Journal of Clinical Anesthesia (2005) 17, 134 – 145

Review article

Anesthesia in the obese patient: Pharmacokinetic considerations Andrea Casati MD (Staff Anesthesiologist)*, Marta Putzu MD (Anesthesia Fellow) Department of Anesthesiology, and Pain Therapy, University of Parma, Parma, Italy Received 2 September 2003; accepted 21 January 2004

Keywords: Obesity; Pharmacokinetics

Abstract The prevalence of obesity has increased 15% up to 20% and represents an important challenge for the anesthesiologist in drug-dosing management. The aim of this work is to provide an overview on physiological changes and pharmacokinetic implications of obesity for the anesthesiologist. Obesity increases both fat and lean masses; however, the percentage of fat tissue increases more than does the lean mass, affecting the apparent volume of distribution of anesthetic drugs according to their lipid solubility. Benzodiazepine loading doses should be adjusted on actual weight, and maintenance doses should be adjusted on ideal body weight. Thiopental sodium and propofol dosages are calculated on total body weight (TBW). The loading dose of lipophilic opioids is based on TBW, whereas maintenance dosages should be cautiously reduced because of the higher sensitivity of the obese patient to their depressant effects. Pharmacokinetic parameters of muscle relaxants are minimally affected by obesity, and their dosage is based on ideal rather than TBW. Inhalation anesthetics with very low lipid solubility, such as sevoflurane and desflurane, allow for quick modification of the anesthetic plan during surgery and rapid emergence at the end of surgery, hence representing very flexible anesthetic drugs for use in this patient population. Drug dosing is generally based on the volume of distribution for the loading dose and on the clearance for maintenance. In the obese patient, the volume of distribution is increased if the drug is distributed both in lean and fat tissues whereas the anesthetic drug clearance is usually normal or increased. D 2005 Elsevier Inc. All rights reserved.

1. Epidemiology of obesity The prevalence of obesity has markedly increased worldwide in the last years, not only in industrialized western countries but also in the developing countries [1]. The prevalence of obesity has been reported to be about T Corresponding author. Servizio di Anestesia e Terapia Antalgica, Azienda Ospendaliera di Parma via Gramsci 14, 43100 Parma, Italy. Tel.: +390521702161; fax: +390521702733. E-mail address: [email protected] (A. Casati). 0952-8180/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2004.01.009

15% to 20% in Europe and up to 22% in the United States [2], with marked differences in distribution according to socioeconomic status [3]. When caloric intake exceeds expenditure, the excess calories are stored in the adipose tissue. If this net positive caloric balance is prolonged, obesity results. Thus, obesity represents a condition in which the quantity of fat tissue is significantly increased, which leads to a significant reduction in life expectancy [4]. The definition of obesity is based on the degree of excess actual body weight from the ideal body weight (IBW) for a certain height. The most widely

Anesthesia implications of obesity used test to define obesity is the evaluation of the body mass index [BMI = body weight (kilograms)/height (meters)2]. A BMI b 25 kg/m2 is considered normal; a BMI ranging between 25 and 30 kg/m2 is considered overweight but at low risk of serious medical complications. Patients with a BMI N 30 kg/m2 or BMI N 35 kg/m2 are defined as obese and morbidly obese, respectively [5]. Another widely used method to estimate the presence and severity of obesity is the determination of the percentage increase of total body weight (TBW) from IBW. Normal weight usually ranges within F10% from IBW; an individual is considered obese when the actual body weight exceeds 120% of the IBW. Determination of IBW is based on anthropometric parameters according to the following formulae: 1. IBW (men) = 49.9 kg + 0.89 kg/cm above 152.4 cm height 2. IBW (women) = 45.4 kg + 0.89 kg/cm above 152.4 cm height Obesity is an important risk factor for several diseases, and it has been clearly demonstrated that a BMI N 30 kg/ m2 increases morbidity and mortality of obese compared with nonobese subjects [6-8]. Morbidly obese patients are more prone to develop diabetes, respiratory failure, hypertension, left ventricular (LV) hypertrophy, atherosclerosis, myocardial ischemia [8-10], and some forms of cancer than nonobese patients [11]. Obesity is also associated with several surgical pathologies [1], whereas the development of laparoscopic techniques has further increased the indication to surgical treatment of obesity, causing less postoperative pain, shorter hospital stay, and faster return to normal life as compared with conventional laparotomic techniques [12-14]. For these reasons, obese patients are presenting more and more frequently for surgical procedures [15]. The changes in body structure induced by obesity result not only in increased anatomic difficulties of access for both the surgeon and anesthesiologist but also in important physiological and pharmacological modifications, which can potentially affect the pharmacokinetic and pharmacodynamic profiles of anesthetic drugs—these conditions make the obese patient a true challenge to the anesthesiologist. The aim of this review is to provide an overview of the international literature on the pharmacological profile of the main anesthetic drugs used for the obese patient.

