Dear Sir,
We are pleased that our article has generated discussion and thank Dr.
Engbers and colleagues for their constructive comments.
We have sought clarification once more from the main manufacturers of
‘open TCI’systems on how their pumps deal with the calculation of the
Schnider model elimination rate constant (k10) in morbidly obese patients,
and based on this we agree that our figure 7 is not in keeping with the
latest software versions implemented in these pumps. For the sake of
clarity, we would like to explain the current situation in some detail.
The Base Primea system (Fresenius-Kabi, Brezins, France) allows the
user to input the actual patient parameters, but will not operate in TCI
mode if the user enters a combination of height and total body weight
(TBW) that yields a body mass index (BMI) >35 for females or a BMI
>42 for male patients (personal communication, Mr. S. Ruton, Fresenius-
Kabi). On the other hand, the Alaris Asena PK system (Carefusion,
Basingstoke, UK) requires the user to first input the patient height and
gender, and then will not allow the user to input a TBW value that
generates a paradoxical LBM value based on the James equation1 (i.e. TBW
and height combination that generate a LBM value that falls on the portion
of the TBW vs. LBM curve with a negative slope) (personal communication,
Mr. M. Richardson, Carefusion).
The nett effect of these software solutions implemented in the
currently available open TCI systems is to prevent the system
microprocessors from applying paradoxical or absurd parameters. The heavy
solid lines in figure 1(a) and l(b) indicate the range of TBW values
within which both systems will operate for males and females respectively
who are 160 cm or 190 cm tall, and the resulting k10 values with the
Schnider model. The light continuous lines indicate the range of values
for these heights, over which paradoxically decreasing LBM values would
result in excessive k10 values if the Schnider model was implemented as
published.2;3
View Image
Whether models are generated by formal mixed-effects modeling
procedures or by more pragmatic methods, we agree with Engbers that it is
dangerous to extrapolate a model beyond the boundaries of the important
characteristics of the population from which it was developed. By
observing the range of TBW values within which the systems will operate
(indicated by the heavy solid lines in figure 1), the reader will notice
that these software solutions also prevent the use of the Schnider model
in morbidly obese patients whose characteristics are significantly
different from those of the subjects from the studies from which the
original Marsh and Schnider models were developed.2-4
We are aware of strategies that clinicians have developed to enable
them to use open TCI systems with the Schnider model for TCI in morbidly
obese patients. Although we do not recommend these practices, we feel that
it is important to mention this issue, to illustrate the inherent and
significant dangers. One option for clinicians who wish to use the
Schnider model in morbidly obese patients is to input a ‘corrected’ TBW
value – typically the user will input the maximum TBW value that the
system will allow for a patient of that height (i.e. a falsely low TBW is
used). As illustrated by the dotted lines in figures 1(a) and 1(b), the
result of this strategy is that all morbidly obese patients of a given
height and gender will be assigned the same TBW, LBM and k10 values, and
all will thus receive the same amount of propofol for a given target
concentration profile. By fixing k10 this strategy fixes the only Schnider
model parameter that usually varies with weight (the only other parameters
with co-variates are the fast re-distribution rate constants which vary
with age). Thus anaesthetists who use the Schnider model in morbidly obese
patients, should know that by inputting falsely low TBW values, they have
generated a model where the infusion rates no longer scale according to
the patient weight. Since propofol is a highly lipid-soluble agent,
maintenance doses are likely to be related to total body weight. There is
thus a real danger that with this strategy insufficient maintenance doses
will be administered to morbidly obese patients.
At present clinicians who wish to administer intravenous anaesthesia to
morbidly obese patients are ‘between the devil and the deep blue sea’ (we
promise not to re-invoke the satanic analogy!). Our personal view is that
with current evidence and knowledge, the most prudent approach is to
manually administer an induction bolus based on an estimate of lean body
mass, and thereafter to administer a manually controlled infusion,
carefully titrated to clinical effect.
We have focused on obese patients, but there are several other groups
who fall outside of the boundaries of the original research, such as the
very young or old, and the critically ill, and in whom the utility of
different models is uncertain. In his letter, Engbers has also touched on
the issue of which model is best in ‘normal’ patients. The study of Glen
and Servin5 which he mentions, is a valuable contribution, but cannot be
regarded as conclusive evidence. A goal of the ‘WorldSIVA Open TCI’
initiative (www.opentci.org) is to attempt to answer precisely these sorts
of questions, by harnessing the statistical benefits of combining data
sets derived from different studies. A recent study resulting from this
initiative, involving a very large dataset, has shown results at odds with
those of Glen and Servin.6 There is clearly some way to go yet.
Finally, we apologise for the error in figure 6. We were aware of it
and have asked the editor to publish an erratum.
A.R. Absalom
V. Mani
T. de Smet
M.M.R.F Struys
References
1. Research on obesity. London: Her Majesty's Stationary Office;
1976.
2. Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL et
al. The influence of method of administration and covariates on the
pharmacokinetics of propofol in adult volunteers. Anesthesiol 1998;
88(5):1170-1182.
3. Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB et
al. The influence of age on propofol pharmacodynamics. Anesthesiol 1999;
90(6):1502-1516.
4. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol
administered as constant rate intravenous infusions in humans. Anesthesia
and Analgesia 1987; 66(12):1256-1263.
5. Glen JB, Servin F. Evaluation of the predictive performance of four
pharmacokinetic models for propofol. Br J Anaesth 2009; 102(5):626-632.
6. Masui K, Upton RN, Doufas AG, Coetzee JF, Kazama T, Mortier EP et al.
The Performance of Compartmental and Physiologically Based Recirculatory
Pharmacokinetic Models for Propofol: A Comparison Using Bolus, Continuous,
and Target-Controlled Infusion Data. Anesth Analg 2009; Oct 27. [Epub
ahead of print](PMID: 19861357).
Legend to Figure 1:
Influence of total body weight and height on the k10 calculated by the
Schnider model (males - figure 1a, females figure 1b) as implemented in
the latest versions of commercially available ‘open TCI’ systems. The
heavy black and blue lines indicate the range of TBW values within which
the systems will operate for patients who heights are 160 and 190 cm
respectively. The light black and blue lines indicate the k10 values which
result from application of the original Schnider equation for k10 outside
of the aforementioned ranges. Finally, the dotted lines indicate the k10
values that result if the systems use the maximum allowed TBW values, and
fix the LBM at the maximum value, for patients whose heights are 160 and
190 cm.
Conflict of Interest:
None declared
