ReviewNeurodevelopmental implications of the general anesthesia in neonate and infants
Introduction
In medicine, pain is one of the most primary symptoms to avoid or treat. Whether the therapeutic approach involves opioids, non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, or in extreme cases, general anesthesia, the minimization of pain is always one of top priorities. This is the case both in humans and in animal models, in which the Institutional Animal Care and Use Committee (IACUC) explicitly requires the maximum reduction of pain in surgeries (Koch, 2003). It is not surprising that anesthesia has become such a prevalent component of the field of medicine, with a dedicated subset of specialists whose area of expertise is the administering and monitoring of anesthesia. In developed nations, general anesthesia comes standard with surgeries for both children and adult patients, although the decision to administer anesthesia to neonates remains contentious and situational. At least for adults, the complications are usually very minor, including nausea and vomiting in a small subset of patients, and mortalities only occur in 1:100,000 cases (Jenkins and Baker, 2003). The complications are far outweighed by the benefits of anesthesia, which spans beyond just analgesic effects. Anesthesia also encompasses sedation and muscle relaxation, which are both highly relevant both in and outside the realm of surgery. In neonates, the anesthetic effects may have long-term neurodevelopmental sequelae, which is the primary focus of this review.
Newborns receive anesthesia for a variety of reasons. Sometimes neonates need to undergo hernia repair or open chest surgery to fix congenital heart defects or pulmonary defects (Menghraj, 2012). Other times, newborn patients need to be anesthetized in order to be immobilized prior to receiving an MRI scan. Nevertheless, general anesthesia is usually reserved as a last resort in neonates. In fact, most neonatal males receiving circumcision surgeries remain unanesthetized. Aside from cost, general anesthesia carries potentially permanent drawbacks. There is an emerging body of evidence that indicates adverse long-term neurological effects of general anesthesia in the young susceptible brain (Flick et al., 2011, Flick et al., 2014, Ing et al., 2014, Sprung et al., 2012, Vutskits et al., 2012, Wilder et al., 2009). It is clear, both in animal models and to an extent through retrospective studies in human patients, that the effects of anesthesia are sensitively correlated with the age of exposure. In terms of behavior deficits, general anesthesia is most detrimental in the two extreme age groups, neonates/infants and the elderly. Both are similar in that they possess nervous systems that are more fragile. The developing brain is primed to undergo apoptosis in order to prune away redundant neurons and establish healthy neural circuitry, while the aged brain faces accelerated neurodegeneration due to senescence and buildup of deleterious byproducts, such as beta-amyloid (Aβ) protein. Both of these two groups are more susceptible to the neurodegenerative insults carried by general anesthesia, leading to widespread apoptotic neurodegeneration and learning impairments that are not otherwise observed in the adult age group (Culley et al., 2003, Erasso et al., 2013, Perouansky and Hemmings, 2009, Stratmann et al., 2009b). Interestingly, the effects are the stark opposite in the adult brain. Instead of inducing learning deficits, general anesthetics can actually reversibly enhance the learning function of 4–5 month old mice via an upregulation of the N-methyl-D-aspartate (NMDA) receptors, which promotes long-term potentiation (Rammes et al., 2009).
It is worth emphasizing that while animal studies have conclusively implicated the neurodegenerative effects related to early general anesthesia exposure, retrospective studies within human patient populations have not been able to conclusively and reproducibly demonstrate similar deficits. Furthermore, general anesthesia still confers many benefits, such as pain relief and muscle relaxation, which in some cases are essential to neonates undergoing surgery or medical imaging. This review aims to objectively compare the current body of evidence available for both animal and human studies in order to provide an updated assessment of the effects of general anesthesia on neurodevelopment, as well as to briefly provide the implications of these studies towards clinical practice.
Section snippets
Brief history of general anesthetics
The term “anesthesia” was first used in 1846 by Oliver Wendell Holmes, a Greek surgeon, to describe a patient who, after inhaling ether vapor, underwent surgery without any apparent suffering (Kissin, 1997, Nuland, 1989). General anesthesia is a combination of medicines that is inhaled or injected intravenously in order to induce a state of unconsciousness (also termed hypnosis) throughout the whole body (Grasshoff et al., 2005, Mashour et al., 2005). Under anesthesia, general anesthetics bring
The developing brain
The developing brain is in a dynamic state of establishing and strengthening neural connections; most of this neural network assembly occurs via activity-dependent mechanisms. The neural activity during periods of maximal synaptogenesis and neuronal pruning may contribute to the neural network organization (Ikonomidou et al., 1999, Poo, 2001). This process is especially prevalent during the developmental window in which axons are growing and finding appropriate targets, and corresponding
Neuroprotective effects of neonatal anesthesia
In previous reports from adult animals and patients, more and more data have shown that general anesthetics have a neuroprotective effect through prevention or reduction of apoptosis, neurodegeneration, traumatic brain injury, and ischemic injury (Burchell et al., 2013, Schifilliti et al., 2010, Wells et al., 1963, Yokobori et al., 2013, Yu et al., 2010). Sevoflurane preconditioning protects neurons and blood–brain-barrier (BBB) against brain ischemia (Anrather and Hallenbeck, 2013, Gidday, 2010
Behavioral and cognitive impairments associated with neonatal anesthesia
The following sections will focus on these four major groups of anesthetics that are commonly administered to neonates and infants: volatile anesthetics, ketamine, benzodiazepines, and propofol. We will review current literature about these agents to assess their neurodevelopmental effects, including learning, memory, and social behavior.
The plausible link between cellular neurotoxicity and cognitive impairments
If the neuronal death itself was directly linked to cognitive impairment, behavioral impairment would be expected immediately after anesthesia-mediated neuronal death. However, animal studies have shown that when anesthesia-induced cell death was observed, cognitive deficits did not occur until about 6 weeks after the exposure (Jevtovic-Todorovic et al., 2003, Satomoto et al., 2009, Stratmann et al., 2009b). Interestingly, these behavioral deficits, including social behavior and spatial learning
Potential therapeutic strategies and implication in clinical stage
One of the benefits of animal models is that they help us to probe into the mechanisms of neurotoxicity, due to the wide array of cellular and molecular biological techniques available. This can improve our understanding of the pathophysiology of anesthesia-associated neurodevelopmental deficits and provide clinical targets for future treatments. For the translational purpose, however, the animal models do not have optimal face validity, due to the differences in the developmental timeline
Summary and conclusion
The development of anesthetics has revolutionized modern medicine. Tens of millions of surgeries are performed under anesthesia every year in the US alone, approximately six million of which are on pediatric populations (DeFrances et al., 2007). Anesthetics can prolong the quality and longevity of human life by enabling increasingly complex surgeries and procedures. However, over recent years, the safety has come under contention after new evidence revealed that anesthesia exposure in immature
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Authors made equal contribution to this paper.