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ANESTHETIC PHARMACOLOGY

Obesity Modestly Affects Inhaled Anesthetic Kinetics in Humans

Hendrikus J. M. Lemmens, MD, PhD^*, Lawrence J. Saidman, MD^*, Edmond I. Eger, II, MD, and Michael J. Laster, DVM

From the *Department of Anesthesia, Stanford University School of Medicine, Stanford, California; and the Department of Anesthesia and Perioperative Care, University of California, San Francisco, California.

Address correspondence and reprint requests to Dr. Hendrikus J.M. Lemmens, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305. Address e-mail to hlemmens{at}stanford.edu.

	Abstract

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BACKGOUND: Few studies have determined the effect of obesity on inhaled anesthetic pharmacokinetics. We hypothesized that the solubility of potent inhaled anesthetics in fat and increased body mass index (BMI) in obese patients interact to increase anesthetic uptake and decrease the rate at which the delivered (FD) and inspired (FI) concentrations of an inhaled anesthetic approach a constantly maintained alveolar concentration (end-tidal or FA). This hypothesis implies that the effect of obesity would be greater with a more soluble anesthetic such as isoflurane versus desflurane.

METHODS: In 107 ASA physical status I–III patients, anesthesia was induced with propofol, tracheal intubation facilitated with neuromuscular blockade, and ventilation controlled with 50% nitrous oxide in oxygen to maintain end-tidal carbon dioxide concentrations between 35 and 45 mm Hg. Isoflurane or desflurane was administered in a 1 L/min inflow rate at FD concentrations sufficient to maintain FA at 0.6 minimum alveolar anesthetic concentration (0.7% or 3.7%, respectively). FD, FI, and FA were measured 5, 10, 20, 40, 60, 90, 120,150, and 180 min after starting potent inhaled anesthetic delivery.

RESULTS: Fifty-nine patients received isoflurane and 48 received desflurane. BMI ranged between 18 and 63 kg/m² and demographic variables did not differ between anesthetic groups. For isoflurane, FD/FA or FI/FA weakly (but significantly) correlated with BMI at 9/18 time points whereas for desflurane FD/FA or FI/FA correlated significantly with BMI at only one time point (P < 0.01). After dividing each group into nonobese (BMI < 30) and obese (BMI 30) patients, with isoflurane, FD/FA or FI/FA was higher in obese patients at four time points whereas there was no difference between nonobese and obese patients for desflurane. Patients receiving isoflurane took longer to respond to command after discontinuing anesthesia but obesity did not increase or decrease awakening time for either isoflurane or desflurane. When BMI was used to normalize FI/FA and FD/FA the median values for isoflurane consistently exceeded the median value for desflurane by factors ranging from 3 to 5, values comparable to the ratios of their blood/gas (3.1), muscle/gas (4.6), and fat/gas (5.4) partition coefficients.

CONCLUSION: BMI modestly affects FD/FA and FI/FA, and this effect is most apparent for an anesthetic having a greater solubility in all tissues. An increased BMI increases anesthetic uptake and, thus, the need for delivered anesthetic to sustain a constant alveolar anesthetic concentration, particularly with a more soluble anesthetic. However, the increase with an increased body mass is small.

	Introduction

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The prevalence of obesity is escalating worldwide. In the United States 32% of adults are obese (body mass index [BMI], i.e., kg/m², 30), and almost 5% of the population are morbidly obese (BMI 40).1 Although it is assumed that obesity may delay recovery, particularly from a lengthy anesthesia,2 it is not clear how changes associated with obesity (such as distribution of fat and increased lean mass) affect the pharmacokinetics of inhaled anesthetics for ordinary durations of anesthesia.

