Anesthetic Uptake Factors

The product of three factors determines anesthetic uptake: solubility (λ), cardiac output (Q), and alveolar-to-venous partial pressure difference (PA - PV).^[1]

Because uptake is a product of the three factors rather than a sum, if any factor approaches zero, uptake must approach zero, and ventilation rapidly produces an FA/FI of 1.0. If solubility is small (as with oxygen), if cardiac output approaches zero (as in profound myocardial depression or death), or if the alveolar-to-venous difference becomes inconsequential (as can occur after an extraordinarily long anesthetic), uptake would be minimal, and FA/FI would equal 1.0.

Solubility

The blood-gas partition coefficient (i.e., blood solubility [λ]) describes the relative affinity of an anesthetic for two phases and therefore the partitioning of that anesthetic between the two phases at equilibrium. For example, isoflurane has a blood-gas partition coefficient of 1.4, indicating that at equilibrium, isoflurane's concentration in blood is 1.4 times its concentration in the gas (alveolar) phase. Equilibrium means that no difference in partial pressure exists (i.e., a blood-gas partition coefficient of 1.4 does not indicate that the partial pressure in blood is 1.4 times that in the gas phase). The partition coefficient indicates the relative capacity of the two phases: a value of 1.4 means that each milliliter of blood holds 1.4 times as much isoflurane as a milliliter of alveolar gas.

A larger blood-gas partition coefficient produces a greater uptake and hence a lower FA/FI ratio. Because the alveolar anesthetic partial pressure is transmitted to the arterial blood and then to all tissues, great blood solubility (as with ether and methoxyflurane [ Table 5-1 ])^{[1] [2] [3] [4] [5] [6] [7] [8]} can delay the development of an anesthetizing brain anesthetic partial pressure.^[1] Such a delay contributed to the removal of ether and methoxyflurane from anesthetic practice. Even the moderate solubility of enflurane, isoflurane, or halothane would slow induction of anesthesia with these agents if we did not compensate for the uptake of anesthetic by delivering a higher concentration (i.e., overpressure) than we hoped to achieve in the alveoli. For example, anesthesiologists may use 4% to 5% halothane to produce an alveolar concentration of 1%. The use of overpressure can equalize the rate of induction among anesthetics with different solubilities. For example, induction of anesthesia with 5% halothane (6.7 times the minimum alveolar concentration [MAC]) is essentially as rapid as induction with 8% sevoflurane (4.3 MAC), despite a nearly fourfold greater solubility of halothane.^[9]

133

Cardiac Output

Greater pulmonary blood flow removes more anesthetic and thereby lowers the FA/FI ratio. A greater uptake and more rapid delivery to the tissues must accelerate the rise in the tissue anesthetic partial pressure and hasten equilibration of the tissue anesthetic partial pressure with the partial pressure in arterial blood.^[10] The more rapid tissue equilibration does not hasten induction of anesthesia because of the lower FA/FI ratio; the accelerated tissue equilibration is to a lower anesthetic partial pressure.

Increased cardiac output has an effect analogous to that of an increased solubility. Doubling solubility doubles the capacity of the same volume of blood to hold anesthetic. Doubling cardiac output also doubles capacity, but in this case by doubling the volume of blood exposed to anesthetic.

Alveolar-to-Venous Anesthetic Gradient

The alveolar-to-venous anesthetic partial pressure difference results from tissue uptake of anesthetic. Were there no tissue uptake, the venous blood returning to the lungs would contain as much anesthetic as the arterial blood that left the lungs. The alveolar (which equals arterial)—to-venous partial pressure difference would be zero.

The factors that determine the fraction of anesthetic removed from blood traversing a given tissue parallel those that govern uptake at the lungs: tissue solubility (i.e., the tissue-blood partition coefficient), tissue blood flow, and arterial-to-tissue anesthetic partial pressure difference. Uptake is the product of these factors. If any factor approaches zero, tissue uptake becomes inconsequential. The capacity of a tissue to hold anesthetic equals the product of the volume of tissue and the solubility of the anesthetic in that tissue.

Blood-gas partition coefficients extend from 0.45 for desflurane to 15 for methoxyflurane (i.e., a 33-fold range) (see Table 5-1 ). In contrast, tissue-blood partition coefficients for lean tissues range from slightly less than 1 to a maximum of 3.4 (see Table 5-1 ); different lean tissues have similar capacities per milliter of tissue relative to blood. Put another way, a given anesthetic has roughly the same affinity for lean tissues and blood. As with blood-gas partition coefficients, tissue-blood partition coefficients define the concentration ratio of anesthetic at equilibrium. For example, a halothane brain-blood partition coefficient of 1.9 means that 1 mL of brain holds 1.9 times more halothane as 1 mL of blood having the same halothane partial pressure.

