Pharmacokinetics of Inhaled Anesthetics

Historical Perspective

The discovery of drugs with anesthetic properties was a landmark event in the history of pharmacology, medicine, and even civilization, in that it made otherwise painful surgical treatments of disease possible. Without a means of providing anesthesia, it was impossible for the modern discipline of surgery to develop. Before the discovery of anesthetic drugs, surgical intervention was limited to simple operations that could be completed quickly.

The first anesthetics were administered by inhalation before the evolution of techniques for intravenous drug administration, and anesthetics remain the most important class of inhaled drugs (barring oxygen, of course). Diethyl ether was first used clinically as a general anesthetic by Long in 1842, and was independently developed by Morton in 1846. Morton's public demonstration of the anesthetic properties of ether at the Massachusetts General Hospital on October 16, 1846, is one of the most important moments in the history of medicine and is now commemorated as Ether Day in Boston and World Anaesthesia Day throughout the world; Long's contribution is also honored as National Doctor's Day in the United States, marking the day that he administered the first ether anesthetic for surgery (March 30, 1842).

Ether remains in clinical use in developing countries given its low cost and relatively high therapeutic index, but its high volatility and explosivity limit its general use. Nitrous oxide was first used for dental analgesia by Wells in 1844, and in 1847 Simpson introduced chloroform (trichloromethane) as a nonexplosive alternative to ether. The first century of anesthesia was dominated by these drugs, of which only nitrous oxide is still widely used.

Since its early origins the practice of anesthesia has been driven by the development of techniques to facilitate the safe delivery of inhaled anesthetics, and these concepts remain important. Administration of drugs by inhalation has a number of unique and important attributes primarily owing to special pharmacokinetic and chemical properties that guide the safe and effective use of inhaled anesthetics.

Classes of Inhaled Anesthetics

General anesthetics include a range of structurally diverse inhaled and injectable compounds that are defined by their ability to induce a reversible comatose state characterized by unconsciousness, amnesia, and immobility. The inhaled anesthetic drugs belong to three broad classes: ethers, alkanes, and gases ( Fig. 3.1 ). (The latter classification is somewhat arbitrary as all inhaled anesthetics are delivered as gases, but gaseous anesthetics are those that normally exist as gases at standard temperature and pressure: nitrous oxide, cyclopropane, noble gases). The ethers and alkanes are volatile liquids (i.e., they have a vapor pressure that is less than atmospheric pressure at room temperature; see later text) and are delivered as vapors (the gas phase in equilibrium with the liquid phase at a given temperature; a condensable gas). The modern era of volatile anesthetics—those halogenated with fluorine—began with the synthesis of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) by Suckling in 1951, which was successfully introduced as an anesthetic in clinical trials in 1956. Subsequent attempts to minimize the adverse effects of halothane (particularly the propensity to develop hepatitis, rare but often fatal, or ventricular arrhythmias) led to the development in the 1960s by Terrell and others of a series of halogenated methyl ethyl ethers, including methoxyflurane (2,2-dichloro-1,1-difluoro-1-methoxyethane), enflurane (2-chloro-1-[difluoromethoxy]-1,1,2-trifluoro-ethane), isoflurane (2-chloro-2-[difluoromethoxy]-1,1,1-trifluoro-ethane), and subsequently in the 1990s, desflurane (2-[difluoromethoxy]-1,1,1,2-tetrafluoro-ethane) and sevoflurane (1,1,1,3,3,3-hexafluoro-2-[fluoromethoxy]propane).

Fig. 3.1, Inhaled anesthetic agents by class, with chemical structure and space-filling model drawn to scale.

Physical Properties

Inhaled drugs differ from intravenous drugs in that their delivery depends on uptake into the blood by the lungs, followed by delivery to their effect sites in the central nervous system in the case of anesthetics. The delivery of inhaled drugs to the lungs depends on the physical properties of the drugs themselves, in particular their solubility in blood and their vapor pressure ( Table 3.1 ).

TABLE 3.1

Properties of Inhaled Anesthetics

(Modified from Eger EI 2nd, Eisenkraft JB, Weiskopf RB. Metabolism of potent inhaled anesthetics. In: Eger EI 2nd, Eisenkraft JB, Weiskopf RB, eds. The Pharmacology of Inhaled Anesthetics . Chicago: Healthcare Press; 2003:167–176.)

