Inhalant Anesthetics: The Basics

Introduction

Inhalant anesthetics are extensively used to provide general anesthesia in both human and veterinary anesthesia. Unique among general anesthetics, inhalants are eliminated from the body primarily through the lungs; hepatic inactivation and renal elimination are not strictly necessary to permit a patient to regain consciousness from inhalant anesthesia. The anesthetist need only vary the partial pressure of the inhalant anesthetic in the patient’s lungs to effect a change in brain partial pressure and resultant depth of anesthesia. The ability to induce and maintain general anesthesia without being totally dependant upon hepatic function to permit the patient to recover consciousness, is a tremendous advantage. It is precisely this functionality which permits comparatively rapid recovery from general anesthesia of long duration. Balancing the safety and flexibility inherent in administering inhalants is the cumbersomeness and complexity of the necessary equipment. To deliver predictable concentrations, liquid inhalant anesthetics are usually first vaporized in a vaporizer and then administered in an enriched concentration of oxygen to a patient via a breathing circuit. These items of equipment are heavy, bulky, and not easily portable and make inhalant anesthesia problematic under field conditions. Despite the complexity and expense of delivery equipment, increased patient safety is a direct result of endotracheal intubation and inspiration of enriched oxygen concentrations that are required by inhalant anesthesia. Observation of depth and frequency of breathing from reservoir bag excursions provides a means of monitoring respiratory function. Positive pressure ventilation may be provided easily to the patient by simply compressing the reservoir bag, thus providing a simple and effective means of supporting ventilation in the patient whose ventilatory drive has been depressed by general anesthesia.

Modern inhalant anesthetics (listed in order of year of introduction) include halothane, methoxyflurane, enflurane, isoflurane, desflurane, and sevoflurane. As a general rule, newer inhalants tend to have increasingly lower solubility and higher chemical stability. Thus, the newest of the inhalant anesthetics, desflurane and sevoflurane, are relatively inert and very insoluble. Many inhalant anesthetics such as halothane and methoxyflurane, undergo extensive metabolism within the liver and to a lesser extent in tissues such as the lungs and kidneys. Several pathways of drug metabolism exist including oxidation, reduction, hydrolysis and conjugation reactions. Metabolism of non-inert inhalant anesthetics can result in the production of metabolites which may cause undesirable side effects such as liver or kidney damage. The potential of producing harmful metabolites is markedly decreased with stable or inert anesthetics because they are not metabolized to a large degree by the liver. Solubility of inhalant anesthetics in body tissues and blood is important in determining how rapidly a given anesthetic will attain an anesthetizing partial pressure in the brain. Agents having low tissue and blood solubility will, if all other factors remain equal, to provide for rapid equilibration of anesthetic partial pressures between the lungs and brain. This rapid equilibration translates clinically into a patient whose depth of anesthesia is extremely responsive to changes in administered concentrations. This relatively rapid responsiveness necessitates careful monitoring of anesthetic depth if a patient is to be prevented from becoming either excessively light or deep. Low tissue solubility also means that For any given period of anesthesia, less total inhalant anesthetic is taken up. Consequently, less total inhalant is presented to and acted upon by the liver which means there is less metabolism and less production of potentially harmful metabolites. Use of rapidly acting inhalant anesthetics may not be advantageous in all settings. An example is methoxyflurane, introduced into anesthesia practice in 1962. Its high blood and tissue solubility translated into slow changes in anesthetic depth, a condition favored by many small animal practitioners of the day. Administration of inhalant anesthetics results in their escape into the anesthesia induction room or operating area. While data from studies are incomplete and inconclusive, breathing of so-called second hand gas is associated with health problems in humans exposed chronically to waste anesthetic gasses. Waste anesthetic gas is removed from anesthesia machines by using some type of anesthetic scavenging device. Anesthetic waste gas scavenging devices add expense and complexity to anesthetic machines and circuits, but when properly installed and maintained, provide an effective means of reducing contamination of the work environment and exposure of personnel to waste gases.

Important Physical Properties of Inhaled Anesthetics

Understanding how an inhalant anesthetic is transferred from the anesthetic vaporizer to the patient’s brain requires knowledge of the physical properties of inhalants and a firm understanding of the processes involved in their uptake from the lungs into the blood. Important physical properties of inhalant anesthetics include vapor pressure, tissue solubility, and potency.

