VOLUME 32, ISSUE 1

Rhashedah Ekeoduru, MD

Associate Professor of Anesthesiology, McGovern Medial School, UT Health Science Center at Houston
Medical Director, Master of Science in Anesthesia Program, Case Western Reserve University at Houston
Houston, TX

Best Clinical Practice: Update on FDA Pediatric Anesthesia-Induced Neurotoxicity Warning

Background Information:

On December 14, 2016, the United States Food and Drug Administration (FDA) issued a safety warning that “repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.1” The warning applies to all of the inhaled anesthetics, benzodiazepines (including the commonly used midazolam syrup), ketamine, barbiturates, and propofol. Essentially all of the commonly used agents for general anesthesia and sedation in pediatrics are implicated, with the exception of opioids and dexmedetomidine.

The warning is based primarily on pre-clinical studies in animals where prolonged exposure to anesthetic agents caused neuronal apoptosis and long-term effects on the animal’s behavior and learning.2 Conversely, specific patterns of neuropsychological derangements following early exposure to general anesthesia have not been conclusively found in children. SmartTots, a collaborative research development between the FDA and the International Anesthesia Research Society purports no overt neurocognitive deficits in human infants after brief (less than three hours duration) anesthetic exposures. 3 Thus, while preclinical evidence in animal models is concerning, current clinical evidence is weak and inconclusive.4,5 The collaborative also emphasizes the need for continued research to eliminate or reduce confounding variables to determine true association.

What we do know is that single, relatively brief exposure to anesthesia does not increase neurobehavioral adverse events in young children5. Regarding multiple anesthetic exposures, the Mayo Anesthesia Safety in Kids study recently published findings of no significant differences between exposed and unexposed children in attention, memory, executive function, expressive language or visual-motor abilities.6 There were also no appreciable differences in intelligence quotient testing in children with single or multiple anesthetic exposures when compared to children who had not received anesthesia. The study did find that multiply exposed children (average anesthesia exposure time of 187 minutes) demonstrated an impairment of fine motor function and processing speed. That being said, these findings are certainly not indicative of devastating neurological outcomes after early anesthetic exposure.

Lastly, to date, the studies examining anesthetic-induced neurotoxicity have explored the effects of anesthetic duration and concentration but have not isolated the effects of anesthesia from those of surgery or the child’s underlying disease.5 There is significant concern that factors like underlying illness, surgery, and hospitalization may also play a role in this process. Children with complicated disease pathology, such as those with cardiac defects, may be more prone to adverse outcomes, with or without anesthetic influence. Experts have noted that specific attention has not been given to intra-operative hemodynamic monitoring. Prolonged, uncontrolled intra-operative hypotension may be a confounder that increases the risk of adverse neurological outcomes. Many argue that we should be more focused on avoidance of and immediate treatment of hypotension in this vulnerable population.

Implications of the FDA Warning in Texas

The FDA advisory was intended to promote transparency by making the public aware of potential anesthesia-related safety concerns. In response, the Texas Medical Disclosure Panel elected to change the standardized state informed consent form for anesthesia and perioperative pain management to include a statement on anesthetic risk in early childhood. The statement requiring a signature from a parent or pregnant patient is in checklist format and specifies: “Prenatal/Early Childhood Anesthesia – potential long-term negative effects on memory, behavior, and learning with prolonged or repeated exposure to general anesthesia/moderate sedation/deep sedation during pregnancy and in early childhood.7”

Provider Response

Inconsistencies in the interpretation of the warning by some anesthesiologists, surgeons and referring physicians (especially pediatricians) led to unnecessary cancellation of procedures. This is problematic because procedures required in this age-group often have a critical window to achieve optimal outcomes. Delaying cases beyond this timeframe can have a negative impact on the child or make the procedures more difficult or dangerous to perform.8 Examples are orchiopexy , cleft lip and palate repair, craniosynostosis, and the Kasai procedure for biliary atresia. The known risks of case delay likely outweigh the theoretical risk of anesthesia-induced neurotoxicity in these cases.

