Anesthesia-Induced Neurotoxicity in Pediatric Patients

Healthful Vitality | 04/07/2019 | By Dr. Sharoon David | Anesthesia-Induced Neurotoxicity in Pediatric Patients

Until the 1980s, it was considered a common practice to perform surgeries on paralyzed or awake infants and children without the administration of deep general anesthesia. The “Liverpool technique” was the common method of anesthesia used for neonates at that time. This technique comprised fundamentally of administering light general anesthesia, typically with nitrous oxide, and a muscle relaxant, such as D-tubocurarine (curare). Here we discuss about anesthesia-induced neurotoxicity in pediatric patients.

This practice was based on the centuries-old notion that infants, particularly those born prematurely, feel little or no pain because of the presence of an immature sensory nervous system. Moreover, the fear of an increased risk of adverse surgical outcomes associated with the use of anesthesia in the pediatric population further led to its avoidance in this age group. [1]

Growing research focusing on the clinical pharmacology

A growing body of research focusing on the clinical pharmacology of anesthetics and analgesics and the clinical outcomes associated with the use of these agents in neonates and infants has emerged over the past two decades. [2] As a result, anesthetic use in the pediatric population has now become an essential practice. Almost 1.5 million neonates receive general anesthesia for a surgical procedure every year. [3]

However, this does not mean that the use of anesthetics in pediatric patients carries no harm. Surgical procedures performed in pediatric patients are often extensive and difficult. Moreover, the significant developmental differences found in the physiology of neonates make the administration of safe anesthesia much more complex and challenging. [4, 5] Anesthesia-induced neurotoxicity in the pediatric population is another extremely important and concerning issue that has plagued health care professionals over the years.   

FDA safety warning

In the year 2016, the U.S. Food and Drug Administration (FDA) issued a safety announcement regarding the administration of anesthetics and sedatives in children less than 3 years of age. The warning stated that the exposure of these agents over multiple procedures or surgeries, or for lengthy periods of time may result in a negative effect on the brain development in children belonging to this age group. However, it was also suggested that a single, relatively brief exposure to anesthetics and sedatives in infants or toddlers was unlikely to affect learning or behavior negatively and that surgeries or procedures in this population should not be avoided or delayed when medically necessary. [6, 7]

Receptor: Gamma-aminobutyric acid (GABA) receptor, N-methyl-D-aspartate

The mechanism of action of all commonly used anesthetic and sedative drug classes involves binding either to the N-methyl-D-aspartate (NMDA) receptor, which is a subtype of glutamate receptor or to the gamma-aminobutyric acid (GABA) receptor. Volatile anesthetic gases, propofol, barbiturates, benzodiazepines, chloral hydrate, and etomidate are some of the examples of GABA-binding agents [8, 9], whereas, the NMDA-binding agents include ketamine and nitrous oxide [10, 11].

The glutamate and GABA neurotransmitter and receptor systems play a fundamental role in the process of neurodevelopment, which begins during the early weeks of gestation and continues throughout early childhood. [12] Due to the mechanism of action of commonly used anesthetic agents, it is quite plausible to think that they may have an effect on the rapidly developing immature brain. Indeed, several studies in animal models have confirmed that the commonly used anesthetic and sedative agents that either block glutamate receptors or increase the inhibitory GABA receptor activity lead to profound neurotoxic effects. [13, 14]

Neurodevelopment

Neurodevelopment involves rapid brain growth in addition to neuroapoptosis (a natural process involving the programmed cell death of unneeded neurons) and synaptic pruning. The process of neuroapoptosis prevents redundant, unused, or damaged neurons from cluttering the rapidly growing brain. Animal studies have shown that massive neuronal cell death by apoptosis may be caused by exposure to GABA agonists and NMDA antagonists. [15] Several studies in young animals have demonstrated that the exposure to general anesthesia and sedative drugs for over 3 hours has the potential of causing extensive loss of nerve cells of the developing brain, and these neurodegenerative changes may result in long-term effects on the learning and behavior of the animals. [14, 16-19]

However, so far there is limited human data available to determine the correlation between neurodevelopmental outcomes and early anesthetic exposure. Two clinical studies involving human participants have recently been published and are worth mentioning, as they may have significant implications in the field of pediatric anesthetic neurotoxicity.

The Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study

The Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study compared neurocognitive function in sibling pairs. The purpose of the study was to determine if the use of anesthetics in infants and children has a long-term negative impact on neurocognitive development. The study enrolled 105 sibling pairs. One of the siblings had received anesthesia in the past at the age of 3 years or younger for the surgical repair of inguinal hernia. The median duration of anesthesia was 80 minutes, with a range of 20 to 240 minutes. The other sibling had never had surgery or anesthesia before 3 years of age and was within 3 years of age range from the exposed sibling. Extensive neurocognitive testing was performed as the sibling pairs returned at the age of 8 to 15 years.

The results of the PANDA study indicated that there was no statistically significant difference in the full-scale IQ score among siblings with and without a single exposure to anesthesia before the age of 3 years. Secondary outcomes using mean scores of attention, memory, executive function, motor and processing speed, visuospatial function, language, or behavior were also found to be virtually identical among the two cohorts. [20]

The General Anesthesia vs. Spinal anesthesia (GAS) study

The General Anesthesia vs. Spinal anesthesia (GAS) study was an international randomized controlled trial that was conducted at 28 neonatal centers in multiple countries. The primary purpose of the study was to determine whether the administration of general versus spinal anesthesia in infants leads to equivalent neurodevelopmental outcomes. The study enrolled 722 infants (mostly boys) who were under 60 weeks of postconceptional age.

The subjects were randomized to spinal anesthesia with bupivacaine versus general anesthesia with sevoflurane for inguinal hernia repair. The mean duration of general anesthesia was 54 minutes. Intelligence and other neurodevelopmental measures were evaluated at the age of 5 years. Full-scale IQ was the primary outcome of the study and was not found to be statistically different among the two groups of subjects. Verbal, processing speed, and performance composite scores were also found to be equivalent. It was, therefore, interpreted that in comparison to awake-regional anesthesia, exposure to slightly less than 1 hour of general anesthesia in early infancy did not alter neurodevelopmental outcomes at the age of 5 years. [21]

The suggestions of the PANDA and the GAS studies

The results of the PANDA and the GAS studies suggest that single, brief exposure to general anesthesia may be safe in infants and children. However, the correlation between repeated or prolonged anesthetic exposure and adverse neurodevelopmental effects in pediatric patients is still not fully determined. Additional high-quality research in the area of pediatric anesthetic neurotoxicity is, therefore, required.    

Nonetheless, it is vital for all healthcare professionals to understand the known benefits as well as the potential risks associated with the use of anesthetics and sedatives in young children. The healthcare professionals should follow the principles of proper patient counseling and discuss in detail the pros and cons of administering general anesthesia with the parents of children who require surgical interventions. While the exposure to general anesthesia in pediatric patients may be associated with an element of risk, delaying a surgical procedure that is required for a life-threatening condition or performing the surgery without adequate anesthesia and sedation is definitely not an option. Yet, we need to explore more about anesthesia-induced neurotoxicity in pediatric patients.

Important points:

• Administration of anesthesia in pediatric patients is an essential practice.
• FDA has issued a warning regarding anesthesia-induced neurotoxicity in pediatric patients
• Animal studies confirm that anesthesia exposure may negatively affect neurodevelopment in young children
• The PANDA and the GAS studies indicate that single, brief exposure to anesthesia may be safe in infants and children
• There is limited human data available to determine the correlation between neurodevelopmental outcomes and prolonged or repeated anesthetic exposure
• Additional high-quality research in the field of pediatric anesthetic neurotoxicity is required.

References:

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