Tissue blood flow, and blood/gas and tissue/blood (tissue solubility) partition coefficients, are primary determinants of inhaled anesthetic uptake. In normal subjects, blood flow to fat accounts for only 5% of the cardiac output. Furthermore, blood flow per kg of fat tissue decreases with increasing obesity and perfusion to fat may equal only 2% of cardiac output in morbidly obese patients.3

In addition to uptake determined by anesthetic delivery in blood to tissues, as described using classic physiologic models,4,5 a significant component of the uptake of inhaled anesthetics into fat tissue may occur by intertissue diffusion. Intertissue diffusion may move anesthetic from more rapidly equilibrating, highly perfused tissues such as kidney and other abdominal organs, into a thin sheet of adjacent fat, such as perirenal fat and omentum or mesenteric fat.3,6,7 Intertissue diffusion might prolong the time to equilibrium between blood and highly perfused tissues acting, in effect, to increase the anesthetic capacity of these tissues.8 The small amount of fat receiving anesthetic by intertissue diffusion may consume a large amount of anesthetic and might equilibrate more rapidly than bulk fat.4,5

Several studies in obese patients have compared some kinetic aspects for inhaled anesthetics with variable results, perhaps because of different experimental conditions.9–14 For example, Strum et al.9 De Baerdemaeker et al.,10 and La Colla et al.13 showed that morbidly obese patients emerge from anesthesia more rapidly after desflurane than after sevoflurane anesthesia. However, Arain et al.11 and Vallejo et al.12 did not find a difference in time to awakening between patients receiving desflurane or sevoflurane. Finally, sevoflurane seems to provide a slightly more rapid washin and washout of anesthetic in morbidly obese patients than does isoflurane.15

No reports describe the effect of increasing BMI and its interaction with increasing anesthetic solubility on inhaled anesthetic uptake while using a rebreathing system. The present study determines the effect of BMI on the delivered (vaporizer, FD)/alveolar (i.e., end-tidal; FA) and inspired (FI)/FA ratios for isoflurane or desflurane in otherwise normal patients having anesthesia for surgical procedures. Because the rebreathed gases include gases from the alveoli, gases from which a portion of anesthetic has been removed, rebreathing produces a difference between FD versus FI and FA. A smaller inflow rate increases rebreathing and magnifies the difference. At a given inflow rate, a larger uptake (e.g., due to either larger size or to greater anesthetic solubility) will increase the difference between FD versus FI and FA. These observations lead to the hypothesis that increasing anesthetic solubility and increasing BMI interact to increase anesthetic uptake and, thus, increase the above ratios.

	METHODS

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After approval from the Stanford Medical Center institutional review board and with informed written patient consent, we studied 107 ASA physical status I–III patients scheduled for nonthoracic surgical procedures under general anesthesia. Age, gender, body weight, and body height of the patients were recorded. After premedication with midazolam titrated according to patient need and administration of oxygen for 3 min, anesthesia was induced with fentanyl, 2–3 µg/kg, and propofol 2–3 mg/kg. When consciousness was lost, a muscle relaxant was given and the trachea intubated. We controlled ventilation and used a fresh gas flow of 6 L/min 50% nitrous oxide in oxygen to rapidly obtain an end-tidal nitrous oxide concentration of 50%. We then decreased the inflow to 1 L/min containing 50% nitrous oxide in oxygen. Ventilation of the lungs was adjusted to maintain end-tidal carbon dioxide concentrations between 35 and 45 mm Hg. Thereafter, tidal volume and ventilatory frequency were not changed, and isoflurane or desflurane administration began. The anesthesia machine was a Narkomed 2B or Fabius GS (North American Draeger, Telford, PA). End-tidal concentrations in the isoflurane group and desflurane group were maintained at 0.7% and 3.7% (approximately 1.1 minimum alveolar anesthetic concentration when combined with nitrous oxide) respectively, by manually adjusting the vaporizer setting. The choice of the inhaled anesthetic was at the attending anesthesiologist’s discretion. Additional fentanyl and muscle relaxants were given as needed (at the discretion of the attending anesthesiologist).

Samples of FD, FI, FA gases were collected in 20 mL syringes at 5, 10, 20, 40, 60, 90, 120,150, and 180 min after initiating delivery of the desflurane or isoflurane. FD samples were obtained from the proximal part of the fresh gas inflow hose. FI samples were obtained during inspiration from the proximal part of the inspiratory breathing hose. FA samples were obtained at the end of exhalation from a catheter inserted to the tracheal end of the tracheal tube.

