SPECIAL ARTICLE
Illustrations of Inhaled Anesthetic Uptake, Including
Intertissue Diffusion to and from Fat
Edmond I Eger II,
MD*,
and Lawrence J. Saidman,
MD†
*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; and †Department
of Anesthesia, Stanford University, Stanford, California
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Although several mathematical and computer simulations of inhaled anesthetic pharmacokinetics have been
devised, their complexity sometimes limits an intuitive
appreciation of the interactions produced by the determinants of kinetics. In this essay, we illustrate the factors that govern inhaled anesthetic pharmacokinetics
with drawings that consider delivery of anesthetic by
ventilation to the lungs and dispersion of the anesthetic
to tissue depots by the circulation. The illustrations incorporate the effects of both blood flow and blood solubility as determinants of the extent of dispersion. They
incorporate tissue volume and solubility as determinants of the capacity of the tissue depots. Capacity to
hold (take up) anesthetic is depicted by areas representing specific tissues, and the extent of anesthetic movement
N
umerous articles, books, book chapters, and
simulations describe the factors governing uptake, distribution, and elimination of potent inhaled anesthetics. Individually, we readily comprehend these factors, but their interactions produce a
complexity that hinders understanding.
This essay uses drawings to enhance understanding. The drawings indicate the relative capacities of
compartments, the occupancy by anesthetics, and the
movements of anesthetic. The total capacities are proportional to the size of circles or ovals representing
tissues, with the lung—specifically, the functional residual capacity (FRC)—acting as the standard (i.e., all
capacities are referenced to the lung capacity—the
FRC—to hold anesthetic). The arrows indicate the
movement of anesthetic: the broader and/or longer
Supported by National Institute of General Medical Sciences
Grant 1P01GM47818.
Dr. Eger is a paid consultant to Baxter Healthcare Corp.
Accepted for publication September 16, 2004.
Address correspondence and reprint requests to Edmond I Eger II,
MD, Department of Anesthesia, S-455, University of California, San
Francisco, CA 94143-0464. Address e-mail to egere@anesthesia.ucsf.edu.
DOI: 10.1213/01.ANE.0000146961.70058.A1
1020
Anesth Analg 2005;100:1020–33
is depicted by the length and breadth of arrows to and
from the areas depicting capacity. The illustrations incorporate increasingly important elements to kinetics, such
as obesity. Obesity increases the depots available for storage of anesthetic, including anesthetic that reaches fat by
intertissue diffusion. Such anesthetic returns to the circulation to delay recovery in healthy and obese patients, particularly with more soluble anesthetics. However, the increased anesthetic in fat occurs at a lower partial pressure
and thus might not influence emergence materially. We
hope that these illustrations will allow anesthesia practitioners to appreciate the interactions of the factors that
govern inhaled anesthetic pharmacokinetics.
(Anesth Analg 2005;100:1020 –33)
the arrow, the greater the movement. The figures illustrate concepts but are not necessarily precise (quantitative) reflections of the kinetics. We begin with a
discussion of the induction of anesthesia in the patient
with normal morphology.
The Four Factors Governing Uptake of
Potent Inhaled Anesthetics
Ignoring the concentration and second gas effects,
four factors govern the uptake and distribution of
potent inhaled anesthetics. On the induction of anesthesia, ventilation (the first factor) brings anesthetic
into the lungs. If the effect of ventilation is unopposed
(Fig. 1), the alveolar concentration of anesthetic rapidly (within 2 min) increases to equal the concentration in the inspired gas. The concentration of anesthetic increases rapidly because the volume moved
through the lungs (alveolar minute ventilation, approximately 4 L/min) exceeds the gaseous volume
contained by the lungs (the FRC; only 2 L). If this effect
of ventilation is unopposed (as suggested in Fig. 1),
then the concentration in the alveoli reaches that in the
inspired gas in approximately 2 min. The administration of oxygen achieves such a rapid change with
©2005 by the International Anesthesia Research Society
0003-2999/05
ANESTH ANALG
2005;100:1020 –33
SPECIAL ARTICLE
EGER AND SAIDMAN
ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
Figure 1. If the effect of a normal 4 L/min alveolar ventilation is
unopposed, then the alveolar concentration of anesthetic rapidly
(within 2 min) approximates the concentration in the inspired gas
because the volume moved through the lungs each minute is twice
the gaseous volume contained by the lungs (the functional residual
capacity; 2 L). VA ⫽ alveolar minute ventilation.
oxygen, as seen from data collected from two patients
(Fig. 2).
However, uptake (the second factor) opposes the
effect of ventilation. The relationship at the concentrations of potent inhaled anesthetics often used is a
simple one: if uptake removes half of the anesthetic
inspired, then the alveolar concentration equals half
the concentration being inspired. If uptake removes
two thirds of the anesthetic, then the alveolar concentration equals one third the concentration being
inspired.
Three elements determine uptake. The first of these,
the one that distinguishes the inhaled anesthetics, is
solubility in blood, defined as the blood/gas partition
coefficient, or ␭. The blood/gas partition coefficient
equals the concentration of anesthetic in blood divided by the concentration in gas when the two phases
are in equilibrium (have the same partial pressure of
anesthetic). Desflurane has the smallest blood/gas
partition coefficient of presently available potent inhaled anesthetics (Table 1), and, accordingly, for a
given alveolar concentration, the uptake of sevoflurane or isoflurane exceeds that of desflurane. These
differences influence the rate of increase in the alveolar concentration, an increase that often is taken as a
surrogate for the rate of the induction of anesthesia;
the rate for desflurane exceeds that of sevoflurane, and
that of sevoflurane exceeds that of isoflurane.
Cardiac output and the alveolar-to-venous (A-v)
blood partial pressure difference constitute the remaining two elements that govern uptake. An increase
in cardiac output (Q) or the A-v blood partial pressure
difference will increase uptake. Uptake (U) may be
calculated as follows:
U ⫽ ␭ ⫻ Q ⫻ 共 A-v兲
For an anesthetic such as desflurane, the initial uptake of anesthetic is less than the amount delivered. At
the start of anesthesia, A-v is maximal because no
anesthetic is in venous blood. Thus, initially, for a
given alveolar concentration (i.e., for A), uptake is
proportional to blood solubility ⫻ cardiac output. For
1021
Figure 2. The authors measured the change in concentration of
end-tidal oxygen (the starting oxygen concentration is given a value
of 0%; the final concentration is given a value of 100%) in two
patients breathing pure oxygen from a nonrebreathing system. The
half-time for the change in concentration is approximately 0.35 min.
desflurane, for a healthy adult, uptake would be proportional to 0.45 ⫻ 5.4 L/min, or 2.43 L/min (proportional to but not equal to except at 100% anesthetic; at,
say, 10% desflurane, uptake would equal 0.1 ⫻ 0.45 ⫻
5.4 L/min, or 0.243 L/min). This is less than the alveolar ventilation (4 L/min); thus, the arrow out of the
lungs (the loss of anesthetic) will be approximately
half as thick as the arrow delivering desflurane into
the lungs (Fig. 3). With sevoflurane, the arrow out of
the lungs (0.65 ⫻ 5.4 L/min, or 3.51 L/min) would be
approximately as thick as the arrow into the lungs,
and for isoflurane, the arrow (1.4 ⫻ 5.4 L/min, or 7.56
L/min) would be nearly twice as thick as the arrow
into the lungs.
