Anesthesia and neurotoxicity to the developing brain: the clinical relevance

Transcription

1 Pediatric Anesthesia ISSN RISKS: REVIEW ARTICLE Anesthesia and neurotoxicity to the developing brain: the clinical relevance Andrew J. Davidson 1,2,3 1 Department of Anaesthesia, Royal Children s Hospital, Melbourne, Australia 2 Department of Paediatrics, University of Melbourne, Melbourne, Australia 3 Anaesthesia Research Group, Murdoch Childrens Research Institute, Melbourne, Australia Keywords anesthesia; toxicity; neonates; neurodevelopment Correspondence Andrew J. Davidson, Department of Anaesthesia, Royal Children s hospital, Flemington Road, Parkville, 3052 Vic., Australia andrew.davidson@rch.org.au Section Editor: Charles Cote Accepted 3 December 2010 doi: /j x Summary Laboratory work has confirmed that general anesthetics cause increased neuronal apoptosis and changes to the morphology of dendritic spines in the developing brains of animals. It is an effect seen with most volatile anesthetics as well as with ketamine and propofol. The effects are dose dependent and seen over particular periods of early development. There is some evidence that rodents exposed to anesthesia during infancy have delayed neurobehavioral development. There are inherent limitations in translating the preclinical data to human practice but the data cannot be ignored. Some human clinical studies have found evidence for an association between major surgery and changes in neurobehavioral outcome, although the evidence is less clear for minor surgery. These associations are certainly at least partly because of factors apart from anesthesia, such as coexisting pathology or the effect of surgery itself. Other clinical studies have found no evidence for an association between surgery and outcome. These studies are also not without limitations. Thus it remains unclear what role anesthesia exposure in infancy actually plays in determining neurobehavioral outcome. To date studies can neither confirm that anesthesia plays a role nor rule it out. Introduction A great deal has recently been written about apoptosis and neurotoxicity of anesthesia to the developing brain. There is increasing evidence that the effect is real in animal models but what is the evidence that exposure to anesthesia alters outcome clinically? The emergence of the issue The finding that general anesthetics trigger apoptosis in developing brain was made almost serendipitously when examining the role of NMDA and other receptors in the etiology of neuroprotection and neurotoxicity (1,2). These findings sparked intense debate; but apart from the animal data several other factors have contributed to the prominence of discussion about neurotoxicty. Parents are naturally concerned about the developmental impact of exposure to drugs in their newborn. During the entire pregnancy women and healthcare professionals are wary of taking or prescribing medication because of the effects that the drugs may have on development. While concern is greatest during organogenesis in early pregnancy, development does not simply cease at birth, and therefore that concern does not, and perhaps should not go away the day the child is born. While we need to be careful not to unduly alarm parents, we would also be very unwise indeed to summarily dismiss any of their concern over potential toxicities of anesthetics, or of any other drugs we administer. There is also an increasing amount of interest and research into all the peri natal factors which may influence neurobehavioral outcome in children. Exposure 716 Pediatric Anesthesia 21 (2011) ª 2011 Blackwell Publishing Ltd

2 to ethanol during pregnancy is one well-known risk factor, but increasingly many other drugs and environmental exposures have been investigated. For example magnesium is one agent which has been shown to cause neuronal apoptosis when given in high doses in the animal model. Apart from exposures to drugs and environmental toxins, there is also interest in the effect of illness, surgery and other major medical interventions in the newborn period. The evidence that any of these factors directly influence outcome is still mixed and hotly debated. In this setting, it is thus not surprising that anesthesia is one exposure that is under investigation. However, it must be remembered that anesthesia is indeed just one of many factors which have been suggested to have a role in neurodevelopmental outcome, and with so many potential determinants, it will inevitably be very difficult to isolate any role that anesthesia may indeed have. Animal data It is now clear that in the experimental animal model exposure of developing brain to most general anesthetics causes some degree of neuronal apoptosis (3 7) as well as changes in dendritic morphology (8 10). Ketamine has also been shown to result in changes in the spinal cord (11). The changes are dose dependent and there is a window when the brain is most vulnerable. Changes in dendritic morphology occur over a more prolonged period than neuronal apoptosis; anesthesia induced neuronal apoptosis occurring in a period which may be equivalent to late pregnancy and the neonatal period while dendritic changes occurring in a period possible equivalent to early childhood. Changes have been reported in the sub human primate as well as in the rodent (12,13). Translating findings across species is inherently problematic so the most relevant studies are those carried out in the primate model. In the first primate study, four groups of monkeys were exposed to ketamine (12). Pregnant mothers at 122 days of gestation were exposed to 24 h of ketamine, 5- and 35-day-old monkeys were exposed to 24 h of ketamine, and lastly 5-day-old monkeys were exposed to 3 h of