CNS development could produce neurotoxicity was published in 1999 (1). Studies in 7-day-old rat pups demonstrated that the potent NMDA-receptor antagonist MK-801, when administered at 0.5 mg/kg intraperitoneally, three times at 8-h intervals, led to widespread apoptotic neurodegeneration in the developing rat brain, as determined by the TUNEL assay (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) and silver staining. This study also tested the acute effects of other NMDA-receptor antagonists, including ketamine. Ketamine was administered "in a series of seven injections spaced evenly over 9 h, each injection delivering a dose of 20 mg/kg, s.c." Twenty-four hours after the first ketamine injection, the animals demonstrated the same pattern of cell degeneration as noted with MK-801, suggesting that under these conditions of administration, ketamine also produces widespread apoptotic neurodegeneration in the developing rat brain. This same publication reported developmental studies in which MK-801 was administered to rat pups of different ages to determine the effect of age on neuronal sensitivity to MK-801. The results indicated sensitivity to MK-801-induced neuronal apoptosis was high, compared with placebo, both at birth and postnatal day 3. The extent of apoptosis increased from postnatal day 3 through postnatal day 7, then decreased sharply between postnatal day 7 and postnatal day 14. By postnatal day 21, the numbers of apoptotic neurons were very low in MK-801-treated rats. The rat fetus also shows sensitivity to MK-801-induced neuronal apoptosis beginning between embryonic days 17 and 19 and continuing through birth. The period of sensitivity in the rat appears to be correlated to some extent with the peak expression of the NR1 subunit of the NMDA-receptor in the developing rat brain.

These data suggest that the rat is most sensitive to NMDA-receptor mediated neurotoxicity during early neuronal pathway development, referred to as the "brain-growth spurt period" or period of synaptogenesis. This period of sensitivity correlates with the expression of NMDA receptors of a particular structural composition during that time period (22). Blockade of NMDA receptors during this period appears to produce widespread neuronal apoptosis in central structures. The apoptotic neurodegeneration noted above refers to active, metabolic, programmed cell death, which is initiated by the nuclei of normally functioning cells when age or state of cell health and condition dictates. This is in contrast to necrotic neurodegeneration, which is defined as cell death caused by the progressive degradative action of enzymes.

Although the findings reported by Ikonomidou et al. in 1999 (1) raised concerns about the safe use of ketamine in neonates and young children, without serum drug levels or levels of anesthesia associated with apoptosis in animals, it was difficult to determine whether there is an appropriate safety margin based on pharmacokinetics or pharmacodynamics for these drugs when given to pediatric patients. It was also, and remains, difficult to determine the potential clinical significance of this discovery, if indeed these animal findings are occurring at clinically relevant concentrations. This has resulted in an FDA-wide Expert Working Group to review the issue. To resolve the issue of human safety, a preliminary study was initiated by the Center for Drug Evaluation and Research (CDER) (Division of Applied Pharmacology Research) that confirmed earlier reports of ketamine-induced apoptosis in 7-day-old rats. This led to a subsequent collaborative effort undertaken by CDER and the National Center for Toxicological Research (NCTR) that expanded on the original study. The goals of the NCTR-CDER study were to confirm and elaborate on the original findings reported by Ikonomidou et al. and to examine the effects of smaller doses of ketamine and shorter durations of treatment with the drug. Scallet et al. (23) confirmed histologically that the ketamine dosing regimen used by Ikonomidou et al. did result in increased neuronal degeneration in 7-day-old rat pups. In contrast to the findings with seven subcutaneous (SC) doses of 20 mg/kg of ketamine, exposure to 10 mg/kg ketamine via the same route and frequency of administration did not increase neuronal degeneration. Likewise, a single SC injection of 20 mg/kg of ketamine also did not increase neuronal degeneration. These data suggest that the reported ketamine-induced developmental neurotoxicity in the rat pup is dependent upon the dose administered and the duration of exposure. Additionally, this study established the relationship between the documented blood levels of ketamine and the extent of neurotoxicity associated with different treatment regimens. The mean concentrations of ketamine in the 7-day-old rat pups are presented in Table 2.

Although a safety margin could be estimated for ketamine based on the rat toxicology data, there are difficulties extrapolating these animal data to the clinical setting. One of the more important extrapolations of risk from animals to humans is the determination of which age groups are most at risk. The period of synaptogenesis during which rodents appear to be most vulnerable to the anesthetic-associated neurodegeneration corresponds to human development that occurs approximately from the third trimester in utero through approximately the third year of life (24); however these cutoffs are only estimates. In addition, there is a second period of accelerated synaptogenesis that occurs during adolescence, and there is some evidence suggesting an increased neurological vulnerability to the effects of alcohol and certain drugs used recreationally during this time period (25). The implications of this observation for the use of anesthetics is even less clear than they are for the younger pediatric population, but concern for this age group should not be rejected at this time.