Concentrations of anesthetic in the sampled gases were determined by gas chromatography. A flame ionization detector gas chromatograph (Gow-Mac 580; Gow-Mac, Bethlehem, PA) equipped with a 4.57 m, 0.22 cm internal diameter column packed with 10% SF96 on WHP, 68/80 mesh, maintained at 50°C with a 6 mL/min carrier flow of N₂ was used. The detector (at 101°C) received H₂ at 25 mL/min and air at 200 mL/min. The gas chromatograph was calibrated before and at intervals during each test using secondary (cylinder) calibration standards. Linearity was obtained over the concentration ranges studied. FD/FA and FI/FA were calculated. The end-tidal concentration of nitrous oxide and the end-tidal concentration of carbon dioxide were read and recorded from monitoring devices routinely used during anesthesia. At the end of surgery, isoflurane or desflurane was discontinued and the fresh gas flow was altered to 10 L/min oxygen. The time interval at which each patient responded to command after discontinuing isoflurane or desflurane administration was recorded.

Uptake per minute of isoflurane and desflurane normalized to the target alveolar concentration (C_TA) were estimated using the following equation:

Uptake = (FI-FA) x (C_TA)/(FA) x 0.6 x V_E

Where, V_E equals minute ventilation and 0.6 x V_E approximates alveolar minute ventilation.

Data are presented as median (interquartile range). Spearman correlation R_s and regression analysis16 were used to examine the association between BMI and FD/FA and BMI and FI/FA. Differences between groups were assessed by the Wilcoxon’s ranked sum test or bootstrap resampling. All analyses were performed with S-PLUS version 6.2 (Insightful Corp., Seattle, WA).

	RESULTS

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Fifty-nine patients received isoflurane and 48 received desflurane. Demographic variables did not differ between groups nor did time of administration of either isoflurane or desflurane (Table 1). As expected, FI/FA and FD/FA were larger for the more soluble drug isoflurane, and were largest for both anesthetics at the beginning of administration (Fig. 1). For isoflurane an increase in FD/FA or FI/FA correlated weakly but significantly with an increase in BMI at half the test time points (Table 2). For desflurane FI/FA correlated significantly with BMI only at 150 min (difference significant; P < 0.01). For both isoflurane and desflurane, significant or not, a positive correlation was found at all time points. There was no correlation between BMI and hemoglobin-oxygen saturation. Thirty-one patients in the isoflurane and 21 patients in the desflurane group were obese (BMI equal to or more than 30). For isoflurane, small statistically significant differences in FD/FA or FI/FA between obese and nonobese patients occurred at four test time points (Fig. 1). No significant differences were found with desflurane (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Plots of FD/FA or FI/FA versus time for isoflurane and desflurane in nonobese and obese patients. *indicates a significant difference between nonobese and obese patients (bootstrap analysis). Note that FD/FA will always be larger than FI/FA and the range of data (1–2.6 vs 1–1.4) on the ordinal scale is approximately four times greater for isoflurane than for desflurane.

Positive correlations of FD/FA and FI/FA with BMI were particularly seen at the later periods of anesthesia. Figure 2 provides such information for the data gathered at 150 min of anesthesia.

View larger version (14K): [in this window] [in a new window]   Figure 2. FD/FA or FI/FA versus BMI at 150 min of anesthesia time. Each line is a smooth through the data obtained by robust locally weighted regression. Note that the range of data on the ordinal scale is approximately four times greater for isoflurane than for desflurane.