Vapors and Gases

Medical gases are often compressed and stored in cylinders for economy of storage. Many gases such as nitrous oxide and carbon dioxide liquefy when sufficiently compressed at room temperature and thus are stored as liquids within cylinders. Other commonly used gases such as oxygen and nitrogen remain in the gaseous state when compressed and stored in cylinders. The reason one substance is stored in its liquid state and another in its gaseous state relates to their critical temperatures. The critical temperature of a substance is that temperature above which the substance is in its gaseous form and cannot be liquefied by compression. For example, the critical temperature of oxygen is -118°C. At any temperature above -118°C, oxygen cannot liquefy under pressure. Nitrous oxide has a critical temperature of 36°C and at room temperature (20°C) it will, when under one atmosphere of pressure (760 mm Hg), exist in the liquid state within a cylinder. Isoflurane, sevoflurane, and all commonly used potent inhalant anesthetics have critical temperatures that are so much higher than room temperature that they exist in the liquid state even at a pressure of only one atmosphere. A vapor is a substance in its gaseous state at a temperature which is below its critical temperature. Water has a critical temperature of 374°C and, not surprisingly, is a liquid at room temperature and one atmosphere pressure. At one atmosphere pressure, water boils at 100°C; the steam generated is due to higher energy molecules of water leaving the liquid phase and entering the gaseous phase. Since (at 760 mm Hg) water boils and thus produces stream at a temperature less than its critical temperature, steam is a vapor and not a gas. Halothane, isoflurane, nitrous oxide, and carbon dioxide are examples of medical "gases" which are actually vapors at room temperature. Although strictly incorrect, we often use the term gas when referring to both gases and vapors.

Vapor Pressure

All commonly used inhalant anesthetics, with the exception of nitrous oxide, exist in the liquid state at atmospheric pressure and room temperature. When liquids are placed into a container, molecules of the liquid escape from the liquid into the surrounding gas space in proportion to the energy state of the liquid. The pressure exerted on the walls of the container by the escaping molecules is known as the saturated vapor pressure of the liquid. The vapor pressure of a substance is a measure of its ability to evaporate. The higher the vapor pressure, the greater the tendency for molecules to leave the liquid state and enter the gaseous state. Vapor pressure is an inherent property of a liquid and is directly related to the energy state or temperature of the liquid (Fig. 1).

Figure 1. As temperature increases more molecules of anesthetic leave the liquid phase and enter the gas phase and vapor pressure increases. Vapor pressure depends only on the characteristics of the liquid (anesthetic) and temperature.

As the energy state of the liquid increases (as temperature increases) more molecules leave the liquid phase to enter the gas phase and vapor pressure increases. Vapor pressure depends only on the characteristics of the liquid and the temperature of the liquid and is unaffected by surrounding atmospheric pressure. An equilibrium state is reached when there is no net movement of molecules between the liquid and gas phases. Vapor pressure thus determines the number of molecules of anesthetic that will be in the gaseous state at any given temperature. Vapor pressure is an important physical property of inhalant anesthetics because the vapor pressure of a liquid inhalant anesthetic determines what the maximum concentration of anesthetic vapor will be at any given temperature.

To calculate the maximum concentration of anesthetic attainable at any given temperature, we must determine what percent of one atmosphere is represented by the vapor pressure of the anesthetic. That is we calculate:

For example the maximum concentration of isoflurane attainable at 20°C is:

Methoxyflurane is an inhalant anesthetic having a low vapor pressure (23 mm Hg) and high blood solubility. The low vapor pressure results in a relatively flat vapor pressure-temperature curve and a maximum attainable concentration of only 3%. The flatness of the vapor pressure-temperature curve indicates that the vapor pressure changes very little as a result of mild changes in ambient temperature. For example, at 20°C the maximum attainable concentration of methoxyflurane is 3%. If the ambient temperature rises to 30°C, the vapor pressure rises to only 27 mm Hg yielding a maximum concentration of 3.6%. In contrast, the vapor pressure (238 mm Hg) and maximum concentration (31%) of isoflurane at 20°C increases to 357 mm Hg and a maximum concentration of 47%. This is typical of the more volatile agents such as halothane, isoflurane, and sevoflurane. These physical properties of methoxyflurane made its administration safe and effective by simple means such as open drop or gauze mask, features that made it attractive for use in laboratory animals such as rats and mice.