Development of Tissue Anesthetic Partial
Pressures at a Constant Alveolar Concentration
At the Start of Anesthesia. The A-v partial pressure
difference decreases radically during the induction of
anesthesia and decreases further with an increasing
duration of anesthesia. Initially, venous blood contains no anesthetic, and A-v is large. In the first minute
of anesthesia, the anesthetic delivered in the ventilation is transferred to the blood coursing through the
lungs, as noted previously, and does so in proportion
to the solubility of the anesthetic (Fig. 3). No anesthetic
returns to the lungs in the first several seconds of
anesthetic delivery. In clinical practice, the anesthesiologist rapidly increases the alveolar anesthetic concentration to one sufficient to the needs of anesthesia.
Thereafter, the anesthesiologist seeks to sustain a relatively constant anesthetic state by maintaining a relatively constant alveolar anesthetic concentration
(1,2). The remaining discussion describes the relationships that produce a constant alveolar anesthetic concentration. What might be required to sustain a target
anesthetic concentration in the patient’s lungs, say,
minimum alveolar anesthetic concentration (MAC)?
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SPECIAL ARTICLE EGER AND SAIDMAN
ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
ANESTH ANALG
2005;100:1020 –33
Table 1. Human Tissue/Gas Partition Coefficients at 37°C (52)a
Tissue
Blood
Brain
Heart
N2O
Desflurane
0.46 (53–59)
[0.44–0.47]
0.49 (59)
0.45 (60,61)
[0.42–0.52]
0.55 (68,69)
[0.54–0.57]
0.55 (68,69)
[0.54–0.57]
0.67 (68,69)
[0.55–0.80]
0.40 (68)
0.65 (61–63)
[0.62–0.69]
1.1 (68,69)
[1.1–1.2]
1.1 (68,69)
[1.1–1.2]
1.3 (68,69)
[1.2–1.4]
0.78 (68)
1.4 (63–66)
[1.38–1.46]
2.2 (25,68,69)
[2.1–2.4]
2.2 (25,68,69)
[2.0–2.5]
2.6 (25,68,69)
[2.3–3.0]
1.4 (68)
0.78 (68,69)
[0.62–0.94]
13 (68,69)
[12–15]
1.7 (68,69)
[1.1–2.4]
37 (68,69)
[34–41]
0.37 ⫾ 0.02
(mean ⫾ sd) (73)
3.6 (25,68,69)
[2.1–4.4]
70 (25,68,69)
[64–77]
0.61 (65,73–76)
[0.54–0.63]
2.4 (61,63,64,66,67)
[2.0–2.6]
4.5 (25,67–69)
[3.4–6.0]
4.1 (25,68,69)
[3.6–4.6]
5.5 (25,67–69)
[5.1–6.4]
3.0 (67,68)
[2.8–3.6]
7.0 (25,67–69)
[3.8–9.5]
137 (67–69)
[136–138]
0.74 (67,73–76)
[0.63–0.86]
0.22 (60,77,78)
[0.20–0.24]
19 (60)
0.34 (62,73,77,78)
[0.26–0.37]
47 (62)
0.54 (73,77–79)
[0.44–0.57]
98 (65)
0.71 (67,73,75,77–80)
[0.66–0.83]
224 (67)
0.47 (70)
Liver
Kidney
Muscle
0.53 (71)
Fat
1.1b
Water
Salinec
Olive oil
yr.
0.46
(54,70,72)
[0.44–0.49]
0.45 (70)
1.4 (81)
Sevoflurane
Isoflurane
Halothane
a
Values are given as the best approximation from the noted citations, with the range (in brackets) of values from the cited studies for adult patients aged 30 –70
b
Estimated from the assumption that 70% of fat has the solubility of oil and 30%, the solubility of blood.
Saline or electrolyte solutions with a similar osmolarity.
c
Figure 3. The arrows into and out of the lungs describe the movement of desflurane, sevoflurane, and isoflurane. Alveolar ventilation carries anesthetic into the lung, and because this delivery is
common to all three anesthetics, the arrows indicating anesthetic
movement into the lungs are the same. Similarly, the volume of
blood passing the lungs, the cardiac output, is the same for all three
anesthetics. However, the effect of this volume is modified by the
capacity of the blood to hold anesthetic: the solubility of the anesthetic as defined by the blood/gas partition coefficient (Tables 1 and
2). We can equate this to the volume of gas passing through the
lungs. For a molecule of desflurane, each liter of blood looks like
0.45 L of gas. For sevoflurane, it looks like 0.65 L of gas. For
isoflurane, it looks like 1.4 L of gas. Thus, the arrows leaving the
lungs differ in thickness; they are thicker for sevoflurane than
desflurane and are thicker for isoflurane than sevoflurane.
The arrow representing cardiac output in Figure 3
actually represents several blood flows (several arrows), one for each tissue of the body (Fig. 4A). The
tissues may be differentiated into three tissue groups
depending on their blood flow and their capacity to
hold anesthetic (Tables 2 and 3) (3– 8). The vessel-rich
group (VRG) consists of brain, heart, liver/intestine,
and kidney. The capacity of the VRG (or any tissue
group) equals the volume of the group (in this case, 6
L; Table 3) times its affinity for the anesthetic, as
defined by the tissue/gas partition coefficient (0.58),
or 3.48 L. Thus, for desflurane, the VRG is less than
twice as large as the 2-L FRC (Fig. 4A).
