Therapeutic Effects and Anesthetic Depth
Although general anesthesia results in a multitude of physiologic alterations, there is no consensus among clinicians and researchers as to which actions are essential to the state of general anesthesia.18 Our view is that the common desired outcomes of general anesthesia include hypnosis (loss of awareness), amnesia (loss of memory), and immobility (suppression of movement in response to pain). Some have argued that analgesia is also an essential component.19 Pain is unquestionably a critical consideration in perioperative care, but the potent sedative–hypnotic effects of most general anesthetics confound the assessment of pain. Hypnosis and amnesia are produced via drug effects on neural networks within the brain, and immobility is primarily mediated by the spinal cord. In short, the major therapeutic actions of the volatile anesthetics take place in the CNS. Beneficial and toxic effects of inhaled anesthetics on other physiologic systems (eg, cardiovascular function, respiration) can thus be regarded as secondary. In this section, we discuss various measurements of anesthetic effects in the nervous system, as well as their limitations.
Because general anesthesia is defined as the loss of normal responses to environmental stimuli, anesthetic depth is most rigorously defined by stimulus–response testing using stimuli that range from benign (eg, spoken commands) to noxious (eg, laryngoscopy or surgical incision).20 In addition, certain consistent pharmacologic effects of anesthetics that are stimulus independent are useful signs of anesthetic depth. Traditionally, both desired and undesired clinical effects have been associated with the various stages and planes of anesthesia introduced by Snow (1847)21 and modified by Guedel (1937).22 These descriptions (Table 38-3) were developed during the era of ether and chloroform anesthesia and are therefore not fully applicable to modern practice.
Table 38-3 Classic Stages and Planes of Inhalational Anesthesia ||Download (.pdf)
Table 38-3 Classic Stages and Planes of Inhalational Anesthesia
- Stage 1 is defined as the time between the normal waking state and the loss of consciousness (hypnosis) caused by an anesthetic agent. There is also mild analgesia in stage 1 anesthesia.
- Stage 2 is associated with loss of awareness and recall (amnesia). Stage 2 is associated with the undesired effects of cardiovascular instability, excitation, dysconjugate ocular movements, and emesis.
- Stage 3 is defined as surgical anesthesia, a state during which movement in response to pain is suppressed. Various planes of anesthesia were described by Guedel22 based on additional physiological signs:
- Plane 1 is associated with deep respiration, coordinated thoracic and diaphragmatic muscular activity, and pupillary constriction.
- Plane 2 is associated with diminished respiration, as well as fixed midline and dilated pupils.
- Plane 3 is associated with continued diaphragmatic movement, diminished thoracic movement, and further pupillary dilation.
- Plane 4 is associated with thoracic immobility and diminished diaphragmatic movement.
- Stage 4 is associated with cessation of spontaneous respiration and medullary cardiac reflexes and may lead to death.
Minimum Alveolar Concentration, Minimum Alveolar Concentration Awake, and Minimum Alveolar Concentration Bar
Minimum Alveolar Concentration
In 1965, Eger introduced the concept of MAC as a stimulus–response measure of anesthetic potency.23,24 MAC is the alveolar concentration of inhaled anesthetic that prevents movement in half of subjects in response to a surgical incision. Thus, MAC is the equivalent of an ED50. (dose of a drug that produces an effect in 50% of subjects) inhibition of movement in response to a specific noxious stimulus. If different noxious stimuli (eg, varying point pressures or electric shocks) are used, the concentration of inhaled anesthetic required to suppress movement increases with stimulus intensity.25 Thus, MAC is most useful for comparing potency among different inhaled agents under the same conditions, with potency being inversely related to MAC. During measurement of MAC, equilibrium between the alveolar gas compartment and the CNS must first be established. Other drugs that modulate awareness (eg, benzodiazepines), pain sensation (eg, opioids), or movement (eg, muscle relaxants) cannot be present. MAC as originally defined depends on atmospheric pressure, but when agent concentration is expressed as a partial pressure, MAC becomes independent of ambient pressure. The MAC values of common inhaled agents in oxygen (Table 38-2) show that N2O is least potent followed by desflurane, sevoflurane, enflurane, isoflurane, and halothane. By definition, an exclusively inhalational anesthetic to a level of 1 × MAC will prevent movement in only 50% of patients. The ED95, which is roughly 1.3 × MAC, may be a more clinically useful value. The ED95 corresponds to 0.9% for halothane, 1.68% for isoflurane, and 1.88% for enflurane.
