Inhaled Anesthetic Uptake, Distribution, Metabolism, and Toxicity

Upstream and Downstream Compartments and Anesthetic Transfer: Bulk Flow and Pressure Gradients

Uptake and distribution of inhaled anesthetic can be readily understood as a series of transfer steps from upstream compartments with high partial pressure to downstream compartments with low partial pressure as depicted in Fig. 20.2 . First, drug is transferred from an anesthesia delivery device, typically an anesthesia machine with a vaporizer designed to deliver specified concentrations (in percent atm) of VA agent, into a fresh gas mixture flowing in a breathing circuit. Second, ventilation transfers gases from the circuit to the alveolar airspace in lung. Third, anesthetic moves by transcapillary diffusion into pulmonary venous blood. Fourth, arterial blood distributes anesthetic to various tissues including the primary target tissue, the CNS. Fifth, venous outflow from tissues converges in the pulmonary artery, and sixth, the mixed venous blood passes through alveolar capillaries where it again equilibrates with alveolar gases.

Gas flow from the anesthesia machine into the breathing circuit is unidirectional. Blood circulation is also largely unidirectional. In transfers from the anesthesia machine (the fresh gas outlet) to breathing circuit and then to alveolar airspace, anesthetic flow can simply be understood as exchange from upstream compartments into downstream compartments. In later steps, such as exchange between alveolar gases and pulmonary capillary blood, flow of anesthetic molecules occurs via diffusion between adjacent compartments separated by a permeable membrane. For simplicity, we have not treated blood as a separate compartment in our model. Distribution of anesthetic to and from various tissues involves both bulk transfer via blood flow and diffusive equilibration across capillary membranes. Note that when anesthetic transfer occurs between gas and blood or between blood and tissue, the effective volume of the downstream compartment must be adjusted with the appropriate partition coefficient (see Table 20.2 ).

Rate of Wash-In of the Circuit: Equilibration Between Vaporizer and Circuit

Equipment for controlled delivery of inhaled anesthetic drugs are described elsewhere in this text (see Chapter 22 ). Wash-in of the ventilator breathing circuit represents an example of bulk transfer exchange, wherein the gas in circuit components is replaced by fresh gases emerging from the gas outlet of the anesthesia machine.

Anesthetic Delivery from the Vaporizer: VA delivery (in liters per minute of gaseous drug) from a vaporizer is closely approximated as the product of the delivered anesthetic concentration (fraction = F _del or partial pressure at 1 atm = P _del ) of the anesthetic in a gas mixture and the fresh gas flow (FGF):

Thus we can readily calculate the volume of delivered gas-phase anesthetic by simply integrating this function over time. In the simplest case where P _del and FGF remain constant,

Fresh Gas Wash-In to the Breathing Circuit: The factors that affect the speed at which the gas mixture delivered from the anesthesia machine replaces gases in the breathing circuit (wash-in) are FGF and the breathing circuit volume (V _circ ). Consider a typical situation where FGF at the beginning of an anesthetic is 6 L/min, and the gas volume inside the components of a breathing circuit is 6 L. If FGF is doubled to 12 L/min, then wash-in will proceed at twice the rate (halving the time). Conversely, if the V _circ doubles to 12 L, then wash-in will proceed at half the rate (doubling the time).

The gas exchange process is independent of the concentration of anesthetic in the circuit, because the exchange is simply through bulk flow and mixing. However, the difference between the delivered concentration and that in the circuit determines the magnitude and direction of net anesthetic gas flow . When the delivered anesthetic partial pressure (P _del ) is greater than that in the circuit (P _circ ), net anesthetic flow is into the circuit (and subsequently the patient). To remove anesthetic from the circuit, P _del must be less than P _circ . When there is no concentration gradient (i.e., equal partial pressures), bulk flow exchange may replace all the old anesthetic molecules with new ones, but there is no net flow and anesthetic concentrations in the circuit remain unchanged.