The Society for Pediatric Anesthesia and the American Academy of Pediatrics released a consensus statement that the “potential risk of negative cognitive or behavioral effects of anesthetic agents remains uncertain and must be placed in the context of the known risks and benefits of both the anesthetic and the related surgical or diagnostic procedure.” They caution against delaying needed surgical or diagnostic procedures.

The American College of Obstetricians and Gynecologists released a statement emphasizing that no currently used anesthetic agents have been shown to have any teratogenic effects in humans at any gestational age when using standard concentrations.8 Obstetricians expressed concern that no pregnant patients were included in clinical anesthetic neurotoxicity studies. Their stance is that the FDA warning should not lead to changes in anesthesia and sedation practices in pregnant women and medically indicated care should not be delayed in the perinatal period.

Practice Implications

The surgical community has not been as swift as the anesthesia community to widely disseminate information about anesthesia neurotoxicity concerns. The topic has not been widely discussed at their national meetings or within their professional societies and to date, it is difficult to find consensus statements from surgical societies. Thus, many of our surgical colleagues may lack knowledge of current practice consensus and guidelines8. Gradually, the public is becoming more aware of the FDA warning. It is imperative that we help our surgical colleagues address neurotoxicity concerns that parents may have. There needs to be cohesion in how we respond when a parent asks if anesthesia is safe for their child. The goal is to reduce parental and provider anxiety and improve pediatric perioperative outcomes.

It should be emphasized that for most short, non-elective procedures, risk discussion should be fairly straightforward since anesthetic exposure lasting less than three hours has not been shown to increase neurotoxicity risk. Complex surgeries, particularly staged procedures requiring multiple and/or prolonged anesthetics, warrant a more detailed risk versus benefit discussion.

Many experts and practitioners have questioned whether it is prudent to communicate to parents the potential risk of neurotoxicity since conclusive research in humans is pending. Anesthesiologist Randall Flick described our dilemma best when exclaiming “anesthesiologists and surgeons are struggling with how-and sometimes whether-to explain a theoretical hazard to parents who are already worried about the real risks of their child’s medical problem and the surgery they need to correct it.9” Regardless of physician interpretation of the data, increasing public awareness and concern obligates the need for a comprehensive discussion about anesthetic risks, benefits and alternatives. It would be helpful to have a unified scripted message to guide anesthesiologists.

Most institutions do not have a prescribed script for counseling patients nor information handouts. They rely on individual anesthesia providers to respond to questions and concerns.8 One solution is to create informational pamphlets written by anesthesiologists and distributed by surgeons, pediatricians and other referring services. Children’s Memorial Hermann Hospital and Texas Children’s Hospital have successfully adopted this practice.

In addition to standardizing how we communicate anesthetic risk in the pediatric population, we need to agree on practice modifications that can be undertaken to reduce exposure, shorten case duration, and minimize risk. If clinically permissible, procedures should be delayed until children are older than age three. Providers may consider using dexmedetomidine as an adjunct to reduce the inhaled anesthetic exposure.10 Some cases can be safely completed utilizing regional anesthesia and minimal sedation.11 Whether using general or regional anesthesia, practitioners should focus on maintaining hemodynamic stability and normal oxygenation.

Along the thread of adjusting clinical practice to reduce anesthetic risk, anesthesiologists should play an instrumental role in reducing the duration of anesthesia by actively advocating for our patients via communication efforts with the perioperative team. This entails delaying induction until the surgeon and all necessary equipment are ready and available. When imaging studies require sedation, we need to discuss the required imaging protocols with the radiologists to determine if scan time can be reduced if the overall anesthetic time will exceed three hours. We have been very successful with opening these lines of communication at Children’s Memorial Hermann Hospital. It will be difficult to negotiate which images may be delayed or shortened because of a heavy reliance on diagnostic imaging to explore differential diagnoses. However, it is worth the effort if future research concludes anesthetic exposure risk is additive.