The VRG receives the largest fraction of the cardiac
output and thus, initially, the largest fraction of the
anesthetic taken up. Accordingly, in Figure 4A, the
largest arrow goes from the lung to the VRG (including the brain, which, although part of the VRG, is
displayed separately for reasons related to intertissue
diffusion, discussed later). Anesthetic also goes to the
muscle group (MG) (and also skin, because skin has
the same perfusion and solubility characteristics as
muscle) and to the fat group (FG). The arrow going to
the muscle is smaller than that going to the VRG
because muscle receives less of the cardiac output, and
the arrow going to the fat is smaller than that going to
muscle because still less of the cardiac output goes to
fat in a healthy, lean adult.
Compare the sizes (capacities) of the tissue groups
with each other and with the FRC (as noted previously, the FRC is the reference for all capacities). Although the VRG receives a large fraction of the cardiac
output, it constitutes only 9% of the body mass, and
the circle indicating its capacity to hold anesthetic is
small (actually two circles, because the brain is part of,
but is separated from, the remaining tissues that constitute the VRG).
The size of the circle for the MG exceeds that of the
circle representing the VRG because muscle (and skin)
make up 50% of the body mass in a lean adult, or
ANESTH ANALG
2005;100:1020 –33
Figure 4. A, We now assume that sufficient anesthetic (in this figure,
desflurane) has been introduced into the lungs to produce a desired
concentration that subsequently will be sustained to maintain anesthesia. The arrow into the lungs (FI) is longer than the arrow out of
the lungs (FA) to compensate for the uptake of desflurane. The
arrow representing desflurane carried from the lungs in Figure
3 has been replaced with several arrows, each representing the
delivery of desflurane from the lungs to the three tissue groups: the
muscle group (MG) (muscle and skin), the fat group (FG), and the
vessel-rich group (VRG), consisting of brain, heart, liver (splanchnic
bed), and kidney. In summary, the arrow(s) to the VRG are thicker
than the arrows to the MG or FG because the VRG receives greater
blood flow. The arrow to the MG is thicker than the arrow to the FG
for the same reason. The circles representing the tissue groups differ
in size because they differ in volume and affinity for anesthetic
(defined by the tissue/gas partition coefficient). Thus, the area of
the circle representing the MG is several times larger than the sum
of the areas representing the VRG because muscle and skin have a
larger volume than the VRG. The area of the circle representing the
FG far exceeds that of muscle because of the much greater fat/gas
versus muscle/gas partition coefficient. B, Anesthesia now has been
maintained for 5 min at the alveolar (lung) concentration established in Panel A. During this time, desflurane has been delivered to
the tissues, and speckled circles representing the anesthetic occupancy of the tissue depots now appear. The speckled circles nearly
completely occupy the VRG because the great blood flow to the
VRG causes its rapid equilibration (filling). In contrast, only a small
amount of the MG and a still smaller amount of the FG are occupied
because of the greater capacity of and lower blood flow to these
tissues. In addition to the delivery of desflurane in blood, desflurane
SPECIAL ARTICLE
EGER AND SAIDMAN
ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
1023
approximately 33 L. The muscle/gas partition coefficient of 0.78 (Table 1) produces an MG capacity of 26
L. Thus, the area of the circle for the MG is 13 times
larger than the area of the oval representing the lung.
Although fat constitutes only 20%–25% of the body
mass in a healthy adult, the circle representing the FG
is much larger than that for muscle because the capacity of fat (because of the enormous solubility of anesthetic in fat) is much larger than that of muscle. (A
fourth tissue group, the vessel-poor group, made up
of ligaments, tendons, cartilage, bone, and other avascular tissues, does not contribute to uptake because of
its minimal or absent perfusion and thus is not considered in this discussion.)
Tissue/Gas Versus Tissue/Blood Partition Coefficients.
The reader may wonder at the use of both Table 1
(tissue/gas partition coefficients) and Table 2 (tissue/
blood partition coefficients). The two tables are simply
connected: a tissue/blood partition coefficient for a
given anesthetic is calculated by dividing a tissue/gas
partition coefficient by the blood/gas partition coefficient for that anesthetic.
The two partition coefficients tell somewhat different
things. A tissue/gas partition coefficient indicates the
relative capacities of all tissues to hold the anesthetic in
question. The product of the tissue volume times the
tissue/gas partition coefficient equals the capacity of the
tissue to hold anesthetic relative to the lung (the reference capacity defined by the FRC). Tissue/gas partition
coefficients also indicate the relative capacity of a given
tissue to hold one anesthetic as opposed to another.
Thus, the capacity of muscle to hold sevoflurane is 2.2
times (i.e., 1.7/0.78) the capacity of muscle to hold desflurane; the capacity of fat to hold sevoflurane is 2.8
times the capacity of fat to hold desflurane.
A tissue/blood partition coefficient allows an estimate of the rate at which an anesthetic partial pressure
may be developed or decreased in a given tissue. This
may make use of the time constant. The time constant
equals the capacity of a tissue to hold anesthetic divided by the flow of blood to that tissue. For example,
is transferred from one tissue to another by intertissue diffusion,
particularly from the VRG and MG to the FG (e.g., from the kidney
to perirenal fat; from the intestine and liver to mesenteric and
omental fat; from the heart to pericardial fat; from dermis to subcutaneous fat; and from muscle to intercalated fat). More is transferred from the VRG to the FG (note the checkered area in the FG)
at this time because the VRG has a greater occupancy (a greater
partial pressure) of anesthetic. The greater intertissue diffusion delivery from the VRG than from the MG is indicated by the larger
(longer) arrow from the VRG to the FG. Finally, a miniscule amount
of desflurane (0.02%) is lost from the VRG (the liver) by metabolism.
Because the tissue depots now have partly filled, the removal of
anesthetic from the lungs is decreased. That is, the arrows from the
lungs indicating removal of anesthetic are partially matched by
arrows from the tissues (particularly the VRG) indicating the return
of some of that anesthetic to the lungs. Thus, uptake of desflurane
decreases, and the arrow indicating delivery of anesthetic to the
lungs by ventilation (FI) decreases in length.
1024
SPECIAL ARTICLE EGER AND SAIDMAN
ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
ANESTH ANALG
2005;100:1020 –33
Table 2. Tissue/Blood Partition Coefficients (Except for Blood/Gas Partition Coefficients)
Tissue
N2O
Desflurane
Sevoflurane
Isoflurane
Halothane
Blood/gas
Brain
Heart
Liver
Kidney
Muscle
Fat
0.46
1.07
1.02
—
—
1.15
2.39
0.45
1.22
1.22
1.49
0.89
1.73
29
0.65
1.69
1.69
2.00
1.20
2.62
52
1.4
1.57
1.57
1.86
1.00
2.57
50
2.4
1.88
1.70
2.29
1.25
2.92
57
Values for this table are derived from those in Table 1.