Mathematically, we can describe the breathing circuit exchange process as a differential equation that incorporates all of the above factors:

If P _del is constant, integrating this equation results in a single exponential function that defines P _circ at any given time following a change in P _del at t = 0:

P _circ approaches P _del following an exponential time course with a time constant of τ = V _circ /FGF. Thus if V _circ = 6 L and FGF = 6 L/min, the exponential time constant will be 1 minute ( Fig. 20.3 ). Each minute results in the fraction of old gas in the breathing circuit dropping by 63.1%, and after 4 minutes, less than 2% old gas remains. The half-life for the process (time for halving the vaporizer-circuit concentration difference) is 0.693 × τ.

Breathing circuit components, such as CO ₂ absorbents and the plastic or rubber of the circuit tubing and connectors, influence the rate of equilibration between vaporizer and circuit, because they absorb VAs, increasing the effective circuit volume. The more hydrophobic VAs absorb more into circuit components, whereas absorption negligibly affects wash-in and wash-out of low-solubility anesthetics.

The clinical relevance of the wash-in process is readily appreciated. An example of the importance of FGF is “priming” the anesthetic circuit for a single-breath induction technique. The FGF setting and the circuit volume influence the required duration of priming. More generally, whenever the vaporizer settings are altered, the speed at which the new settings influence the wash-in or wash-out of the circuit (and subsequently the patient) will depend on FGF. Open (nonrebreathing) anesthetic breathing circuits are designed to have low exchange volumes and to be used with high fresh-gas flows. These features allow rapid changes in the delivered anesthetic concentration, while minimizing rebreathing of exhaled gases. The choice of an open versus rebreathing system influences the impact of various other factors that can affect uptake and distribution of inhaled anesthetics downstream from the breathing circuit. Some of the subsequent figures show models for both conditions.

Equilibration Between Circuit and Pulmonary Airspace

Transfer of anesthetic gases from the breathing circuit to the pulmonary airspace is another bulk exchange process similar to that from vaporizer to breathing circuit. In this case, gas flow via ventilation is cyclical and bidirectional, and the factors that determine the rate of anesthetic exchange are minute ventilation (MV) and total pulmonary airspace volume (V _pulm ). Because transfer from the circuit to the lungs represents anesthetic flow out of the circuit, we alter Eq. (20.3) to include both inflow to the circuit and outflow from the circuit,

where P _pulm is a weighted average of the anesthetic partial pressure in dead space and alveolar space.

Eq. (20.5) describes how rebreathing affects the inhaled (breathing circuit) anesthetic concentration. Most inhaled anesthetics are delivered using a rebreathing circuit, which includes one-way flow valves and adsorbent material to chemically remove exhaled CO ₂ . Rebreathing depends primarily on the balance between fresh gas flow and MV. The anesthetic gas in the breathing circuit represents a mixture of fresh gas and exhaled gases. Increased fresh gas flow reduces rebreathing, whereas increased MV increases rebreathing.

The Alveolar Anesthetic Concentration

The alveolar anesthetic concentration (P _alv or F _A ) is a critically important factor in anesthetic uptake and distribution because (1) it is in rapid equilibrium with circulating blood and highly perfused tissues, including target tissues in the CNS, and (2) P _alv can be measured in exhaled end-tidal gases. Thus, except during periods of rapid change, P _alv in exhaled breath represents a useful estimate of the anesthetic concentration in the patient’s CNS and other highly perfused organs.

Because only alveolar gas is relevant to transpulmonary exchange of anesthetic into and out of the body, alveolar ventilation ( ${\dot{\text{V}}}_{\text{alv}}$ ) is the proper gas flow to calculate anesthetic exchange into this part of the pulmonary airspace,

where ${\dot{\text{V}}}_{\text{alv}}$ is MV corrected for dead space ventilation.

