Editorial

Anesthesia and Neurodegeration: Where is the Missing Link?

Juan Carlos Ibla

Associate in Cardiac Anesthesia Children’s Heart Institute Children’s National Medical Center Correspondence address: 111 Michigan Avenue, N.W. Washington, DC 20010 Assistant Professor in Anesthesia and Pediatrics George Washington University, Washington D.C. Correo electrónico: jibla@cnmc.org

Recibido: agosto 15 de 2011. Enviado para modificaciones: agosto 17 de 2011. Aceptado: agosto 26 de 2011.

Advances in anesthetic management of pediatric patients now afford a safe clinical environment for the repair of complex congenital defects. Parallel evolution of technology in surgical approaches, constantly challenge the limits of physiology and demand the expansion of clinical practice to uncharted territories. This is clearly exemplified in the growing concern of the long-term safety of anesthetics agents in pediatric patients with multiple or prolonged exposures to certain groups of anesthetics. Over the past decade, cumulative experimental data in animals and clinical studies in humans suggest that anesthesia during critical stages of brain development can result in accelerated neurodegeneration with potential detrimental effects.

The effects of pharmacologic agents designed to antagonize the normal neurotransmission have been implicated directly in cognitive deficits related to learning skills and neurodevelopment. Specifically, N-methyl-D-aspartate (NMDA) receptor antagonist have been demonstrated in animal and in vitro models to accelerate mechanisms of apoptosis by allowing the cell to prematurely engage in the normal cell cycle, resulting in apoptosis and cell death. These studies have identified a dose dependent aberrant induction of cell cycle proteins Cyclin-D1, Cyclin-dependent Kinase 4, E2F1 and Bim in primary neurons co-incubated with the NMDA receptor antagonist Ketamine (1). Expression of these proteins correlated with known markers of apoptosis (caspase-3 expression) both in vivo and in vitro. Although there may be numerous mechanisms by which NMDA receptor antagonism promote early apoptosis in cultured cells, this data supports the theory that cell cycle activation may play an important role in the potential cognitive effect suggested by clinical studies using Ketamine as primary anesthetic agent. This study did not evaluate potential cognitive effects in animals receiving Ketamime and is limited to findings in cell culture and fixed animal brains.

Another group of agents commonly used in the anesthetic management of pediatric patients which enhances normal neurotransmission trough γ-aminobutyric acid (GABA) has been implicated in anesthesia-related neuroapoptosis. Studies in this area are of extreme interest since wildly use inhaled agents (Isoflurane); known for their safety profile in all age groups, now endure questions regarding their effect on the developing brain. Brambrick, et.al, describe a model using neonatal primates exposed to five hours of inhaled Isoflurane in tracheal intubated and mechanically ventilated animals. Using histopathologic methods, sections of the forebrain and midbrain were analyzed by immunohistochemistry demonstrating a substantial increase in the density of apoptotic neurons in animals exposed to Isoflurane compared to controls (32.5 apoptotic cells/mm3 versus 2.5 apoptotic cells/mm3, P < 0.008) (2). This remarkable effect was most notable in the visual cerebral cortex of Isoflurane anesthetized animals. Despite maintaining physiological homeostasis during the experimental period of exposure to Isoflurane, this data suggest that wide-spread and severe neuoroapoptosis can occur in the absence of hemodynamic changes and clear neurologic deficits. However, this study does not address the reversibility of any of these changes, and did not attempt to correlate the degree of neuroapotosis with any functional measure of brain activity. To date, Isoflurane has not been linked to temporary or permanent visual chances in humans, and raises the question whether the findings by Brambrick, et.al, are exclusive to the Rhesus Macaque brain. Moreover, It is unclear from this data that Isoflurane-induced neuroapoptosis documented by immunohistochemistry has long term significant cognitive consequences.

Numerous studies in children have attempted to evaluate the effect of anesthetics on cognitive or behavioral development. Some of these studies have focused on retrospective data of infants requiring single or multiple anesthetics and the statistical correlation with diagnosis of learning disabilities in reading, writing and math skills. In the study by Wilder, et al., a retrospective cohort of children requiring general anesthesia before the age of four years old was compared to matched controls who did not receive general anesthesia (3). Individuals who received a single anesthetic were not associated with the diagnosis of learning disability, however 2 or more anesthetics showed statistical correlation (hazard ratio = 1.59; 95 % confidence interval, 1.06-2.37, and hazard ratio = 2.60; 95 % confidence interval, 1.60-4.24, respectively). Although this data is suggestive of a temporal relationship between exposure to anesthetic agents and learning disability, it cannot causatively implicate any specific anesthetic agent or technique due to multiple confounding factors. One can speculate that children requiring multiple anesthetics may carry genetic factors that predispose them to learning disabilities, independently of their exposure to anesthesia.

Another such example is the hernia repair study by DiMaggio, et.al., in which a large cohort of individuals covered under the Medicaid system were retrospectively screen for diagnosis of behavioral disorders and hernia repair (4). The authors concluded that there was a positive and statistical significant association between hernia repair under the age of three years of age and increased risk for behavioral and developmental disorders (4.4 % versus 1.2 %). This study has several limitations in design and data collection that preclude a scientific association between any specific anesthetic agent, dosage or time of exposure of anesthetics to a defined cognitive disorder. The authors admit that the lack of data on both hernia and control groups regarding the degree of prematurity and the clinical conditions of ex-premature individuals while in the NICU are significant confounding factors, since premature children have higher incidence of developmental and behavioral disabilities at baseline.

Collectively these studies highlight the complexity of this issue and potentially help design studies aimed at measurable prospective targets and more mechanistic approaches. The Food and Drug Administration (FDA) designated a group of scientists and clinicians (Anesthetic and Life Support Drugs Advisory Committee) to evaluate the current body of information and to make recommendations regarding the true risk of anesthetics in children. The FDA advisory committee has met twice (2007 and 2011) and despite expanding clinical and basic science data suggestive of an association of anesthetic agents and behavioral disorders, concluded that at this time there is insufficient information to warrant any changes in pediatric anesthesia practice.

Despite the lack of clear association between exposure to anesthetic agents and developmental and behavioral disorders, practitioners administering these drugs to children must be aware of hidden potential side effects. The practice of Anesthesia is complex and requires the skilled use of a multitude of pharmacologic agents designed to control systematically the function of all body systems while surgery is performed. It is not surprising that such interruption of a delicate neonatal balance may result in future and long lasting consequences. The real question is what should we change and to what extent? While surgery in the fetus and neonates is part of routine pediatric surgical practices and withholding life saving procedures on this basis will be inappropriate, the limits of safety must be determined with utmost precision. A responsible anesthesia approach should continue to practice according to currently accepted guidelines, disclose to the public our critical understanding of the data and most importantly search for better ways to further study this issue.

1. Soriano SG, LiuQ, Li J, et al. Ketamine Activates Cell Cycle Signaling and Apoptosis in the Neonatal Rat Brain. Anesthesiology 2010;112:1155-63

2. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-Induced Neuroapoptosis in the neonatal Rhesus Macaque Brain. Anesthesiology 2010;112:834-41

3. Wilder RT, Flick RP, Sprung J, et al. Early exposure to Anesthesia and Learning disabilities in a population-based birth cohort. Anesthesiology 2009;110;796-804

4. DiMaggio C, Sun LS, Kakavouli A, et al. A Retrospective Cohort Study of the association of Anesthesia and Hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol 2009;21:286-91