Agent	Boiling Point (°C) at 1 Atm	Vapor Pressure (mm Hg) at 20°C	MAC For 40-Yr-Old in O ₂ (%)	Blood:Gas Partition Ratio at 37°C	Oil:Gas Partition Ratio at 37°C
Halothane	50.2	243	0.75	2.4	224
Enflurane	56.5	172	1.7	1.8	97
Isoflurane	48.5	240	1.2	1.4	98
Sevoflurane	58.5	160	2	0.65	47
Desflurane	22.8	669	6	0.45	19
Nitrous oxide	−88.5	39,000	104	0.47	1.4
Xenon	−108.1	—	60–70	0.14	1.9

Vapor pressure is the partial pressure of a vapor in thermodynamic equilibrium with a liquid—that is, the partial pressure at which the rate of liquid evaporation into the gaseous phase equals the rate of gaseous condensation into liquid. Vapor pressure varies nonlinearly with temperature according to the Clausius-Clapeyron relationship ( Fig. 3.2 ). The boiling point is the temperature at which the vapor pressure equals ambient atmospheric pressure. Substances that have high vapor pressures at room temperature (e.g., many of the inhaled anesthetics) are volatile. Partial pressure is the portion of the total pressure of a gaseous mixture supplied by a particular gas; for an ideal gas, this is the mole fraction of the mixture multiplied times the total pressure of the gas. Inhaled anesthetic partial pressures are commonly expressed as volume percent (vol%), which is the percent of the total volume contributed by a particular gas, or for an ideal gas, the mole percent. At standard temperature and pressure, the volume percent times total pressure equals the partial pressure, but importantly, partial pressure changes with temperature.

Fig. 3.2, Pressure and temperature relationships. A, A qualitative state diagram for water. The vapor pressure is the pressure at which the liquid and gaseous phases are in equilibrium for a given temperature, as indicated by the line between the liquid and gaseous phases in the state diagram. B, Vapor pressure data for a number of common anesthetics. Note that the vapor pressure of desflurane is much higher at a given temperature than the vapor pressure of the other agents, and that the vapor pressure of desflurane reaches 760 mm Hg (or 1 atm) at approximately 22.8°C (its boiling point), indicating that it will boil in a warm room.

The solubility of a gas is the amount of gas that can be dissolved homogenously into a solvent at equilibrium; it is a function of the partial pressure of the gas above the liquid solvent and the ambient temperature. Solubility depends on the solvent—for example, polar substances tend to be more soluble in polar solvents. According to Henry's law, for a given solvent at a given temperature the amount of gas dissolved in solution is directly proportional to the partial pressure of the gas. Relative solubilities can be described according to the partition ratio (also known as the partition coefficient), which is defined as the ratio at equilibrium of the concentration of the dissolved gas in one solvent to the concentration of the dissolved gas in the other solvent (or in the gaseous phase). At equilibrium the partial pressure of the dissolved gas in the two solvents is equal, even though the concentrations are not ( Fig. 3.3 ). The concentration of a gas in a liquid is derived by multiplying the gas partial pressure times its solubility expressed as its solvent:gas partition ratio (at standard temperature and pressure). For inhaled anesthetics, the blood:gas partition ratio is critically important to alveolar uptake. More soluble agents, such as ether or halothane, have high blood gas partition ratios and take longer to reach an equilibrium between inhaled and exhaled partial pressure owing to their greater uptake into blood and tissues. Conversely, less soluble agents, such as nitrous oxide and desflurane, dissolve in lower quantities and approach equilibrium more rapidly (see later text). Following Henry's law, the solubility of gases such as inhaled anesthetics in aqueous liquids increases at lower temperatures. Various tissues also have tissue-specific partition ratios that depend largely on their biochemical composition. This determines relative anesthetic uptake and concentrations in each tissue. Because of differing partition ratios, the actual concentrations can be very different between various tissues at equilibrium even though the partial pressure will eventually be the same, and even two agents with low blood:gas partition ratios, such as nitrous oxide and desflurane, will differ in their rate of uptake into the central nervous system (CNS) because their CNS:blood partition ratios differ. Fig. 3.4 demonstrates that even after a 10-minute wash-in period the differences in partial pressure are pronounced as the different tissue compartments take up the agent.