Agents having higher vapor pressures will obviously generate correspondingly higher maximum concentrations at room temperature. Agents having high vapor pressures require delivery from precision vaporizers to ensure administration of precise and predictable concentrations needed to meet the varying conditions of clinical use. Anesthetic vapor pressure is an important consideration in the design and development of anesthetic vaporizers. Modern, variable bypass, precision vaporizers such as the Ohmeda Tec 4 and the Drager Vapor 19.2, are designed to deliver precise concentrations of anesthetic over a range of environmental temperatures. Variable bypass precision vaporizers are agent specific, in that they are designed to work with one specific agent or more precisely, one specific vapor pressure curve. The operator simply turns the stylus to a desired concentration and the vaporizer, designed both for the vapor pressure of the agent and to compensate for ambient temperature, delivers the desired concentration. It is indeed possible to obtain clinically acceptable concentrations of anesthetic from an anesthetic vaporizer other than the agent for which it was designed if the anesthetics have similar vapor pressure curves. Such is the case for isoflurane (VP=238 mm Hg at 20°C) and halothane (243 mm Hg at 20°C), or for sevoflurane (160 mm Hg at 20°C) and enflurane (172 mm Hg at 20°C). Although studies [1,2] have verified that clinically acceptable concentrations result, manufacturers of precision vaporizers do not recommend using an agent other than that specified for a specific precision, variable bypass vaporizer.

In contrast to the low vapor pressure exhibited by methoxyflurane, desflurane has a relatively steep vapor pressure curve and a high vapor pressure of 664 mm Hg at 20°C. Small increases in ambient temperature make it quite likely that the vapor pressure of desflurane will approach atmospheric pressure and thus cause the liquid desflurane to boil, theoretically allowing a maximum concentration of 100% to be delivered. Due to its high vapor pressure, desflurane is more difficult to administer in controllable concentrations compared to an agent of lower vapor pressure such as sevoflurane or halothane. Rather than depending upon ambient heat to drive the vaporization process, the Ohmeda Tec 6 desflurane vaporizer contains an electric element which heats the liquid desflurane to 41°C, a temperature at which desflurane has a vapor pressure of 1440 mmHg. The electronic Tec 6 vaporizer then meters the correct amount of desflurane vapor with carrier gas to deliver the desired concentration of desflurane.

Solubility

The combination of a solute within a solvent - a solution - is commonplace in anesthesia. Injectable drugs are examples of solutions that consist of solids within a liquid; thiopental, a short-acting barbiturate, is a specific example. Thiopental may be prepared as a solution of varying concentration depending upon the anesthetic application. For reasons of safety it is most often prepared as a 2.5% solution (25 mg/ml) for administration to small animals. To prepare a more concentrated solution, more solute need only be added to the existing solvent. As more and more thiopental powder (solute) is added to the solvent (sterile water), more thiopental goes into solution until an equilibrium is reached where the number of molecules entering the solution equals the number of molecules leaving the solution. When equilibrium is reached, the solution is said to be saturated with the solute. The concentration of the solute within the solution at saturation is a measure of its ability to dissolve within the solvent, i.e., a measure of its solubility. Solubility is temperature dependant. For solutions of solids in liquids, the higher the temperature, the greater the number of molecules of solid will be able to dissolve in a liquid before saturation is reached. An increase in temperature increases the kinetic energy of the solid and thus increases the likelihood that its lattice structure will break down and allow the solid (the solute) to mix with or become soluble in the liquid. In effect, the increased temperature increases the energy state of the molecules within the solid making those molecules approach the energy state of the liquid molecules. In contrast, for solutions of gases in liquids, an increase in temperature has an opposite effect in that as temperature increases the kinetic energy of the gas (the solute) increases and tends to keep the molecules in a gaseous state. The higher energy state of the gas molecules decreases the likelihood that the gas will mix with the liquid and stay in solution; the result is decreased solubility of the gas in the liquid as temperature increases.