2. Factors affecting pharmacokinetics in obesity Ideally, the anesthesiologist should warrant a 100% success rate of surgical anesthesia with a 100% reversibility of the condition itself and no complication or side effects. Accordingly, to provide a safe and effective anesthesia, the anesthesiologist must adjust the doses of the drugs used to

135 provide anesthesia based on the patient’s characteristics, producing complete protection from surgical injury and with minimal risks of side effects. Moreover, the modern balanced general anesthesia involves the application of a complex and multipharmacological treatment, where several drugs are coadministered to cover the 3 main components of anesthesia: hypnosis, muscle relaxation, and protection from the sympathetic response induced by surgical stress [16]. The physiological changes produced by obesity can markedly affect the distribution, binding, and elimination of anesthetic drugs [15,17-19], and severe adverse events can easily occur if drug dosing is based only on the actual body weight. Systemic absorption of oral drugs does not seem to be significantly affected by obesity [15,18,19], although some authors reported a delay in gastric emptying in the obese patient [20]. Obesity increases both fat and lean masses of obese as compared with nonobese subjects of the same age, height, and sex [18,19]. The increase in lean body mass represents 20% to 40% of total excess of weight; however, the percentage of fat mass per kilogram of TBW increases more than does the lean mass, resulting in a relative decrease of the percentage of lean mass and water of obese as compared with nonobese subjects of the same age, sex, and height [18,19]. These changes in tissue distribution produced by obesity can markedly affect the apparent volume of distribution of the anesthetic drugs. Furthermore, there are other changes induced by obesity that can affect the pharmacokinetic profile of anesthetic drugs, such as the absolute increase in total blood volume and cardiac output (CO) and alterations in plasma protein binding [15,19]. It also must be pointed out that changes in respiratory and cardiovascular functions as results of obesity may influence the absorption and elimination of inhalation anesthetics, which represent an important component in modern balanced anesthesia. Obesity-induced changes in the hemodynamic status and regional blood flow can further affect anesthetic drug pharmacokinetics. Fat tissue receives about 5% of CO, whereas viscera and lean tissues receive 73% and 22% of CO, respectively [18,19]. However, it has been reported that blood flow per gram of fat is reduced in the obese as compared with the nonobese patient [21,22], suggesting that blood flow could be proportionally lower in fat than in lean mass in obese individuals [18]. Moreover, the reduction in cardiac performance induced by obesity itself could further reduce tissue perfusion. The effects of obesity on drug binding to the plasma proteins are still unclear. It has been reported that the increased concentrations of triglycerides, lipoproteins, cholesterol, and free-fatty acids may inhibit protein binding of some drugs, increasing their free plasma concentrations [23]. On the other hand, the increase in concentrations of acute phase proteins, including a 1-acid glycoprotein, observed in the obese patient may also increase the degree of binding of other drugs, reducing their free-plasma concentrations [24,25].

136 Finally, the pharmacokinetic profile of anesthetic drugs can be affected by changes in their elimination related to the obesity-induced changes of liver and kidney functions. Obese patients usually show a fatty degeneration of the liver, which may further degenerate in liver fibrosis [26,27]. These changes can potentially affect hepatic clearance. Nonetheless, hepatic clearance is usually normal or even increased in the obese patient [15]. Renal clearance increases in obesity because of the increase in kidney weight, renal blood flow, and glomerular filtration rate [28], and it has been demonstrated that creatinine clearance is increased in healthy obese subjects in proportion to the estimated fat-free mass [29]. However, the changes induced by obesity contribute with time in developing a more severe glomerular injury, leading to chronic renal disease [28,30]. In obese patients with renal dysfunction, the estimation of creatinine clearance from standard formulae is inaccurate, and the dosing of renally excreted drugs must be adjusted according to the measured creatinine clearance [31].

A. Casati, M. Putzu of total respiratory compliance, functional residual capacity, expiratory reserve volume, and total lung capacity [38-40]. These changes are further affected by anesthesia [41] and surgical procedure [42]. In recent years, the use of laparoscopic procedures has also markedly increased in the obese patient, but the abdominal insufflation with carbon dioxide required by the laparoscopic technique, as well as the need for special patient positioning, further affect the respiratory system during anesthesia [43,44]. The reduction in lung volumes and increase in ventilation/perfusion mismatching increase the risk for hypoxemia during and after surgery. Intraoperatively, the addition of positive end-expiratory pressure may improve arterial oxygenation, but it also reduces CO and oxygen delivery [45]. On the contrary, in the postoperative period, the depressant effects of analgesic and anesthetic drugs on respiratory system may represent a true hazard for patient safety, increasing the risks for postoperative hypoxia [46]. Accordingly, the choice of the best pharmacological strategy, as well as the appropriate drug dosing during induction and maintenance of anesthesia, can influence the safety of the obese patient after surgery.