Fig. 3.3, Blood:gas partitioning of inhaled anesthetics at 37°C. At equilibrium, the partial pressures of the anesthetics in the gas and liquid (blood) phases (100 mL of each) are equal (15 mm Hg for 2 vol% at standard atmospheric pressure of 760 mm Hg). In contrast, blood concentrations differ depending on the drug specific blood:gas partition ratios (λ). Note that λ increases ~4% per 1°C decrease in temperature.

Fig. 3.4, Tissue partial pressures of anesthetics. Results of a Gas Man simulation (Med Man Simulations, Inc., Boston, MA) of a 70-kg patient administered sevoflurane for 10 minutes at 2.56 vol% in 8 L/min of 100% O 2 . The delivered inspiratory and measured end-tidal concentrations of sevoflurane are shown, together with the partial pressure and concentration of anesthetic in arterial blood, mixed venous blood, the vessel-rich, vessel-poor, lean, and fat groups. If allowed to run until full equilibration between compartments, the partial pressures of anesthetic would equalize, while the concentrations measured as volume percent will differ according to the tissue:gas partition ratios.

Measuring Anesthetic Potency as MAC

The potency of inhaled anesthetics is commonly expressed using the concept of minimum alveolar concentration (MAC) as described by Eger and colleagues. The MAC of an anesthetic vapor is the steady-state concentration at which 50% of “normal” (healthy, nonpregnant, adult) human subjects under standard conditions (normal body temperature, 1 atm, no other drugs) do not move (are immobile) in response to a defined stimulus (surgical incision; laboratory studies often substitute application of a tail clamp to rodents). Although MAC is defined in terms of a gas concentration in volume percent or fractional atm at 1-atm ambient pressure, it is the partial pressure and resultant concentration at the effect site that is critical to the pharmacologic response (immobility). Thus anesthetic potency expressed in terms of alveolar partial pressure or tissue concentration is constant for a given physiologic state. MAC is expressed as a gas concentration at 1-atm ambient pressure. The vaporizer setting in volume percent delivers an equivalent alveolar partial pressure that varies with atmospheric pressure; this is significant at high altitudes where higher inspired concentrations are required to produce a given tissue partial pressure/concentration. The MAC of an inhaled agent is analogous to the EC ₅₀ (effective concentration in 50% of subjects) of intravenous agents; hence, more potent agents have lower MAC values. MAC is defined using only one behavioral component of anesthesia—the lack of a motor response (immobilization) to a painful stimulus—and reflects primarily spinal effect sites (see Chapter 11 ). The MAC concept has been extended to other endpoints including MAC awake (for emergence), MAC blunted autonomic response, and so on.

Although MAC was originally developed as a simple method of comparing the potency of inhaled anesthetics, it has emerged as an important clinical tool. Anesthesiologists often formulate an anesthetic plan by targeting a certain MAC multiple for a given patient, procedure, and anesthetic technique (although strictly speaking MAC is a single point on a nonlinear curve, so there are limitations to this approach). The pervasive influence of MAC in the daily practice of anesthesia makes it one of the most important unifying concepts in anesthetic pharmacology. Further consideration of the factors that influence MAC (e.g., age, body temperature, adjuvant drugs, genetics) is provided in Chapter 11 .

Monitoring Inhaled Anesthetic Delivery

Differences Between Inhaled and Intravenous Anesthetic Delivery

Administering volatile anesthetics by inhalation using a calibrated vaporizer affords several fundamental advantages compared with intravenous drug delivery ( Fig. 3.5 ). Because uptake of inhaled anesthetic diminishes as equilibrium between alveolar and pulmonary venous partial pressures is approached, the vaporizer setting reflects the anesthetic concentration in blood and therefore at the site of drug action owing to rapid uptake in well-perfused tissues (including the CNS). This enables accurate administration of the inhaled drug to a target concentration (with an upper limit above which the partial pressure cannot rise). Moreover, the end-expired concentration can be measured and confirmed by respiratory gas monitoring, ensuring that the targeted concentration has been achieved (pharmacokinetic exactness). The pharmacodynamic significance of the measured concentration is standardized in terms of MAC, providing pharmacodynamic exactness.

Fig. 3.5, Comparison of delivery of anesthetics by inhalation (upper panel) or intravenous infusion (lower panel) at the beginning of the total intravenous anesthesia era (circa 1995). Inhalational delivery provides both pharmacokinetic and pharmacodynamic accuracy because known concentrations can be titrated by adjusting the vaporizer to known target concentrations (minimum alveolar concentration [MAC] ) without accumulation and usually with minimal metabolism.