The solubility of a specific gas or vapor in a specific liquid is an inherent property of the gas and as mentioned above, is influenced by ambient temperature; as with solids, solubility is defined as the total amount of solute (gas) dissolved within a solvent (liquid) at equilibrium. Equilibrium exists when the number of gas molecules entering the liquid equals the number of gas molecules leaving the liquid, that is, when there is no net movement of gas molecules. Since gases move from areas of high partial pressure to areas of low partial pressure, at equilibrium the partial pressure of the gas in each phase must be identical. The concentration of a gas in single-phase environments is directly proportional to its partial pressure (PP). Therefore in single-phase situations, i.e. where only gases exist, molecules move from regions of high PP or high concentrations to areas having lower PP or lower concentrations. This relationship is more complicated when two-phase environments exist such as when gasses diffuse from the alveoli into blood. In these situations the solubility of the gas in blood also must be taken into account. The relationship between PP and concentration still exists, but is modified by the solubility (α) of the anesthetic in blood such that the concentration, or more precisely the volume of gas dissolved, is proportional to solubility times PP, hence:

This relationship is illustrated in Figure 2 where two identical liquids fill two separate but identical containers.

Figure 2. Two identical liquids fill two separate but identical containers. One liter of a gas is introduced into each container; the gas on the left is highly soluble in the liquid while the gas on the right has low solubility in the liquid. After equilibration, when the number of gas molecules entering the liquid phase equals the number leaving the liquid phase, the partial pressure of the gas in the two phases (gas and liquid) will be identical. However, the concentration or amount of gas within the liquid phase will differ between the two containers because of their differing solubility.

Into each container, 1 liter of a gas is introduced and allowed to equilibrate. The gases differ from each other in that the gas on the left has high solubility in the liquid while the gas on the right has low solubility in the liquid. In each container at equilibrium, when there is no net movement of gas molecules between the gas and liquid phases, the partial pressure of the gas in the two phases (gas and liquid) will be identical, but the concentrations of the gases in the two phases differ between the two containers because of their differing solubility in the liquid. Solubility of gases in liquids may be expressed by one of several coefficients which express ratios of the amount of gas dissolved in a liquid at a specified temperature to that present in the gaseous phase under conditions of equilibrium. Although there are a number of coefficients that are used to describe the solubility of a gas within a liquid, the most popular coefficient when working with anesthetics is the partition coefficient (PC). The PC of an anesthetic gas is a measure of its solubility in a specific solvent (usually blood or tissue) at a specified temperature and is defined as the ratio of gas concentrations in the two phases at equilibrium. By convention the PC is stated as the ratio of solvent to gas; thus we speak of blood:gas solubility or tissue:gas solubility. Figure 3 and Figure 4 depict the relationship between alveolar gas and the pulmonary blood. In Figure 3 the partial pressure of gas in the blood and alveoli during conditions of equilibrium are associated with a concentration of 2 volumes% in the blood and 1 volume% in the alveoli, a blood:gas ratio of 2.0. In Figure 4 the gas partial pressures within the blood and alveoli are associated with a concentration of 2 volumes% in the blood and 4 volumes % in the alveoli, a blood:gas ratio of 0.5. When the partial pressures are in equilibrium between two phases the concentrations of anesthetic in the 2 phases may not be equal. The discrepancy between partial pressure and concentration exists because of the unique solubility of different anesthetic gases in blood. As we shall soon see, solubility plays a key role in the onset, offset and rapidity with which depth of anesthesia may be altered.

Figure 3. When the partial pressure of gas in the alveoli (gas phase) is in equilibrium with the partial pressure of the gas in blood (liquid phase) there are 2 volumes% of gas in blood and 1 volumes% in alveolar gas, a blood:gas ratio of 2.0.

Figure 4. When the partial pressure of gas in the alveoli (gas phase) is in equilibrium with the partial pressure of the gas in blood (liquid phase) there are 2 volumes% of gas in blood and 4 volumes% in alveolar gas, a blood:gas ratio of 0.5.

