Introduction
More than 20 millions of patients each year have surgeries in the USA. The majority of these surgeries are performed under general anesthesia. About 80% of them receive volatile anesthetics as their primary anesthetics [
1]. Since the first use of ether, a volatile anesthetic, in 1842, volatile anesthetics have be the major class of general anesthetics used in the clinical practice for near 160 years.
Although it is still controversial among the experts, it is generally accepted that general anesthesia minimally includes the following components: unconsciousness, insensateness, analgesia and amnesia. Many experts will also add muscle relaxation and bluntness of cardiovascular response to surgical stimulation into the components of general anesthesia. Volatile anesthetics, unlike most intravenous anesthetics, have pharmacological properties to provide all components of general anesthesia [
2]. Thus, volatile anesthetics are full general anesthetics and, theoretically, single volatile anesthetic can be used to provide a patient with full general anesthesia for surgery. In addition, volatile anesthetics take effects very quickly. Most patients anesthetized by these drugs recover smoothly and quickly. With the aid of modern equipment, their use is very easy and their concentrations can be accurately monitored. For these reasons, volatile anesthetics have been popular drugs used in clinical practice. Modern volatile anesthetics that are used in the USA include isoflurane (CHF
2-O-CHCl-CF
3), sevoflurane (CH
2F-O-CH-(CF
3)
2) and desflurane (CHF
2-O-CHF-CF
3). Halothane (CF
3-CHBrCl) was used clinically for more than 40 years and started to be phased out during 1990s as newer volatile anesthetics become popular. All of these volatile anesthetics are halogenated hydrocarbons.
In addition to the anesthetic properties, volatile anesthetics have been thought to have neuroprotective effects for a long time [
3,
4]. Although the potential for volatile anesthetics to induce cell injury has been reported previously, there is a recent surge of concern on the safety of volatile anesthetics [
5‐
7]. These two possible effects of volatile anesthetics, neuroprotection and neurotoxicity, and their implications in clinical practice will be discussed here. A brief overview of mechanisms of general anesthesia will be provided because providing general anesthesia is the main indication for using volatile anesthetics in humans and animals and this overview will facilitate the discussion of volatile anesthetics-induced neuroprotection and neurotoxicity.
Overview of mechanisms for volatile anesthetics-induced anesthesia
Although general anesthetics are among the most commonly used drugs in clinical practice, the mechanisms for them to induce anesthesia are not fully understood. An early theory to explain anesthesia mechanism for volatile anesthetics is the Meyer-Overton rule [
8]. It states that anesthetic potency increases with lipid solubility. This theory implies that general anesthetics are dissolved in the lipid fraction of brain cells to change the activity of these cells, which leads to anesthesia. Strong evidence to support the Meyer-Overton rule is the finding that there is a linear relationship between the solubility of volatile anesthetics in olive oil and their anesthetic potency [
8]. Although the Meyer-Overton rule was the dominant theory to explain general anesthesia for many decades, many findings have questioned the correctness of this theory. For example, enantiomers of anesthetics have the same lipid solubility but different anesthetic potencies [
9]. There are also many non-immobilizers that are similar to volatile anesthetics in chemical structures and lipid solubility but do not have significant anesthetic properties [
10].
A very popular theory developed in the last 3 decades to explain general anesthesia is the protein hypothesis. It states that general anesthetics bind and act on specific proteins to change their functions and cell activity, which results in anesthesia [
11]. Consistent with this hypothesis, functions/activities of numerous proteins have been found to be affected by anesthetics. These proteins include receptors, ion channels and neurotransmitter transporters whose changes in functions can alter the activity of the brain cells [
2,
11,
12]. Since there are excitatory and inhibitory neurotransmissions in the central nervous system (CNS), a simply view of the protein hypothesis is that general anesthesia is induced by inhibiting the excitatory neurotransmission and/or enhancing the inhibitory neurotransmission. Since glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitor neurotransmitters, the role of their receptors in general anesthesia has been a focus of study in the last 3 decades [
2,
11,
13].
The most convincing data obtained so far are on GABA receptors, especially the GABA
A receptors. Multiple studies have shown that general anesthetics at clinically relevant concentrations enhance GABA receptor activity. Specific target sites in the receptors have been extensively studied by using site-directed mutagenesis [
13,
14]. It has been shown that S270 in the α2 subunit of the GABA
A receptors is critically important for the enhancement of GABA
A receptor activity by volatile anesthetics [
15]. Mice with mutation on this amino acid residue have a reduced sensitivity to isoflurane [
16]. Also, various studies with other mutations of the GABA
A receptors in mice have suggested the importance of these receptors in anesthetic effects [
14]. Finally, GABA
A receptor antagonists have been shown to reverse anesthetic effects [
17].