In contrast, direct access to the circulation as required in intravenous anesthesia delivery does not prevent indefinite uptake of drug (see Fig. 3.5 , lower panel). Without the aid of a computer model, the infusion rate of an intravenous anesthetic does not reveal much about the resulting concentration in blood, preventing accurate administration targeted to a known concentration. There is currently no commercially available device to measure the concentration of intravenous anesthetics in real time, preventing equivalent pharmacokinetic exactness (delivering a targeted concentration). Even if concentrations of intravenous drugs were measurable in the clinical setting, the meaning of a given concentration is not common knowledge to most practitioners who practice without target controlled infusion technology (e.g., practitioners based in the United States; see Chapter 2 ). In contrast to the early days of total intravenous anesthesia, the therapeutic windows for most intravenous anesthetics are now well characterized (e.g., the steady-state propofol concentrations required to achieve adequate anesthesia in 50% of patients, among many others). Despite these advances, available computer-controlled pumps, although accurate and sophisticated, fall short of the theoretical appeal and practical convenience associated with the delivery of volatile anesthetic via the lung. Target-controlled infusion technology (see Chapter 2 ) partly addresses these shortcomings.

Agent Analysis

A number of technologies can be used to analyze the amount of agent being delivered to the patient. These are usually implemented in a sidestream, or diverting, system that takes a sample of gas from as close to the patient as feasible. In contrast, mainstream systems require attaching the analyzer hardware directly to the end of the endotracheal tube. Delivered volatile anesthetic concentration can be determined using mass spectrometry, Raman spectral analysis, infrared spectrometry, refractometry, or oscillating crystal technology. Nitrous oxide can be detected with mass spectrometry, Raman analysis, or infrared spectrometry. Monitoring of delivered anesthetic concentration allows detection of volatile anesthetic uptake and elimination, vaporizer malfunctions, and estimation of anesthetic depth based on MAC values and age-derived nomograms. Additionally, low-flow anesthesia can be more easily implemented if the delivered anesthetic concentration is being monitored. That said, prediction of arterial/effect site concentrations of anesthetic from end-tidal concentrations is difficult and subject to inaccuracies owing to dead-space ventilation, for example, which can have significant effects on uptake times in the beginning of an anesthetic.

Monitoring Neurophysiologic Effect

Although hemodynamic stability under anesthesia is relatively straightforward to monitor, it is surprisingly difficult to monitor the neurophysiologic effect of a given end-tidal concentration of an inhaled anesthetic. This is of particular concern in patients also receiving neuromuscular blockers, who could potentially be aware but unable to move. Monitoring methods focus on the complexity of the electroencephalogram (EEG), which transitions from rapid disorganized activity during wakefulness to slow coherent activity with decreasing levels of arousal. A number of measures of the complexity of EEG, such as dimensional complexity, spectral edge, and spectral entropy, have all been proposed as valuable measures of arousal or awareness. The most frequently used commercial system currently is the BIS (Medtronic, Boulder, CO), which uses a proprietary algorithm to measure electromyography and correlations in power between different frequency bands of the EEG to develop an index that the manufacturer claims can predict awareness under anesthesia. That said, alternative systems that rely on processed EEG, such as the SedLine (Masimo, Irvine, CA), are making inroads into the market. Initial reports suggested that use of the BIS within an anesthetic protocol leads to an absolute risk reduction of awareness under anesthesia of 0.74% compared with anesthesia care outside of the protocol (B-Aware trial). Subsequent studies that did not use BIS within an anesthetic protocol failed to reproduce this result. Another randomized clinical trial that compared a structured anesthetic protocol based on the BIS with an anesthetic protocol based on end-tidal anesthetic gas concentration (B-Unaware trail) found that BIS neither lowered the incidence of anesthesia awareness nor reduced the administration of volatile anesthetic gas. This conclusion was then confirmed in a separate study using patients at high risk of awareness under general anesthesia. This led the study group to discourage anesthesiologists from attempting to use BIS values to titrate anesthesia. The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland addressed accidental awareness during general anesthesia in 2014. This audit showed that practitioners in the United Kingdom were selectively using depth of anesthesia monitors, which were used in only 1% of cases involving volatile anesthetics without neuromuscular blockade but in 23% of cases involving total intravenous anesthesia with neuromuscular blockade (which had an almost fourfold increase in risk of accidental awareness during general anesthesia).