Alveolar Uptake of Anesthetic into Pulmonary Blood

During inhaled anesthetic induction, anesthetic flows from alveolar gas to pulmonary blood across the alveolar/capillary interface separating these compartments and is driven by the partial pressure gradient between alveolar gas (P _alv ) and mixed venous blood (P _MV ) entering the pulmonary arteries. The net flow of anesthetic reverses during anesthetic wash-out when P _alv drops below P _MV . Anesthetic uptake into blood also depends on the pulmonary blood flow (which is typically close to cardiac output, $\dot{\text{Q}}$ ) and the blood’s capacity to solvate anesthetic from the gas state (the blood/gas partition coefficient, λ _b/g ):

We therefore correct Eq. (20.6) to reflect both anesthetic inflow into alveolar airspace and its uptake into blood:

Thus, during an inhaled anesthetic induction, the rate of increase of P _alv relative to P _circ is governed by (1) alveolar ventilation, (2) cardiac output, and (3) anesthetic solubility in blood. Increased ventilation delivers more anesthetic from circuit to alveoli and increases P _alv /P _circ ( Fig. 20.4 ). Importantly, increased pulmonary blood flow removes more anesthetic from alveoli, thereby decreasing the rate of increase in alveolar concentration of anesthetic (P _alv /P _circ ) ( Fig. 20.5 ). Indeed, significant decreases in cardiac output are suspected when end-tidal CO ₂ (ETCO ₂ ) decreases and end-tidal concentration of VA increases. The more soluble an anesthetic is in blood (i.e., the higher its λ _b/g ), the greater is the capacity for each volume of blood to take up anesthetic from alveolar gases (i.e., the larger the effective blood flow). Thus as λ _b/g increases, P _alv /P _circ increases more slowly ( Fig. 20.6 ).

Other Factors That Affect the Rate of Rise of P _alv

Other factors affecting alveolar uptake of anesthetic include ventilation-perfusion matching and the absolute concentration of anesthetic in alveolar gases.

Pulmonary Dead Space. Dead space (ventilated but not perfused pulmonary regions) reduces effective alveolar ventilation (see Eqs. 20.7 and 20.8 ), and thus slows anesthetic uptake. This effect is strongest under conditions of high FGF and low blood-solubility agents, where alveolar ventilation is the limiting factor in uptake. Under conditions of low FGF and a highly blood-soluble agent, increased dead space, by reducing initial uptake, serves to maintain the inhaled anesthetic concentration (P _circ ), which creates a compensatory increase in P _alv and subsequent uptake.

Pulmonary (Right to Left) Shunting. Pulmonary right to left shunting can be physiologic, pathologic, or iatrogenic, such as during one-lung ventilation. Right-to-left shunting results in a difference between P _alv and the partial pressure of anesthetic in arterial blood (P _art ). This is because arterial blood represents a mixture of shunted mixed venous blood combined with blood that has equilibrated with alveolar gases ( Eq. 20.9 ). Because such shunts also reduce transcapillary gas exchange in the lung and slow anesthetic uptake ( Eqs. 20.7 and 20.8 , after correcting pulmonary blood flow for shunt), right-to-left shunting sustains P _circ , an effect that is more pronounced for highly soluble drugs compared with insoluble anesthetics. Thus shunt reduces the ratio of P _art 😛 _alv more for insoluble anesthetics, such as N ₂ O ( Fig. 20.7 ):

