|Year : 2008 | Volume
| Issue : 1 | Page : 5
General Anaesthetic - Induced Neurotoxity
Editor, IJA, India
|Date of Web Publication||19-Mar-2010|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bajaj P. General Anaesthetic - Induced Neurotoxity. Indian J Anaesth 2008;52:5
General anaesthesia is one of the great advances of medicine and allows ever more complicated surgery to be performed safely, including on patients at the extremes of age. However miraculous, general anaesthesia is not without risk, a fact we and our patients acknowledge and accept to enjoy its benefits. But, is central nervous system toxicity one of those risks ? Our clinical experience says "no" but accumulating laboratory data say "yes".
Neurotoxicity is usually defined as a structural change or functional alteration of the nervous system resulting from exposure to a chemical, biological, or physical agent  . It can be acute, subacute, or silent (i.e., evident only months to years after exposure ), with the latter form being most controversial and difficult to prove. Vulnerability to neurotoxicity is especially high during development, when the blood brain barrier is not fully developed, neurogenesis and synaptogenesis are occuring at high rates, and neurotransmitters have different effects than they do in adult brain (e.g., GABA is excitatory ) and perform functions besides neurotransmission (e.g., regulate stem cell proliferation and differentiation). Well - known examples of agents highly toxic to the developing central nervous system include lead and ethanol. At the other extreme, the old brain may be vulnerable to neurotoxicity for different reasons. The mature brain, like the developing brain, contains immature cells that develop into neurons and get incorporated into functional neuronal circuits. It also has regions constantly remodeling synaptic connections in a rapid, highly dynamic process known as synaptic plasticity, which is the foundation of learning and memory and fundamental to healthy brain function. However, the old brain suffers from the ravages of age, including shrinkage of neurons, loss of various neurotransmitters and receptors, a markedly lower rate of neurogenesis and synaptogenesis, and accumulation of potentially toxic byproducts such as the Alzheimer's disease peptide, β amyloid (Aβ) ) Thus, the old brain has reduced reserve, meaning that, because of its limited ability to compensate, insults that would go unnoticed at a younger age may become evident in the form of functional impairments (e. g, congnitive decline ).In this sense, the old brain is also vulnerable to neurotoxicity. So, are general anaesthetics neurotoxins during development and/ or aging? General anaesthetics are obviously chemical and biological agents; indeed, they are among the most potent centrally acting drugs in common clinical use. They share the property of interfering with neurotransmission to the point of producing coma and do this largely by either positively modulating inhibitory GABA neurotransmission or antagonizing glutamate-mediated excitatory neurotransmission  .
A key point is that vulnerability to general -anaesthetic-induced neurotoxicity is not uniform throughout development. Vulnerability is maximal during the period of intense synaptogenesis otherwise referred to as the brain growth spurt ,, . This occurs at different times in different species. In humans, synaptogenesis and the brain growth spurt begin around midgestation and continue through the 2nd year of life  , meaning that this issue potentially has broad implications for patients requiring obstetrical or paediatric anaesthesia and surgery during these critical times. Not surprisingly, there is quite a bit of controversy and concern about it. ,, .
Considering that the developing brain is fundamentally different from the mature brain in a myriad of ways, there is likely to be more to it. Two of these differences are especially relevant to this discussion. First, neurogenesis, gliogenesis and synaptogenesis are much more robust in the developing than mature brain. In fact, an excess of cells is produced and those that are unsuccessful in making synaptic contacts are eliminated via the natural pruning process of apoptosis.  Second, whereas activation of GABA receptors mediates inhibition in the mature CNS, the opposite effect-depolarization and excitation - occurs in developing neurons.  Accordingly, one can hypothesize that general anaesthetics delivered at a critical time might trigger neuroapoptosis by unbalancing the normal relationship between excitation and depression, possibly interfering with neurotrophin- dependent survival  and signaling the brain that vast numbers of cells are unnecessary and should be eliminated. If this is true, it implies properties fundamental to general anaesthetic action may be the signals for millions of nerve cells to commit suicide in the developing brain.
Is the old brain similarly vulnerable? Probably not in the same way, for reasons given earlier, the adult brain is, in general, less vulnerable to environmental toxins than the developing brain. But, like the developing brain, the old brain makes new neurons , and has neurons constantly in the process of active remodeling and synaptogenesis. , These may be points of vulnerability but few studies have addressed the impact of general anaesthesia on these processes in the old brain. There are still reasons to worry. The brain loses the capacity for plasticity and neurogenesis over time, leaving the aged brain with less "reserve" meaning that small toxic events could have greater impact on brain function. In terms of acute neurotoxicity, ketamine and nitrous oxide, alone or in combination, produce vacuolization in cerebrocortical neurons (which corresponds to swelling of mitochondria and endoplasmic reticulum) of adult and aged animals, with the aged brain being more sensitive to ketamine and a nitrous oxide-ketamine drug combination.  The old brain also becomes susceptible to neurodegeneration over time. Alzheimer's disease (AD), a dementing, neurodegenerative disorder, is a good example; AD becomes more common with age, afflicting about 50% of elders aged 80-85 years. The pathophysiology of AD is hotly debated but the prevailing view is that β amyloid (Aβ). A small protein formed by cleavage of a larger precursor, amyloid precursor protein (APP), is a major player  . Soluble Aβ inhibits neurotransmission and is implicated in cognitive impairment that develops before the full blown disease,  if the Aβ burden is sufficiently large, as it is in AD, it deposits, forming amyloid plaques, induces a neuroinflammatory response, and kills neurons.  It is therefore of considerable interest that some general anaesthetic agents  affect the properties and processing of Aβ. Isoflurane and halothane at clinically relevant concentrations increase the oligomerization of Aβ in cultured nonneural cells and also increase its toxicity.  Likewise, isoflurane increases activity of β -secretase (BACE), the enzyme that forms Aβ, and induces Aβ -dependent apoptosis in cultured neural cells over expressing APP.  As such, it is clear that isoflurane and halothane can affect Aβ processing, change its physical properties, and augment its neurotoxic qualities, at least in vitro. To date, however, no studies have examined whether the same events occur in vivo, so the clinical relevance of these results are uncertain.
Indeed, talk of general anaesthetic-mediated neurotoxicity is alarming to those of us who administer general anaesthesia for a living- not to mention to our patients and their families. But let's be clear on what the data don't say. They don't say that general anaesthetics produce neurotoxicity in patients. No studies have demonstrated general anaesthetic-induced neurotoxicity in non-human primates, let alone humans, either neonatal or old, at clinically relevant dosages or durations of exposure.Given existing data, however, studies in nonhuman primates are urgently needed and are currently underway.
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