Metabolism and Degradation

Metabolism

Metabolism of volatile anesthetics varies up to 1000-fold between specific agents and is catalyzed chiefly via cytochrome P450 enzymes in the liver ( Table 3.2 ), primarily by CYP 2E1. Hence patients exposed to agents that induce cytochrome P450 2E1 (CYP 2E1; e.g., ethanol, barbiturates) can have increased metabolism (see Chapter 4 ). Metabolism is inhibited by the agents themselves at the higher concentrations present during anesthesia, but it is enhanced during elimination of residual anesthetic during the recovery phase, which is more prolonged and extensive for the soluble agents.

TABLE 3.2

Degree of Metabolism, Metabolites, and Enzymes Involved for Various Agents

(Modified from Kharasch ED, Thummel KE. Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology . 1993;9:795–807; Restrepo JG, Garcia-Martín E, Martínez C, et al. Polymorphic drug metabolism in anaesthesia. Curr Drug Metab . 2009;10:236–246.)

Agent	Degree of In Vivo Metabolism (%)	Metabolites	Enzymes Catalyzing Metabolism
Halothane	15–40	Inorganic bromide, fluoride	CYP 2E1 and, to a lesser extent, CYP 3A4 and CYP 2A6
Enflurane	2.4	Inorganic fluoride	CYP 2E1
Isoflurane	0.2	Trifluoroacetic acid, inorganic fluoride	CYP 2E1
Sevoflurane	2–5	Inorganic fluoride	CYP 2E1
Desflurane	0.02	Inorganic fluoride	CYP 2E1

CYP, Cytochrome P450.

Halothane is the most extensively metabolized of the modern agents. Its extensive metabolism (up to 40% of absorbed dose) has a significant impact on its elimination kinetics, in contrast to other agents. It is also unique among volatile agents in undergoing significant reductive metabolism by CYP 2A6 and 3A4, although this is minor compared with its oxidative metabolism. Nitrous oxide and xenon are not metabolized.

Although the agents themselves have certain adverse effects (e.g., cardiac depression), a number of other adverse reactions to anesthesia, particularly hepatic and renal toxicity, are mediated by their metabolites. As a result, agents that undergo little metabolism have become more popular, whereas agents that undergo more metabolism, such as halothane and methoxyflurane, have fallen into disuse. Discussion of specific metabolites and their organ toxicity is found in Chapter 11 .

Chemical Degradation

At temperatures exceeding 50°C in the presence of soda lime carbon dioxide (CO ₂ ) absorbent, and somewhat even at 40°C as often exists in absorbents, sevoflurane undergoes base catalyzed degradation to produce the vinyl ether compound A (fluoromethyl-2,2-difluoro-1-(trifluoromethyl), or FDVE) and trace amounts of compound B (2-(fluoromethoxy)-3-methoxy-1,1,1,3,3-pentafluoropropane). FDVE causes renal tubular necrosis in rats, but toxicity is species-dependent. Human exposure has no clinically significant effects even with low-flow sevoflurane generating FDVE exposures of more than 400 ppm hours, although biochemical markers of renal injury have been reported with high compound A exposure in some studies. More modern CO ₂ absorbents based on lithium hydroxide have been designed to minimize production of compound A during normal use.

Carbon Monoxide Production

The passage of volatile anesthetics through dry CO ₂ absorbents can produce potentially life-threatening concentrations of carbon monoxide. Severe carbon monoxide poisoning with carboxyhemoglobin levels approaching 40% has been reported in association with desflurane. Carbon monoxide production is insignificant with sevoflurane and halothane, intermediate with isoflurane, and highest with desflurane and enflurane. The quantity of carbon monoxide produced depends on fresh gas flow, the quantity of dry absorbent, and the water content of the absorbent; barium hydroxide–containing absorbent (Baralyme) produces more carbon monoxide than soda lime. No carbon monoxide is produced when the water content of soda lime exceeds approximately 4.8%, or the water content of Baralyme exceeds 9.7%. Baralyme has been removed from the market. With modern absorbents, this concern is largely obviated, with only small amounts of carbon monoxide production (peak concentrations <116 ppm) with desiccated Drägersorb (Dräger, Lübeck, Germany); Medisorb (Vyaire Medical, Lake Forest, IL); and Spherasorb (Intersurgical, East Syracuse, NY), and no appreciable formation with Amsorb (Armstrong Medical Ltd., Coleraine, Northern Ireland); LoFloSorb (Intersurgical, Wokingham, England); Superia, or lithium hydroxide. The reaction by which carbon monoxide is produced is unclear; for desflurane the cascade probably begins with base-catalyzed extraction of a proton from the difluoromethyl ethyl group. The absence of this moiety in sevoflurane, methoxyflurane, and halothane thus explains the insignificant production of carbon monoxide by these agents.