Concentration and Second Gas Effects. The absolute concentration of anesthetic influences its uptake and that of other gases. In the previous discussion and illustrations, it was presumed that an inhaled anesthetic represents a small fraction of the inhaled gas mixture and that transalveolar uptake of the anesthetic results in a decrease in P _alv and negligible changes in alveolar gas volume. However, when the anesthetic represents a large fraction of the inhaled gas mixture, its rapid uptake results in a smaller relative alveolar anesthetic concentration drop, because the volume of alveolar gas also decreases. This is known as the concentration effec t. In an imaginary situation where a patient is breathing 100% anesthetic, uptake into pulmonary blood reduces the volume of anesthetic gas in the alveoli without altering its concentration or partial pressure (oxygen-induced atelectasis occurs through a similar mechanism). A typical situation, illustrated in Fig. 20.8 , is delivery of 66% N ₂ O with 33% O ₂ and 1% isoflurane. Assuming cardiac output equals 5 L/min, the initial rate of N ₂ O uptake is given by Eq. (20.7) as 5000 mL/min × 0.47 × 0.66 atm = 1550 mL/min, indicating that a large fraction of N ₂ O is taken up into blood during the first few breaths. If we assume that half the N ₂ O and half the isoflurane are rapidly taken up following the first breath of this gas mixture, then alveolar volume drops by 33.5% and the remaining alveolar gas contains 33 parts N ₂ O, 33 parts O ₂ , and 0.5 parts isoflurane (49.6% N ₂ O, 49.6% O ₂ , and 0.8% isoflurane). Despite 50% uptake of N ₂ O, the significant reduction in alveolar gas volume results in a concentration of remaining alveolar N ₂ O that is only 24% less than its initial value.

The second gas effect is also evident in this example: the rapid uptake of N ₂ O and reduced alveolar gas volume sustains P _iso near its original inspired value and increases alveolar ${\text{P}}_{{\text{O}}_2}$ , thereby augmenting uptake of these gases. The rapid uptake of N ₂ O into blood also results in an effective increase in MV, because more gas from the breathing circuit is passively drawn into lung as alveolar gas is rapidly absorbed. These effects have been demonstrated in humans and lab animals. Recent clinical studies and mathematical modeling indicate that, because of ventilation-perfusion heterogeneity, the second gas effect is greater in arterial blood than in expired gas, influenced by the blood solubility of VAs, and significantly affects anesthetic onset at relatively low rates of N ₂ O uptake.

Distribution of Anesthetic into Tissues

Blood exiting the pulmonary capillaries enters the pulmonary vein and the left heart. Inhaled anesthetics are then distributed via arterial blood to various body tissues. The rate of increase of anesthetic partial pressure within each tissue is determined by tissue-specific arterial blood flow ( $\dot{\text{q}}$ ), effective volume (the product of anatomic volume and tissue/blood partition coefficient, ${\text{λ}}_{\text{t/b}}$ ), and the anesthetic partial pressure gradient between arterial blood and the tissue,

where i designates a particular organ or type of tissue. Values used in model calculations are summarized in Table 20.2 . The time required for anesthetic partial pressure equilibration between arterial blood (P _art = P _alv ) and a specified tissue is shorter if its blood flow is high, and longer if that tissue has a large effective volume ( Figs. 20.2 and 20.9 ).

Traditionally, anesthetic distribution has been described for four distinct tissue groups. The vessel-rich group (VRG) includes the heart, brain, lungs, spinal cord, liver, and kidney. Together, these organs compose approximately 10% of the adult human body mass; however, they receive approximately 70% of cardiac output under normal resting conditions. As a result, time constants for anesthetic equilibration between blood and these organs are typically only a few minutes (see Table 20.2 ). Of particular interest is the equilibration time for the CNS, where anesthetic effects are mediated. After the highly perfused VRG tissues, skeletal muscle is the next compartment to equilibrate with inhaled anesthetics. Muscle composes approximately 40% of body mass in a healthy adult, making muscle the largest single compartment based on weight. Moreover, most inhaled anesthetics partition into muscle more than into brain, resulting in an increased effective volume for anesthetic uptake into this compartment. At rest, muscle receives about 10% to 15% of cardiac output (20 mL/kg/min), but this value can increase dramatically during exercise, stress, fever, or other states associated with high cardiac output. Taken together, these factors generally result in slow equilibration between anesthetic in blood and muscle, with typical time constants of hours (see Table 20.2 ). The third tissue group is fat , which in a healthy adult composes less than 25% of body mass and receives approximately 10% of cardiac output. Potent VAs partition avidly into fat; therefore, fat represents the largest effective volume for uptake of these drugs (see Fig. 20.2 , Table 20.2 ). The extremely large effective volume coupled with low blood flow results in very slow equilibration of anesthetics between blood and fat, with time constants approaching days. A fourth group, including skin, cortical bone, and connective tissue, is referred to as vessel poor tissues . These tissues compose 10% to 15% of an average adult body while receiving less than 5% of cardiac output at rest. Induction of general anesthesia impairs normal sympathetic nervous function, resulting in increased blood flow to normally cool skin in the extremities. The blood volume represents approximately 7% of body mass and may be considered another compartment for anesthetic uptake, while also conveying drug to other tissue compartments.

