Web Box 15.2 Of Special Interest: Can PCP or Ketamine Cause Damage to the Developing Brain?

Infants and young children sometimes must be anesthetized for medical procedures, whether to perform surgery or to sedate the patient for the purpose of diagnostic imaging such as MRI. As mentioned earlier, the primary application of ketamine in human medicine is as a pediatric anesthetic. Thus, pediatric anesthetists had to be concerned when research using laboratory rats, mice, and non-human primates, beginning in the 1990s and continuing to the present time, found increased apoptotic cell death, disrupted neurogenesis (formation of new nerve cells), and other damaging effects in the brains of infants exposed to ketamine either once at a high dose or multiple times at lower doses (reviewed in Cheung and Yew, 2019). Longer-term studies additionally demonstrated behavioral deficits in the exposed animals, particularly with respect to cognitive function. Moreover, such neurotoxicity appears to be a more widespread property of general anesthetics since volatile (i.e., gaseous) anesthetics that work by enhancing GABAA receptor activity also exert neurodegenerative effects in young animals (Chiao and Zuo, 2014).

The reader can readily see that this is a major concern, since physicians cannot simply stop administering general anesthesia to their pediatric patients. The question that needs to be answered is: does exposure to a general anesthetic, whether ketamine or a volatile anesthetic, cause harmful effects on neurodevelopment in humans? Because we can’t conduct histological examinations of the brains of living children who were treated with an anesthetic, most human studies in this area use cognitive indicators (e.g., IQ, educational performance, etc.) as the key outcome measures. A recent commentary by Warner and colleagues (2018) discussed how difficult it is to isolate the single variable of anesthetic exposure from all the other variables that influence later behavior, cognition, or affect (Figure 1). Despite this difficulty, several well-designed, large-scale studies have been performed that show no discernible causation* of adverse outcomes from pediatric anesthetic use (Barnes, 2020). On the other hand, the possibility exists that subtle and/or later-appearing effects of early life anesthesia have not yet been identified, particularly in those individuals who have experienced multiple anesthetic exposures. In an attempt to reconcile the state of current evidence with the possibility of yet-unrecognized harms, recent reviews of this literature have generally taken a nuanced position whereby parents should not be unduly alarmed if their child requires general anesthesia (Nemergut et al., 2014; Davidson and Sun, 2018; McCann and Soriano, 2019). But at the same time, caution dictates that practitioners should do their utmost to minimize exposure of their pediatric patients to these agents.

A flow diagram of long term neurodevelopmental and psychosocial outcomes of a child. Peri-procedural factors such as procedure which include physiologic stress, length of stay, pain; medications that include anesthetics or sedatives, analgesics, others; pre procedural child characteristics which include affect, behavior and cognitive abilities. Contextual factors such as family that include functions; external environment that include socioeconomic status. All these factors have an effect on the acute child responses. These responses after the influence of the moderators give rise to the same early and long term responses such as affect, behavior and cognitive abilities.

Figure 1 Framework identifying the factors that may influence neurobehavioral outcomes following medical procedures requiring anesthetic use. Determining whether anesthetic exposure during infancy or early childhood causes adverse effects on later neurobehavioral development is extremely challenging because of the many other factors that influence developmental trajectories. These factors include the pre-existing characteristics the child brings into the procedure, peri-procedural (around the time of the procedure) factors consisting of the elements of the procedure itself and other medications that may have been administered, and contextual factors consisting of the internal family environment and external environmental features such as socioeconomic status, housing and neighborhood characteristics, etc. The contextual factors are shown to continue moderating both early evolving and longer-term responses of the child. (After Warner et al., 2018.)

Footnote

* The use of the word “causation” here is quite important. As Barnes (2020) points out, there may be an “association” of early anesthesia exposure with poorer outcomes later on when one compares exposed to non-exposed infants. But this association could easily be an outcome of the fact that infants needing anesthesia for a medical procedure are likely to be less healthy that comparable infants that don’t need such a procedure.

References

Barnes, R.K. (2020). “Pediatric anesthetic neurotoxicity”: Time to stop! Anesth. Analg., 131, 734-737.

Cheung, H.M., and Yew, D.T.W. (2019). Effects of perinatal exposure to ketamine on the developing brain. Front. Neurosci., 13:138. doi: 10.3389/fnins.2019.00138.

Chiao, S., and Zuo, Z. (2014). A double-edged sword: Volatile anesthetic effects on the neonatal brain. Brain Sci., 4, 273-294.

Davidson, A.J., and Sun, L.S. (2018). Clinical evidence for any effect of anesthesia on the developing brain. Anesthesiology, 128, 840-853.

McCann, M.E., and Soriano, S.G. (2019). Does general anesthesia affect neurodevelopment in infants and children? BMJ, 367:16459. doi: 10.1136/bmj.16459.

Nemergut, M.E., Aganga, D., and Flick, R.P. (2014). Anesthetic neurotoxicity: what to tell the parents? Pediatr. Anesth., 24, 120-126.

Warner, D.O., Shi, Y., and Flick, R.P. (2018). Anesthesia and neurodevelopment in children. Perhaps the end of the beginning. Anesthesiology, 128, 700-703.

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