Uptake and Distribution

General Principles

During the wash-in period, the partial pressure of an inhaled gas in the alveoli increases exponentially to approach that of the inspired fresh gas concentration. This ratio reflects the uptake of anesthetic from the inhaled gas into the blood as well as from blood into the tissues. Assuming no uptake of gas, the alveolar concentration ( F _A ) approaches the inspired gas concentration ( F _I ) with first-order kinetics:

\frac{d}{d t} (\frac{F_{A}}{F_{I}}) = - \frac{t}{τ},

$\frac{d}{d t} (\frac{F_{A}}{F_{I}}) = - \frac{t}{τ},$

where t is time and τ is the wash-in time constant, which is the ratio of the capacity of the reservoir into which the gas is delivered (the circuit volume plus the lung volume of the patient) to the flow rate at which it is delivered. Thus τ is the time it takes to fill the system once at the current fresh gas flow. If the circuit starts with no anesthetic at time zero and the inspired gas concentration does not change, then

\frac{F_{A}}{F_{I}} = 1 - e^{- \frac{t}{τ}}

$\frac{F_{A}}{F_{I}} = 1 - e^{- \frac{t}{τ}}$

where e is Euler’s number. After a single time constant has elapsed (when t = τ), F _A is 0.63 F _I ; at time t = 2τ _, F _A = 0.86 F _I ; at t = 3τ, F _A = 0.95 F _I ; and at t = 4τ, F _A = 0.98 F _I ( Fig. 3.6 ).

Fig. 3.6, Wash-in of nitrous oxide (N 2 O), desflurane, sevoflurane, isoflurane, and halothane. The rate at which the alveolar concentration ( F A ) approaches the inhaled concentration ( F I ) for a fixed minute ventilation and cardiac output reflects the solubility of the drug in blood, with wash-in of the least soluble (nitrous oxide and desflurane) being the fastest.

The response to a drug depends on the concentration of the drug at its effect site (e.g., a receptor expressed in brain or spinal cord) and is usually not the plasma concentration (see Chapter 1 ). This is typically modeled by considering the human body as being made up of multiple compartments, one of which is the effect site. The concentration of an inhaled anesthetic in brain, for example, depends on the relative solubilities of the drug in brain and blood (the brain:blood partition ratio), which in turn depends on the partial pressure of the anesthetic in the alveoli measured as the end-tidal concentration. At equilibrium, the end-tidal anesthetic concentration reflects the concentration of anesthetic in the blood, and for these highly lipid-soluble drugs that easily cross membranes, at the effect site. The effect of an inhaled anesthetic thus depends on its concentration at its effect site and not on total absorbed mass of drug. The total absorbed mass is a significant determinant of the kinetics of uptake and elimination, however.

Determinants of Wash-In

The rate of wash-in of the anesthetic is determined by both the rate of delivery to the alveoli and the rate of removal from the alveoli by uptake into blood. Factors that affect the rate of delivery to the alveoli include the inspired concentration, the time constant of the delivery system (which is determined by fresh gas flow and circuit volume), anatomic dead space, alveolar minute ventilation, and functional residual capacity (FRC). Factors affecting the rate at which anesthetic is removed from the alveoli include the solubility of anesthetic in the blood, cardiac output, and the partial pressure gradient between alveolar gas and mixed venous blood. These concepts are illustrated in the classic uptake curves shown in Fig. 3.7 .

$Fig. 3.7, Factors affecting the rate of anesthetic wash-in (equilibration between the inspired fraction and the expired fraction) include solubility, cardiac output, fresh gas flow, and minute ventilation. F A , Alveolar concentration; F I , inhaled concentration.$

The gradient between inspired and alveolar anesthetic concentrations drives the increase in alveolar concentration of inhaled drugs. Alveolar ventilation determines the rate at which alveolar gas concentration equilibrates with the concentration in the circuit. A change in FRC changes the total volume of the system and thereby alters τ. As a result, an obese patient with reduced FRC will have faster wash-in ( Fig. 3.8 ). The early rapid increase in F _A / F _I represents the equilibration of anesthetic with the circuit and airways unopposed by alveolar uptake. The rate of change in F _A / F _I slows as alveolar concentrations increase and uptake into blood and tissues lead to increased venous concentration, which reduces the alveolar-to-venous concentration gradient and slows uptake. For more soluble agents with greater uptake, the knee in the curve occurs at lower F _A / F _I ratios.