After discontinuing anesthetic administration, patients receiving desflurane responded to command sooner than patients receiving isoflurane (Table 1). Obese and nonobese patients responded to command equally rapidly after either isoflurane (420

s [median and quartiles] and 420

s, respectively) or desflurane (258

s and

s, respectively). When BMI was used to normalize the approach of FD and FI to FA {i.e., ([FD/FA]-1/BMI) and ([FI/FA]-1/BMI); Table 3} the median values for ([FD/FA]-1/BMI) for isoflurane consistently exceeded the median value for desflurane by a factor of approximately 4.5, a factor exceeding the factor for the ratio of their blood/gas partition coefficients (3.1), equal to the ratio for their muscle/gas coefficients (4.6), and only slightly less than the ratio for their fat/gas coefficients (5.4).17 The median values for ([FI/FA[-1/BMI) for isoflurane also consistently exceeded the median value for desflurane but now with a factor of approximately 2.7, a factor close to the ratio of their blood/gas partition coefficients (3.1), and less than either the ratio for their muscle/gas coefficients (4.6), or the ratio for their fat/gas coefficients (5.4).17

Uptake per minute, normalized to the target alveolar concentration for isoflurane, correlated significantly with BMI and weight at all time points, but correlated less consistently for desflurane (Table 4). As would be expected, the concentration of anesthetic needed to be delivered (FD) at a constant alveolar concentration (FA) consistently correlated with uptake for both anesthetics. Finally, with two exceptions (desflurane at 150 and 180 min), BMI was correlated with minute volume of ventilation. This correlation would be expected if BMI is associated with metabolic rate.

	DISCUSSION

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As anticipated, we found that FD/FA and FI/FA progressively decreased with increasing duration of anesthesia in both normal and obese patients (Fig. 1). We found that values for FD/FA and FI/FA for isoflurane consistently exceeded those for desflurane (Fig. 1), doing so by amounts consistent with their differences in solubility in blood and in lean and fat tissues.

Our results indicate that BMI modestly affects FD/FA and FI/FA for isoflurane, and minimally affects these ratios for desflurane (Table 2). We found no effect of obesity on awakening time after either anesthetic. The absence of a major effect of BMI (i.e., of fat with either anesthetic) may have been due to the short duration of anesthetic administration relative to the long time constants (the time to reach 63% of equilibrium) for the equilibration of desflurane or isoflurane with fat.4,5 The time constants for fat are 2110 and 1350 min for isoflurane and desflurane, respectively.5 These long time constants far exceed the duration of anesthetic administration in routine clinical practice and in the present study. The decreased perfusion of fat in obese patients further limits the impact of uptake by larger amounts of fat. That is, these factors minimize differences in uptake in normal versus obese patients over the entire period of study.

However, uptake by intertissue diffusion to fat (rather than from blood flowing to fat) from adjacent well-perfused tissues adds another influence of increasing obesity. Intertissue diffusion would rapidly increase during the first several minutes of anesthesia because well-perfused tissues quickly equilibrate with their perfused blood and, thus, quickly provide a reservoir from which adjacent fat can draw anesthetic. The time constants for highly perfused tissues, such as kidney, intestines, liver, and heart, are short, tissue/blood partition coefficients, and tissue blood flows suggest time constants of a few minutes.4,5 These tissues quickly develop appreciable anesthetic partial pressures that can be transferred to adjacent fat (i.e., anesthetic can move from these tissues to fat) early in anesthesia. Thus, perirenal fat, mesenteric fat, omental fat, and pericardial fat each may add to the uptake of anesthetic.

Intertissue diffusion would be augmented further by movement of anesthetic from dermis to subcutaneous fat or from muscle to intercalated fat. Such augmentation would take longer to develop than that from highly perfused tissues because of the lesser blood flow to skin and muscle and a consequent slower development of anesthetic partial pressures in these tissues. That is, the impact of such intertissue diffusion would increase over the 3 h of the present study, whereas the intertissue diffusion from highly perfused tissues would be apparent within minutes.