3. Obesity and related changes in cardiovascular and respiratory systems Tubular reabsorption increases in the obese patient [30], which in turn initiates volume expansion of the extracellular volume. Although total extracellular volume is increased in obese persons, the circulating blood volume on a volume/ weight basis is decreased to nearly 50 mL/kg as compared with 75 mL/kg in lean persons [32]. Splanchnic blood flow of obese persons is about 20% higher than that of lean persons, whereas cerebral and renal blood flow are almost normal [32]. The increase in circulating volume also results in a high-resting CO despite the relatively poor blood supply to the adipose tissue [33], resulting in hypervolemia and hypertension. Mild to moderate hypertension is reported in up to 60% of obese patients, whereas 5% to 10% of obese patients have severe hypertension [15,34]. In times, this condition leads to LV dilation, increased LV wall stress, compensatory LV hypertrophy, and LV diastolic dysfunction [35,36]. Similar changes also occur in the right ventricular (RV) structure, which is further affected by pulmonary hypertension related to sleep apnea and obesity hypoventilation syndromes [37]. Cardiovascular changes are also associated with several metabolic abnormalities, such as diabetes, dyslipidemia, and atherosclerosis, resulting in a very high risk for subendocardial ischemia in the presence of perioperative tachycardia and/or hypertension. These relevant changes in cardiovascular function can markedly influence the pharmacodynamics of anesthetic drugs, such as inhalation and intravenous general anesthetics, which are known to depress cardiovascular function. Moreover, the respiratory system is markedly affected by obesity, which can cause both mechanical and pulmonary changes. The increased weight of the thoracic and abdominal components of the chest wall results in significant reduction

4. Effects of obesity on pharmacokinetics of anesthetic drugs 4.1. Thiopental sodium and propofol Since its introduction in 1934, thiopental sodium is still the most widely used drug for intravenous induction of general anesthesia [47]. Its chemical-physical properties (oil/water partition coefficient ranging between 58/1 and 63/1, with a percentage of ionization at pH 7.4 of 61.3%) provide thiopental with a very easy and fast penetration through the different tissue barriers, making it an ultra–short-acting and potent drug for general anesthesia induction [47-50]. Induction with thiopental has been reported to increase the odds of critical respiratory events in the postoperative period nearly 2-fold [51]. However, no clinical differences in the effects on functional residual capacity and management of general anesthesia induction have been reported between thiopental and propofol, the other widely used drug for intravenous induction [52,53]. As with other highly lipophilic drugs, the modification of tissue distribution, as well as physiological changes induced by obesity, affects the pharmacokinetics and pharmacodynamics of thiopental. Jung et al [54] evaluated thiopental disposition in 8 lean and 7 obese patients undergoing abdominal surgery. The volume of distribution was larger in obese (7.94 F 4.5 L/kg TBW) than in nonobese patients (1.9 F 0.6 L/kg TBW). No differences in total clearance of thiopental were reported [0.21 F 0.06 mL/(kgd h) in obese vs 0.18 F 0.08 mL/(kgd h) in nonobese subjects]. However, the elimination half-life of thiopental was significantly longer in obese (27.8 hours) than nonobese patients (6.33 hours), a difference that was primarily a

77

114

Lorazepam

Midazolam

6.8

7.5

547T

8.6 44.7

311TT

131T

17.9 291.9T

Obese

0.1

0.141 0.99 0.14 4.8

1.74

1.23

1.4 2.09 1.533

Control

LD indicates loading dose; MD, maintenance dose. T P b .05 vs control group subjects. TT P b .01 vs control group subjects.