Fig. 3.8, Effect of functional residual capacity (FRC) on wash-in for a fixed minute ventilation (V) and cardiac output. Patients with lower FRCs relative to their minute ventilation have more rapid wash-in. F A , Alveolar concentration; F I , inhaled concentration.

Special Factors

For a fixed cardiac output, a left-to-right shunt (which recycles blood through the lungs) does not affect wash-in unless it alters the ventilation to the perfused lung. A right-to-left shunt (where systemic venous blood bypasses the lungs), however, can significantly slow the rate of wash-in. Right-to-left shunt effects are much more prominent with poorly soluble anesthetics (i.e., nitrous oxide and desflurane).

A number of differences contribute to the faster wash-in observed in infants and children compared with adults. Volatile anesthetics are less soluble in neonates, likely secondary to lower serum protein and lipid concentrations. Tissue solubilities, particularly in the muscle group, are also lower in children than in adults. Finally, the cardiac output in neonates is disproportionately distributed to the vessel-rich group compared with adults, enhancing drug delivery to the CNS.

Tissue Uptake

Initially during wash-in, hydrophobic anesthetics are avidly taken up by the tissues and the anesthetic partial pressure of venous blood returning to the lungs is low. As anesthetic partial pressure in the tissues approaches the alveolar partial pressure, venous anesthetic partial pressure increases to approach alveolar partial pressure. As a result, the anesthetic partial pressure gradient between alveolar gas and venous blood decreases, diminishing the rate of uptake.

Factors that govern tissue uptake of anesthetics are analogous to those that govern uptake from the alveoli: tissue solubility, tissue blood flow and the arterial blood:tissue partial pressure gradient. Tissues can be classified into four groups based on their relative blood flow: vessel-rich group (brain, heart, kidney, and liver; contributing 10% to body mass and receiving 75% of cardiac output); lean group (muscle and skin; contributing 50% to body mass and receiving 20% of cardiac output); vessel-poor group (bones and connective tissue; contributing 20% to body mass and receiving <1% of cardiac output); and fat (contributing 20% to body mass and receiving ~5% of cardiac output). The time constant (τ) for wash-in of each group is defined as follows:

τ = \frac{V λ}{Q}

$τ = \frac{V λ}{Q}$

where V is the volume of tissue, Q is the tissue blood flow, and λ is the tissue:blood partition ratio. Based on tissue-specific differences in each of these factors, equilibration times from shortest to longest are vessel-rich group (VRG), lean tissue group, vessel-poor group, and fat (which has such low blood flow that it usually fails to equilibrate on a clinical time scale). The large mass of the lean tissue group makes it the largest tissue reservoir, and its lower blood flow relative to the VRG means that it continues to take up anesthetic after the VRG approaches equilibrium. Again, more soluble agents have longer time constants as the result of more extensive tissue uptake. The rate of rise of the F _A / F _I curve thus is determined by the amount and rate of uptake of the different compartments of interest. ( Fig. 3.9 ) The slower rate of rise in the second phase of uptake evident in the F _A / F _I relationship reflects saturation of the VRG and slower equilibration of other (mainly lean) tissue groups. In practice, the rate of rise of anesthetic is rarely a significant issue, however, since most anesthetic techniques begin with administration of a bolus of intravenous agent.

Fig. 3.9, The F / F curve is determined by uptake of different compartments, for fixed F , minute ventilation, and cardiac output. Uptake is proportional to 1 − F/F , which is the area above the F/F curve. Each colored area thus represents schematically a different compartment: functional residual capacity (FRC, blue) , vessel-rich group (VRG, green) , muscle group (MG, orange) , fat group (FG, yellow) . FA , Alveolar conI centration; FI , inhaled concentration; Iso , isoflurane; MV , minute ventilation; NO , nitrous oxide; RR , respiratory rate; Sevo , sevoflurane; TVA , inspired tidal volume; TVI , expired tidal volume.

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