An additional concern for extrapolating the animal findings to humans is that the neuroapoptosis noted in the rodent model is not a reversible toxicity, and it is not clear how these animal histological findings could be detected or monitored in a clinical setting. Most pediatric surgical procedures are not elective, that is, they cannot be postponed indefinitely without incurring some degree of risk. Clearly it is unacceptable not to provide anesthesia for these surgical procedures.

To address these challenges, it was determined that studies in nonhuman primates would likely provide the best assessment of the potential for ketamine to produce widespread neuroapoptosis in humans. The nonhuman primate model was chosen to investigate the relevance of these findings because human studies are not possible, and the nonhuman primate is more like the human in terms of neuronal cytoarchitecture and development (22). It is the general consensus of the scientific community that nonhuman primate studies are the most definitive means to obtain critical information necessary to adequately address the concerns raised by the rodent studies in the most expedited manner. Due to limitations regarding resources and funds for such extensive laboratory studies, CDER and NCTR nominated ketamine to the National Toxicology Program for study (unanimously approved, but not funded), and then, with the help of other government organizations, initiated studies in nonhuman primates to determine susceptibility to ketamine-induced neurotoxicity during the period of synaptogenesis. Due to the inherent complexity of establishing a breeding colony of ketamine-naïve monkeys, and the longer gestational period and reduced number of offspring in nonhuman primates, data from these studies have been outpaced by rodent data being generated outside the Agency.

As the primate studies were in development, additional data were being generated in several academic laboratories. Table 3 summarizes several key studies that have been reported in the literature. Because numerous anesthetics function as NMDA antagonists, other anesthetics and combinations of anesthetics have been evaluated for their potential to produce neurodegeneration in the developing brain. These studies have also been included in Table 3 and are described below.

Fredriksson et al. (8) showed that a single dose of ketamine administered to a 10-day-old mouse resulted in a significant increase in cellular degeneration in the parietal cortex. In contrast, a single dose of diazepam induced neuroapoptosis more prominently in the laterodorsal thalamus. The combination of ketamine and diazepam showed greater neuronal toxicity than ketamine alone. However, diazepam did not enhance the ketamine-induced functional deficits measured 2 mo after injection, including deficits of habituation to the test chamber in spontaneous motor activity studies, deficits of acquisition learning, and retention memory in the radial arm maze learning test.

Collectively, these studies suggest that rats and mice are both sensitive to NMDA-antagonist and GABAergic-agonist effects. Anesthetic drugs other than ketamine may also be neurotoxic to the developing rodent CNS. Most concerning is that a combination of drugs may produce greater toxicity than individual drugs. The data also suggest that the neurotoxicity appears to be correlated with behavioral changes in the animal models. As mentioned before, it is difficult to know how to extrapolate these animal findings to a pediatric surgical patient population.

	FDA’S ONGOING SCIENTIFIC INVESTIGATIONS

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NCTR and CDER, under the direction of NCTR, are continuing to coordinate efforts with ongoing studies in the primate model and the design of future studies with ketamine, as well as to expand the evaluation to other anesthetics and anesthetic regimens (34). These studies are summarized in Table 4. Our completed in vitro studies demonstrated cell death in neurons cultured from the rat forebrain after prolonged exposure to ketamine at concentrations of 10 or 20 µM. However, no cell death was evident at exposures to ketamine concentrations of 0.1 or 1.0 µM (35). Studies conducted with cultured monkey frontal cortical neurons produced the same results (36). These data suggest that, under the in vitro conditions tested, both rat and primate cortical neurons are vulnerable to NMDA-antagonist neurotoxicity. However, they also suggest that there are ketamine concentrations and durations of exposure that do not produce apoptosis in vitro. This information suggests that there might be a margin of safety for the use of ketamine in vivo and that there may be safety margins for the other anesthetics currently used in the clinical setting.

