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EDITORIAL

Anesthetizing the Obese


Bruce Green, DClinPharm,* and Sarah C. McLeay, BSc(Hons)

Thou seest I have more flesh than another man, and


therefore more frailty.
William Shakespeare, 1564 1616

hy after 25 years of clinical use is there suddenly so


much interest in propofol? Paracelsus wisely recognized that the dose makes the poison, and it
makes you wonder if recent media reportsa have stirred up
niggling reminders that propofol dosing is more of an art than
a science.
Part of this artistic license has resulted from the milligramper-kilogram dose,1 which attempts to normalize exposure
across subjects of differing body size. However, since propofols approval, the worlds body composition has changed,
with obesity prevalence in the United States adult population
(classified as a body mass index [BMI] 30 kg/m2) increasing
from 13.4% in 19602 to 33.9% in 2008.3 Whats more, were
getting bigger, prompting the World Health Organization to
recategorize obesity into simple obesity (BMI 30 34.9 kg/m2),
severe obesity (3539.9 kg/m2), morbid obesity (40 49.9
kg/m2), and super morbid obesity (BMI 40 kg/m2).4 One
must surely question whether dosing strategies developed in
leaner populations remain applicable to todays demography.
For propofol, and other drugs, a body of research has
questioned whether drug doses based on total body weight
(TBW) can be reliably transported to the obese. If so, the
following assumptions would need to be true: that volume
of distribution, which defines initial drug dose, is twice as
large for a 200-kg subject compared with a 100-kg subject
and that clearance (CL), which determines maintenance
dosing, is twice as fast in the respective 200-kg subject.b The
first assumption might not be unreasonable if the drug is
lipid soluble and distributes into fat. However, for hydrophilic drugs, volume of distribution is more likely to be
linearly related to lean body weight (LBW) rather than
TBW. The second assumption, that CL is twice as fast in a
200-kg subject, seems implausible unless adipose tissue

metabolizes the drug or the functional capacity of metabolizing organs, e.g., the liver and kidney, are linearly related
to TBW. There is little evidence supporting this second
assumption because 99% of metabolic processes occur
within lean tissues.6 It is perhaps not too surprising then
that CL seems best linearly related to LBW rather than
TBW.7 The upshot in clinical practice is that subjects of
different body compositions should expect a similar drug
exposure if maintenance doses are determined on a milligram amount per kilogram of LBW. And here lies a
challenge: LBW has been prohibitively difficult to use in the
clinic, because accurate measurement via dual x-ray absorptiometry, for example, is not practical. Bioelectrical
impedance analysis (BIA) is more readily available as
demonstrated by Ingrande et al.,8 although more frequently, equations developed by James in 1976 are used to
estimate LBW.9 These equations cannot, however, be extrapolated to the obese because of numerical inconsistencies whereby LBW declines at certain weights and
heights.7,10 New semimechanistic LBW equations developed in 2005 are transportable to the obese, with readers
directed to the article by Janmahasatian et al.11 for a
complete derivation.
For propofol, there is clearly much confusion when
dosing the obese, with most prior work unable to help
anesthetists. The reason is that the obese have often been
excluded from studies, or James LBW equations have been
used to describe pharmacokinetic (PK) parameters. As
such, CL has been reported to increase linearly with TBW12
or vary with some form of James LBW13,14 (Fig. 1). The
empirical suggestion by Servin et al.15 of corrected
weight was a possible metric that might be applicable to
dosing the obese, although some have questioned its suitability in clinical practice.16,17 Trial design, subject population, and James LBW equations are responsible for the
variety of relationships between TBW and CL shown in
b

Even though he wasnt obese, did propofol contribute toward the death of
Michael Jackson?
From the *Model Answers Pty. Ltd., Brisbane; and School of Pharmacy, The
University of Queensland, Brisbane, Australia.
Accepted for publication October 3, 2010.
Conflict of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Bruce Green, DClinPharm, Director, Model
Answers, Suite 4, Level 18, 333 Ann St., Brisbane, Australia 4000. Address
e-mail to modelanswers@gmail.com.
Copyright 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318212eae8