MAC is altered by age and physiologic, genetic, and pharmacologic factors. MAC decreases with age (Fig. 38-14). Standard MAC values are those for patients around age 40 years. MAC is highest within the first year of life (age 6-12 months) and decreases with advancing age.26,27
Minimum alveolar concentration (MAC) varies with age. MAC is maximal in the first year of life and decreases with age. The figure shows the relationship on a semi-logarithmic scale. The equation of the line is MAC/MAC40 = 1.32 × 10-0.00303Age, or a 6.7% decrease in MAC per decade.26
Physiologic factors such as temperature influence MAC. For each decrease in core temperature by 1°C, MAC decreases by 5%. Other physiologic extremes that affect CNS function (eg, hypoxia, hypercapnia, acidosis, hypotension) also decrease MAC.
Whether MAC is affected by gender is controversial. Elderly women require 26% less xenon than age-matched men. In young men and women, however, MAC for desflurane does not significantly differ.28 MAC is reduced in parturient women.29 Increases in either progesterone or endogenous opiates (endorphins) during pregnancy have been proposed to account for this decreased anesthetic requirement, but these theories have not been substantiated by experiment.
Genetic factors play a role in determining MAC. Mice of varying genomic backgrounds are differentially susceptible to volatile anesthetics such as halothane, isoflurane, and sevoflurane.30 In humans, patients with naturally red hair have a significantly higher desflurane MAC than other patients (Fig. 38-15).31 Ninety percent of the red heads tested had mutations reducing expression of the melanocortin-1 receptor gene. Genetically altered (knock-out) mice lacking the melanocortin-1 receptor gene also display a modest increase in MAC for desflurane, isoflurane, sevoflurane, and halothane.32
Minimum alveolar concentration (MAC) values are increased in natural redheads. The figure depicts data reported by Liem et al.31 On average, red heads require about 20% higher alveolar concentrations of desflurane to prevent movement. Columns represent averages and error bars represent standard deviations.
Pharmacologic factors alter MAC. The addition of 70% N2O reduces the anesthetic requirements of other inhaled agents by 55% to 70% (Table 38-2). MAC is an additive phenomenon when 2 or more inhaled agents are combined.33 Adjunct opiate or benzodiazepine administration reduces MAC. Whereas acute alcohol intoxication reduces MAC, chronic intake of alcohol or sedatives can increase MAC, a phenomenon known as cross-tolerance.34
MAC reflects the effects of inhaled anesthetics in the spinal cord. In animal models, MAC has been shown to be primarily dependent on anesthetic effects on the spinal cord and not the brain.35,36 Anesthetic-induced immobility is likely attributable to suppression of spinal motor neuron function, observed as a diminished Hoffmann's reflex (H-reflex) and F-wave amplitudes.37,38 Suppression of movement and H-reflex amplitude by sevoflurane follow similar dose-response relationships in humans.39
Minimum Alveolar Concentration—Awake
MAC-awake is the concentration of inhaled anesthetic that inhibits appropriate responses to spoken commands in half of patients.26 The ratio of MAC-awake to MAC is not consistent among inhaled agents. It is fairly constant for the halogenated volatiles (roughly 0.35 × MAC), and significantly higher for N2O,40 which likely reflects their different mechanisms of action (see Chapter 37).
Functional recovery from anesthesia is influenced by MAC-awake for the specific agent as well as its elimination kinetics. Therefore, the time required to awaken after an anesthetic, especially a long one, depends on what concentration of the anesthetic was used relative to its MAC-awake. If the inhaled concentration was 2 × MAC-awake, then only a 50% reduction in Palv will be needed before the patient awakens, which is usually rapidly achieved for most agents. If higher concentrations were used, then emergence may be more than proportionately slowed because the slower phases of agent elimination will have a more dominant effect (see Elimination of Inhaled Anesthetics via Ventilation).
Similar to MAC, MAC-awake is reduced in elderly adults, by hypothermia and by the presence of other drugs with hypnotic activity (ethanol, benzodiazepines, anticonvulsants, antidepressants).26 MAC-awake is also reduced by neuraxial blockade (spinal or epidural) despite intact cranial nerve function.41-44 This effect is believed to be caused by diminished ascending signals from the spinal cord, which stimulate cortical arousal via the brainstem. MAC-awake is decreased by high doses of opiates, but this reduction is smaller than that of MAC.45
MAC-awake (hypnosis) is associated with volatile anesthetics effects on the cerebral cortex. Gamma range (25-100 Hz) signals from different cortical regions become desynchronized during the transition from conscious to unconscious states.46,47 Synchrony in specific cortical circuits, particularly the thalamocortical network, is believed to be associated with higher cognitive function, and its interruption may account for loss of consciousness.48 Loss of "functional connectivity" among various cortical networks during anesthesia has been demonstrated by functional brain imaging studies.49,50
Low concentrations of inhaled anesthetics block memory more than awareness.40 When inhaled agents are given at MAC-awake, only a small fraction of "aware" experimental subjects (those responding to spoken commands) can recall events.51 Amnesia is likely caused by effects on the limbic network, including the amygdala and hippocampus. Lesions in the basolateral amygdala produce resistance to the amnestic effects of sevoflurane in animals.52 Volatile anesthetics both attenuate hippocampal activity and inhibit long-term potentiation of hippocampal synapses that is associated with memory formation.53,54
Minimum Alveolar Concentration for Blockade of Autonomic Responses
Minimum alveolar concentration for blockade of autonomic responses (MAC-BAR) is the alveolar anesthetic concentration that suppresses cardiovascular responses to surgical incision in half of patients.55 MAC-BAR is typically greater than MAC. For example, MAC-BAR for desflurane is 1.66 × MAC.55 Similar to MAC and MAC-awake, MAC-BAR is reduced by opiates.20
Limitations on Traditional Anesthetic Depth Measurements
Stimulus–response testing is usually impractical in clinical settings. Neuromuscular blocking drugs ablate motor responses to both painful (MAC) and benign (MAC-awake) stimuli. Techniques for maintaining a motor response capability are laborious. As a result, autonomic signs such as blood pressure, heart rate, diaphoresis, tearing, and pupillary responses are often the only accessible data for assessing depth of anesthesia. These signs are valuable but unreliable guides to anesthetic depth and are confounded by drugs and diseases that impair cardiac or autonomic nervous system functions.
