Anaesthesia and Brain Development: What do We Know?
There is increasing evidence from animal models that exposure to general anaesthetics causes accelerated neuronal apoptosis in the developing brain. There is also human cohort data demonstrating an association between surgery in the neonatal period and poor neurodevelopmental outcome.
Animal evidence
A recent review has provided an excellent summary of the animal evidence1. The animal data originally arose from research into foetal alcohol syndrome. Several independent groups have now confirmed that widespread accelerated neuronal apoptosis occurs in neonatal rodents after exposure to a variety of anaesthetic agents including: isoflurane2,3, benzodiazepines4, N2O3 and ketamine4. Combinations of agents such as N2O, midazolam and isoflurane2 or benzodiazepines and ketamine4 cause a greater degree of apoptosis. Neuronal degeneration has also been demonstrated in vitro after exposure to isoflurane and propofol5. In rodents, several groups have also demonstrated that exposure to anaesthesia is associated with long-term behavioural changes, and learning and memory deficits2.
Mechanism
Apoptosis is the organized or programmed cell death. There are many triggers for apoptosis and some degree of neuronal apoptosis is normal during brain development. The exact mechanisms whereby anaesthetics trigger apoptosis are unclear although the receptors involved (GABA and NMDA) are the same as those seen with the apoptosis and neurodevelopmental changes after exposure to ethanol. The mechanism may be via alterations in neuronal activity. There are critical periods in early postnatal life when the normal development of neuronal circuits is activity-dependent, and alterations to activity in the developing nervous system produce effects that can have long term consequences. Alternatively the toxicity may be specifically related to age dependent changes in post receptor function or receptor morphology. Peak periods of apoptosis correspond to peak periods of receptor change; the NMDA receptor subunits differing in the neonatal period compared with adults, and the GABA receptor having different post receptor action.
Species
Early findings were criticized as experimental conditions may be construed to be significantly different to conditions experienced by human neonates. Differences included, concurrent oxygen, nutrition or blood glucose management, while other issues to consider in translating animal to human data include the therapeutic index of the agents and plasticity of human brain. However more recent studies have demonstrated that apoptosis occurs in spite of careful control of glucose and ventilation. Dose response studies have also been completed. The MAC for isoflurane in mice is 2.3% and apoptosis occurs with exposure to 0.75% isoflurane for 4 hours, 1.5% for 2 hours and 2% for one hour. Toxicity has now also been demonstrated in larger animals. Ketamine results in more apoptosis in rhesus monkeys exposed on post natal day 5-6 but not on day 356. Five day old piglets exposed to a combination of isoflurane, N2O and midazolam have 15-20 fold more apoptosis compared to controls, or piglets anaesthetised with just opioid (fentanyl)7.
In animal experiments the period of peak susceptibility corresponds to the peak in synaptogenesis (post natal day 7 in the rat). Although correlating stages of animal neural development with human brain development is imprecise, day 7 in the rat may be equated with the neonatal period in humans while the total period of synaptogenesis in humans runs from the third trimester to the age of 1 year. It is possible that as the human brain takes a longer time to develop, it may have an increased capacity for accommodating apoptotic injury without any clinically significant adverse effect to long-term neurological development.
Human cohort data
Several human cohort studies have demonstrated an association between surgery in the neonatal period and poor neurodevelopmental outcome8,9. Premature infants who underwent laparotomy had poorer neurodevelopmental outcome compared to matched controls10, and children who are born with oesophageal atresia have increased long-term learning emotional and behavioural problems compared to the general population. A large cohort study by the Victorian Infant Collaborative Group found a clear association between surgery in preterm babies and poor sensorineural outcome at 5 years of age11. There is also a link between surgery for patent ductus arteriosus (PDA) and outcome. Many of these babies have plenty of reasons for poor outcome apart from anaesthesia, including the condition requiring surgery, coexisting malformations, prematurity, sepsis, cardiovascular instability or the inflammatory and stress effects of major surgery itself. None of these studies provide evidence for an association between anaesthesia per se and poor outcome.
Solving the problem
It will always remain questionable if the animal evidence can be extrapolated to humans and existing human cohort data provides no clear link with anaesthesia, but the question is of sufficient concern to warrant further investigation. Parents were always reassured that anaesthesia has no long term effects on infants. It seems now that such reassurance may need to be qualified. The concept that drugs may influence long term outcome in babies is not new. The effects of drugs on the foetus are well recognised and many parents will diligently avoid all unnecessary drugs and chemicals during pregnancy. In contrast to most organs, the brain undergoes substantial development well beyond the usual period of organ development in the first trimester. It is therefore reasonable to seriously consider the effect of agents on the brain during infancy. The FDA is currently considering the issue and will soon release an advisory related to anaesthesia exposure in the neonatal period. A randomised trial, a twin cohort study and further primate work are all underway to address the safety of general anaesthesia in neonates.
The other major consideration is that neonates do not undergo elective surgery. Surgery can rarely be delayed. It is now well established that outcome after major surgery is worse without anaesthesia and analgesia. The risks of poor analgesia may far out weight the risks of triggering neuronal apoptosis. However in some circumstances regional anaesthesia provides a viable alternative to general anaesthesia. Also apoptosis has not been seen after large doses of opioid anaesthesia. It may be that opioid based anaesthesia provides the best way to ablate the stress related complications while also avoiding any potential apoptotic toxicity.
1. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007;104(3):509-20.2. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23(3):876-82.
3. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007;In press.
4. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;146(2):189-97.
5. Al-Jahdari WS, Saito S, Nakano T, Go to F. Propofol induces growth cone collapse and neurite retractions in chick explant culture. Can J Anaesth 2006;53(11):1078-85.
6. Zou X, Divine B, Sadovova A, et al. Ketamine-induced neurotoxicity in developing monkeys: a histochemical study. Society for Neuroscience Annual Meeting 2006, Georgia World Congress Centre.
7. Rizzi S, Carter L, Jevtovic-Todorovic V. Clinically used general anesthetics induce neuroapoptosis in the developing piglet brain. Society for Neuroscience Annual Meeting 2005, Washington Convention Center, Washington DC.
8. Walker K, Holland AJ, Winlaw D, Sherwood M, Badawi N. Neurodevelopmental outcomes and surgery in neonates. J Paediatr Child Health 2006;42(12):749-51.
9. Ludman L, Spitz L, Wade A. Educational attainments in early adolescence of infants who required major neonatal surgery. J Pediatr Surg 2001;36(6):858-62.
10. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999;15(7):496-9.
11. Surgery and the tiny baby: sensorineural outcome at 5 years of age. The Victorian Infant Collaborative Study Group. J Paediatr Child Health 1996;32(2):167-72.
Time of Presentation
1530