Data from initial NCTR-CDER primate studies have been submitted for publication and presented in abstract form. In a poster presented at the Society for Neuroscience Annual Meeting in November of 2005, Slikker et al. (37) reported on findings of ketamine-induced neurotoxicity in prenatal rhesus monkeys after IV infusions of ketamine administered to pregnant females at doses sufficient to maintain a steady-state anesthetic plane for 24 h on gestational day 122, followed by a 6-h washout period. Examination of tissue isolated from the frontal cortex of the monkey fetus revealed enhanced cell death consistent with an apoptotic mechanism. Although the peak plasma concentrations of ketamine in the pregnant monkeys in these studies (10–22 µg/mL) were about 10 times higher than those observed in humans, the dose used was the minimum sufficient to maintain the desired plane of anesthesia. Parallel studies examining the distribution of neuronal damage in the prenatal monkey brain tissue suggested a differential pattern of damage in the monkey compared with that seen in the neonatal rat. The abstract noted that "Unlike in neonatal rats, only a few degenerating neurons could be identified in the ketamine-treated fetal monkey hippocampus, thalamus, basal ganglia, hypothalamus, or amygdala. However, extensive neuronal cell death occurred in the superficial neocortical layers and in the allocortex of ketamine-treated, but not control, monkeys. Interestingly, small cells immunopositive for proliferating cell nuclear antigen were also observed in the superficial neocortical layers of the ketamine-treated monkeys, suggesting the possibility of some compensation for the neuronal loss" (38). Whether the observed cell death affects overall brain function, or whether the injured brain tissue can recover with no loss of normal function, remains to be seen.

	WHAT IS CURRENTLY NOT KNOWN

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There are no clinical data providing evidence suggesting that the use of anesthetics in the neonate or young child is associated with signs of developmental neurotoxicity. However, there are currently no validated tools to address this issue in the clinical setting. Furthermore, from a regulatory perspective, there are important questions that need to be addressed including:

1. Are the findings for ketamine and other anesthetics in rodent models of anesthetic toxicity applicable to humans? Can the findings in primates serve as the bases for the safe use of these drugs clinically?
   
2. Can the effects of ketamine be extrapolated to other drugs with similar pharmacologic actions?
   
3. How do the doses tested in rodents relate to the doses used clinically?
   
4. Are there doses and durations of treatment that will not produce evidence of neurotoxicity in nonclinical studies?
   
5. Would such exposures translate to clinically effective dosing regimens?
   
6. Are there drugs or drug combinations that will not produce the neurotoxic effects in animals or humans?
   
7. How do risks associated with anesthesia compare to risks associated with delay of surgical intervention or the use of alternative therapy?
   
8. If there are behavioral changes noted in nonclinical studies, are the changes permanent, or is there compensation, adaptation or recovery?
   

	THE PATH FORWARD

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There are many issues to be resolved before a definitive assessment of the risk posed by anesthetics to the developing brain can be made. The information that follows describes the courses of action that are underway or tentatively planned at the FDA. Input from the anesthesia community, particularly through the professional societies, as well as from the pharmaceutical industry, would play an important role in shaping these plans. Venues for exchanging ideas will be publicly announced as the opportunities arise.

Discussions between NCTR and CDER have resulted in the following plans for research as funding permits. As neuronal apoptosis and necrosis related to ketamine use have been demonstrated in juveniles of both the rodent and primate species studied, a NOAEL dose and duration of exposure and window of developmental vulnerability will be sought in the primate model. Identification of such a dose–duration combination will allow demonstration of a safety margin, or lack thereof, for human use. This will serve as the first step toward appropriate labeling regarding use in neonates and young children. Studies to evaluate the potential functional significance of ketamine-induced neurotoxicity in the monkey model are also planned. The potential cognitive effect of ketamine exposure during the period of vulnerability in the monkey model of neurotoxicity will be assessed through a variety of functional tasks to determine whether the insults that accompany long-duration ketamine anesthesia during the perinatal period manifest as cognitive difficulties later in life. The specific cognitive functions to be assessed will include learning, motivation, and visual and position discriminations. These tasks have been shown, in monkeys, to be sensitive to perturbations by drug exposures during development (39). In addition, options for a noninvasive in vivo screening procedure will be explored with the intent to identify a method to image the brain of ketamine-exposed animals at various times after drug administration with the ultimate intent to establish a way to monitor potential neuronal apoptosis in the clinical setting.

While the focus on ketamine may appear to be excessive compared with its use clinically, the demonstration of neurological injury with its use, the establishment of NOAEL dosing for its use in an animal that includes validation of neurological testing, and the determination of a safety margin for use in humans mark a significant achievement. As mentioned previously, the focus on ketamine should not be viewed as suggesting it has relatively more, or less, risk than other anesthetic drugs. The path forward will include other, more frequently used anesthetics, following the scientifically valid and clinically useful precedent we set for ketamine.