Remifentanil

Atracurium 8.5 Vecuronium 59.0 Rocuronium Sufentanil 346

13.0 90.1

Control

0.07T

0.067 0.47TT 0.09T 5.8

2.66TT

1.25

4.7TT 1.8 2.81T

Obese

2700

404 325 0.45 1780

530

4000

197.2 28.3 1600

Control

3100

444 260 0.03 1990

472

6000TT

416.3T 24.3 2300

Obese

19.8 min 133 min 70 min 135 min

2.27 h

23.9 h

6.3 h 4.1 40 h

Control

19.7 min 119 min 75 min 208 minT

5.94 hTT

33.5 hTT

27.8 hTT 4.05 95 hTT

Obese LD reduced LD and MD based on TBW LD adjusted to TBW, MD adjusted to IBW LD adjusted to TBW, MD adjusted to IBW LD adjusted to TBW, MD adjusted to IBW Dose calculated on TBW Dose calculated on IBW Reduced infusion rate LD based on TBW, MD reduced Dosage based on IBW

Volume of distribution (L) Volume of distribution (L/kg TBW) Total body clearance (mL/min) Terminal elimination half-life Dose recommendations

Pharmacokinetic parameters of the main anesthetic drugs given to obese and nonobese subjects

Thiopental Propofol Diazepam

Drug

Table 1

[100]

[90] [91] [94] [97]

[73]

[71]

[54] [4] [70]

Reference

Anesthesia implications of obesity 137

138 function of the increased volume of distribution induced by obesity (Table 1). Interestingly, Jung et al also reported that obese patients required significantly less thiopental for intravenous (3.9 mg/kg TBW) than did the nonobese patients (5.1 mg/kg TBW). Similar findings also have been reported by Dundee et al [55] who evaluated the minimal thiopental dose required to abolish the eyelash reflex in 2206 consecutive inductions and demonstrated that obese patients required less thiopental than lean subjects. Using a pharmacokinetic model to predict the effects of several parameters on thiopental plasma concentrations after intravenous administration, Wada et al [56] suggested that although obese people require more thiopental on a milligram-basis, they also appear to be more sensitive when dose is adjusted proportionally to body weight and should probably receive a dose proportional to lean body mass. To date, little information is available on the continuous infusion of thiopental. Cloyd et al [57] collected serum samples from 2 patients (1 obese and 1 nonobese) treated with continuous infusion of thiopental for uncontrollable seizures. They reported an elimination half-life of 86.4 hours after a 35-g dose infused over 11.4 days in the obese patient as compared with 38.4 hours after a 19.7-g dose infused over 3.3 days in the nonobese patient. The increased half-life observed in the obese patient was associated with a larger volume of distribution (8.4 L/kg in the obese vs 4.0 L/kg in the nonobese patient), whereas clearance remained unchanged [67 mL/(hd kg) for a total dose of 385 mg/kg in the obese patient and 72 mL/(hd kg) for a total dose of 393 mg/kg in the lean patient]. Continuous infusion of thiopental is never used for maintenance of general anesthesia; however, no changes in dose regimen seem to be required when providing a continuous infusion. Propofol is the second most extensively used intravenous anesthetic. It is a highly lipophilic drug with very fast onset and short, predictable duration of action because of its rapid penetration of the blood-brain barrier and distribution to the central nervous system, followed by rapid redistribution to inactive tissue depots, such as muscles and fat [58]. Because of its favorable pharmacokinetic properties, propofol is also ideally suited for maintenance of total intravenous anesthesia (TIVA). Juvin et al [59] reported that postoperative immediate and intermediate recoveries after propofol anesthesia was similar to that observed with isoflurane and longer than that obtained with desflurane. However, several studies have reported on the effectiveness and safety of TIVA with propofol in morbidly obese patients [60-62]. The availability of new technological supply, such as the use of target-controlled infusion systems, also improved the ease of propofol administration [63]. Servin et al [64] evaluated the pharmacokinetics of propofol in 8 obese and 10 normal-weight patients and demonstrated that both volume of distribution (1.8 F 0.65 L/kg in obese vs 2.0 F 0.9 L/kg in nonobese subjects) and clearance [24.3 F 6.2 mL/(kgd min) in obese vs 28.3 F 6.6 mL/(kgd min) in nonobese subjects] were significantly

A. Casati, M. Putzu correlated with TBW (r = 0.76 and r = 0.76, respectively). Because of the simultaneous increase in the volume of distribution and clearance, propofol elimination half-life was similar in obese (29.1 F 13.4 minutes) and nonobese (24.2 F 12.3 minutes) patients, and there were no signs of propofol accumulation or of any prolongation of its duration (Table 1). In this study, the obese patients opened their eyes when blood propofol concentration reached 1 lg/L, which was similar to the awakening concentration reported for nonobese patients [65]. Kakinohana et al [66] evaluated the use of a target-controlled infusion of propofol in 3 obese patients and found that the calculated blood concentrations of propofol at emergence from anesthesia ranged from 1.5 to 1.7 lg/mL. Similar findings have been reported by Saijo et al [67] who demonstrated that propofol concentration calculated at the effect site when the bispectral index value recovered to 80 was around 1.5 lg/mL; these target concentration values of propofol have also been reported during sedation in the nonobese patients [68]. According to these pharmacokinetic data, the dose regimen of propofol for both induction and maintenance of general anesthesia in obese patients should be based on actual body weight, as in lean subjects. Igarashi et al [69], analyzing 2 cases of intraoperative awareness during TIVA with propofol and fentanyl, suggested calculating the infusion rate of propofol based on actual body weight both in normalweight and obese patients. However, the cardiovascular effects of very large doses of propofol remain uncertain in the obese patients, especially considering the physiological changes induced by obesity on cardiovascular homeostasis.