As stated previously, increased cardiac output results in increased anesthetic uptake and a slower rate of rise of P _alv . Clinical studies confirm that, other factors being equal, increasing cardiac output slows the induction of general anesthesia with inhaled anesthetics. This result can seem counterintuitive when increasing cardiac output increases uptake of anesthetic into the patient’s body and hastens its delivery to the tissues. However, during induction, the anesthetic partial pressure in blood and downstream tissue compartments cannot be higher than that in the upstream alveolar compartment. Increased cardiac output slows the rise of P _alv and thus also slows the rate of increase of the anesthetic partial pressure in blood (P _art ), the CNS (P _CNS ), and other highly perfused tissues. The extra anesthetic uptake is primarily into muscle, which is a large tissue compartment with a high capacity for anesthetic and is where much of the excess cardiac output flows. For example, a 50% increase in cardiac output can more than double muscle blood flow, diverting the majority of anesthetic to muscle, lowering P _alv , and thus slowing anesthetic uptake into target tissues in the CNS. If one could manipulate inhaled anesthetic delivery to maintain constant P _alv , which may be achievable with automated feedback control of vaporizer output and FGF, then increased cardiac output might have a different effect. Model simulations where P _alv is maintained at a constant level show that uptake into VRG tissues, including brain tissue, increases more rapidly as cardiac output increases.

In pediatric patients, the balance of cardiac output to various tissue beds differs from that in adults. Thus, although cardiac output per kilogram body weight is larger in children than in adults, anesthetic induction in young children is more rapid than in adults, because a disproportionate amount of perfusion goes to the vessel rich organs, such as the brain.

The equilibrium distribution volumes for most inhaled anesthetics are extremely large, with the largest compartment by far being fat. However, equilibration with fat is so slow that this compartment usually plays a relatively minor role in the pharmacokinetics of inhaled anesthetics. During a typical general anesthetic lasting from 30 minutes to several hours, the blood, VRG organs, and muscle are the compartments into which inhaled anesthetics mostly distribute.

Although the model in Fig. 20.2 illustrates anesthetic distribution only via arterial blood flow, intertissue diffusion takes place between abutting tissues that have large interfacial surface areas. In particular, direct diffusion from organs with high anesthetic partial pressures to abutting tissues with low partial pressure and high capacity for anesthetic uptake may also contribute to drug distribution. Examples of this process include anesthetic diffusion from the heart, liver, and kidneys to surrounding fat in the pericardium and abdomen.

The Mixed Venous Anesthetic Partial Pressure

The anesthetic partial pressure in mixed venous blood entering the pulmonary circulation is a weighted average of the venous outflows from all tissues and organs, which converge in the right ventricle:

As P _MV rises, the gradient driving uptake of inhaled anesthetics from alveoli weakens. The difference between the delivered (inspired) and the alveolar (end-expiratory) anesthetic concentrations also shrinks, causing transpulmonary uptake to slow ( Eq. 20.7 ). Systemic (left to right) shunting causes P _MV to increase more rapidly than it would in the absence of such shunts. When blood flow to other tissues remains normal and the left-to-right shunt simply represents excess cardiac output, the resulting increase in anesthetic uptake ( Eq. 20.7 ) is offset by the increase in P _MV , resulting in a slight increase in the rate of anesthetic delivery or uptake into the brain, muscle, and other tissues. In cases where large left-to-right shunts result in reduced blood flow to other tissues, anesthetic equilibration in those tissues will be relatively slow.