ketamine. Increased apoptosis was only seen in the monkeys at 122 days gestation and 5 days of age that were exposed to 24 h of ketamine, with no increased apoptosis seen in the 35-dayold monkeys or the 5-day-old monkeys exposed to only 3 h of ketamine. Large doses of ketamine were used as monkeys need large doses of ketamine to have any sedative or anesthetic effect. Indeed for most intravenous anesthetics both rodents and monkeys require considerably higher doses for an effect. In contrast, there is very little variation across species in dose required for an effect with volatile anesthetics. In a more recent study Brambrink et al. (13) demonstrated increased neuronal apoptosis after 5 h of % inhaled isoflurane in 6-day-old rhesus monkeys. This is close to 1 MAC for a monkey, and also close to 1 MAC for humans (I MAC in human neonates and infants is about %). The mechanism underlying anesthesia induced neuronal apoptosis and change in dendritic morphology is unclear, but may be attributed to reduced synaptic activity which results in a reduction in trophic factors such as BDNF, or it may be attributed to excitotoxicty after upregulation of NMDA receptor (14). There is also some evidence, albeit inconsistent, that animals exposed to anesthesia in their infancy have subsequent deficits in learning and other behavioral changes (3,4,7). There are also some interesting data demonstrating some agents mitigate the effects of anesthesia induced apoptosis. Lithium (15), xenon (16) and dexmedetomidine (17) have all been shown to reduce the toxicity. In the animal model it is well recognized that anesthetic agents can have a neuroprotective role. It is therefore interesting to examine the relative neurotoxicity and neuroprotective role of anesthetics in settings where neuronal injury may be triggered from other causes. Few studies have done this. In some studies, low doses of ketamine (too low to cause apoptosis per se) were indeed found to reduce the injury and loss of function caused by inflammation (18,19). Translating animal data to clinical settings The laboratory research was not driven by recognized or well-defined associations between clinical anesthesia and subsequent neurobehavioral issues. This makes it particularly difficult to link the laboratory findings to clinical practice and there remain substantial questions when trying to translate these laboratory findings. Areas of uncertainty in translation to humans are: the exact period of vulnerability, the dose required to cause injury (animals require high doses of intravenous anesthetics and most studies have exposed animals to long periods of anesthesia), the clinical outcome likely to be seen, and the role of anesthesia among the other factors which contribute to injury. It is never a given that laboratory findings are always clinically relevant; there are many examples of laboratory findings which are difficult to translate to clinical practice, for example, neuroprotection of general anesthetics. It is possible to argue that the laboratory findings are likely to be irrelevant to humans because of factors Pediatric Anesthesia 21 (2011) ª 2011 Blackwell Publishing Ltd 717

3 such as the relatively longer period of development and normal apoptosis in humans and the greater care given to humans during anesthesia, or it could be argued that humans have more capacity for recovery. But totally dismissing the laboratory findings because of theoretical limitations in translation is no more logical than blindly accepting them. In summary, the changes seen in laboratory work are indeed real and given the laboratory evidence and purported mechanisms, there is no reason to think that some degree of neuronal apoptosis would not be triggered by exposure to anesthetics in humans; especially given the primate data. The important question is the clinical relevance. Clinical evidence Prior to the animal data being published, several human cohort studies had demonstrated an association between major surgery in the neonatal period and poor neurodevelopmental outcome (20 23). Premature infants who underwent laparotomy had poorer neurodevelopmental outcome compared with matched controls (24), and children who are born with esophageal atresia have increased long-term learning emotional and behavioral problems compared with the general population (25). Many of the babies in these studies had other malformations, had major surgery or were very premature; all significant confounding factors when looking at anesthesia exposure and outcome. More recently, several large cohort study studies have been designed to specifically address the question of neurotoxicity of anesthesia to the developing brain. Wilder et al. (26) used a large established birth cohort maintained at the Mayo Clinic. Looking at children who had surgery or not before the age of 4 they found the risk of learning disability increased with the number of anesthetics a child had received. Interestingly, there was no evidence for an increased risk of association after just one exposure. The association between disability and multiple exposures to anesthetics persisted when adjustment was made for chronic illness. In a small pilot study, Kalkman et al. (27) tested the feasibility of using a cohort of children who had urological surgery at various ages. In their small sample, they found no evidence for an association between timing of surgery and neurobehavioral outcome, and concluded that a much larger study would be required to rule out any such association. Di Maggio et al. (28) performed a cohort study using the New York State medicaid records comparing children who had hernia repair before the age of 3 matched with those who had no surgery. After adjusting for several