Elsevier

Experimental Neurology

Volume 272, October 2015, Pages 50-60
Experimental Neurology

Review
Neurodevelopmental implications of the general anesthesia in neonate and infants

https://doi.org/10.1016/j.expneurol.2015.03.028Get rights and content

Abstract

Each year, about six million children, including 1.5 million infants, in the United States undergo surgery with general anesthesia, often requiring repeated exposures. However, a crucial question remains of whether neonatal anesthetics are safe for the developing central nervous system (CNS). General anesthesia encompasses the administration of agents that induce analgesic, sedative, and muscle relaxant effects. Although the mechanisms of action of general anesthetics are still not completely understood, recent data have suggested that anesthetics primarily modulate two major neurotransmitter receptor groups, either by inhibiting N-methyl-D-aspartate (NMDA) receptors, or conversely by activating γ-aminobutyric acid (GABA) receptors. Both of these mechanisms result in the same effect of inhibiting excitatory activity of neurons. In developing brains, which are more sensitive to disruptions in activity-dependent plasticity, this transient inhibition may have longterm neurodevelopmental consequences. Accumulating reports from preclinical studies show that anesthetics in neonates cause cellular toxicity including apoptosis and neurodegeneration in the developing brain. Importantly, animal and clinical studies indicate that exposure to general anesthetics may affect CNS development, resulting in long-lasting cognitive and behavioral deficiencies, such as learning and memory deficits, as well as abnormalities in social memory and social activity. While the casual relationship between cellular toxicity and neurological impairments is still not clear, recent reports in animal experiments showed that anesthetics in neonates can affect neurogenesis, which could be a possible mechanism underlying the chronic effect of anesthetics. Understanding the cellular and molecular mechanisms of anesthetic effects will help to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. Therefore, in this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies.

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

References (167)

  • F.J. Kong et al.

    Fetal exposure to high isoflurane concentration induces postnatal memory and learning deficits in rats

    Biochem. Pharmacol.

    (2012)
  • S.N. Lee et al.

    Glutamate transporter type 3 knockout mice have a decreased isoflurane requirement to induce loss of righting reflex

    Neuroscience

    (2010)
  • G.A. Mashour et al.

    Mechanisms of general anesthesia: from molecules to mind

    Best Pract. Res. Clin. Anaesthesiol.

    (2005)
  • R.J. McMurtrey et al.

    Isoflurane preconditioning and postconditioning in rat hippocampal neurons

    Brain Res.

    (2010)
  • M.E. Ogle et al.

    Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1alpha

    Neurobiol. Dis.

    (2012)
  • J.W. Olney

    New insights and new issues in developmental neurotoxicology

    Neurotoxicology

    (2002)
  • M.G. Paule et al.

    Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys

    Neurotoxicol. Teratol.

    (2011)
  • V. Pesic et al.

    Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia

    Int. J. Dev. Neurosci.

    (2009)
  • C. Allene et al.

    Early NMDA receptor-driven waves of activity in the developing neocortex: physiological or pathological network oscillations?

    J. Physiol.

    (2010)
  • O. Altay et al.

    Isoflurane attenuates blood–brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice

    Stroke

    (2012)
  • J. Anrather et al.

    Biological networks in ischemic tolerance — rethinking the approach to clinical conditioning

    Transl. Stroke Res.

    (2013)
  • P. Arhem et al.

    Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling

    Neuropsychopharmacology

    (2003)
  • P.G. Barash et al.

    Clinical Anesthesia

    (2009)
  • P.E. Bickler et al.

    The inhaled anesthetic, isoflurane, enhances Ca2 +-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia

    Anesth. Analg.

    (2006)
  • P. Bittigau et al.

    Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • A. Boscolo et al.

    Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain

    Anesthesiology

    (2013)
  • A.M. Brambrink et al.

    Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain

    Anesthesiology

    (2010)
  • A.M. Brambrink et al.

    Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain

    Ann. Neurol.

    (2012)
  • A. Briner et al.

    Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis

    Anesthesiology

    (2010)
  • S.R. Burchell et al.

    Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury

    J. Investig. Med.

    (2013)
  • L. Cao et al.