Thus, a modestly greater uptake might be expected in fat subjects where the surface area of fat adjacent to lean tissues is larger.18 Unlike the 1–2 day time constants for the development of anesthetic partial pressures in fat due to anesthetic brought by perfusion to fat, the time constants for intertissue diffusion to fat might be counted in minutes or hours.4,5 One would expect this reasoning to apply both to isoflurane and desflurane, but with a relatively greater sustained impact for isoflurane because of its greater solubility in fat and, thus, slower equilibration of fat by intertissue diffusion.4,5 The effect of intertissue diffusion also might be more apparent with isoflurane because of the overall greater solubility and uptake. That is, the "noise" of measurement might be less than with desflurane where the smallness of the FI/FA and FD/FA ratios would predispose to greater experimental inaccuracies. In the present study, the fewer subjects, especially obese subjects, studied with desflurane would increase the effect of such noise.

Obesity is associated not only with an increased fat tissue mass, but also an increased fat-free mass which accounts for 20%–40% of the excess bodyweight. Fat-free mass includes highly metabolically well-perfused tissues such as organ and muscle mass.19,20 The time constants for muscle mass are 80 and 49 min for isoflurane and desflurane, respectively, in normal subjects.5 Therefore, within the time frame of the surgeries in this study, uptake in fat-free mass would be expected to increase more and be sustained longer with increasing BMI with the more soluble isoflurane. This reasoning, too, might explain the greater trend toward significant correlations of BMI and FI/FA and FD/FA for isoflurane than for desflurane.

In a partial rebreathing (semiclosed) system with a fresh gas flow less than the minute volume, FD must exceed FI to compensate for the depletion of anesthetic (by uptake) in the rebreathed gas. We used a low (low relative to minute ventilation) fresh gas flow of 1 L/min to increase the FD to FA difference and enhance our ability to assess the effect that increased BMI, and thus uptake, might have on FD/FA. In other words, a decrease in fresh gas inflow rate should exaggerate the effect of rebreathing (uptake) and, thus, increase the difference between FD and FA. Indeed, we found that BMI determined uptake (Table 4).

Finally, changes in pulmonary mechanics consequent to obesity might have influenced some of the kinetic differences between isoflurane and desflurane. The obese patient has a smaller functional residual capacity and a greater tendency to alveolar collapse. Shunting of blood through the pulmonary circuit influences both end-tidal and arterial anesthetic partial pressures: a greater solubility influences end-tidal values more and arterial values less.21 In this study, we did not measure the degree of shunting. Despite our use of 50% nitrous oxide, and consequently lesser concentrations of oxygen, we found no significant effect of increasing BMI on oxyhemoglobin saturation in the isoflurane or the desflurane group. However, if all patients were combined, we found a significant correlation at 90, 120, and 150 min, but the correlation coefficients were small (–0.25 to –0.37; i.e., explaining only 6%–14% of the variability in saturation). Thus, if shunting were present, it would seem to affect the later time points.

However, a further analysis did not suggest that FD/FA and FI/FA might be most affected by altered pulmonary shunting at these later time points. We correlated saturation with FD/FA and FI/FA at each time point and, for 36 such comparisons, we found a weak but significant correlation at 20 min for both FD/FA and FI/FA for isoflurane. For desflurane, we found a significant correlation for FD/FA at 60 min and for FI/FA at 10 min. That is, we found significance in only 4/36 comparisons, and none of these were at the times when oxyhemoglobin saturation correlated significantly with BMI. We conclude that any effect of shunting was trivial.

In summary, our results indicate that increasing BMI modestly increases FD/FA and FI/FA, and that this effect is most apparent for an anesthetic having a greater solubility in all tissues. An increased BMI increases anesthetic uptake and, thus, the need for delivered anesthetic to sustain a constant alveolar anesthetic concentration, particularly with a more soluble anesthetic.

	Footnotes

 
Accepted for publication July 24, 2008.

Supported by NIH grant 1PO1GM47818.

Dr. Eger is a paid consultant to Baxter Healthcare Corp.

Lawrence J. Saidman is editor of the Correspondence section for the Journal. This manuscript was handled by Tony Gin, Section Editor for Anesthetic Clinical Pharmacology, and Dr. Saidman was not involved in any way with the editorial process or decision.

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