potential confounding factors, they found children who had hernia repair had twice the risk of diagnosis of behavioral or developmental disorder. Using the Mayo birth cohort Sprung et al. (29) compared children who were born by cesarean section under general anesthesia, those born by cesarean delivery under regional anesthesia and those born by vaginal delivery. They found that children born by cesarean delivery under regional anesthesia had less risk of a learning difficulty than those born by vaginal delivery and no difference between those born by cesarean under general anesthesia and vaginal delivery. The reason for this result is unclear. To explore the possibility that the regional blockade was protective, the same group went on to compare those born without general anesthesia by vaginal, with and without regional analgesia, and found no difference in risk of learning disability (30). In a recent Dutch twin study, Bartels et al. (31) studied the association between anesthesia exposure and school performance in 1143 monozygotic twin pairs. In discordant twin pairs (where one twin was exposed to anesthesia and the other was not), there was no difference between twins in school performance. Limitations with clinical evidence It is proving to be a very difficult to interpret the clinical data from these studies. This is partly because the animal data cannot precisely inform the age of exposure that is important, the duration of anesthetic likely to cause injury and the outcome which is most likely to be relevant. The animal data suggest that exposure is most likely to be relevant during late pregnancy or early infancy. However, it is plausible that the period of vulnerability may be longer. Studies which include mostly older children are easier to perform, but may not answer the question if the period of vulnerability is indeed confined to pregnancy or the neonatal period. Similarly studies which find no evidence of association with short exposure may not be generalisable to longer periods of exposure, and studies finding evidence for an association with longer exposure may not be generalisable to short exposures. As children become older, they develop an increasingly complex array of skills and abilities, and more psychometric tests can be applied to evaluate ever more subtle changes in an increasing range of neurobehavioral domains. We do not know which domain is most likely to affected most by anesthesia related apoptosis. Summary scores like IQ, or coarse measures, such as diagnosis of developmental delay and 718 Pediatric Anesthesia 21 (2011) ª 2011 Blackwell Publishing Ltd

4 school grade may miss subtle effects confined to specific areas. By contrast, broad batteries of detailed tests are increasingly likely to find at least one association purely by chance. The delay between testing and exposure also raises logistic problems. As a child gets older, the tests are better able to detect a significant and permanent change. Testing children at an early age will only detect major neurological problems and psychometric tests in young children are poor at predicting later outcome. Thus prospective studies take several years and may suffer from loss to follow-up. Retrospective studies may be quicker, but exposure cannot be controlled and/or data of exposure may be incomplete, and the anesthesia techniques may be outdated. The largest problem, however, is one of confounding factors. Children do not have anesthesia for no reason. It is usually associated with surgery or a diagnostic procedure. The surgery may result in inflammatory or humeral stress that may itself influence outcome. Surgery may also be associated with metabolic, hemodynamic, and respiratory events that may influence outcome. Infants having surgery or diagnostic procedures are very likely to have pathology which will also influence neurobehavioral outcome. Infants who require surgery may be septic, premature or have genetic or chromosomal abnormalities; all of which can be associated with both developmental delay and the need for surgery. Large cohort studies may adjust for some of these confounding factors but such adjustment of known confounders is never perfect, and it is impossible to adjust for unknown confounding factors. Most importantly it is almost impossible to ever adjust for the surgery itself as children do not have surgery with no anesthesia. Using a twin study design minimizes the effect of environment and genetics on the association. However, even twin studies are not without possible bias. If there is a genetic predisposition to the condition that required surgery then those not having surgery, and hence not exposed may in fact be at greater risk of subsequent poor outcome as the child may suffer from the condition without the benefit of surgery; thus masking any toxic effect of the anesthesia (32). Lastly the significance of any anesthesia neurotoxicity may be even more difficult to unravel when we consider the potential benefits of anesthesia. It is well described that infants undergoing major surgery who have inadequate anesthesia or analgesia have a poorer outcome. It is presumed that surgery and pain result in harmful metabolic, immunologic and humoral responses that could at least partly be reduced by anesthesia and analgesia (33). Thus if we compare neurobehavioral outcome in neonates that have had major surgery the protective effect of anesthesia may result in those who have had larger doses of anesthesia having a better outcome than those who had light anesthesia, while in neonates who have only minimally invasive surgery any neurotoxic effect and hence poor neurobehavioral outcome may be greater in those who had the greater exposure to anesthesia compared with