A cognition-enhancing drug called CX546 prevents the neurodegenerative effects of repeated anaesthesia in infant mice by promoting neuronal changes associated with learning and by protecting neurons from death.
Millions of children have surgery under general anaesthesia each year. Studies of infant animals show that neurodegeneration and long-term neurobehavioural impairments arise when general anaesthesia is used at crucial periods of brain development, especially following high doses and prolonged exposures to anaesthetics1. Studies in humans have been controversial — some have reinforced these findings, particularly among infants who have had multiple anaesthetics and surgeries2, whereas a case–control study3 and an interim analysis4 of a recent randomized trial have been more reassuring. Writing in Science Translational Medicine, Huang et al.5 report that a drug called CX546 confers neuroprotection in infant mice that are repeatedly exposed to the anaesthetic molecule ketamine.
Ketamine is thought to act predominantly by blocking signalling through NMDA receptor proteins6, which are activated by the excitatory neurotransmitter molecule glutamate. The authors examined the effects of ketamine anaesthesia on neuronal activity in the brains of infant mice. In vivo imaging experiments revealed that neuronal activity decreased during post-anaesthesia recovery in treated animals compared to untreated animals. Analysis of proteins at the synaptic junctions between neurons showed that, after repeated anaesthesia, expression of NMDA receptors was reduced in adulthood, as was expression of another class of glutamate receptor proteins, AMPA receptors.
CX546 is part of a group of cognition-enhancing drugs called AMPAkines that assist excitatory neurotransmission through AMPA receptors. Huang and colleagues found that CX546 prevented ketamine-induced death of brain neurons in infant mice, restored the expression of AMPA and NMDA receptors, and preserved neuronal activity in vulnerable brain regions. Moreover, the drug improved neurobehavioural outcomes, for example by rescuing the learning deficits that are associated with repeated ketamine anaesthesia (Fig. 1). Finally, the authors showed that CX546 partially rescued the remodelling of dendritic spines — tiny neuronal structures whose formation and elimination are crucial for processes such as learning. These structures cannot be correctly remodelled following repeated ketamine anaesthesia7,8.
Glutamate is the most prominent excitatory neurotransmitter in the central nervous system, and plays a crucial part in the processes of neural-circuit strengthening (through sustained activity) and elimination (through weak activity). CX546 enhances glutamate-mediated neurotransmission and strengthens circuits by increasing neuronal activity. This is probably how the drug provides neuroprotection when it is given immediately after the periods of low neuronal activity that follow repeated ketamine anaesthesia.
Several AMPAkines are already in clinical trials in adults as treatments for a range of conditions, including Parkinson's disease, schizophrenia and autism9. Huang et al. speculate that CX546 might hold promise as a therapy to prevent neuronal defects in human infants undergoing surgery and anaesthesia.
Widely varying recommendations and mitigation strategies have been proposed in response to the debate around anaesthetic-induced neurotoxicity in human infants10. In 2012, a public–private collaboration between the US Food and Drug Administration and the International Anesthesia Research Society, called SmartTots, recommended delaying elective surgery that uses general anaesthesia until patients are at least three years old whenever possible11. Subsequently, these authorities amended their recommendations to advocate balancing the risks and benefits to guide individual treatment decisions12.
For many types of paediatric surgery, such a delay is either not feasible or would probably do more harm than good. For instance, delayed repair of congenital heart defects could cause death or neurological deficits — a much greater risk than the potential consequences of exposure to a general anaesthetic. Similarly, many head and neck procedures performed during infancy and early childhood foster optimal neurodevelopment by correcting impairments in hearing, vision, speech or feeding, or by removing airway obstructions. In these cases, avoiding general anaesthesia is simply not practical. However, local or regional anaesthesia can sometimes be used to reduce dose requirements for general anaesthetics, to provide postoperative pain relief, or, in selected cases, to act as a primary anaesthetic4.
