The FDA Warning on Anesthesia Drugs

This past December, the FDA required that a warning be added to labels of many anesthetic drugs (Table 1) stating “repeated or lengthy use of general anesthetic or sedation drugs during surgeries or procedures in children younger than 3 years of age, or in pregnant woman during the final trimester may affect development of children's brains.” The FDA's definition of “lengthy” was greater than 3 hours of exposure.”1 This was not a “black box” warning per se, but rather an effort by the FDA to highlight a growing concern and alert anesthesia providers that a discussion of the concern of the “potential adverse effects of anesthesia on brain development” should take place in the informed consent process.The data from animal models have convincingly found changes in brain development related to exposure to anesthetic/sedative drugs, including nitrous oxide which was not on the list. How these animal models, many of which have rodents in cages rather than human infants and toddlers that are encouraged and stimulated, to name just one difference, translate to our children is far from clear. Many recent human studies, including the General Anesthesia Compared to Spinal Anesthesia (GAS)2 and Pediatric Anesthesia Neurodevelopment Assessment (PANDA)3, provide evidence that a single general anesthetic exposure does not affect intelligence or neurocognitive development. More studies are needed regarding repeated or prolonged exposure to anesthetic agents. We are awaiting the publication of the Mayo Safety of Anesthesia in Kids (MASK) study that will hopefully shed some insight on these questions.Regardless, as doctors our primary dictate is to Do No Harm. So, we all take this concern quite seriously. There is no question that if a child needs surgery for a serious illness or congenital disease, caregivers should not withhold anesthesia for months or years out of concern for impaired neurocognitive development, still unproven. But, the most common surgeries for children with general anesthesia include ear tube placement, tonsillectomy and dental surgery for caries. I am not an ENT surgeon but if my child's hearing could be impaired by repeated otitis media or they had obstructive sleep apnea from enlarged tonsils, I would personally consent to anesthesia for these procedures which might take 15 – 45 minutes – a so called brief anesthetic exposure. But what of general anesthesia for dental decay?Dentist anesthesiologists (DAs) are the only dental anesthesia providers who routinely anesthetize children 1 -2 years old. Infants generally do not have dental decay requiring treatment and congenital defects, such as cleft lip/palate and other craniofacial abnormalities, are usually managed by specialized hospital teams. Most dentist anesthesiologists have criteria for the selection of pediatric patients deemed safe for general anesthesia in the office setting. Children at least 18 months of age, 10 kg of body weight and ASA I or non-cardiopulmonary ASA II are common criteria for many DAs. For the youngest in this age group, the treatment may consist of restoration of only the 4 Maxillary incisors. As the children get older, we commonly see the 4 primary first molars with or without the 4 Maxillary incisors requiring treatment. As children get closer to 3 years of age, when the second primary molars have erupted, we start approaching 12 – 16 primary teeth requiring treatment for aggressive caries.As dentists, DAs appreciate the importance of the teeth to overall health and psychological well being of children and their parents. But, as anesthesiologists, are we always considering the benefit-risk ratio of a functional, pain-free, aesthetic dentition vs. the potential neurocognitive effects of general anesthesia? Should we, for instance, counsel parents and their dentists to have the 4 Maxillary incisors extracted in a procedure with mask sevoflurane anesthesia taking at most 10 minutes from induction to emergence vs. what, for some operating dentists, may be a 90-minute restorative procedure? What if we know of other dentists who could accomplish that same quality restorative procedure in 30 minutes? Many of us have seen children provided anesthesia when they were 20 months old for aggressive caries of the primary first molars and 4 Maxillary incisors only to be seen again one year later for treatment of the primary second molars. Do we delay general anesthesia until after 3 years of age since now multiple anesthetics before age 3 are needed? Is 3 years the magic age such that we should consider discussing with the treating dentist to delay dental treatment 4 months for a 32-month-old child? What if only early caries are present? Can we then wait 4 months? What if the child is in pain with abscessed teeth? All of us have seen children who developed facial cellulitis from untreated caries that required incision and drainage under general anesthesia with intravenous antibiotics and a hospital stay. And then these children needed another general anesthetic to treat the remaining dentition! Do we extend this line of questioning to children who have had ear tubes or tonsillectomy and now will have “multiple” anesthetics due to a needed dental procedure? Is there a difference in our thinking if the previous anesthetic was a 15-minute ear tube anesthetic vs. a longer hypospadias repair anesthetic?No one has the answers to any of these questions. Every situation is different. There are additionally too many other variables beyond the dental and anesthesia issues to also consider. For instance, social factors, such as distance that economically disadvantaged parents have to travel for dental treatment to name just one, have to be considered. At the same time, we cannot be cavalier in our approach to this emerging concern and just throw up our hands and say all children should be treated if the operating dentist chooses to do so. I have always felt that the anesthesia provider is the ultimate last chance patient advocate in the surgical process. As independent anesthesia providers not involved in the surgical procedure, we are the gatekeepers taking all aspects of the procedure, without regard to economic incentives, and the anesthesia into perspective. We must always do what we feel is in the best interest of the patient. As dentist anesthesiologists, we are arguably more knowledgeable about dental procedures than our physician anesthesia colleagues are regarding medical surgical interventions. We are, therefore, in an ethically more challenging position to take all these competing factors into consideration.In the meantime, the American Society of Anesthesiologists, the American Academy of Pediatrics, Society of Pediatric Anesthesia, International Anesthesia Research Society and the Society for Obstetric Anesthesia and Perinatology have issued a joint statement regarding this concern which we can use with our parents and caregivers. In part it states: “While there is abundant animal data concerning suspected toxicities in prolonged and multiple anesthetics, the accumulated human data suggest that one brief anesthetic is not associated with cognitive or behavioral abnormalities in children. Most but not all studies in children do however suggest an association between repeated and or prolonged exposure and subsequent difficulties with learning or behavior. It is not yet known whether the anesthetic drug or some other factor is responsible for these findings. Rigorous research to further characterize any possible associations is ongoing.”4One or two more studies will not settle the issue of a possible relationship between anesthesia and neurocognitive development any time soon. In the meantime, perhaps the American Society of Dentist Anesthesiologists can develop their own consensus statement for dentist anesthesiologists as this matter will be with us for many years to come.