A larger tissue capacity relative to flow increases the transfer of anesthetic from blood to tissue. However, it

TABLE 5-2 -- Tissue group characteristics

	Tissue Group
Characteristic	Vessel-Rich	Muscle	Fat	Vessel-Poor
Percentage of body mass	10	50	20	20
Perfusion as percentage of cardiac output	75	19	6	0
Adapted from Eger EI II: Uptake of inhaled anesthetics: The alveolar to inspired anesthetic difference. In Eger EI II: Anesthetic Uptake and Action. Baltimore, Williams & Wilkins, 1974, pp 77–96.

takes longer to fill up a tissue with a large capacity relative to blood flow. It takes longer for a tissue such as muscle to equilibrate with the anesthetic partial pressure being delivered in blood, and this sustains the arterial to muscle anesthetic partial pressure difference (and hance uptake) for a longer time. With its high perfusion per gram, brain equilibrates rapidly with the anesthetic partial pressure brought to it in arterial blood. Per milliliter of tissue, muscle has about one-twentieth the perfusion of brain, and muscle takes about 20 times as long as brain to equilibrate. Uptake of anesthetic by muscle continues long after uptake by brain has ceased.

Fat-blood coefficients are significantly greater than 1, particularly those for more potent anesthetics (see Table 5-1 ) and range from 2.3 (nitrous oxide) to 51 (halothane) to 61 (methoxyflurane). Each milliliter of fat tissue contains 2.3 times more nitrous oxide or 51 times more halothane than a milliliter of blood having the same nitrous oxide or halothane partial pressure. This enormous capacity of fat for anesthetic means that most of the anesthetic contained in the blood perfusing fat is transferred to the fat. Although most of the anesthetic moves from the blood into the fat, the anesthetic partial pressure in fat increases very slowly. The large capacity of fat and its low perfusion per milliter prolong the time required to narrow the anesthetic partial pressure difference between arterial blood and fat.

Tissue Groups

The algebraic sum of uptake by individual tissues determines the alveolar-to-venous partial pressure difference and therefore uptake at the lungs. However, we do not need to analyze the effect of individual tissues to arrive at the algebraic sum; instead, we can group tissues by their perfusion and solubility characteristics (i.e., features that define the duration of a substantial arterial-to-tissue anesthetic partial pressure difference). Four tissue groups result from such an analysis^[1] ( Table 5-2 ).

The brain, heart, splanchnic bed (including liver), kidney, and endocrine glands make up the vessel-rich group (VRG). These organs comprise less than 10% of the body weight but receive 75% of the cardiac output. This great perfusion delivers a relatively large volume of anesthetic and permits an initially large uptake of anesthetic by the VRG. However, the small tissue capacity relative to perfusion produces a rapid equilibration with a time to half-equilibration (i.e., the time at which the VRG anesthetic partial pressure equals one half of that in arterial blood) of 1 minute for nitrous oxide to 2 minutes for halothane (longer for halothane because of its higher tissue-blood partition coefficient and therefore greater capacity) (see Table 5-1 ).

134

For a substantial period after the first 8 minutes, muscle and skin (i.e., the muscle group [MG]) determine uptake. Muscle and skin have similar blood flow and solubility (lean tissue) characteristics. A lower perfusion (about 3 mL of blood per 100 mL of tissue per minute) separates this group from the VRG (70 mL of blood per 100 mL of tissue per minute). Although about one half of the body bulk is muscle and skin, this volume receives only 1 L/min of blood flow at rest; this tissue group receives and initially takes up one fourth of the amount of anesthetic delivered to the VRG. During induction, most of the anesthetic delivered to the MG is removed from its blood flow. Unlike the VRG, the MG continues to remove anesthetic from its blood supply for a long time. The time to half-equilibration ranges from 20 to 25 minutes (nitrous oxide) to 70 to 80 minutes (sevoflurane or halothane). Long after equilibration of the VRG has taken place, muscle continues to take up substantial amounts of anesthetic. MG approaches equilibration in 2 to 4 hours.

After equilibration of the MG, only fat (i.e., the fat group [FG]) serves as an effective depot for uptake. In a normal, lean patient, fat occupies one fifth of the body bulk and receives a blood flow of about 400 mL/min (i.e., perfusion per 100 mL of fat nearly equals the perfusion per 100 mL of resting muscle). During the initial delivery of anesthetic to tissues, the FG has access to only 40% of the anesthetic delivered to the MG (i.e., blood flow to the FG is 40% of that to the MG). Fat also differs from muscle in its higher affinity for anesthetic, and this greatly lengthens the time over which it absorbs anesthetic. The equilibration half-time of the FG ranges from 70 to 80 minutes for nitrous oxide to 30 hours for sevoflurane and halothane.

A fourth tissue group, the vessel-poor group (VPG) consists of ligaments, tendons, bone, and cartilage (i.e., lean tissues that have little or no perfusion). The absence of a significant blood flow means that this group does not participate in the uptake process even though it makes up one fifth of the body mass.