Table 3. Values Used in the Construction of Figures
Variable
Volume (L)
Tissue/blood partition coefficienta
Desflurane
Sevoflurane
Isoflurane
Tissue/gas partition coefficientb
Desflurane
Sevoflurane
Isoflurane
Time constants (min) (6,7)
Desflurane
Sevoflurane
Isoflurane
Blood flow (mL/min) per 100 mL of tissue
Compartment diameterc
Desflurane
Sevoflurane
Isoflurane
VRG
6
MG
33
FG
14.5
ITG
2.9
1.30
1.70
1.60
1.73
2.62
2.5
29
52
50
29
52
50
0.58
1.10
2.24
0.78
1.70
3.50
13
34
70
13
34
70
4.32
5.65
5.32
30.1
38.1
57.8
56.7
4.54
1226
2198
2114
2.37
230
412
396
12.6
1.32
1.82
2.59
3.58
5.30
7.70
9.73
15.7
22.5
4.35
7.00
10.1
VRG ⫽ vessel-rich group; MG ⫽ muscle group; FG ⫽ fat group; ITG ⫽ intertissue diffusion group, a subset of the FG.
a
Tissue/blood partition coefficients, averaged from Table 2.
b
Tissue/gas partition coefficients calculated as the blood/gas partition coefficient times the tissue/blood partition coefficient.
c
The compartment diameters are given relative to the lung compartment diameter. These are calculated as the square root of (tissue volume in liters)(tissue/
gas partition coefficient)/2, where 2 (liters) is the volume of the lung.
consider the VRG. For this essay, we attribute a blood
flow of 30.1 mL/min to each 100 mL of tissue. (Note
that this is an average and would be more for some
tissues [e.g., gray matter] and less for others [e.g.,
white matter].) For desflurane, each 100 mL of VRG
has a capacity of 100 mL ⫻ 1.30, the desflurane VRG/
blood partition coefficient (Table 3). This gives a time
constant of 130 mL/30.1 mL/min, or 4.3 min. Now,
the time constant always is the time to reach 63% of
equilibrium, and this invariable connection makes the
time constant useful. Thus, the partial pressure of
desflurane in the brain may reach 63% of the arterial
partial pressure in 4.3 min.
Half-time (50% of equilibrium) values also may be
calculated with this technique: the half-time equals the
time constant times 0.7. Thus, the half-time for the
VRG for desflurane equals 3.0 min and for sevoflurane
equals 4.0 min. For fat, the half-times are 860 min for
desflurane and 1540 min for sevoflurane.
How are these thoughts illustrated in the Figure
4B drawing for 5 min (and for later drawings)? At
5 min, the VRG has reached two thirds of the way to
equilibration. Accordingly, the arrow leaving the
brain is two thirds as long as the arrow to it (i.e., two
thirds as much anesthetic leaves as enters). Also, the
amount of desflurane lodged in the brain (the
area of the speckled circle in the brain) is two thirds
the size of the circle representing the capacity of
the brain). In contrast to the VRG, equilibration
of the MG has just begun. With a time constant of
38.1 min, equilibration is but 15% complete, and the
area of the speckled circle representing desflurane
in the MG is 15% of the area of the circle representing the capacity of the MG—and the arrow returning to the lungs from the MG is 15% of the arrow
going to the MG. For the FG at 5 min, equilibration
equals 0.4%, and the area of the speckled circle is
very small relative to the large circle representing
fat capacity.
A small amount of anesthetic (overall, approximately 0.02% of what is taken up) is lost from the
liver by metabolism of desflurane (metabolism is the
ANESTH ANALG
2005;100:1020 –33
third factor that governs the uptake and distribution
of potent inhaled anesthetics). A larger amount of isoflurane (0.2%) and sevoflurane (5%) is lost in this manner.
By 5 min, uptake by the VRG has decreased substantially. This, and a slight decrease in uptake by the
MG, decreases the inspired concentration (FI) needed
to sustain the alveolar concentration (FA) at MAC.
Thus, at 5 min, the arrow representing FI is only 29%
longer than the arrow representing FA.
Intertissue Diffusion. Something else appears at
5 min. Some anesthetic delivered to parts of the VRG
transfers to adjacent tissues, particularly fat, by intertissue diffusion (the fourth factor that governs the
uptake and distribution of potent inhaled anesthetics).
Perl et al. (9) suggested the importance of intertissue
diffusion to anesthetic uptake and distribution 40 yr
ago. Thus, anesthetic moves from intestine to mesenteric and omental fat; from kidney to perirenal fat; and
from heart to pericardial fat. The area of the thin
checkered layer at the edge of the FG represents the
amount of anesthetic transferred to the fat participating in the anesthetic transfer from the VRG to fat.
Anesthetic may also be transferred from skin to subcutaneous fat or to fat that is interwoven (intercalated)
into muscle (consider prime, choice, commercial, and
cooker cuts of beef). However, at this point in the
anesthetic process, the partial pressure of anesthetic in
skin and muscle is much less than that available in the
VRG, and the amount transferred is smaller than the
amount transferred from the VRG. Another intertissue
transfer occurs from gray matter to white matter (10).
These transfers by intertissue diffusion mean that a
small part of the VRG (part of the intestine, liver,
kidney, and heart) and part of the muscle/skin are
slower to reach equilibrium because anesthetic is continuously lost to adjacent fat. Thus, intertissue diffusion decreases the arrow returning from the VRG (excluding the brain) to the lung. As we shall see shortly,
intertissue diffusion loss from the MG will also limit
the size of the arrow returning from muscle.
Both direct and indirect evidence support the notion
that anesthetic transfers from one tissue to another or
part of one tissue to another part of that tissue (e.g.,
gray matter to white matter) (10). A perirenal rim of
anesthetic in perirenal fat directly demonstrates the
movement of anesthetic from kidney to fat (8). The
capacity of nitrous oxide to diffuse through plastics
(11–14) and natural membranes (15–18) provides further evidence. However, the most convincing evidence for the importance of intertissue diffusion to
anesthetic uptake comes from studies of inhaled anesthetic elimination. These indicate that intertissue diffusion accounts for approximately 30% of the anesthetic taken up (3–7). These studies estimate that
intertissue diffusion occurs with time constants of
SPECIAL ARTICLE
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
1025
approximately 200 – 400 min for potent inhaled anesthetics: the time constant increases in proportion to the
fat/blood partition coefficient (Table 3).