Alternative anaesthetic agents such as dexmedetomidine and xenon are currently under investigation for use in the clinic, on the basis of animal data13 suggesting that they cause less neurotoxicity than ketamine or the widely used inhalation anaesthetics sevoflurane and isoflurane. Dexmedetomidine and xenon are not complete anaesthetics by themselves at clinically achievable doses, and there are some practical barriers to implementation. Nonetheless, both hold some promise for drastically reducing the doses of conventional anaesthetics that are required to maintain a general anaesthetic state.
Several questions should be addressed before testing CX546 in clinical trials. First, is the neuroprotective action of CX546 specific for ketamine, or can the drug also protect against anaesthetics that act on different neuronal circuits? Second, how crucial is the timing of CX546 administration for its neuroprotective effect? Huang et al. gave CX546 to infant mice after anaesthesia, but delivering it during anaesthesia and surgery might change the dose requirements.
Third, because AMPAkines have been shown to stimulate respiration14, it is possible that the neuroprotective benefit of CX546 is partly due to respiratory stimulation. This in turn remedies the low levels of oxygen and high levels of carbon dioxide in the blood that could be induced by ketamine and other anaesthetics. Huang et al. did not analyse respiration during or after anaesthesia, so this remains to be investigated. Finally, the potential adverse effects of exposing brains to CX546 during crucial periods of their development must be assessed.
Preventive medicines have previously caused considerable harm15. For a medication to be beneficial in a preventive role, the average number of patients that can be treated before one person is harmed (the 'number needed to harm') must be extremely high, and the average number of patients who must be treated before one extra person benefits compared to the previous regime (the 'number needed to treat') must be comparatively low. Clinical-trial designs for a CX546 neuroprotection study in infants undergoing surgery would face serious challenges16, and would require an extensive preclinical toxicology programme that tested infant animals from several species.
From the standpoints of ethics, risk–benefit and effect size, it might be appropriate to conduct a clinical trial among infants who are already having repeated or prolonged surgical procedures or who require long-term sedation. These infants have complex and varied medical conditions and a range of confounding factors that would make a prevention trial difficult, but not impossible. It would be unethical not to use a trial design that is randomized, double blind, prospective (one that studies subjects after enrolment, rather than retrospectively) and controlled15,16.
Huang et al. are to be commended for an innovative study, which introduces a plausible, mechanism-based potential preventive treatment for anaesthetic-induced neurotoxicity in infants. Their work adds to our understanding of the mechanisms that underpin ketamine's activity, its effects and the potential interventions that could optimize neurodevelopment in infants undergoing surgery and anaesthesia.
Disma, N., Mondardini, M. C., Terrando, N., Absalom, A. R. & Bilotta, F. Paediatr. Anaesth. 26, 6–36 (2016).
Wang, X., Xu, Z. & Miao, C.-H. PLoS ONE 9, e85760 (2014).
Sun, L. S. et al. J. Am. Med. Assoc. 315, 2312–2320 (2016).
Davidson, A. J. et al. Lancet 387, 239–250 (2016).
Huang, L., Cichon, J., Ninan, I. & Yang, G. Sci. Transl. Med. 8, 344ra85 (2016).
Brown, E. N., Purdon, P. L. & Van Dort, C. J. Annu. Rev. Neurosci. 34, 601–628 (2011).
Hayashi, H., Dikkes, P. & Soriano, S. G. Paediatr. Anaesth. 12, 770–774 (2002).
Vutskits, L., Gascon, E., Tassonyi, E. & Kiss, J. Z. Toxicol. Sci. 91, 540–549 (2006).
Urban, K. R. & Gao, W.-J. Front. Syst. Neurosci. 8, 38 (2014).
Rappaport, B. A., Suresh, S., Hertz, S., Evers, A. S. & Orser, B. A. N. Engl. J. Med. 372, 796–797 (2015).
Maze, M. Can. J. Anaesth. 63, 212–226 (2016).
van der Schier, R., Roozekrans, M., van Velzen, M., Dahan, A. & Niesters, M. F1000Prime Rep. 6, 79 (2014).
Sackett, D. L. Can. Med. Assoc. J. 167, 363–364 (2002).
Davidson, A. J. et al. Paediatr. Anaesth. 25, 447–452 (2015).