5. Benzodiazepines Benzodiazepines are highly lipophilic drugs, and the excess fat tissue in obese patients significantly influences their disposition. Abernethy and Greenblatt evaluated in several studies the effects of obesity on the disposition of different benzodiazepines, including diazepam, alprazolam, nitrazepam, lorazepam, and midazolam [18,70-73]. All of these studies showed a significant increase in both volume of distribution and elimination half-life, with a significant correlation between lipid solubility and the extent of their distribution in the excess fat. For premedication, conscious sedation, or induction of general anesthesia, the anesthesiologist may use benzodiazepines. Among different benzodiazepines, midazolam is undoubtedly one of the most extensively used drugs by anesthesiologists because of its relatively shorter half-life as compared with other benzodiazepines [74]. It has been demonstrated that after a single intravenous dose of midazolam, the intensity and duration of action of its sedative effects depend much more on the extent of drug distribution than on the rate of elimination and clearance. The initial distribution half-life of midazolam ranges between 14 and 22 minutes [73]. Greenblatt et al

Anesthesia implications of obesity [73] also compared the pharmacokinetics of a 5-mg intravenous bolus of midazolam in 20 obese volunteers (range, 121%-263% IBW) and in a population of normal, healthy adults matched for age, sex, and smoking habit. Total volume of distribution was nearly 3 times larger in obese than normal-weight subjects and remained greater than that of nonobese subjects even after correction for total weight. The elimination half-life was prolonged significantly from a mean of 2.7 hours in nonobese patients to 8.4 hours in obese patients; however, this was related to the increased volume of distribution because no differences in total clearance were reported between obese (472 mL/min) and nonobese subjects (530 mL/min). These findings indicate that the presence of an excess of adipose tissue does not alter the liver capacity for midazolam biotransformation (Table 1). Based on these findings, when using a single intravenous dose of benzodiazepines irrespective of whichever drug is used, the dose should be increased at least in proportion to TBW because the volume of distribution increases disproportionately with the degree of fat tissue accumulation [73]. On the contrary, if a continuous infusion is used, the dose should be adjusted based on ideal body rather than TBW because total clearance is not substantially changed as compared with nonobese subjects.

139 choice for obese patients because of their more rapid and consistent recovery profile [80-82]. When comparing the wash-in and wash-out kinetics of sevoflurane in obese and nonobese patients, Casati et al [83] did not report significant differences in the alveolar to

(A) FA/FI

Obese

1

Nonobese

*

0,8

0,6

0,4

0,2

0 0

6. Volatile anesthetics Obese patients are traditionally reported to have a slower emergence from anesthesia because of a delayed release of volatile drugs from the excess fat tissue. However, it must also be considered that the reduced blood flow to the fat tissue limits the delivery of inhalation drugs to these stores, whereas slow emergence could be accounted for by an increased central sensitivity [15]. On the other hand, comparable recovery times have been reported in obese and nonobese subjects after anesthetic procedures lasting 2 to 4 hours [75]. Old inhalation anesthetics, such as methoxyflurane, halothane, and enflurane, all had high lipid solubility coefficients, and previous investigations have documented an increased biotransformation of these drugs in obese compared with nonobese patients [76-78]. These studies showed a significant increase in both bromide and fluoride levels in the serum, suggesting the presence of a reductive halothane metabolism possibly associated with hepatotoxicity. In the same studies, it also has been reported that halothane metabolism was prolonged in obese patients [76-78], whereas serum concentrations of inorganic bromide remained elevated for up to 2 weeks after the anesthetic procedure because the volatile drug was released progressively from adipose tissue stores [79]. New inhalation drugs, such as desflurane and sevoflurane, have much lower lipid solubility compared with earlier drugs and have been suggested as the volatile anesthetic of

10

20

30

Minutes of Administration

(B) FA/FA0

*

1

Obese

Nonobese

* * 0,8

* * 0,6

0,4

0,2

0 0

1

2

3

4

5

Minutes of Elimination *

P < 0.05 vs Nonobese patients

Fig. 1 The wash-in (A) and wash-out (B) curves of sevoflurane measured in obese and nonobese patients (values are presented as mean F SD) [83].