Conclusion

In summary, there is no current conclusive evidence that anesthetics cause perceptible long-term neurological deficits. What is factual is that there is a real risk of causing neurological injury when one withholds amnesia, analgesia and/or hypnosis. Almost all currently available anesthetics are implicated in the FDA warning leaving no practical alternatives for anesthetic sedation. When treatment cannot be delayed, the best practice approach should be to shorten anesthetic duration, minimize the concentrations of offending agents and to enhance communication efforts.

Future research will hopefully address some of these questions: Are certain children at a higher risk for neurotoxicity? How does underlying pathology increase neurotoxicity risk? Is the risk additive following multiple anesthetics? If anesthetic agents have a negative impact, can aggressive tutoring and occupational therapy help children overcome resultant learning or behavioral deficits? What component of the learning disabilities are secondary to genetic perturbations versus environmental exposure? Are certain medications neuroprotective? Is there a range of risks depending on pre-existing pathology? When do symptoms first appear?

The ability to more definitively answer these questions and others will enhance our ability to provide outstanding care for our pediatric patients.

Take Home Points:

  • Brief anesthetic exposure (<3 hours) in children younger than age 3 is thought to be safe.
  • Repeated and/or prolonged exposure (>3 hours) is associated with difficulty with learning and behavior.
  • The FDA warning applies to all commonly used inhaled and intravenous anesthetics with the exception of dexmedetomidine and opioids.
  • Do not cancel necessary procedures in this age group due to fear of neurotoxic effects alone.
  • Texas state-wide informed consent form details potential pediatric anesthesia-induced neurotoxicity risk.
  • Anesthesiologists must counsel parents about the current expert consensus opinions so that they may make informed decisions.
  • Some of our surgical colleagues may not be aware of the most recent consensus opinions, so we must collaborate with them to ensure that the entire team is following the best practices.
  • Prolonged intra-operative hypotension is thought to be a contributing factor to poor anesthetic outcomes in this age-group.
  • Anesthesiologists should advocate for shortening diagnostic procedures requiring general anesthesia in this patient population, when possible.

References:

  • FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-review-results-new-warnings-about-using-general-anesthetics-and Published December 14, 2016. Accessed July 12, 2019.
  • Sanders RD, Hassell J, Davidson AJ, Robertson NJ, Ma D. Impact of anaesthetics and surgery on neurodevelopment: an update. Br J Anaesth 2013;110: Suppl 1:i53-i72.
  • Orser BA, Suresh S, and Evers AS. Smart Tots update regarding anesthetic neurotoxicity in the developing brain. Anesth Analg 2018; 126(4).
  • Davidson AJ, and Sun LS. Clinical Evidence for any effect of anesthesia on the developing brain. Anesthesiology 2018; 128: 840-853.
  • Davidson A, Vutskits L. The new FDA drug safety communication on the use of general anesthetics in young children: what should we make of it? Paediatr Anaesth. 2017;27:336-337.
  • Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavior outcomes after exposure of young children to procedures requiring general anesthesia. The Mayo anesthesia safety in kids (MASK) study. Anesthesiology 2018; 129:89-105.
  • Texas Health and Human Services communication: Texas Medical Disclosure Panel Enacts Change to Anesthesia Informed Consent Form. https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/tx-med-disclosure/tmdp-anesthesia-consent.pdf Published December 22, 2017. Accessed November 4, 2019.
  • Pinyavat T, Saraiya NR, Chen J, et al. Anesthesia exposure in children: Practitioners respond to the 2016 FDA drug safety communication. J Neurosurg Anesthesiol. 2019;31(1):129-133.
  • Grady D. Researchers warn on anesthesia, unsure of risk to children. New York Times. February 25, 2015. https://www.nytimes.com/2015/02/26/health/researchers-call-for-more-study-of-anesthesia-risks-to-young-children.html
  • Andropoulos DB. Effect of anesthesia on the developing brain: infant and fetus. Fetal Diagn Ther 2018; 43:1-11.
  • Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcomes at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicenter, randomized controlled trial. Lancet 2016; 387:239-250.

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