A few lines of evidence have shown the involvement of glutamate receptors, especially the N-methyl-D-aspartic acid (NMDA) receptors (a subtype glutamate receptors), in the mechanisms of general anesthesia. General anesthetics at clinically relevant concentrations can work as NMDA receptor antagonists [
13,
18]. Knockout of a subunit of the NMDA receptors in mice significantly reduces the anesthetic potency of nitrous oxide, an inhalation anesthetic [
19]. Finally, blockage of NMDA receptors has been considered as the major mechanism for the effects of ketamine [
20], an intravenous anesthetic.
Multiple other proteins, such as voltage-gated channels, background channels and neurotransmitter transporters, may be anesthetic targets [
2,
12,
13,
21]. This implication is mostly based on the evidence that anesthetics affect the activity of these proteins. In some cases, limited in vivo animal data are available to support their role in anesthesia mechanism. However, additional evidence is needed to establish this role for most of these proteins.
Associated with the protein hypothesis, identifying the mechanisms of general anesthesia at a system level has been a research focus in recent years. General anesthesia has been commonly described as "putting patients to sleep" in a layman term. In fact, sleep and general anesthesia share many features [
22]. For example, the electroencephalographic patterns of patients who are in non-rapid eye movement sleep or under general anesthesia are very similar [
22‐
24]. Their brain functional images are similar, too [
22,
25,
26]. However, there are significant differences between normal sleep and general anesthesia. For example, it is easy to wake up a person from sleep. Consciousness recovery from general anesthesia can be achieved only after the anesthetics are eliminated from the brain. In supporting this system-based and sleep-like view of general anesthesia mechanisms, injection of the GABA
A receptor agonist muscimol into the tuberomammillary nucleus, a brain region that is involved in sleep, but not the surrounding brain structures, causes hypnosis to rats [
17]. This finding suggests that general anesthesia involves specific target proteins in specific brain regions.
Prospective
Volatile anesthetics have been used in clinical practice for near 160 years and are still the most commonly used anesthetics worldwide. There are at least three very active research fields regarding volatile anesthetic effects in the CNS: anesthesia mechanisms, anesthetics-induced neuroprotection and neurotoxicity. The latter two effects seem contradictory to each other. Although there is solid evidence from numerous studies for volatile anesthetics-induced neuroprotection in animals, clinical data to support this effect are relatively weak. Data on volatile anesthetics-induced neurotoxicity in animal studies are accumulated rapidly. However, there are no human data for this effect yet. There is no prospective and randomized clinical trial yet to evaluate volatile anesthetics-induced neuroprotection or neurotoxicity. Such data may be very difficult or even impossible to get for anesthetics-induced neurotoxicity because it is not ethical to anesthetize a large number of people to determine anesthetic neurotoxicity. Although data from surgical patients may provide some hints on this effect, it is not possible to separate the anesthetic effects from the effects of many other factors associated with surgery. On the other hand, it is possible to design a clinical study to determine volatile anesthetics-induced neuroprotection by using non-surgical patients.
Logically, it is not difficult to understand that volatile anesthetics can have both neuroprotective and neurotoxic effects. It is often true that everything in our daily lives has two sides: the good and bad sides. For example, an appropriate amount of exercises is good for health. However, over-exercise is harmful. Volatile anesthetic preconditioning- and postconditioning-induced neuroprotection often requires anesthetic exposure for less than 1 h in animal studies [
46]. This length of exposure has not been found to cause significant cell death. The shortest exposure for volatile anesthetics to cause brain cell injury is 2 h in both in vivo and in vitro studies. Most of them have anesthetic exposure for 4 h or longer [
5,
71].
Cell responses may be different when they are exposed to anesthetics in the presence or absence of insult/stress. Studies have shown that anesthesia/anesthetics reduce stress responses of surgical patients [
96]. However, unnecessary inhibition of baseline cell activity by anesthetics, as is the case for almost all laboratory studies on the anesthetics-induced neurotoxicity, may cause imbalance of the cell activity, which ultimately leads to cell injury. Since virtually almost all currently used anesthetics have been shown to cause brain cell injury in the laboratory studies [
5,
71], one has to wonder what anesthesiologists can use to anesthetize the patients and how reliable those laboratory studies are to simulate clinical situations. In addition, clinicians have to weigh the risk and benefit of using general anesthetics for surgical patients. Clearly, general anesthesia is necessary and beneficial in most of these cases.
Acknowledgements
This study was supported by a grant (R01 GM065211 to Z Zuo) from the National Institutes of Health, Bethesda, Maryland, by a grant from the International Anesthesia Research Society (2007 Frontiers in Anesthesia Research Award to Z Zuo), Cleveland, Ohio, by a Grant-in-Aid from the American Heart Association Mid-Atlantic Affiliate (10GRNT3900019 to Z Zuo), Baltimore, Maryland and the Robert M. Epstein Professorship endowment, University of Virginia.
Competing interests
The author declares that they have no competing interests.
Authors' contributions
This manuscript was solely prepared by ZZ, MD, Ph.D.