Response Surface Modeling of Propofol-Remifentanil Interaction on Ventilatory Control and Bispectral Index

DJF Nieuwenhuijs, E Olofsen, DS Ward, FHM Engbers, J Vuyk, RR Romberg, LJ Teppema, EY Sarton, and A Dahan.

Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Intravenous anesthetics and opioids are frequently combined for monitored anesthesia care. Respiratory depression is a serious side effect of both anesthetics and opioids. Therefore we quantified the nature of the interaction (additive versus synergistic) of the combination of remifentanil and propofol on ventilatory control and bispectral index of the EEG (BIS).

Methods: The effect of steady state concentrations of remifentanil and propofol, given separately and in combination, was assessed in 22 healthy male volunteers. After measurement of resting ventilation, the ventilatory response to steady-state hypercapnia was assessed. The ranges of target blood concentrations of remifentanil and propofol were 0 - 3.5 ng/ml for remifentanil and 0-2 mg/ml for propofol. In each subject at least one control, remifentanil alone, propofol alone and propofol-remifentanil combined measurement were obtained (i.e. at least 4 measurements per subject). The nature of interaction was assessed by response surface modeling¹ using the pharmacodynamic model:

E(C_r,C_p) = E₀ ^. [1- {(C_r ^. (l_r)^1/g + C_p ^. (l_p)^1/g )^g } ^. I(Q) ]

where E₀ is the baseline value, C_r and C_p are the concentrations of remifentanil and propofol respectively and l denotes the degree of depression of the respective drug at a concentration halfway its range in the design (in our case 1 ng/ml and 1 mg/ml). We opted to use the factors l, instead of using C₅₀`s, because these cannot be well estimated as they typically lie well above the applied concentration ranges. g is a nonlinearity parameter and I(Q) is a smooth function (spline) of Q which equals C_r /( C_r + C_p). I(Q) is characterized by parameters I_max and Q_max denoting the maximum value of the interaction and the value of Q at which I(Q_max) = I_max respectively. The population model parameters for resting ventilation (Vi), resting end-tidal PCO₂ (P_ETCO₂), ventilation at a fixed end-tidal PCO₂ of 55 mmHg (V55) and BIS were estimated by NONMEM using a population approach. The Akaike criterion was used to determine significance of nonlinearity (g¹1) and synergism (I_max>1). Values are population estimate ± SE.

Results: A total of 94 responses were obtained at different drug combinations. The ranges of the measured arterial remifentanil and propofol concentrations were 0-2 ng/ml and 0-2.6 mg/ml, respectively. Table 1 gives the result of the NONMEM analysis. Synergistic interactions were found for all parameters, except for the BIS, where we found an inert interaction.

Conclusions: Our results are clinically important as they show that at the relatively low doses at which remifentanil and propofol exhibit only additive interactions with respect to suppression of somatic and autonomic responses to noxious stimulation and stress,² the interaction on ventilatilatory depression is synergistic. Note however, that our subjects were without pain and stress. Extrapolation of our data to patients in pain should therefore be done with care. Our data are relevant to patients on remifentanil and propofol given a regional block to undergo their surgery.

REFERENCES:

1. Dahan et al. Anesthesiology 2000 94: 982-91. 2. Mertens. PhD thesis 2002, Leiden University, Leiden.

	Vi L/min	V55 L/min	PETCO2 mmHg	BIS
Baseline value	9.4 ± 0.3	31.4 ± 1.5	41.2 ± 0.1	96.7 ± 0.3
l remifentanil^†	27.7 ± 0.1	57.7 ± 0.1	15.4 ± 0.1	-
l propofol^†	12.6 ± 0.1	44.3 ± 0.1	4.2 ± 0.1	17.8 ± 0.1
Imax (Q)*	1.9 ± 0.2	1.2 ± 0.1	1.3 ± 0.2	-
g**	0.5 ± 0.1	0.4 ± 0.1	0.7 ± 0.1	1
C50 remifentanil^#	3.3	0.7	5.6	-
C50 propofol^$	16.0	1.4	36.9	2.6

Table 1. Estimated population model parameters.

C₅₀`s are extrapolated. Q_max was never significantly different from 0.5.

^†percentage depression at 1ng/ml (remifentanil) and 1mg/ml (propofol),

*>1 denotes synergy, ^**1 denotes nonlinearity, ^#(ng/ml), ^$(mg/ml).