The FDA MedWatch Warning: What Does it Mean for Pediatric Anesthesiologists and Pediatric Pain Specialists?
By Rae Brown, MD, FAAP
Chair, FDA Advisory Committee on Anesthetics and Analgesics
Interest in the neurotoxicity of general anesthetic agents and sedatives has increased in recent months because of a decision by the FDA to publish a warning on the use of prolonged or repeated anesthetics or sedatives in children up to the age of three years and during the third trimester of pregnancy. This notice advised clinicians of a possible association between cognitive and behavioral issues later in life when patients are exposed to general anesthetic agents and/or sedatives for extended periods of time, multiple times before the age of three, or in utero. The agents implicated include all the volatile anesthetics, ketamine, midazolam, lorazepam, diazepam, propofol and barbiturates. Opioids have not been found to cause increased apoptosis in animals. Though epidemiological data seems to support this finding in humans, there are, of course, no pathological studies in humans demonstrating the CNS abnormalities widely recognized in all species of animals tested and correlated with learning and memory disturbances in laboratory animals.
Though unstated, it is assumed that the Agency provided this warning to recognize the increasing animal data and to alert all clinicians that discussions about these anomalies should be included when assessing risk and benefit of surgical or diagnostic procedures in infants and children. Pediatric Anesthesiology groups as well as the American College of Surgeons and the American Academy of Pediatrics, while noting that this information is relevant, cautioned the public about the risks of failure to intervene surgically or failure to treat pain adequately (?) when a condition warrants. Overall pediatric anesthesia professionals anesthetize millions of children each year safely. This record is corroborated by recent studies in children, under controlled conditions, which demonstrate the safety of anesthesia care when delivered appropriately for short periods. Less information is known about children requiring long term pain medication and/or sedatives for treatment of acute, chronic or procedural pain (e.g. ICU sedation)
The change in labeling by the FDA is one of the few actions that the Agency can take to bring the accumulating information to the attention of clinicians. Laboratory and epidemiological data have been available for 15 years and the decision by the Agency, charged with protecting the public health, is appropriate in this context. Highlighting this evidence allows parents and clinicians to have science-based discussions about what is best for the infant or young child. Out of an abundance of caution, this dialogue should include all relevant information until that information is disproven.
To be clear, this is not a black box warning. Anesthetic agents and sedatives appear to be safe when used at reasonable clinical doses for short periods. There has been no suggestion of the lack of safety of these agents under appropriate conditions.
Anesthesiology and Pain Management professionals will be asked by parents about the evolving nature of this subject and how it will affect their child. Pediatric anesthesiologists have already been approached by the national media for comments about the meaning of these findings. In reflecting on the nature of these findings, care providers should take care to place the risk of a brief anesthetic or sedative in the context of the requirement for surgical or diagnostic intervention, and the overall safety of pediatric care in general. Parents should also take solace in our profession’s drive to reduce the doses of drugs that are administered to children with developing nervous systems and the continued search for new safer agents. Dexmedetomidine is one such agent. In laboratory studies and in clinical doses, it may be protective.