Potency

The potency of inhalant anesthetics is an expression of the relationship between the administered dose of anesthetic and the anesthetic effect that is obtained. The most popular expression of the potency of an inhalant anesthetic is its Minimum Alveolar Concentration (MAC) or that alveolar concentration which prevents gross, purposeful movement in 50% of patients exposed to a noxious stimuli [3]. The MAC value of an anesthetic is similar to a pharmacologic ED50 and permits comparisons of inhalant anesthetics on an equipotent basis. The importance of MAC as a measure of potency becomes obvious when, for example, we wish to evaluate the cardiovascular effects of inhalant anesthetics. Since all inhalant anesthetics depress cardiovascular function in a dose dependant manner and each possesses its own potency, comparisons of the cardiovascular effects of each inhalant must be made at equivalent depths of anesthesia, and not at identical inspired concentrations; that is, they must be performed at identical potencies or MAC levels. While the site of action of all inhalant anesthetics is the brain, it is the concentration of anesthetic at the alveolar level that is measured to determine the MAC value for any given anesthetic. If the alveolar concentration of an inhalant is held constant for a sufficient period of time, equilibrium of partial pressures will occur between the alveolar gas and the brain such that the partial pressure of anesthetic in the alveoli will closely reflect that of the brain. Whilst measurement of brain anesthetic concentrations is technically possible, estimates of alveolar concentrations through the measurement of airway gases, specifically end-tidal gases, is much safer for the patient, easier to perform and is commonplace in clinical anesthesia.

MAC values are determined in young healthy animals, without administration of additional CNS depressants such as sedatives or tranquilizers. MAC, by definition, means that half the population will respond when exposed to a noxious stimulus while half will not; thus to anesthetize 95% of a surgical population, clinically useful concentrations of inhalant anesthetics must be at least 25 to 30% greater than MAC. Expressing concentrations of anesthetic as multiples of MAC "levels the playing field" for all inhalant anesthetics in that the MAC value standardizes potency to the same value for each inhalant. Thus 1 MAC of isoflurane is equivalent to 1 MAC of sevoflurane although the concentrations required to reach 1 MAC (1.3% for isoflurane, 2.25% for sevoflurane) are quite different. Thus it is much more informative to report concentrations of inhalants as MAC multiples since the potency of each inhalant is implicit in the MAC value. The MAC value for an inhalant anesthetic will vary between species, but the variation seen with most potent inhalants is remarkably small. MAC values for several inhalant anesthetics and species are listed in Table 1.

Uptake and Distribution of Inhalant Anesthetics

Inhalant anesthetics must enter the CNS to produce general anesthesia. Numerous theories have developed to explain the precise mechanism by which inhalant anesthetics reversibly disrupt CNS communication and produce general anesthesia. Recent theories propose that the inhalant anesthetics alter the structure of receptor proteins present within cell membranes [4], specifically GABA receptors [5-7].

Although the precise mechanism by which inhalants produce their effects is unknown, it is generally agreed that the principle site of action is the brain. Inhalant anesthetics enter various tissues of the patient by moving along a partial pressure gradient, from an area of high partial pressure to an area of lower partial pressure. During induction, the high partial pressure of an inhalant within the breathing circuit is transferred to the patient’s alveolar gas space. The inhalant then enters the circulating blood and is transferred to the brain causing the CNS depression we associate with general anesthesia.

Delivery of Anesthetic to the Alveoli

The partial pressure of anesthetic in the brain is controlled by the partial pressure of anesthetic in the alveoli. The alveoli are the site at which the inhalant gains entrance to the circulating blood volume. The alveolar partial pressure is analogous to the tip of a hypodermic needle for an injectable anesthetic such as thiopental. When inducing anesthesia with an injectable agent such as thiopental, several factors affect speed of induction. The concentration of the thiopental solution, the volume injected, and the rate of injection all influence how fast a patient will become anesthetized. For inhalant anesthetics similar factors influence induction, recovery, and the ability to change anesthetic depth.

Figure 5. The administered dose of an inhalant anesthetic depends upon the alveolar partial pressure which is influenced by many factors, one of them being the vaporizer setting.