140 inspiratory fraction ( FA/F I) (Fig. 1A), whereas the wash-out curve of sevoflurane ( FA/FA0) was slower in obese patients as that in nonobese patients (Fig. 1B). However, no differences in the FA/FA0 ratio were reported 5 minutes after sevoflurane discontinuation between obese and normal-weight subjects. Salihoglu et al [84] demonstrated the usefulness and advantages of sevoflurane over TIVA because of the possibility of progressive induction of anesthesia with the face mask, whereas Torri et al [85] also showed that the washin and wash-out kinetics of sevoflurane are significantly faster than those of isoflurane in the obese patient. Nonetheless, to date, few data are currently available on the pharmacokinetics of sevoflurane in the obese patient. Higuchi et al [86] reported significantly higher fluoride serum concentrations after sevoflurane anesthesia in obese (51 F 2.5 lmol/L) than nonobese patients (40 F 2.3 lmol/ L). However, researchers did not find significant differences in fluoride serum concentrations between obese (30 F 2 lmol/L) and nonobese (28 F 2 lmol/L) patients [87], and no signs of renal dysfunction have been demonstrated [88].

7. Muscle relaxants Muscle relaxants are polar and hydrophilic drugs. Accordingly, these drugs are distributed to a limited extent in excess body fat [19]. It has been reported that obese patients require significantly more pancuronium than nonobese subjects for the maintenance of 90% paralysis throughout surgery [89]. Varin et al [90] evaluated the pharmacokinetics and pharmacodynamics of atracurium in morbidly obese and nonobese patients and reported no difference in elimination half-life (19 F 0.7 minutes in both obese and nonobese patients), volume of distribution at steady state (8.6 F 0.7 L in obese and 8.5 F 0.7 L in control patients), and total clearance (444 F 29 mL/min in obese and 440 F 25 mL/min in control patients). In the same study, the authors also observed that although atracurium concentrations were higher in the obese than nonobese patients, there was no difference between the 2 groups in the time of recovery from neuromuscular blockade. Schwartz et al [91] evaluated the pharmacokinetic and pharmacodynamic profiles of vecuronium administered to 7 obese and 7 normal-weight subjects and showed that when the data were calculated on the basis of IBW, total volume of distribution (791 F 303 vs 919 F 360 mL/kg), plasma clearance [4.65 zF 0.89 vs 5.02 F 1.13 mL/(mind kg)], and elimination half-life (119 F 43 vs 133 F 57 minutes) did not differ between obese and nonobese patients. Nonetheless, the authors reported a difference in duration of action of vecuronium in obese patients compared with nonobese subjects. Because obesity did not alter the distribution or elimination of the drug, the prolonged action of vecuronium was considered related to the excess dose administered as a result of the drug being given on the basis of TBW.

A. Casati, M. Putzu Therefore, the authors suggested the use of IBW rather than actual body weight in calculating the dosage of vecuronium in obese patients (Table 1). Evaluating different anthropometric variables as predictors of duration of action of atracurium-induced block, Kirkegaard-Nielsen et al [92] reported that TBW was a strong predictor of duration of action of a 0.5-mg/kg induction dose of atracurium and suggested that the atracurium dose be reduced to 0.23 mg for each kilogram of TBW above 70 kg. Fisher et al [93] assessed the role of several covariates, including obesity, on the pharmacokinetic and pharmacodynamic profiles of doxacurium, a long-acting nondepolarizing muscle relaxant. They showed that obesity decreased both doxacurium’s clearance (1.1% per percentage above IBW) and its neuromuscular junction sensitivity (0.4% per percentage above IBW). Accordingly, the authors suggested that obese patients be dosed based on IBW. More recently, Puhringer et al [94] evaluated the pharmacokinetics of rocuronium bromide in 6 obese and 6 normal-weight patients receiving balanced general anesthesia. The volume of distribution at steady state was 208 F 57 mL/kg in normal-weight patients and 169 F 37 mL/kg in obese patients. Distribution and elimination half-lives, as well as mean residence time, were 15 F 4, 70 F 24, and 53 F 10 minutes in normal-weight subjects and 17 F 4, 75 F 25, and 51 F 19 minutes in obese patients, respectively. Finally, no differences were observed in plasma clearance, indicating that the pharmacokinetics and pharmacodynamics of rocuronium were not altered by obesity. Because of changes in upper airway anatomy and reduced tolerance to apnea of obese patients, airway control and tracheal intubation are often difficult in this patient population. For this reason, succinylcholine is often preferred to nondepolarizing neuromuscular blockers in rapidly securing the airway. Rose et al [95] constructed a single-dose response curve for succinylcholine in 30 obese patients during thiopental-fentanyl anesthesia to determine the doses of succinylcholine producing 50% (ED50), 90% (ED90), and 95% (ED95) depression of neuromuscular function. With this experimental model, these authors showed that the potency estimates for succinylcholine in obese patients (BMI N 30 kg/m2) are comparable to those of similarly aged nonobese subjects when dosing is calculated based on total body mass and not lean body mass. Although several new muscle relaxants have been introduced into our practice, succinylcholine is still frequently used in cases of risk for difficult intubation, and this is the case for the obese patient. Succinylcholine is a depolarizing muscle relaxant whose duration of action is primarily determined by the level of pseudocholinesterase activity in the blood and the volume of extracellular fluid space. Bentley et al [96] reported that increasing weight is associated with increased pseudocholinesterase activity, which could be related to the increased metabolic activity that occurs in obesity. They advised that in adult obese

