Anesthesia-induced Developmental Neurotoxicity in Pediatric Population

Abstract

Anesthetics and sedatives may cause long-term negative neurocognitive consequences in children. Many clinical reports on this subject have had a profound impact on the field of clinical pediatric anesthesiology. Findings from animal models suggest that early exposure to anesthesia might cause neurocognitive impairment and apoptotic cell death in the brain. Even though the findings from the experimental animals cannot be directly translated to the use of anesthesia in pediatric population due to many variable factors, parents and government regulatory bodies have become sensitive and attentive to the potential adverse effects of anesthesia in children. Multiple epidemiological investigations in human have added to the growing body of evidence showing neurological impairment and cognitive decline after early anesthetic exposure. This is supported by several outcome indicators, including validated neuropsychologic testing, educational interventions for neurodevelopmental or behavioral disorders, and academic performance or school readiness. These outcomes have been evaluated in clinical studies involving children who have been subjected to general anesthesia. The primary goal of this article is to critically review the clinical findings, perform systematic analyses of the evidence, discuss potential underlying mechanisms of neurotoxicity, the pathophysiology of anesthesia-induced developmental neurotoxicity involving mitochondria, endoplasmic reticulum, and lysosomes, and the ethical considerations of pediatric anesthesia. Although detailed well-controlled clinical studies are warranted, the evidence so far support that the potential adverse effects of surgical anesthesia to induce neurotoxicity in pediatric population are not exaggerated.

Keywords: Anesthesia-induced developmental neurotoxicity; Apoptotic pathways; Congenital heart disease; Endoplasmic reticulum; GABA agonist; Hypoxia; Lysosomes; Mitochondrial dysfunction; NMDA antagonist; Neuroapoptosis; Neurocognitive impairment; Neurodevelopmental outcomes; Neurogenesis; Neurotoxicity; Pediatric anesthesia; Synaptogenesis.

Figure 1:

Potential underlying mechanisms of neurotoxicity involving suppression of signaling and excitotoxicity leading to neuronal apoptosis through intrinsic and extrinsic pathways. BDNF, brain-derived neurotrophic factor; GABAA, gamma-amino butyric acid receptor A which is an ionotropic receptor and ligand-gated ion channel; NMDA, N-methyl-D-aspartate is a glutamate receptor; tPA, tissue plasminogen activator is a serine protease.

Figure 2:

An overview of the key cellular targets in the pathophysiology of general anesthesia (GA)-induced developmental neurotoxicity. The key mechanisms by which GA cause harm to developing neurons are illustrated by red arrows and crosses. There are two main kinase routes that growth factors use to transduce survival signals, and GA prevents neurons from receiving these signals. Also, GA can cause cytochrome c exudation and cell death by directly inducing ROS production, genetic and epigenetic abnormalities, and mitochondrial instability. When neuroprotective techniques are activated, the black borders mark the locations at which neurotoxicity is reversed. BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; ROS, reactive oxygen species.

Figure 3:

A schematic depicting the developmental neurodegenerative pathways brought about by anesthesia. Mitochondria, the endoplasmic reticula (ER), and lysosomes are the key components of three different pathways: (i) Anesthesia-induced activation of inositol 1,4,5-trisphosphate receptor (InsP3R) is part of the ER-dependent pathway that causes an abrupt increase of cytosolic Ca²⁺ and excessive calcium (Ca²⁺) release. The result is a decrease in the levels of bcl-xL, a protein that protects mitochondria from cell death, which triggers cytochrome c leakage in the cytoplasm. To trigger the mitochondrial apoptotic pathway, which in turn causes DNA fragmentation and neuronal death, cytochrome c must first activate caspase-9 and caspase-3. (ii) In the mitochondria-dependent pathway, anesthesia-induced ROS up-regulation damages neuronal organelles, mitochondria, and the endoplasmic reticulum (ER) in particular, and causes excessive lipid peroxidation of lipid membranes. Overproduction of autophagosomes and a rise in autophagic load result from the removal of damaged mitochondria, which can become an unmanageable source of reactive oxygen species (ROS) and cytochrome c, and damaged endoplasmic reticulum (ER), which can become an uncontrollable source of cytosolic calcium (Ca²⁺). (iii) A lysosome-dependent mechanism regulates Ca²⁺ uptake into lysosomes through nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channels (TPCs). When the intraliposomal Ca²⁺ level rises, lysosomal activity is activated, leading to the creation of autophagic vacuoles, lysosomal and autophagosome fusion, and neuronal “self-eating.” It is not yet known if anesthesia directly affects lysosomal activation (via NAADP-gated TPCs in particular), but it is thought that anesthesia indirectly causes it by increasing cytosolic Ca²⁺ from the ER.