Transcript For group S

Performance of the Marsh and Schnider pharmacokinetic-dynamic model to
target a clinical steady-state, when using effect-site controlled titration of
propofol.
Coppens Marc,MD,1 Vereecke Hugo EM,MD,PhD,1 Van Limmen Jurgen GM,MD,1 Schnider Thomas,MD,PhD,2
Struys Michel MRF,MD,PhD3,4
1Department of anesthesia, University Hospital Gent,
3Department of anaesthesia, University Medical
Belgium 2Institute for Anesthesiology, Kantonsspital, St. Gallen, Switzerland
Center Groningen, University of Groningen, Groningen, The Netherlands,
4Ghent University, Belgium
Introduction:
Methods:
For propofol, several pharmacokinetic-dynamic (PKPD) models
are available to control commercialized target controlled
infusion (TCI) pumps.
° Ethical committee approval and patient informed consent
° 40 patients (ASA 1 and 2) randomized in two groups
° Both groups received propofol at 300ml/h
° Meanwhile:
1) CePROP calculated respectively by Marsh (group M)
or Schnider (group S) parameters
2) Name calling every 15 seconds.
We compared both PKPD models in their ability to maintain a
clinical steady-state at the point of “loss of response to name
calling” (LORNC), while titrating propofol according to the
respective calculated effect-site concentrations of propofol
(CePROP). We hypothesize that an accurate PKPD model will
result in a comparable time course for CePROP, the clinical effect
and the cerebral hypnotic drug effect, as reflected by bispectral
index (BIS).
Results:
Table 2 shows demographic data. No significant differences
were found between studygroups. The mean time to LORNC
was 163 (+/-25) for group M and 164 (+/-30) for group S. The
average BIS value at LORNC was 59 (+/-12) for group M, and
59 (+/-14) for group S.
In group M, all patients had ROC at a mean time of 401(+/102) seconds versus only one in group S after 505 sec.
For group M, the mean BIS reached steady state after 6
minutes, but only after ROC had occurred. (Figure 1)
For group S mean BIS reached steady-state after 10
minutes, at levels of anesthesia compared to mean BIS at
LORNC. (Figure 2)
° At “loss of response to name calling” (LORNC)
° the corresponding CePROP = effect-site controlled TCI target
1) using Marsh PKPD model (Group M)
2) using Schnider PKPD model (Group S)
° 20 minutes of studyperiod:
Bispectral Index (BIS-XP®, Aspect Medical systems, USA)
Name calling was repeated every 15 seconds until
1) end of the study period (20minutes)
2) or until “return of consciousness” (ROC).
Statistical analysis:
All data was captured using RUGLoopII Software (Demed, Belgium). Demographic data was studied with
ANOVA or Mann Whitney U test depending on normality testing. For every individual patient, BIS was
averaged per minute. In every group, mean BIS (+/-SD) was calculated for every study minute.(Figure 1
and 2) “Steady state” in cerebral hypnotic drug effect was defined as the lack of significant differences in
mean BIS within the population for several consecutive minutes (anova with Tuckey Kramer correction for
multiple comparisons) (p<0.05)
Table1: PKPD
Model parameters
V1
V2
Marsh
0.228
L/kg
0.463
L/kg
4.27 L
18.9-0.391
x
(age-53)L
Schnider
N
age year (SD)
height cm(SD)
weigt kg (SD)
Gender (M/F)
LBM (SD)
Group M
20
33.05 (7.69)
170.8 (5.66)
62.2 (10.53)
2/18
47.24 (6.53)
Group S
20
33.1 (6.81)
169.3 (7.66)
65.75 (9.20)
3/17
48.50 (5.83)
Discussion : By using the CePROP at LORNC, predicted by
Marsh or Schnider, respectively, as a target for further effectsite controlled TCI, we found that the two models resulted in
very different clinical conditions. In the Marsh group,
patients woke up again as depicted by a fast increasing BIS. In
the Schnider group, patients trended to a deeper anesthetic
level then intended at first, only equalibrating after 10 minutes.
K12
(min-1)
K13
(min-1)
K21
(min-1)
K31
(min-1)
Ke0
(min-1)
Time to
Peak Effect
(min)
2.893
L/kg
0.119
0.112
0.042
0.055
0.0033
0.26
4.5
238 L
0.443+0.0107 x
(weight-77) - 0.0159 x
(LBM-59) + 0.0062 x
(height - 177)
0.302 0.0056 x
(age -53)
0.196
[1.29-0.024x(age-53)]
: [18.9-0.391x(ag-53)]
0.0035
0.456
1.69
Figures:
Figure1:
Mean BIS (+/-SD) over time in Group M
+ CePROP versus Time (*=steady state)
Marsh
10
Ce prop (ug/ml)
Table 2:
Demographics
V3
K10
(min-1)
Figure2:
Mean BIS (+/-SD) over time in Group S
+ CePROP versus Time (*=steady state)
Schnider
10
8
8
Ce prop (ug/ml)
1) The Marsh PKPD model(1) uses weight as a
covariate to adapt propofol titration (Table 1)
2) The Schnider PKPD model(2) uses age, weight,
gender and lean body mass. (Table1)
6
4
2
6
4
2
0
0
0
200
400
600
800
TIME (sec)
1000 1200 1400
0
200
400
600
800
1000 1200 1400
TIME (sec)
The differences in both groups originate from the difference in
the prediction of the plasma-effect site equilibration. During non
steady state conditions at induction, the CePROP as predicted by
Marsh shows a slower increase due to the longer plasma
effect-site equilibration time(=ke0, table 1). As a result, we found
that, compared to Marsh, the time course of CePROP calculated
by Schnider PKPD parameters, is closer to the time course of
the cerebral hypnotic drug effect, as measured by BIS.
Conclusion:
Compared to the marsh model, the time course of CePROP calculated
by the Schnider PKPD model, is closer to the time course of the
cerebral hypnotic drug effect, as measured by BIS.
References:
1.
Marsh B, et al Br J Anaesth 1991:41-8.
2.
Schnider TW, et al Anesthesiology 1997;86:10-23.