Numerous factors affect anesthetic sensitivity (including unknown genetic factors), resulting in widely varying individual anesthetic requirements. Too little anesthetic puts patients at risk for intraoperative awareness (see below). Conversely, deep anesthesia for all patients is neither feasible nor advisable. Deep inhalational anesthesia in patients with cardiac disease, hypovolemia, and other critical illnesses predictably causes profound hypotension and organ hypoperfusion. Healthy patients may tolerate deep anesthesia, but it may result in a slow emergence and a high incidence of side effects. Recent research suggests that excessively deep general anesthesia may accelerate the pathogenesis of neurodegenerative diseases such as Alzheimer dementia56-58 and may be associated with increased late mortality.59 The delivery of sufficient but not excessive anesthesia while providing optimal surgical conditions represents a central challenge for anesthetists.
Electroencephalographic Measurement of Anesthetic Depth
Given that the modern practice of general anesthesia frequently includes neuromuscular blockade to provide immobility, narcotics to provide analgesia, and other drugs to control autonomic activity, the essential therapeutic effects of general anesthetics are hypnosis and amnesia (ablation of awareness and memory). These effects, which are mediated in the brain, are also the most difficult to assess clinically. Monitors that analyze electrical signals from the brain can provide anesthetists with more data to individually titrate the depth of general anesthesia to achieve these endpoints. In addition, titration to individual needs has been shown to reduce anesthetic dosage, resulting in faster emergence in some settings.60,61
A number of techniques based on electroencephalography (EEG) have been developed and used. Fourier transformation of raw EEG data enables the derivation of median power and spectral edge frequencies.62 Other EEG analyses assess bispectral phase relationships, burst suppression, and entropy. The bispectral index (BIS; Covidien, Boulder CO) is a proprietary algorithm based on burst suppression, near-burst suppression, beta-band power, and phase relationships between delta- and theta-waves.63 The patient state index (PSI; Physiometrix, Inc., N. Billerica, MA) is based on EEG component relationships between the frontal and occipital regions.64 Entropy monitors (eg, S/5, General Electric [Datex-Ohmeda], Helsinki, Finland) analyze entropy (randomness in frequency and phase relationships) using both EEG and frontal electromyography (EMG).65 Some of these monitors are now available for clinical use to provide additional information and help prevent undesired side effects such as awareness during general anesthesia. For most patients, EEG indices such as BIS and spectral entropy correlate with the alveolar concentration of volatile anesthetics (Fig. 38-16).66 Monitors based on stimulus–response are also being developed for clinical use. Auditory evoked potentials can be used to assess anesthetic-induced unconsciousness and may be used in conjunction with other EEG parameters.67 A recent innovation is the use of transcranial magnetic stimulation in conjunction with EEG to detect loss of consciousness.68 Nonetheless, all of these monitors have considerable limitations. Further research in identifying neural correlates of consciousness is needed to improve the utility of monitors that assess the depth of anesthesia.
Correlation between processed electroencephalographic (EEG) parameters and volatile anesthetic concentration. A. Time course of state entropy (SE), response entropy (RE), bispectral index (BIS), and burst suppression ratio (BSR) of a single patient. Each symbol represents an EEG parameter of a 5-sec epoch. B. End-tidal sevoflurane concentration (Cet) and calculated effect site concentration (Ceff) during the same time course in the same patient. [Reprinted with permission from Ellerkmann RK, Liermann VM, Alves TM, et al. Spectral entropy and bispectral index as measures of the electroencephalographic effects of sevoflurane. Anesthesiology. 2004;101:1275-1282.]