Since alveolar partial pressure of an inhalant anesthetic influences the speed of induction of anesthesia, it is important to understand what factors influence alveolar partial pressure. Alveolar partial pressure of an inhalant anesthetic is a balance between what is delivered to the alveoli from the breathing circuit and what is removed from the alveoli by the pulmonary blood flow; two factors influence delivery of inhalant anesthetic to the alveoli from the breathing circuit:

• The inspired concentration or partial pressure of anesthetic
• The alveolar ventilation of the patient

Increasing either of these two factors will cause the alveolar partial pressure to approach that of the breathing circuit. As an extreme example let us consider the delivery of a gas from a breathing circuit to the alveoli in the absence of any removal of that gas by the pulmonary blood. Such a condition exists when a gas insoluble in blood such as nitrogen (PC = 0.014) is inhaled. A gas of infinite insolubility will not be removed from the alveoli by the pulmonary blood and the alveolar partial pressure will be determined solely by the factors which determine delivery to the alveoli from the breathing circuit, i.e., the inspired anesthetic partial pressure and the degree of alveolar ventilation. In the absence of uptake by pulmonary blood, the maximum partial pressure attainable in the alveoli will be the concentration inspired from the breathing circuit; the time necessary to achieve that maximum depends upon the ratio of the gas volume of the lung (functional residual capacity) and the rate of gas flow through the lung (alveolar ventilation). The larger the alveolar ventilation in relation to the functional residual capacity of the lung, the more rapidly the alveolar partial pressure will approach that of the anesthetic circuit. In the absence of uptake by blood, the concentration (C) of the inhalant within the alveoli as a percentage of the concentration of the inflowing gas may be calculated from C = 1 - 1/eKT where e is the base of the natural logarithm, K is a constant equal to the flow through the container (F; L/min) divided by the volume of the container (V; L), and T is time. From this formula it may be shown that when the rate of flow/minute into the circuit is equal to the volume of the alveolar gas space, then after 1, 2 and 3 minutes of flow the concentration of anesthetic within the alveoli will be 63%, 86% and 95%, respectively, of the inflowing gas anesthetic concentration. Thus by manipulating the factors which control delivery of inhalant anesthetic (inspired concentration and alveolar ventilation), the anesthetist can control the maximum alveolar partial pressure of anesthetic that will be attained.

Uptake of Anesthetics into Blood

The theoretical rates of change of alveolar anesthetic concentrations described in the preceding section are not achieved during the course of clinical anesthesia because anesthetic is removed from the alveoli and enters the pulmonary blood, a process that slows the rate of rise of anesthetic in the alveoli. The alveolar partial pressure is transferred through the circulating blood volume to the brain where the anesthetizing effects of anesthetics occur. The three factors that influence uptake of anesthetic from the alveoli into the pulmonary blood are:

• The solubility of the anesthetic.
• The patient’s cardiac output.
• The alveolar-venous anesthetic partial pressure difference.

Increases in any of these factors will in turn increase the uptake of anesthetic from the alveoli into the pulmonary blood. Recall that it is the development and maintenance of an anesthetizing partial pressure or concentration of an anesthetic within the alveoli that is critical to the development of an anesthetizing anesthetic partial pressure within the brain. At equilibrium, the partial pressure existing within the alveoli is transferred through the circulatory system to the brain. In this regard, the circulating blood flow is analogous to a hydraulic pressure line. Pressure applied to one end is transferred through the fluid and is present at the opposite end. In a similar fashion, the partial pressure of anesthetic generated at the alveoli is transferred through the blood and is present at the brain. A high alveolar partial pressure thus results in a high brain anesthetic partial pressure while a low alveolar partial pressure results in a low brain partial pressure. The actual concentration of anesthetic within the alveoli, circulation, and brain is important only to the degree that it participates in the development of an anesthetizing partial pressure. Regardless of the actual concentration of inhalant anesthetic that exists within the circulating blood, it is the partial pressure exerted by the inhalant anesthetic which results in general anesthesia.