    Isoflurane induces learning impairment that is mediated by interleukin 1beta in rodents

    PLoS One

    (2012)
  • H. Chen et al.

    Prolonged exposure to isoflurane ameliorates infarction severity in the rat pup model of neonatal hypoxia–ischemia

    Transl. Stroke Res.

    (2011)
  • D. Chen et al.

    Ion channels in regulation of neuronal regenerative activities

    Transl. Stroke Res.

    (2014)
  • S. Chen et al.

    An update on inflammation in the acute phase of intracerebral hemorrhage

    Transl Stroke Res

    (2015)
  • S. Chiao et al.

    A double-edged sword: volatile anesthetic effects on the neonatal brain

    Brain Sci.

    (2014)
  • M.T. Colonnese et al.

    NMDA receptor currents suppress synapse formation on sprouting axons in vivo

    J. Neurosci.

    (2005)
  • D.J. Culley et al.

    The memory effects of general anesthesia persist for weeks in young and aged rats

    Anesth. Analg.

    (2003)
  • P. De Koninck et al.

    Sensitivity of CaM kinase II to the frequency of Ca2 + oscillations

    Science

    (1998)
  • M. De Roo et al.

    Anesthetics rapidly promote synaptogenesis during a critical period of brain development

    PLoS One

    (2009)
  • C.J. DeFrances et al.

    National Hospital Discharge Survey: 2005 Annual Summary With Detailed Diagnosis and Procedure Data

    Vital Health Stat. Series 13, Data from the National Health Survey

    (2007)
  • C. Dezfulian et al.

    Clinical application of preconditioning and postconditioning to achieve neuroprotection

    Transl. Stroke Res.

    (2013)
  • J. Dobbing et al.

    Quantitative growth and development of human brain

    Arch. Dis. Child.

    (1973)
  • Y. Dong et al.

    The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels

    Arch. Neurol.

    (2009)
  • R.C. Dutton et al.

    Isoflurane causes anterograde but not retrograde amnesia for Pavlovian fear conditioning

    Anesthesiology

    (2002)
  • S.R. El Azab et al.

    Effect of VIMA with sevoflurane versus TIVA with propofol or midazolam-sufentanil on the cytokine response during CABG surgery

    Eur. J. Anaesthesiol.

    (2002)
  • R.P. Flick et al.

    Cognitive and behavioral outcomes after early exposure to anesthesia and surgery

    Pediatrics

    (2011)
  • R.P. Flick et al.

    Anesthetic-related neurotoxicity in the young and outcome measures: the devil is in the details

    Anesthesiology

    (2014)
  • J.A. Forsythe et al.

    Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1

    Mol. Cell Biol.

    (1996)
  • N.P. Franks et al.

    Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels

    Science

    (1991)
  • N.P. Franks et al.

    Molecular and cellular mechanisms of general anaesthesia

    Nature

    (1994)
  • Cited by (86)

    • Spatial and temporal alterations of developing oligodendrocytes induced by repeated sevoflurane exposure in neonatal mice

      2023, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Globally, millions of surgical children get benefits from general anesthesia every year [1].

    • Infected branchial cleft cyst in a newborn

      2022, Journal of Pediatric Surgery Case Reports
      Citation Excerpt :

      When seen two weeks later, surgical management of the BCA was discussed, including resection in the next 1–2 months to reduce risk of infection recurrence. As there was a risk of injury to other neck structures and of increased surgical complexity after an acute infection with residual inflammation, the team and family decided on watchful waiting [3–8]. Over the following months, the sinus drained intermittently so excisional surgery was performed at 11 months of age.

    • Bedside Intervention for Neonatal Hydrometrocolpos and Imperforate Hymen

      2022, Urology
      Citation Excerpt :

      Treatment of hydrometrocolpos under general anesthesia in the OR has increased risks and costs compared to bedside management. Neonatal exposure to general anesthesia can potentially impact the development of the central nervous system, which could lead to long-lasting changes in cognitive and behavioral functioning such as deficiencies in learning, memory, and social functioning.13 In addition, OR procedures can add significant expense with the high cost of facility fees.

    View all citing articles on Scopus
    1

    Authors made equal contribution to this paper.

    View full text