Fifty Minutes into Anesthesia. By 50 min, the brain
has completely equilibrated with the desflurane partial pressure brought to it from the lungs (Fig. 5A; the
area of the speckled circle representing desflurane
completely overlies the circle representing the capacity of the brain to hold desflurane, and the arrow
returning from the brain to the lungs is as long as the
arrow to the brain). Were it not for losses by intertissue diffusion, the desflurane partial pressure in the
MG would reach 74% of the partial pressure delivered
to it from the lungs (the area of the speckled circle
would be 74% of the area of the larger circle representing the MG). The arrow returning from the MG to
the lungs is approximately two thirds of the arrow to
the MG. By 50 min, additional anesthetic is transferred
from the VRG and muscle/skin to fat by intertissue
diffusion. Some of the anesthetic transferred by intertissue diffusion returns to the VRG (at 50 min, the fat
affected by intertissue diffusion has reached 20%
equilibration, in contrast to bulk fat—the FG—which
has reached only 4% equilibration; thus, uptake by
bulk FG continues essentially unchanged). Because of
transfer of anesthetic by intertissue diffusion, the arrow returning from the VRG continues to be smaller
than the arrow going to the VRG. The decreased uptake by muscle and by intertissue diffusion is reflected
in a smaller FI needed to sustain FA; the FI arrow now
is 12% longer than the FA arrow.
How Does Sevoflurane Differ from Desflurane? Both
desflurane and sevoflurane are classified as poorly
soluble potent inhaled anesthetics but, on average,
sevoflurane is twice as soluble in blood and tissues as
is desflurane (Tables 1–3). The drawings in Figure 5
reflect these differences. The capacities of the VRG,
MG, and FG to hold sevoflurane exceed those capacities for desflurane, and the areas of the circles representing these tissue groups are larger. Although the
amount of sevoflurane taken up into these tissues and
transferred by intertissue diffusion is also larger, the
rate of equilibration is slower (equilibration is less
complete). Loss of sevoflurane by metabolism is 100
times greater, but even this larger loss does not materially affect uptake. Whereas the arrow indicating the
FI for desflurane is 12% greater than the arrow representing FA, for sevoflurane the arrow is 21% greater.
This is an example of something called “overpressure,” the use of a larger concentration to sustain a
target alveolar concentration. For more soluble anesthetics, the overpressure needed (the extent to which
FI must exceed FA) can be substantial.
Two-Hundred Minutes into Anesthesia. By 200 min,
except for the portion involved in intertissue diffusion, the MG has equilibrated with the desflurane
brought to it, and the blood from muscle returns to the
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
Figure 5. A, By 50 min of anesthesia, the vessel-rich group (VRG) has
filled (e.g., the speckled area completely occupies the circle representing the capacity of the brain), and the muscle group (MG) has nearly
filled. The fat group (FG) is far from (only 4%) filled because of its
enormous capacity. However, the part of the FG occupied by intertissue diffusion is appreciable, having reached 20% of its final level, and
desflurane now returns from and is delivered to fat by intertissue
diffusion. Because of the filling of the MG, the uptake decreases from
that found at 5 min, and the arrow indicating delivery of anesthetic to
the lungs by ventilation (FI) further decreases in length. FA ⫽ arrow out
of the lungs. B, Sevoflurane differs from desflurane in both blood and
tissue solubility. These differences are reflected in the breadth of the
arrows indicating anesthetic moved in blood and in the area of the
circles representing the tissue depots. As with desflurane, the VRG has
filled except for that portion subject to loss by intertissue diffusion. The
MG has not filled as much with sevoflurane as with desflurane because
the MG capacity relative to delivery (in particular, the muscle/blood
partition coefficient) is greater for sevoflurane than for desflurane.
Similarly, the FG, including the portion of the FG receiving anesthetic
by intertissue diffusion, is less filled with sevoflurane. Consequently,
uptake of anesthetic continues at a higher rate with sevoflurane than
with desflurane, and the arrow indicating delivery of anesthetic to the
lungs by ventilation (FI) is longer for sevoflurane than for desflurane.
lungs with nearly as much desflurane as when it left
the lungs (Fig. 6A). Thus, the area of the speckled
circle indicating desflurane in the MG nearly completely occupies the capacity of the MG, and the arrow
ANESTH ANALG
2005;100:1020 –33
from the MG to the lung approaches the one from the
lung. Anesthetic continues to be transferred from
muscle/skin to fat by intertissue diffusion, and this
keeps the arrow from MG to lung smaller than the
arrow to MG. At this time, approximately 58% of the
anesthetic transferred by intertissue diffusion returns
to the VRG (the intertissue arrow from the FG is now
half the size of the arrow to the FG). Because of the
transfer of anesthetic by intertissue diffusion, the arrow returning from the VRG continues to be smaller
than the arrow going to the VRG. The bulk FG (i.e.,
that not involved in intertissue diffusion) continues to
remove nearly all anesthetic brought to it. The desflurane present in bulk fat is substantial, but by 200 min,
only 15% equilibration has been achieved. The marked
decrease in uptake by muscle and by intertissue diffusion is reflected in a decreased uptake at the lung
and a decrease in the size of FI relative to FA; the FI
arrow now is only 5% greater than the arrow indicating FA.
How Does Isoflurane Differ from Desflurane? Isoflurane is approximately four times more soluble than
desflurane in blood and tissues, and thus the representations of tissues for isoflurane (Fig. 6B) are four
times (sometimes more) larger than those for desflurane (Fig. 6A). As with desflurane, by 200 min, the
VRG and MG have equilibrated with the isoflurane
(speckled circles) brought from the lungs— except for
the portions connected to fat by intertissue diffusion.
Relatively more isoflurane is transferred by intertissue
diffusion and by transfer to bulk fat, but the extent of
equilibration is less than with desflurane (40% vs 58%
for intertissue diffusion and 9% vs 15% for bulk fat).
Uptake to fat by these two routes produces a need for
a greater FI for isoflurane. The arrow indicating FI is
20% greater than the FA arrow for isoflurane and only
5% greater for desflurane.
Rebreathing and the Vaporizer Setting
Needed to Sustain a Constant Alveolar
Anesthetic Concentration
Thus far, we have considered the inspired concentration of anesthetic (FI) needed to sustain a constant
alveolar concentration (FA). FI will equal the concentration delivered from the vaporizer (FD) if the inflow
rate equals or exceeds minute ventilation, but if
minute ventilation exceeds inflow rate (i.e., if rebreathing occurs), then FD must be more than FI to
compensate for the effect of rebreathed gas depleted of
some anesthetic (i.e., containing gas with a concentration equal to FA; Fig. 7). The inflow rate usually is set
at something less than minute ventilation, often between 1 and 3 L/min. A slower inflow rate increases
the economy of anesthesia, retains heat, and increases
the humidity of respired gases.