Anesthetic Solubility

Just as molecules of a solid (a solute) will dissolve into a liquid (solvent), so too will gas molecules dissolve into a liquid such as blood, or into tissues such as brain and fat. As mentioned previously, differences in solubility exist between inhalant anesthetics and solubility has important implications for speed of onset and recovery from anesthesia. Inhalants having high solubility in blood as evidenced by high PC values, produce slower inductions into and recoveries from anesthesia compared to inhalants with low PC values. The reason that inductions using highly soluble inhalants are slower is due to the fact that they move readily into the circulating blood which has a large capacity for these inhalants. As a result, an anesthetizing partial pressure and concentration in the alveoli and thus in the brain are only achieved slowly. In contrast, the behavior of an inhalant having lower solubility in blood is such that little of the less soluble inhalant moves from the alveoli into the circulating blood because it has less capacity for the inhalant. As a result the blood becomes saturated more quickly with the inhalant, the alveolar to venous anesthetic partial pressure difference (see below) decreases which further slows the uptake of inhalant from the alveoli. The net effect is that the alveolar partial pressure and concentration rise more quickly to an anesthetizing level (MAC or some multiple thereof) and this high alveolar partial pressure is transmitted through the circulatory system to the brain resulting in a rapid anesthetic effect. The influence of solubility on anesthetic uptake and speed of onset and recovery is greatest when a significant partial pressure differences exists between the alveoli and blood, a difference that exists during induction, recovery and whenever the vaporizer setting is adjusted. Thus solubility of the inhalant may have a significant impact on how rapidly the depth of anesthesia is changed under these conditions. Assuming all other factors remain equal, we may predict that a less soluble inhalant will provide a more rapid induction and recovery from anesthesia and enable a more rapid change in the depth of anesthesia compared to a more soluble inhalant. This is precisely what is seen clinically; sevoflurane is associated with a more rapid induction and recovery and affords the anesthetist the ability to alter anesthetic depth more rapidly compared with an agent of higher solubility such as halothane.

Cardiac Output of the Patient

For a variety of reasons a patient’s cardiac output may change frequently during anesthesia. An increase in cardiac output will influence the uptake of inhalant from the alveoli into blood, more so for inhalants of high blood:gas solubility than for those of low blood:gas solubility. An increase in cardiac output increases the volume of blood presented to the alveoli per unit time and the larger volume of blood presented to the alveoli allows comparatively larger volumes of inhalant to move readily into the circulating blood which serves to lower the partial pressure of inhalant within the alveoli. This lower alveolar inhalant partial pressure and concentration are transmitted through the circulating blood to the brain resulting in a low brain anesthetic partial pressure and concentration.

Figure 6. Effect of cardiac output on alveolar anesthetic concentration. In the graphic above, alveoli and blood are depicted as square boxes; alveoli are above and blood is below. A potent inhalant anesthetic is depicted as green circles. Blood in contact with the alveoli carries anesthetic away to the various tissue groups. If ventilation remains unchanged, an increase in cardiac output removes more anesthetic from the lung and slows the rate of rise of anesthetic in the alveoli. (Adapted from: Eger EI. 1974 [8] Available from amazon.com ).

The net effect of an increase in a patient’s cardiac output is a delay in the development of a sufficiently high alveolar and brain inhalant partial pressure and concentration. Decreases in cardiac output produce the opposite effect; a smaller volume of blood is presented to the alveoli, uptake is reduced and alveolar and brain inhalant partial pressures remain elevated. The clinical implications of changes in cardiac output are an increase in the speed of induction and a more rapid change in anesthetic depth in patients having decreased cardiac output, and a decreased speed of induction and a less rapid change in anesthetic depth in patients having an increased cardiac output. Patients having decreased cardiac output should be monitored closely for signs of anesthetic depth because they may change depth of anesthesia much more rapidly than a normal patient.

The Alveolar-venous Anesthetic Partial Pressure Difference

The difference in partial pressure between the alveoli and the pulmonary blood provides the pressure gradient along which the inhalant anesthetic will diffuse. The larger the gradient (i.e., the greater the alveolar-venous difference), the greater is the driving force to transfer inhalant anesthetic from the alveoli to the blood. As long as a partial pressure gradient exists between the alveoli and the pulmonary blood, inhalant will move down this gradient until equilibrium is reached. When equilibrium occurs, there is no partial pressure gradient and thus there is no net movement of inhalant from alveoli to blood. At the start of inhalant anesthesia, the lack of any partial pressure gradient between the alveoli and the pulmonary blood prevents transfer of anesthetic into the blood and permits a rapid wash in of inhalant from the breathing circuit into the alveoli. The alveolar inhalant partial pressure soon rises creating a gradient between alveoli and blood. The development of this gradient permits rapid transfer of inhalant from the lung into the pulmonary blood As inhalant is progressively taken up by the pulmonary blood, the blood returning to the lung from the tissues contains nearly the same partial pressure of inhalant as it had when it left. Because the inhalant partial pressures of the alveoli and pulmonary blood are now nearly identical, the gradient and thus the uptake from the alveoli is greatly reduced. An alveolar-venous anesthetic partial pressure gradient must exist for uptake of anesthetic to occur. Accordingly, changes in inhalant solubility and patient cardiac output will have no effect on uptake of anesthetic or speed of induction if a gradient does not exist.

