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: Abstract The prevalence of obesity has increased 15% up to 20% and represents an important
Obesity;
challenge for the anesthesiologist in drug-dosing management. The aim of this work is to provide an
Pharmacokinetics
overview on physiological changes and pharmacokinetic implications of obesity for the anesthesi-
ologist. 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: acasati@ac.pr.it (A. Casati).
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 reduc-
tion 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

0952-8180/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.jclinane.2004.01.009
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, atheroscle-
rosis, 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 pharmaco-
dynamic profiles of anesthetic drugs—these conditions
make the obese patient a true challenge to the anesthesiol-
ogist. 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 anesthe-
sia: 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 elimina-
tion 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, cho-
lesterol, 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, ob-
served in the obese patient may also increase the degree of
binding of other drugs, reducing their free-plasma concen-
trations [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].
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 hypoventi-
lation 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
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 laparo-
scopic 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.
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 manage-
ment 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 non-
obese patients (6.33 hours), a difference that was primarily a
Table 1 Pharmacokinetic parameters of the main anesthetic drugs given to obese and nonobese subjects
Anesthesia implications of obesity

Drug Volume of distribution (L) Volume of distribution (L/kg TBW) Total body clearance (mL/min) Terminal elimination half-life Dose recommendations Reference
Control Obese Control Obese Control Obese Control Obese
Thiopental 1.4 4.7TT 197.2 416.3T 6.3 h 27.8 hTT LD reduced [54]
Propofol 13.0 17.9 2.09 1.8 28.3 24.3 4.1 4.05 LD and MD based on TBW [4]
Diazepam 90.1 291.9T 1.533 2.81T 1600 2300 40 h 95 hTT LD adjusted to TBW, MD [70]
adjusted to IBW
Lorazepam 77 131T 1.23 1.25 4000 6000TT 23.9 h 33.5 hTT LD adjusted to TBW, MD [71]
adjusted to IBW
Midazolam 114 311TT 1.74 2.66TT 530 472 2.27 h 5.94 hTT LD adjusted to TBW, MD [73]
adjusted to IBW
Atracurium 8.5 8.6 0.141 0.067 404 444 19.8 min 19.7 min Dose calculated on TBW [90]
Vecuronium 59.0 44.7 0.99 0.47TT 325 260 133 min 119 min Dose calculated on IBW [91]
Rocuronium 0.14 0.09T 0.45 0.03 70 min 75 min Reduced infusion rate [94]
Sufentanil 346 547T 4.8 5.8 1780 1990 135 min 208 minT LD based on TBW, [97]
MD reduced
Remifentanil 6.8 7.5 0.1 0.07T 2700 3100 Dosage based on IBW [100]
LD indicates loading dose; MD, maintenance dose.
T P b .05 vs control group subjects.
TT P b .01 vs control group subjects.
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 non-
obese 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 normal-
weight 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 anesthesi-
ologist may use benzodiazepines. Among different benzo-
diazepines, midazolam is undoubtedly one of the most
extensively used drugs by anesthesiologists because of its
relatively shorter half-life as compared with other benzo-
diazepines [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 midazo-
lam ranges between 14 and 22 minutes [73]. Greenblatt et al
Anesthesia implications of obesity 139

[73] also compared the pharmacokinetics of a 5-mg choice for obese patients because of their more rapid and
intravenous bolus of midazolam in 20 obese volunteers consistent recovery profile [80-82].
(range, 121%-263% IBW) and in a population of normal, When comparing the wash-in and wash-out kinetics of
healthy adults matched for age, sex, and smoking habit. sevoflurane in obese and nonobese patients, Casati et al [83]
Total volume of distribution was nearly 3 times larger in did not report significant differences in the alveolar to
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 signifi- (A)
cantly from a mean of 2.7 hours in nonobese patients to 8.4
Obese Nonobese
hours in obese patients; however, this was related to the FA/FI 1
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 0,8 *
indicate that the presence of an excess of adipose tissue
does not alter the liver capacity for midazolam biotrans-
formation (Table 1).
0,6
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 dispro- 0,4
portionately 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 0,2
because total clearance is not substantially changed as
compared with nonobese subjects.
0
0 10 20 30
6. Volatile anesthetics Minutes of Administration

Obese patients are traditionally reported to have a slower (B)

emergence from anesthesia because of a delayed release of
volatile drugs from the excess fat tissue. However, it must FA/FA0 1 * Obese Nonobese

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 0,8
increased central sensitivity [15]. On the other hand, *
comparable recovery times have been reported in obese
and nonobese subjects after anesthetic procedures lasting *
0,6
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 0,4
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 0,2
levels in the serum, suggesting the presence of a reductive
halothane metabolism possibly associated with hepatotox-
icity. In the same studies, it also has been reported that
halothane metabolism was prolonged in obese patients 0
[76-78], whereas serum concentrations of inorganic bromide 0 1 2 3 4 5
remained elevated for up to 2 weeks after the anesthetic Minutes of Elimination
procedure because the volatile drug was released progres-
* P < 0.05 vs Nonobese patients
sively from adipose tissue stores [79].
New inhalation drugs, such as desflurane and sevoflur- Fig. 1 The wash-in (A) and wash-out (B) curves of sevoflurane
ane, have much lower lipid solubility compared with earlier measured in obese and nonobese patients (values are presented as
drugs and have been suggested as the volatile anesthetic of 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 nor-
mal-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 wash-
in 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 non-
obese 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 pharmacodynam-
ic 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. Nonethe-
less, 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 predic-
tors 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 pharmaco-
dynamic profiles of doxacurium, a long-acting nondepola-
rizing 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 anesthe-
sia. 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 rocuro-
nium 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 fre-
quently 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 lipophil-
ic drugs. Schwartz et al [97] evaluated the pharmacoki-
netics 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 half-
life (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 extra-
hepatic 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 fre-
quently 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 anesthe-
sia 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 perioper-
ative 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 intra-
abdominal 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 differ-
ences 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 pharmacodynam-
ics 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 param-
eters 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 anesthet-
ic 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 succi-
nylcholine 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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