July 2011 Volume 113 Number 1

This is somewhat of a simplification. CL determines the required maintenance dose of a drug when steady-state concentrations are reached. For
drugs that display single compartmental pharmacokinetics (PKs), steady
state is achieved immediately after the loading dose is administered. For
propofol and other drugs that display multicompartmental PKs, true steady
state might not be achieved during the course of dosing because of drug
transfer between compartments. The actual induction dose required to
achieve anesthesia may therefore depend on the rate of administration, rate
and extent of transfer to the peripheral compartments, and effect-site
hysteresis. Furthermore, for target-controlled infusion in effect-site targeting
mode, the doses are adjusted by the device to best achieve steady state
within the effect-site rather than in the central (i.e., plasma) compartment
(see Absalom et al.5 for more information). However, it is still central volume
of distribution and elimination CL that have the greatest influence on
required loading and maintenance doses, respectively, to achieve and
maintain pseudosteady-state/stable concentrations.

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EDITORIAL

models are transportable across a wide range of body compositions. More recent studies have attempted to do this,20,21
although some approaches cause confusion by failing to
consider the limitations of design on covariate selection.22 It is
therefore refreshing that Ingrande et al.8 are prospectively
assessing BIA for dosing propofol in the obese and exploring
a hypothesis based on mechanistic reasoning rather than
empiricism and tradition. They also note that LBW estimated
by the Janmahasatian et al. equation11 is a practical approach
in the clinic where BIA is unavailable.
In conclusion, we propose that it is time to move
forward and update PK models in TCI devices with ones
that are transportable to the obese. Lets stop making up
fudge factors for TCI devices and perhaps consider Janmahasatian et al.s LBW as a metric to dose propofol across a
population that includes the obese.
DISCLOSURES

Figure 1. Propofol clearance predicted by a range of pharmacokinetic


models for a 30-year-old man with a height of 1.75 m. *Unpublished
data from S. C. McLeay, G. A. Morrish, C. M. Kirkpatrick, and B. Green.

Figure 1, some of which12,13 appear in target-controlled


infusion (TCI) devices to help dose propofol. To prevent
overdosing using these devices, work-around solutions
have been implemented by the manufacturers; e.g., TBW is
capped at 150 kg in the Diprifusor system (AstraZeneca,
Cheshire, UK) and LBW is capped at maximal values for
the Base Primea system (Fresenius, Brezins, France).c More
recently, for remifentanil TCI, which incorporates James
LBW, La Colla et al.18 developed a metric termed fictitious
height to avoid underdosing in the obese! Does one not
find it frightening that given all of todays technological
advances we use fudge factors when dosing anesthetic
drugs in at least one-third of the adult population?
On a side note, it would be unusual for any clinician to
dose patients without considering, for example, their age,
concomitant medications, or hair color.19 Furthermore,
because doses are often titrated to effect, some may argue
that new dosing recommendations are unnecessary. Bouillon and Shafer10 recognized this perspective, stating that
We are clearly skilled at getting close to the right dose.
Isnt close close enough? They continue, however, to
discuss the need for a sound scientific foundation to obtain
the correct dose based on size. Indeed, it is this close
enough mindset that might hinder further research on
body size, PKs, and dose development for the obese.
Given the mounting evidence that propofols current dose
strategies and PK models are inadequate for the obese, the
Open TCI Initiative (http://opentci.org) has made data publicly available in the anticipation that universal dosing algorithms be developed. We propose that mechanistic PK models
and dosing strategies use these data if necessary, but ensure
c

The PK parameter set in this system was developed by Schnider et al.13


where V, and therefore loading dose, does not vary with weight. Consequently, obese patients could be underdosed during induction but overdosed for maintenance.

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Name: Bruce Green, DClinPharm.


Attestation: This author has prepared the manuscript and
approved the final manuscript.
Conflict of interest: None.
Name: Sarah C. McLeay, BSc(Hons).
Attestation: This author has prepared the manuscript and
approved the final manuscript.
Conflict of interest: SCM was supported by a grant from
Pfizer Global R&D.
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ANESTHESIA & ANALGESIA

Anesthetizing the Obese

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19. Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG,
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