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
1027
Figure 7. This drawing illustrates the movement of gases (see arrows) in a conventional anesthetic circuit and demonstrates the
importance of rebreathing and anesthetic uptake to the concentration of anesthetic that must be delivered from the anesthetic machine (the vaporizer or FD) to sustain a target concentration in the
alveoli (FA). The concentration that is inspired (FI) results as the
algebraic sum of FD and FA as modified by various flow rates. FI is
drawn into the lungs: part of the inspiration fills the dead space, and
part fills the alveoli and becomes FA (a smaller concentration because of uptake). A combination of FI and FA is exhaled and moves
down the expiratory limb and from thence to the inspiratory limb,
where it is joined by FD to produce a new FI. A larger FI/FA ratio
will demand a greater FD/FI ratio. However, the extent to which a
greater FD/FI ratio is demanded will depend on the inflow rate
(total gas delivery from the anesthetic machine). If the inflow rate
equals minute ventilation, then FD will equal FI, and the FD/FI ratio
will equal 1.0. As the inflow rate decreases, the FD/FI ratio must
increase as a function of both inflow rate and uptake (the FI/FA
ratio). In subsequent graphs, the details pictured in this figure are
reduced to a simple circle.
Two factors affect the FD required to sustain FA at a
constant level. First, if FA differs but slightly from FI
(i.e., if uptake is small), then the rebreathing of some
Figure 6. A, By 200 min of desflurane administration, both the
vessel-rich group (VRG) and the muscle group (MG) have essentially filled (e.g., the speckled areas completely occupy those capacities). The bulk fat group (FG) remains mostly unfilled (only 15%).
However, the part of the FG occupied by intertissue diffusion now
has reached 58% of its final level, and appreciable amounts of
desflurane now return from and are delivered to fat by intertissue
diffusion. Uptake further decreases from what it was at 50 min, and
the arrow indicating delivery of anesthetic to the lungs by ventilation (FI) further decreases in length. FA ⫽ arrow out of the lungs. B,
Isoflurane exceeds both desflurane and sevoflurane in blood and
tissue solubility. These differences are reflected in the breadth of the
arrows indicating anesthetic moved in blood and in the area of the
circles representing the tissue depots. As with desflurane, the VRG
has filled with isoflurane except for that portion subject to loss by
intertissue diffusion. The FG, including the portion of the FG receiving anesthetic by intertissue diffusion, has received more isoflurane but is less filled (40% as opposed to 58%) because the capacity
of fat for isoflurane is so much greater than the capacity of fat for
desflurane. Consequently, uptake of anesthetic continues at a faster
rate with isoflurane than with desflurane (or sevoflurane), and the
arrow indicating delivery of anesthetic to the lungs by ventilation
(FI) is longer for isoflurane than for desflurane. C, The obese patient
differs from the normal-weight patient in the larger amount of
depot fat. This increase slightly affects the VRG (it may modestly
increase blood flow to heart, liver, and kidney) or the MG but
greatly affects the size of, blood flow to, and intertissue diffusion to
the FG (compare Panel C with Panel A). Thus, more desflurane is
stored in bulk fat and by intertissue diffusion (the areas are increased), but the proportions of fat occupied do not change (15% for
bulk fat and 58% for intertissue diffusion). Uptake is increased, and
the FI/FA ratio is increased thereby.
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
gas containing FA will minimally affect the FD required to sustain FA at a constant level. Conversely, an
increase in the difference between FI and FA increases
the FD required. Second, an increase in rebreathing
(i.e., as occurs with a decrease in inflow rate) increases
the amounts of rebreathed gas containing FA and
therefore will increase the FD required to sustain constant FA. The next drawings superimpose the effect of
rebreathing on previous drawings.
Five minutes into anesthesia, FD for desflurane must
exceed FI by 137% if the inflow rate is set at 0.5 L/min
(Fig. 8A). However, if the inflow rate is 2 L/min, then
FD needs to be only 30% more than FI. The figure
shows the extra (added) percentage needed in FD to
sustain the FI. Note that the complexity of the system
depicted in Figure 7 is reduced to just a circle in Figure
8.
At 50 min of anesthesia with desflurane, equilibration of the VRG and partial equilibration of the MG
markedly decrease uptake and thus decrease the effect
of rebreathing (Fig. 8B). Now, even at an inflow rate of
0.5 L/min, FD must exceed FI by only 44%, and at 1
L/min the difference is 21%. The substitution of
sevoflurane for desflurane increases these differences
because of the greater solubility and uptake associated
with sevoflurane (Fig. 8C). At a 1 L/min inflow (the
slowest inflow rate suggested by the sevoflurane
package label), FD must exceed FI by 48%, rather than
the 21% needed with desflurane.
At 200 min of desflurane anesthesia, equilibration of
the VRG and the MG and the partial equilibration of
bulk fat and fat served by intertissue diffusion further
decrease uptake and, thus, decrease the effect of rebreathing (Fig. 9A). Now, even at an inflow rate of 0.5
L/min, FD must exceed FI by only 7%. In contrast, at
200 min of isoflurane anesthesia, continued uptake by
bulk fat and intertissue diffusion and the greater solubility of isoflurane increase the needed FD (Fig. 9B).
At an inflow rate of 0.5 L/min, FD must exceed FI by
94%; at 1 L/min, by 46%; and at 2 L/min, by 22%.
These effects are summarized for the three potent
inhaled anesthetics for the relationship for FD/FA and
FI/FA in Figure 10. The effects of solubility (isoflurane
⬎ sevoflurane ⬎ desflurane) and inflow rate are
apparent.
Factors Influencing Uptake and the
Development and Elimination of an
Anesthetizing Concentration
Several factors influence uptake and the development
and elimination of an anesthetizing concentration of
an inhaled anesthetic. The importance of solubility is
obvious from the preceding discussion. Solubility is
the crucial factor that distinguishes one anesthetic
from another. Increasing duration deposits increasing
amounts of anesthetic in depots such as muscle and fat
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2005;100:1020 –33
and thereby tends to delay recovery (19,20). An increase in ventilation hastens the increase in the alveolar concentration of a potent inhaled anesthetic, with
a greater effect with more soluble anesthetics (21). By
increasing uptake (at least initially), an increase in
cardiac output hinders the rate of increase of the alveolar concentration of anesthetic and has a greater
effect with more soluble anesthetics (21). Ventilation/
perfusion inequalities complexly influence inhaled anesthetic kinetics (22). Aging decreases the rate of increase of the alveolar concentration of a potent inhaled
anesthetic (23,24), and solubility changes with increasing age (25). Body habitus may also influence pharmacokinetics. We next will examine this point in detail
because its effect has not been described fully and
because habitus is changing in ways that importantly
affect anesthesia.
