Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil

被引:36
作者
Bouillon, T
Schmidt, C
Garstka, G
Heimbach, D
Stafforst, D
Schwilden, H
Hoeft, A
机构
[1] Univ Bonn, Dept Anesthesia & Intens Care Med, D-5300 Bonn, Germany
[2] Univ Bonn, Dept Urol, D-5300 Bonn, Germany
[3] Univ Gottingen, Dept Anesthesia & Crit Care Med, D-3400 Gottingen, Germany
[4] Univ Erlangen Nurnberg, Dept Anesthesia & Crit Care Med, D-8520 Erlangen, Germany
关键词
indirect response model; opioids; respiratory depression;
D O I
10.1097/00000542-199907000-00023
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Background: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. Methods: After institutional approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 mu g . kg(-1). min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2] = 0.5) over a tightly fitting continuous positive airway pressure mask The infusion was discontinued when a cumulative dose of 70 mu g/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PECO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred. During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (Pa-CO2). A mamillary tno-compartment model was fitted to the pharmacokinetic data. The Pa-CO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing Pa-CO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. Results: The indirect response model adequately described the time course of the Pa-CO2. The following pharmacodynamic parameters were estimated (population means and Interindividual variability): EC50, 60.3 mu g/l (32%); the elimination rate constant of carbon dioxide (K-cl), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4 (28%) (fixed according to literature values). Simulations revealed the pronounced role of Pa-CO2 in maintaining alveolar ventilation in the presence of opioid. Conclusions: The model described the data for the entire opioid-Pa-CO2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.
引用
收藏
页码:144 / 155
页数:12
相关论文
共 35 条
[1]   PLASMA-CONCENTRATIONS OF ALFENTANIL REQUIRED TO SUPPLEMENT NITROUS-OXIDE ANESTHESIA FOR GENERAL-SURGERY [J].
AUSEMS, ME ;
HUG, CC ;
STANSKI, DR ;
BURM, AGL .
ANESTHESIOLOGY, 1986, 65 (04) :362-373
[2]  
BEAL SL, 1992, NONMEM USERS GUIDES
[3]   THE EFFECT OF DRUGS ON THE RESPIRATORY RESPONSE TO CARBON DIOXIDE [J].
BELLVILLE, JW ;
SEED, JC .
ANESTHESIOLOGY, 1960, 21 (06) :727-741
[4]   A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect [J].
Billard, V ;
Gambus, PL ;
Chamoun, N ;
Stanski, DR ;
Shafer, SL .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1997, 61 (01) :45-58
[5]   BLOOD-GAS ANALYSIS - EFFECT OF AIR BUBBLES IN SYRINGE AND DELAY IN ESTIMATION [J].
BISWAS, CK ;
RAMOS, JM ;
AGROYANNIS, B ;
KERR, DNS .
BRITISH MEDICAL JOURNAL, 1982, 284 (6320) :923-927
[6]  
Borgbjerg FM, 1996, PAIN, V64, P123, DOI 10.1016/0304-3959(95)00088-7
[7]   THE STEADY-STATE AND REBREATHING METHODS COMPARED DURING MORPHINE ADMINISTRATION IN HUMANS [J].
BOURKE, DL ;
WARLEY, A .
JOURNAL OF PHYSIOLOGY-LONDON, 1989, 419 :509-517
[8]   Sex-related differences in the influence of morphine on ventilatory control in humans [J].
Dahan, A ;
Sarton, E ;
Teppema, L ;
Olievier, C .
ANESTHESIOLOGY, 1998, 88 (04) :903-913
[9]   COMPARISON OF 4 BASIC MODELS OF INDIRECT PHARMACODYNAMIC RESPONSES [J].
DAYNEKA, NL ;
GARG, V ;
JUSKO, WJ .
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1993, 21 (04) :457-478
[10]   RESPIRATORY RESPONSES INDUCED BY THE ACTIVATION OF SOMATIC NOCICEPTIVE AFFERENTS IN HUMANS [J].
DURANTI, R ;
PANTALEO, T ;
BELLINI, F ;
BONGIANNI, F ;
SCANO, G .
JOURNAL OF APPLIED PHYSIOLOGY, 1991, 71 (06) :2440-2448