Elimination of Inhalant Anesthetics

The elimination of inhalant anesthetics is essentially the reverse of uptake. The anesthetist decreases the partial pressure of anesthetic within the breathing circuit, thus decreasing the inspired inhalant partial pressure. The alveolar-venous partial pressure gradient reverses; the partial pressure of inhalant now being greater within the blood compared to the alveoli. Inhalant anesthetic is carried from the tissues in the venous blood to the lung where the partial pressure gradient favors movement of anesthetic out of the blood and into the alveoli. Just as with induction, inhalant will continue to move from the blood to the alveoli as long as this partial pressure gradient exists. The patient’s alveolar ventilation removes the inhalant from the alveoli replacing it with fresh gas devoid of anesthetic. Just as increased alveolar ventilation increases delivery of inhalant from the circuit to the alveoli, so too does increased alveolar ventilation increase removal of inhalant from tissues by maintaining an alveolar-venous anesthetic partial pressure difference which facilitates the transfer of inhalant out of tissues into the breathing circuit. The two factors of inhalant solubility and patient cardiac output affect elimination of inhalants in a manner identical to their effects on uptake. As during induction, any factor which affects the partial pressure of inhalant within the alveoli will affect the partial pressure of inhalant within the brain. Agents having a high blood solubility will be taken up by the blood and tissues in large volumes and during the elimination phase these large volumes will continue to be delivered from the tissues via blood to the alveoli and thus tend to oppose and slow the effect of alveolar ventilation on the alveolar partial pressure of the inhalant. The alveolar inhalant partial pressure remains relatively high and as does the brain anesthetic partial pressure, the net result of which is a prolonged elimination of anesthetic from the brain and a slow recovery from anesthesia. Clinical experience confirms the fact that recoveries occur much more slowly with a soluble agent such as methoxyflurane compared with an agent of lower solubility such as sevoflurane.

Similar to the effect of solubility, increased cardiac output during recovery will tend to deliver more inhalant to the alveoli and oppose the effect of alveolar ventilation to decrease alveolar inhalant partial pressure. The high alveolar inhalant partial pressure is transmitted through the blood and maintains a high brain inhalant partial pressure and, as a consequence, recovery from anesthesia is delayed.

The duration of anesthesia also has a large influence on the elimination of inhalant anesthetics, especially highly soluble inhalants, and therefore upon the speed of recovery. The capacity of individual body tissues for an inhalant anesthetic is determined by its solubility in each specific tissue. The greater the tissue solubility of an inhalant and the greater the absolute mass of the tissue into which the inhalant can dissolve, the longer will be the period of elimination for any given duration of anesthesia. Animals anesthetized with the very soluble inhalant methoxyflurane (PC = 12.0) will have a much longer elimination time and thus a much longer recovery from anesthesia than will animals anesthetized with isoflurane (PC = 1.4) for the same period of time. Thus the duration of inhalation anesthesia further compounds the slower elimination of an inhalant with high solubility simply because it allows more time for the inhalant to diffuse into body tissues which act as storage depots. During recovery, the mass of inhalant dissolved in the tissue depots moves out of the tissues into blood which carries it to the alveoli for elimination by alveolar minute ventilation. The large quantity of inhalant anesthetic being delivered to the alveoli opposes the effect of alveolar ventilation to lower the alveolar anesthetic partial pressure, the net effect being a slower decrease in the alveolar partial pressure as well as the inhalant partial pressure in the brain. Using the same reasoning, one might predict that a patient anesthetized with halothane for a short period of time would have a more rapid recovery compared to a patient anesthetized for a longer period of time assuming that identical alveolar concentrations of halothane were administered.