Anesthetic Neurotoxicity

Basic Science of Anesthetic-Induced Developmental Neurotoxicity

Determining the root cause of the neurotoxic effect of CNS depressant drugs on the developing brain is complicated by the myriad of molecular targets and the still unknown mechanistic pathway to achieve general anesthesia. AIDN has been demonstrated in laboratory models, both in vivo and in vitro, by exposure to most anesthetic and sedative drugs commonly administered to pediatric patients (also see Chapter 34 ). A comparable pattern of neurodegeneration and impaired neurocognitive development has been described with the perinatal administration of inhibitory drugs. AIDN was first described more than 40 years ago in fetal and postnatal rats exposed to halothane, but its impact was not fully publicized to both the scientific and lay community until a 1999 report that emphasized that ketamine increased neurodegeneration in neonatal rat pups. Subsequently, it was found that the combination of commonly used anesthetic drugs, isoflurane, nitrous oxide, and midazolam, not only induced neuroapoptosis but resulted in deficits in hippocampal synaptic function and learning behavior.

Anesthesia removes sensory input and suppresses normal neural traffic, which in turn diminishes the trophic support required for neurogenesis and context-dependent modulation of neuroplasticity. However, several reports have described neuronal cell death mechanisms such as excitotoxicity, mitochondrial dysfunction, aberrant cell cycle reentry, trophic factor dysregulation, and disruption of cytoskeletal assembly. - Although GABA acts as an inhibitory drug in the mature brain, it is an excitatory agent during early stages of brain development because of the preponderance of the immature Na/K/2Cl transporter protein NKCC1, which produces a chloride influx leading to neuron depolarization. Therefore GABA remains excitatory until the GABA receptors are switched to the normal inhibitory mode, when the mature chloride transporter, KCC2, is expressed, which actively transports chloride out of the neural cell.

Age-Dependent Vulnerability of Anesthetic

Neural development progresses through several steps that include neurogenesis, neuronal morphogenesis, and synaptogenesis. Neurogenesis starts with the creation of progenitor cells, which proliferate and differentiate into neurons or glial cells. As neurons undergo terminal differentiation into a postmitotic state, they can no longer replicate. Dendrites and axons extend from the cell body to form functional synapses with other neurons. CNS neural development (up to 70%) is regulated by early elimination during the embryonal stage and programmed cell death after birth. Redundant neural progenitor cells and neurons that do not migrate properly or make synapses are physiologically pruned by apoptosis.

Critical periods of plasticity during brain development are modulated by environmental cues and have been implicated in perceptual development. Likewise, the perioperative environment can influence brain development. Anesthetic drugs are powerful modulators of neuronal circuits and have an impact on the constant flux of CNS development and remodeling in both health and disease states. Because neurogenesis is ongoing throughout life, from the fetus to the elderly, these neural progenitor cells are vulnerable to the toxic effects of anesthetic drugs. Exposure to isoflurane produces neuronal cell death in brain regions where neural progenitor cells reside. Therefore susceptibility to AIDN extends from the fetal period to late adulthood.

Brain growth spurt in most species is likely the time of maximal susceptibility to AIDN. This time corresponds with the time of maximal synaptogenesis. The growth spurt of the human brain occurs in the last trimester of gestation until about 3 to 4 years of age. Neuroinformatic mapping of the development of corticospinal tracts across species demonstrates that 7-day-old rat pups (the most common laboratory animal model) are neurodevelopmentally closer to 20- to 22-week-old human fetuses. The timing of maximal brain growth during development is species dependent. Rodents are altricial species, and much of their neurodevelopment occurs postnatally. This time period occurs from about postnatal day 6 through postnatal day 21. Simian species, including humans, are usually considered precocial and typically have a longer gestation because offspring are born at a relatively advanced stage of development. Rhesus monkeys are susceptible to anesthetic-induced neuroapoptosis when exposed as fetuses or up to day 6 of life. - Exposure of pregnant rats to anesthetics results in increased apoptosis in the brains of the fetuses. Administration of anesthetics to neonatal rodents leads to increased apoptosis and stunted axonal growth and dendritic arborization. In contrast, anesthetic exposure in juvenile rat models does not increase apoptosis but leads to enhanced dendritic formation and synaptic density.

Characterization of AIDN