Anesthesia implications of obesity patients succinylcholine be administered on the basis of total rather than lean body weight.

8. Opioids New synthetic opioids, such as fentanyl, sufentanil, and, more recently, remifentanil, are widely used during anesthesia induction and maintenance to control the sympathetic responses to tracheal intubation and surgical stress. According to their n-octanol and water-partition coefficients, all these synthetic opioids are highly lipophilic drugs. Schwartz et al [97] evaluated the pharmacokinetics of sufentanil in 8 obese and 8 control patients. Calculation of pharmacokinetic variables after a single intravenous bolus of 4 lg/kg of sufentanil demonstrated an increased volume of distribution in the obese (9.1 F 2.8 L/kg IBW) as compared with nonobese subjects (5.1 F 1.7 L/kg IBW), with a markedly prolonged elimination halflife (208 F 82 minutes in obese vs 135 F 42 minutes in normal-weight subjects). The total volume of distribution was positively correlated with the degree of obesity, whereas plasma clearance was similar in both obese [32.9 F 12.5 mL/(mind kg) IBW] and nonobese [26.4 F 5.7 mL/(mind kg) IBW] patients. In contrast, the volume of distribution calculated on TBW was not significantly different between the 2 groups, indicating that the drug was similarly distributed in the excess body mass and lean tissues. Accordingly, the loading dose should account for total body mass. However, the slower elimination of sufentanil reported in obese subjects suggests that infusion or maintenance doses be reduced carefully, especially considering the increased risk for postoperative hypoxemia [43-45]. Obesity also has been demonstrated to prolong the elimination half-life of alfentanil, whereas no significant differences in fentanyl’s pharmacokinetics were reported between obese and nonobese individuals [98]. Although definite conclusions cannot be made from the limited studies, these findings suggest that dose regimens for fentanyl, sufentanil, and alfentanil be based on lean body mass rather than actual weight (Table 1). Remifentanil is a new fentanyl congener recently introduced into the market. Its most interesting characteristic is that it is susceptible to hydrolysis by blood and tissue esterases, resulting in rapid metabolism to essentially inactive products. Remifentanil has been shown similarly effective as the 2 congener molecules, fentanyl and alfentanil, in preventing cardiovascular changes after tracheal intubation in morbidly obese patients [99]. Egan et al [100] evaluated the pharmacokinetics of remifentanil in 12 obese patients and 12 matched lean subjects. The estimates of volumes of distribution were less than expected for lipid-soluble molecules and revealed only modest distribution into body tissues, but no differences were reported between obese and lean subjects. Moreover, the clearance of remifentanil was similar in the 2 groups,

141 with a mean of 3.1 L/min in obese and 2.7 L/min in nonobese patients (Table 1). These values are substantially greater than hepatic blood flow, which is because of remifentanil’s widespread extrahepatic metabolism. The study of Egan et al [100] also demonstrated that remifentanil pharmacokinetic parameters are more closely related to lean body mass than TBW. Accordingly, remifentanil dosing also should be based on IBW, which is closely related to lean body mass and is easier for the clinician to estimate [101].

