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Correspondence  |   October 2005
The “Anesthetic Cascade”: Fact or Fiction?
Author Notes
  • University of Tuebingen, Tuebingen, Germany.
Article Information
Correspondence
Correspondence   |   October 2005
The “Anesthetic Cascade”: Fact or Fiction?
Anesthesiology 10 2005, Vol.103, 904-905. doi:
Anesthesiology 10 2005, Vol.103, 904-905. doi:
To the Editor:—
In a recent issue of Anesthesiology, John and Prichep1 outlined a neurophysiologic theory of anesthesia. According to this theory, loss of awareness and amnesia are produced in six steps. In steps 1 and 2, depression of the brainstem reticular activation system causes diminution of availability of acetylcholine, resulting in decreased reactivity of the limbic system and block of memory storage. In steps 3 and 4, further depression of the reticular activation system results in closure of thalamic gates, thereby blocking reverberations in the thalamocortical system. Finally, in steps 5 and 6, parietal–frontal transactions are blocked, prefrontal cortex is depressed, and unconsciousness occurs.
After this sequence of events, brainstem cholinergic neurons should be significantly depressed at subhypnotic and hypnotic anesthetic concentrations (steps 1 and 2), leading to decreased cholinergic activation of the thalamocortical system. However, studies on the effects of anesthetics on neurons in brainstem cholinergic nuclei report a moderate (approximately 20%) decrease in activity at anesthetic concentrations twofold higher than those producing sedation and amnesia.2 Furthermore, blockers of brain acetylcholine receptors should be potent hypnotics, if decreased cholinergic activation of the thalamocortical system is a central mechanism of anesthetic action. However, this is clearly not the case. Clinically used hypnotics such as propofol and etomidate do not induce unconsciousness via  blocking acetylcholine receptors.3 Taken together, the authors’ statement that anesthetic-induced sedation and amnesia are causally related to a decreased concentration of acetylcholine in the brain is not backed by experimental evidence.
In steps 3 and 4, it is assumed that further depression of the reticular activation system is resulting in closure of thalamic gates. Unlike most other anesthetics, etomidate and ketamine do not attenuate thalamic information transfer in the somatosensory system when applied at hypnotic concentrations.4,5 Obviously, depression of thalamic gating is not a necessary requirement for producing unconsciousness, as assumed by an “anesthetic cascade.” In addition, it is difficult to follow John and Prichep’s implicit assumption that different anesthetic agents produce unconsciousness via  the same neurophysiologic mechanism. This issue clearly needs careful elucidation.
In the last step of the model, it is proposed that prefrontal cortex is depressed to reduce awareness: The anesthetic cascade explains unconsciousness by a bottom-up approach: The starting point is in the brainstem. At higher concentrations, the prefrontal cortex gets involved. However, experimental data available so far seem to be better explained by a top-down approach. There is considerable evidence that cortical neurons are more sensitive to anesthetic treatment compared with neurons in the brainstem.3,6 
How might anesthetic agents work? Ion channels, highly sensitive to general anesthetics, exist in almost all parts of the central nervous system, including the neocortex, hippocampus, amygdala, thalamus, and spinal cord.7,8 There is increasing evidence that the amnestic, sedative, and hypnotic properties of anesthetic agents are mediated by molecular targets located in diverse neural networks. For example, studies in knockout mice showed that a specific γ-aminobutyric acid type A receptor subtype, most prominently expressed in the hippocampus, is involved in learning and memory.9 This receptor is significantly modulated by very small concentrations of isoflurane.10 Therefore, molecular targets located in hippocampal pyramidal cells most probably contribute to the amnestic properties of isoflurane.
What about anesthetic-induced sedation? Benzodiazepines and intravenous anesthetics produce sedation via  γ-aminobutyric acid receptors, present in the cerebral cortex in high densities.11,12 There is a linear relation between the reduction in metabolic blood flow that occurs during propofol-induced hypnosis and the known regional benzodiazepine binding sites, suggesting that cortical γ-aminobutyric acid receptors mediate anesthetic-induced depression of cortical networks in humans.13 A similar conclusion has been drawn from animal studies. Recent investigations showed that neocortex is a major substrate of sedative and hypnotic concentrations of volatile anesthetics.6 The presence or absence of brainstem cholinergic nuclei had no influence on the depressive effects of volatile anesthetics on spontaneous firing of cortical neurons. Similarly, anesthetic-induced alterations of rhythmic brain activity, in particular attenuation of γ oscillations or induction of θ/δ oscillations have been observed in isolated cortical circuits, in the absence of subcortical structures.14,15 All of these data indicate that sedation, and in part hypnosis, are largely mediated by molecular targets located in the cerebral cortex.
With the above arguments, I do not intend to state that brainstem cholinergic nuclei and sleep pathways are irrelevant in the context of anesthesia. They probably come into play. Instead, my criticism addresses the theoretical concept: John and Prichep’s theory is a unitary theory of anesthetic action. The authors do not assume that a single ion channel causes amnesia and hypnosis, but they assume that a single neural substrate does it. Approximately 10 yr ago, Kendig,16 Eger et al.  ,17 and Kissing18 proposed a different theory. They argued that anesthetics produce different aspects of anesthesia at different sites in the central nervous system by different molecular targets. That is, anesthesia is composed of elementary components, largely independent on each other. This “old” idea is in line with many recent findings. For example, the sedative and hypnotic actions of intravenous anesthetics can be distinguished by the subtype of γ-aminobutyric acid receptor that is involved.19,20 For example, amnesia and sedation are distinct components of anesthetic action that can be separated experimentally.21 All of these observations argue against a unitary brain mechanism producing the diverse aspects of anesthetic action in the central nervous system. They argue against something like an anesthetic cascade as well.
University of Tuebingen, Tuebingen, Germany.
References
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