Concurrent with the in vivo primate studies involving ketamine, other suspect anesthetic and sedation drugs will be assessed using in vitro methods with neuronal tissue cell cultures to determine the conditions under which anesthetic drugs may produce neurotoxicity. The drugs thus identified will then be rank-ordered to establish priority for future in vivo testing based on a combination of factors including extent of use in the pediatric population and the dose and duration of exposure required in the in vitro studies to induce cell damage. These drugs will then be rank-ordered, studied in rodent models and then, if indicated, in the primate model with a goal of establishing safety margins for human use.

The results of the primate studies currently underway with ketamine will impact how other anesthetics will be evaluated for safety and efficacy in pediatric patients. Table 5 lists the anesthetic drugs with no marketing protection for which FDA and National Institute of Health have requested pediatric studies. How and even whether, those studies will be conducted will be influenced by the animal research under way. Table 6 lists the anesthetic analgesic drugs with market protection for which FDA has formally issued a pediatric written request. It is also likely that new NMDA-antagonist and GABA-agonist drug products submitted to the FDA for approval for use in humans will have to undergo further nonclinical testing in juvenile animals before clinical trials in the vulnerable segment of the pediatric population can be contemplated.

As many of these drugs are used in combination, especially in the course of anesthesia, in vitro and in vivo studies will be conducted, initially using the more common combinations, in an effort to determine whether the neurodegenerative effects are additive, synergistic or, perhaps, diminished compared with the neurodegeneration found with the individual drugs.

In addition to the above, the feasibility of conducting an epidemiological study in neonatal and young pediatric surgical patients will be considered. The design and end points selected for such a study would likely rely heavily on the findings from the primate behavioral study both in terms of validation and powering the study. A number of concerns would need to be addressed, as they would likely confound the results. Among other things, these include the level of prenatal care, concurrent medical problems, adjusting for the condition(s) which led to surgical intervention, adjusting for anesthetics used, and the level of health and health care during the neonatal, infancy, and early childhood periods. It may be difficult to rely on a negative finding in such a study as evidence of safety, and it may be relatively easy to dismiss any positive findings based on the number of confounding variables. Nonetheless, such a study may prove helpful for refining future research efforts.

	SUMMARY

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The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate GABA-ergic signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems, or to induce more or less neurotoxicity, is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components. The lack of information to date precludes the ability to designate any one anesthetic or regimen is safer than any other.

Clinicians caring for pediatric patients have long had to cope with the reality that most marketed drugs approved by the FDA are approved only for use in adult patients. Some of the challenges involved in conducting pediatric studies, and affecting labeling changes based on them, have been recently discussed (41,42). Data to assess appropriate dosing and to evaluate safety and efficacy of many older drugs commonly used in pediatric patients are limited. With the publication of a number of nonclinical rodent studies suggesting that the use of anesthetic drugs in pediatric patients may be associated with neurotoxicity, CDER and NCTR have taken an active role in obtaining the information required to evaluate the potential clinical significance of these findings. CDER and NCTR have conducted studies to clarify the exposure levels that produced the rodent neurotoxicity, and initiated studies in the primate model to evaluate the potential clinical significance of the findings and to identify, where possible, safety margins for use of these drugs in pediatric patients.

The NCTR and CDER are collaborating to generate scientific knowledge concerning the potential effects of anesthetic drugs on the developing CNS. These data will provide critical information for the clinician. However, these are only the first steps in the effort to gather and assess data that will allow appropriate modifications to the product labels and inform the medical community of safety risks, if any. An important component of any path forward will be input and assistance from the anesthesia community and the pharmaceutical industry. The contribution each of these partners can make in providing guidance and conducting studies is not under-estimated by the FDA. In the interim, clinicians are advised to continue to tailor the care of their pediatric patients based on the patient’s condition, to attempt to minimize exposure to potentially offending drugs when possible, to consider alternative therapies as may be available, and to remain vigilant as new information is developed.

	ACKNOWLEDGMENTS

 
The authors would like to thank the following individuals for their insights and assistance in the preparation of this manuscript: Douglas Throckmorton, MD, Deputy Director, Center for Drug Evaluation and Research (CDER); William Slikker, Jr, PhD, Director, National Center for Toxicological Research; John Jenkins, MD, Director, Office of New Drugs (OND), CDER; David Jacobson-Kram, PhD, Associate Director Pharmacology and Toxicology, OND, CDER; Kenneth Hastings, PhD, Associate Director of Pharmacology and Toxicology, ODE II/III, OND, CDER; Joseph Hanig, PhD, Deputy Director, Division of Applied Pharmacology Research, CDER; Robert Meyer, MD, Director, Office of Drug Evaluation II (ODE II), OND, CDER; Curtis Rosebraugh, MD, Deputy Director, ODE II, OND, CDER.

	Footnotes

 
Accepted for publication December 4, 2006.

	REFERENCES

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