Animal Studies Indicate General Anesthetics Administered During Critical Stages of Brain Development Cause Detrimental Impairments in Synapse Formation and Cognitive Function

General anesthesia administered to the developing animal brain depresses much needed neuronal activity and communication resulting in long-lasting cognitive impairment, according to an article published in the August issue of Current Opinion in Anesthesiology. Author Dr. Vesna Jevtovic-Todorovic, SmartTots Scientific Advisory Board Member and Professor of Anesthesiology and Neuroscience at the University of Virginia Health System, claims proper brain development depends on undisturbed neuronal communications – a process modulated by anesthetic exposure in animals. Currently, insufficient data are available to either support or refute whether similar effects occur in children.

The most sensitive period of brain development in both animals and humans seems to occur during a peak of synaptogenesis – a period of substantial synapse formation responsible for building neuronal circuits capable of transmitting cellular signals. Studies in animal models over the past decade affirm that commonly used anesthetics, whether administered alone or in combination, can cause significant neuronal cell death and improper synapse formation.  According to Jevtovic-Todorovic, these effects are detrimental to brain development and function in both rodents and nonhuman primates.

“Recent studies conducted by the National Center for Toxicological Research (NCTR) demonstrate that a single commonly used anesthetic, ketamine, can cause significant and persistent cognitive impairment in rhesus monkeys when administered during a critical period of their brain development,” said Jevtovic-Todorovic. “These impairments are long-lasting and raise reasonable concerns regarding the safety of anesthetics given to our children.”

In the August issue of Neurotoxicology and Teratology, NCTR investigators discuss their recent findings regarding a clinically relevant combination of isoflurane (at 1%) and nitrous oxide (at 70%). The group confirmed that this anesthetic combination caused significant neuronal cell death in the developing monkey brain after just 8 hours of exposure. Further, they suggest that the neuronal damage observed in the monkey model exceeded the damage demonstrated in the rodent suggesting increased sensitivity in monkeys – an alarming result considering the genetic similarities between nonhuman primates and humans. The authors suggest, however, that the monkeys may have been exposed during a more vulnerable stage of development compared to the rodents, as developmental periods between species are not precisely equivalent.

“One of the most difficult aspects of translating data across species is variance in developmental timelines,” said Jevtovic-Todorovic. “However, it appears that timing of anesthetic exposure is unanimously important and warrants careful consideration.”

SmartTots, a public-private partnership between the International Anesthesia Research Society and the US Food and Drug Administration, is working to centralize research efforts needed to translate animal data which question the safety of anesthetics. SmartTots is focused on determining the precise stages of developmental vulnerability in humans and the extent to which similar neuronal damage may occur in children.

“Understanding the most sensitive periods of human brain development is critical to determining and mitigating any potential harm,” said Jevtovic-Todrovic. “SmartTots is working with the scientific and medical communities at large to address scientific and clinical gaps and ensure the safe use of anesthetics and sedatives in children.”