Obesity, an Epidemic That Has Implications
for Anesthesia
Excess fat (a body mass index [BMI] ⬎25 kg/m2) in
North America and other parts of the world has
reached epidemic proportions (26 –28). From 1991 to
1998, the percentage of United States citizens with a
BMI ⬎30 kg/m2—i.e., obesity—increased by 50% (29).
Obesity at all levels (morbid to overweight by 40
pounds) presents a growing challenge to the anesthesiologist, who must deal with a decreased FRC and a
decreased compliance (30), an increased incidence of
intra- and postoperative atelectasis (31), difficulty in
tracheal intubation (32), an increase in airway resistance that may resemble asthma (30), an increased
capacity to metabolize anesthetics such as halothane
(33) or enflurane (34) (but not, apparently, sevoflurane) (35), a greater surgical demand for relaxation,
and more (36). Anesthesia may exaggerate the decrease in FRC far more in obese patients than in
normal-weight patients (37).
Of immediate relevance to this report is the need to
restore the obese or overweight patient to his or her
preanesthetic state as rapidly as possible after surgery.
The obese or overweight patient presents kinetic issues that may delay recovery and, thereby, add to the
risk of anesthesia. A few kinetic studies have been
performed in patients. Obesity increases uptake in two
ways. The greater fat burden increases the blood flow
directed to bulk fat, and uptake by the FG must increase. Obesity also may increase fat surfaces accessible by intertissue diffusion (e.g., intraabdominal fat
and fat intercalated in muscle), and this, too, must
increase uptake.
Compare the conditions displayed in Figure 6A to
the condition found with obesity (Fig. 6C). The larger
FG in Figure 6C increases the deposition of desflurane
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
1029
Figure 9. A, Rebreathing and inflow rate minimally affect the delivered concentration (FD) required to sustain a constant alveolar
concentration (FA) of desflurane at 200 min into anesthesia because
of the minimal uptake of desflurane (the small FI/FA ratio). B,
However, with isoflurane at 200 min, rebreathing considerably affects the FD required to sustain the FA because of the appreciable
uptake of isoflurane (the appreciable FI/FA ratio) even this late in
anesthesia. MAC ⫽ minimum alveolar anesthetic concentration;
VRG ⫽ vessel-rich group; FI ⫽ concentration that is inspired.
Figure 8. A, Rebreathing considerably affects the delivered concentration (FD) required to sustain a constant alveolar concentration (FA) of
desflurane at 5 min into anesthesia. The right portion of the figure
reproduces part of the drawing provided as Figure 4B. The left portion
indicates the proportional amount the FD must exceed FI to keep FA
constant. The importance of inflow rate is great at this early time in
anesthetic delivery. B, However, after 50 min of anesthesia, rebreathing
has much less effect on the FD required to sustain the FA of desflurane
because of the marked decrease in uptake (the decrease in the FI/FA
ratio). The inflow rate has much less influence at this time in anesthetic
delivery. C, However, after 50 min of sevoflurane anesthesia, rebreathing has more effect on the FD required to sustain the FA than with
desflurane (B) because of the greater uptake of sevoflurane. MAC ⫽
minimum alveolar anesthetic concentration; VRG ⫽ vessel-rich group;
FI ⫽ concentration that is inspired.
into bulk fat and into fat reached by intertissue diffusion. The larger uptake by fat is reflected in a larger
arrow for FI.
In summary, the increased size of the FG differentiates
the obese patient from the normal-weight patient in several ways. First, the larger volume of fat requires an
increased blood delivery of anesthetic to bulk fat, a delivery that continues throughout the course of anesthesia. Obesity increases cardiac output (38). Despite a
greater flow of blood to fat, bulk fat never equilibrates or
begins to approach equilibration with the anesthetic
brought to it, even with prolonged anesthesia. Second,
the larger volume of fat presents a larger surface for
anesthetic transfer by intertissue diffusion, particularly
transfer from intestine to omental and mesenteric fat, but
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
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2005;100:1020 –33
also from muscle to intercalated fat and from dermis to
subcutaneous fat. Thus, the morbidly obese patient may
have three times as much fat as the normal-weight patient and a roughly proportional increase in anesthetic
acquired by intertissue diffusion. Third, the press of
abdominal contents on the diaphragm can decrease the
lung size (FRC). Fourth, the increased fat, the increased
need to perfuse fat, and an increased work of breathing
modestly increase metabolism, cardiac output, and
breathing.
Obesity does not change the VRG or the MG: these
tissues do not change in size or perfusion consequent
to obesity (except that hepatic size and blood flow
may increase). However, the VRG and MG are important because they serve as conduits for the anesthetic
stored by intertissue diffusion. Another minor change,
an increase, may occur with hepatic metabolism of
anesthetic.
Recovery from Anesthesia
Figure 10. A, The ratio of the delivered to alveolar anesthetic concentrations (FD/FA) to sustain the FA at a constant concentration (assumed
in this case to be the minimum alveolar anesthetic concentration
[MAC]) at a 2 L/min fresh gas inflow rate shows the effect of solubility
and of increasing duration of anesthesia. Increasing solubility, and,
thus, greater uptake, increases the ratio. Increasing the duration of
anesthesia decreases uptake and thus decreases the ratio. B, Decreasing
the fresh gas inflow rate to 1 L/min increases the FD/FA ratio needed
to sustain the FA at a constant concentration. Qualitatively, this is true
for all three anesthetics, but the increase is largest for the most soluble
anesthetic (isoflurane), is next largest for the anesthetic of intermediate
solubility (sevoflurane), and is least for the least soluble anesthetic
(desflurane). The graph for sevoflurane is truncated because the package label warns against using sevoflurane at a 1 L/min inflow rate for
more than 2 MAC-hours. C, Both solubility and duration of anesthesia
influence uptake and hence the FI/FA ratio. It is this ratio (i.e., uptake)
that determines the influence of inflow rate as seen in Panels A and B.
Two elements determine recovery. First is the concentration of anesthetic in the effect compartment (i.e.,
where the anesthetic causes anesthesia) that permits
awareness, or MACawake. MACawake differs among
inhaled anesthetics and between inhaled and IV anesthetics (Fig. 11) (39 – 41). Similar values are found for
MACawake for desflurane, isoflurane, and sevoflurane, and thus this factor does not distinguish among
the anesthetics in time to recovery.