those who had a light anesthetic. In summary; so far currently published clinical studies cannot confirm or rule out the possibility that anesthesia-related neuronal apoptosis and dendritic changes may result in clinically relevant neurobehavioral changes. The NICU and PICU The operating room is not the only area where anesthetic neurotoxicity may be relevant. Ketamine and midazolam, both implicated in potential toxicity, are also frequently given in the NICU and PICU (34). In these settings, they may be given for much longer periods of time. However, determining the clinical relevance of any toxicity in these settings is perhaps even harder than for the operating room as these children often have multiple comorbidities which may also influence outcome. So far there is mixed evidence. A Cochrane review found some evidence for a worse short-term outcome in neonates that had prolonged midazolam infusion (35). By contrast, the Epipage cohort study found no evidence for an association between sedation exposure and outcome (36); however, in this study many children received opioids for sedation rather than midazolam. Where to from here for research There is at least one trial and several further cohort studies that are underway or recently completed (37 40). Although these studies have some of the inherent limitations mentioned above, the increasing volume of data from numerous different studies will still greatly assist in identifying which, if any children are at risk, and in what neurobehavioral domains changes are seen. This will inform future trials. Further animal data will continue to provide information on mechanism and potentially also assist in determining domains of neurobehavioral outcome most likely to be relevant. If neurotoxicity is found to be clinically relevant, animal data will guide prevention strategies. The International Anesthesia Research Society and U.S. Food and Drug Administration have launched a specific joint initiative (SAFETOTS) to fund and pro- Pediatric Anesthesia 21 (2011) ª 2011 Blackwell Publishing Ltd 719

5 mote further investigation into the issue of neurotoxicity of anesthesia and the developing brain. It is important to remember that even if anesthesia exposure is found to be clinically irrelevant, there is still the well-described association between major surgery in neonates and neurobehavioral outcome (20 23). As mentioned above, this association is likely to be attributed to many factors. Research should not just focus on the neurotoxicity of anesthesia. Many of the other factors which may contribute to poor outcome (such as pain, inflammation, stress and cardiorespiratory stability during surgery) are well within the domain of pediatric anesthetists. The question still remains how can we provide the best anesthesia and preoperative management for these children to reduce any neurobehavioral risk? Answering this question will be challenging and involve far more than just determining if anesthesia is toxic to developing brain. Clinical implications So what are the implications of the animal and clinical studies for clinical pediatric anesthesia? In short, there are still insufficient data to make firm and specific recommendations. Nonetheless, the U.S. Food and Drug Administration and the International Anesthesia Research Society have recently posted a summary of the issues on their web site ( smarttots/). They acknowledge that Research using juvenile animal models show that exposure to some anesthetics and sedatives is associated with memory and learning deficits and other neurodegenerative changes in the central nervous system. Insufficient human data exists to either support or refute the possibility that similar effects could occur in children and that Early medical research suggests that some anesthetic drugs may be safer than others when used with infants and children younger than 4 years old However, dangers to infants and children from anesthesia are unproven at this point. There is no direct evidence that anesthetics are unsafe for children. They conclude that Children do not undergo surgery requiring anesthesia unless the surgery is essential to their health. If a child needs surgery, postponing that surgery until the child is older than 4 years of age would likely create far more risk than proceeding with anesthesia and surgery as soon as necessary. Currently, there is no scientific basis for delaying essential surgery. Parents of children requiring surgery should consult an anesthesiologist or other qualified physician for advice about an individual child s situation. We do know that neonates are a higher risk group for respiratory and cardiovascular complications of anesthesia. Without better evidence that current anesthesia practice is indeed associated with poor neurobehavioral outcome because of neurotoxicity, it would be very unwise indeed to propose any change in technique which might increase the risk of these cardiovascular or respiratory complications. Similarly any decision to delay surgery or diagnostic procedures which require anesthesia should also be made with a clear understanding that any real added risk of delay is being weighed against a still nebulous and unknown risk of toxicity. When discussing the issues with parents we need to be cautious not to cause undue alarm, but we must also not be too quick to dismiss any concern. The animal data are real, and there is also some human evidence for an association between major surgery and neurobehavioral outcome, but at this stage the exact role that anesthesia plays in determining clinically relevant neurobehavioral outcomes remains very unclear. References 1 Ikonomidou C, Bosch F, Miksa M et al. 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