9. Local anesthetics Regional anesthesia and analgesia techniques are frequently used in obese patients to reduce the risks related to airway control and postoperative respiratory depression induced by general anesthetics or opioids used for pain treatment [15]. Accordingly, combined spinal-epidural anesthesia or integrated epidural and light general anesthesia are widely used in this patient population [102-104]. In addition, peripheral nerve blocks, when allowed by the surgical procedure, are useful to further minimize perioperative morbidity of the obese patient. Nonetheless, anatomic changes induced by obesity render most regional anesthesia techniques extremely challenging because of technical difficulties in identifying the usual bony landmarks. Moreover, fatty infiltration of epidural space, as well as increased blood volume caused by the increased intraabdominal pressure, may reduce the volume of the epidural space [105,106], resulting in an unpredictable spread of the local anesthetic solution and block height [107]. This situation can lead to potentially severe complications, such as respiratory and cardiovascular failures, induced by the effects of motor and sympathetic blockade extending above T5 [108]. Absorption of local anesthetic solutions used for regional anesthesia techniques are markedly influenced by the site of injection—intercostal blocks result to fastest absorption rate followed by epidural and spinal blockades, whereas peripheral nerve blocks and local infiltration are associated with the slowest absorption rate [109]. Abernethy and Greenblatt [110] evaluated lidocaine disposition in 25 obese and 31 nonobese patients and showed that elimination half-life was markedly prolonged in obese (2.7 F 0.2 hours) vs nonobese patients (1.6 F 0.06 hours). This finding was not associated with changes in clearance (1.4 F 0.1 L/min in obese and 1.3 F 0.08 L/min in nonobese subjects) but was likely related to the increase in the total volume of distribution (325 F 20 L in obese and 209 F 15 L in nonobese patients). Nonetheless, when correcting the volume of distribution for TBW, no differences were observed between obese (2.67 F 0.22 L/kg TBW) and normal-weight subjects (2.71 F 0.18 L/kg TBW), suggesting that lidocaine’s volume of distribution increases in parallel with body weight.

142

10. Discussion and conclusion Although obesity is a disease with an increasing prevalence (especially in Western developed countries) and obese patients more and more frequently undergo surgical procedures requiring anesthesia, only a few studies have evaluated the pharmacokinetics and pharmacodynamics of drugs used to provide anesthesia in the obese patient. Furthermore, studies available often have several limitations mainly because of small sample sizes as well as use of single rather than repeated doses. Obesity has varying effects on pharmacokinetic parameters of anesthetic drugs according to lipid solubility and diffusion through different tissues. According to the general principles of pharmacokinetics, drug dosing must be based on the volume of distribution for the loading dose and on clearance for maintenance. If changes in the volume of distribution of the anesthetic agent indicate that drug distribution is restricted to lean tissues only, the loading dose will be calculated on IBW. On the contrary, if the drug is equally distributed in lean and fat tissues, the loading dose will be calculated on TBW. For maintenance regimen, dosage is usually adjusted based on the clearance of the drug in the obese as compared with nonobese subject. If the clearance is similar or reduced in the obese patient as compared with nonobese subject, maintenance dose is usually calculated based on IBW. If the clearance of the drug increases with obesity, maintenance regimen should be calculated based on TBW. Even if obesity is associated with the development of histological abnormalities in liver potentially affecting hepatic clearance of some anesthetic drugs, the metabolic drug clearance of these drugs is usually normal or even increased in the obese subject. However, other pharmacodynamic factors may further affect anesthetic drug dosing in the obese patient because hyposensitivity (such as for atracurium or other muscle relaxants) or hypersensitivity (such as for thiopental) to the anesthetic effect may require further changes in drug dosing for the obese patient. Benzodiazepines are usually used for premedication and conscious sedation, and their loading dose should be adjusted on actual weight whereas maintenance doses should be calculated on IBW. The agents mainly used for anesthesia induction are thiopental and propofol, and their regimen should be based on TBW with a reduction of loading dose for thiopental only because of the increased sensitivity of the obese patient to the action of this agent. The loading dose of lipophilic opioids should be based on TBW whereas maintenance doses should be reduced because of the higher sensitivity of the obese patient to the depressant effects of these agents. The new opioid, remifentanil, has interesting properties for anesthetic management of the obese patient, which is preventing the risks related to accumulation of opioid drugs. Initial reports suggest that remifentanil’s dosage be based on IBW rather than on actual body weight.

A. Casati, M. Putzu Neuromuscular blockers are polar hydrophilic drugs with no significant changes in pharmacokinetic parameters induced by obesity. However, dosing of these drugs based on actual body weight results in a longer duration of action, suggesting that ideal rather than TBW should be used to calculate their dosing regimen in the obese patient. The only exception could be the use of succinylcholine, where the increased pseudocholinesterase activity suggests that succinylcholine should be administered based on total rather than lean body weight in adult obese patients. Inhalation anesthetics provide the anesthesiologist with the advantage of controlling not only the administration of the drug but also its elimination through the modification of patient ventilation at the end of the procedure. Moreover, the newer drugs, sevoflurane and desflurane, have a very low lipid solubility and represent a good option when adjusting the anesthetic plan during surgery and providing rapid emergence at the end of surgery with potentially reduced depressant effects postoperatively.

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