The second element that determines recovery is the
clearance of anesthetic from the effect site. Several
factors influence clearance. Anesthetic in tissue depots
and the solubility of the anesthetic in blood (the
blood/gas partition coefficient) will determine the
rate of decrease of anesthetic in the arterial circulation
during recovery from anesthesia because solubility
determines the clearance of anesthetic at the lungs. If
the solubility (␭) of the anesthetic is very small, most
of the anesthetic will be cleared by ventilation and will
thus not recirculate and delay recovery. The equation
given after this paragraph shows that as ␭ approaches
0, clearance approaches 100% (42). That is, a low solubility allows clearance of most of the anesthetic by
the lungs, leaving little to recirculate and delay recovery. At zero solubility, it does not matter how much
anesthetic is stored in tissue depots; no anesthetic can
reach the arterial blood. The duration of anesthesia or
body habitus cannot affect recovery. However, if the
solubility is appreciable, some anesthetic will not be
cleared (Fig. 12), will recirculate, and will delay recovery.
% Clearance ⫽ 100 ⫻ VA/ 共 ␭ ⫻ Q ⫹ VA兲
By allowing deposition of more anesthetic in tissue
depots (compare Figs. 4 – 6), an increasing duration of
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2005;100:1020 –33
Figure 11. As a fraction of the concentration of anesthetic (in blood
or in end-tidal gas) that produces immobility in response to noxious
stimulation, the concentration at which awareness occurs differs
among anesthetics. Thus, awakening from a pure nitrous oxide
anesthetic at minimum alveolar anesthetic concentration (MAC) (as
might be obtained in a pressure chamber) might be more rapid than
awakening from a desflurane anesthetic at 1 MAC because a larger
fraction of desflurane would have to be eliminated before awakening could occur.
anesthesia delays recovery. That is, an increasing duration can increase the delivery of anesthetic from the
MG and FG, and (if not cleared at the lungs) this will
delay recovery from anesthesia.
As in healthy patients, the morbidly obese patient
may awaken sooner after desflurane than after isoflurane or propofol (43). Immediate awakening also may
occur more rapidly after desflurane than after sevoflurane anesthesia (44). Similarly, sevoflurane appears to
provide a slightly more rapid washin and washout of
anesthetic in the morbidly obese patient than does
isoflurane (45), and the use of sevoflurane may allow
an earlier recovery from anesthesia (46,47) and an
earlier discharge of the morbidly obese patient from
the postanesthesia care unit than does isoflurane (46).
What strategies might be used to hasten recovery?
As noted above, one is the selection of less-soluble
anesthetics, a strategy that increases the clearance at
the lungs. Also, if the lower solubility extends to a
lower tissue/blood partition coefficient in cerebral tissues, the lower solubility will shorten the time constant for the brain. This, too, adds to the speed of
recovery.
On the induction of anesthesia, “overpressure” can
compensate for the hindering effect of greater solubility. Thus, we may provide an inspired concentration
of 4% or 5% halothane to more rapidly produce an
alveolar concentration of 1% to 2%. However, we have
no such ability during recovery; we cannot supply a
negative anesthetic partial pressure for the patient to
breathe. However, we can take advantage of the ventilatory component (VA) in the above equation. As VA
increases, the percentage clearance increases (at very
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EGER AND SAIDMAN
ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
1031
Figure 12. The percentage of anesthetic cleared at the lungs is
inversely related to anesthetic solubility.
large values for VA, the percentage clearance approaches 100%.
However, increasing VA introduces two limiting
factors. First, when hyperventilation ceases, the decrease in Paco2 produced by hyperventilation results
in apnea or depressed ventilation (48), and this hinders further anesthetic elimination. Second, the decrease in Paco2 produced by hyperventilation decreases cerebral blood flow (49) and, thus, lengthens
the time constant for elimination of anesthetic from
the central nervous system. This, too, slows recovery.
We can compensate for these two limiting factors by
adding carbon dioxide to the inspired gases during
hyperventilation at concentrations sufficient (e.g., 5%)
to prevent a decrease in Paco2 (50). Such a strategy
produces a more rapid recovery (51).
Summary
The factors that govern inhaled anesthetic pharmacokinetics may be illustrated with drawings that consider delivery of anesthetic by ventilation to the lungs
and dispersion of the anesthetic to tissue depots by the
circulation. Both blood flow and blood solubility determine the extent of dispersion. Tissue volume and
solubility determine the size of the tissue depots.
These illustrations may incorporate several other factors that influence kinetics, including increasingly important elements such as obesity. An increased incidence of morbid and lesser levels of obesity presents
several kinetic concerns to the anesthesia practitioner.
Obesity increases the depots available for storage of
anesthetic, particularly anesthetic that reaches fat by
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ILLUSTRATIONS OF INHALED ANESTHETIC UPTAKE
intertissue diffusion. Such anesthetic returns to the
circulation to delay recovery in normal-weight and
obese patients, particularly with more soluble anesthetics. However, the increased anesthetic in fat occurs
at a lower partial pressure and thus might not influence emergence materially.
Appendix 1
1. Uptake by a given tissue is calculated as
共Qt兲共 MAC兲共 ␭ 兲 / 共 etime/TC兲 ,
where Qt is tissue blood flow, ␭ is the blood/gas
partition coefficient, e is the natural logarithm, time is
in minutes from the start of anesthesia, and TC is the
time constant for the tissue in question (Table 3).
2. Total uptake (Ut) is the sum of the uptakes by the
individual tissues.
3. The ratio of the inspired to alveolar anesthetic
concentrations (FI/FA) is calculated as
关Ut ⫹ 共 VA兲共 FA兲兴 / 共 VA兲共 FA兲 ,
where VA is alveolar minute ventilation, assumed to
be 4 L/min, and FA is the alveolar concentration. For
this discussion, we assume that FA is MAC.
4. The ratio of the delivered (vaporizer) to alveolar
concentrations (FD/FA) is calculated as
关Ut ⫹ 共 A兲共 B兲兴 / 关共 FA兲共 VD兲兴 ,
where A ⫽ (0.4 ⫻ FA) ⫹ (0.6 ⫻ FI), making the assumption that 40% of gas lost through the overflow is
alveolar and 60% is inspired. B ⫽ Vd – Vo, where Vd
is the volume of gas delivered to the system (i.e., the
fresh gas inflow) and Vo is the gas lost through the
overflow (Vd ⫺ carbon dioxide taken up).
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