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Titolo:
CONCENTRATION-EFFECT RELATIONSHIP, HEMODY NAMICS AND RESPIRATION FOLLOWING INFUSION OF THE STEROID TYPE HYPNOTIC ELTANOLONE IN HEALTHY-VOLUNTEERS
Autore:
HERING W; IHMSEN H; UHRLAU C; SCHUTTLER J;
Indirizzi:
UNIV ERLANGEN NURNBERG,ANASTHESIOL KLIN,KRANKENHAUSSTR 12 D-91054 ERLANGEN GERMANY
Titolo Testata:
Anasthesist
fascicolo: 12, volume: 45, anno: 1996,
pagine: 1142 - 1150
SICI:
0003-2417(1996)45:12<1142:CRHNAR>2.0.ZU;2-0
Fonte:
ISI
Lingua:
GER
Soggetto:
PREGNANOLONE EMULSION; EEG-ANALYSIS; ANESTHESIA; PROPOFOL; INDUCTION; SURGERY; HUMANS;
Keywords:
ELTANOLONE; PHARMACOKINETICS; CONCENTRATION-EFFECT RELATIONSHIP; HYSTERESIS; HEMODYNAMICS; RESPIRATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
20
Recensione:
Indirizzi per estratti:
Citazione:
W. Hering et al., "CONCENTRATION-EFFECT RELATIONSHIP, HEMODY NAMICS AND RESPIRATION FOLLOWING INFUSION OF THE STEROID TYPE HYPNOTIC ELTANOLONE IN HEALTHY-VOLUNTEERS", Anasthesist, 45(12), 1996, pp. 1142-1150

Abstract

During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic eltanolone(pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of eltanolone after arterialblood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects. Material and methods. Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075mu g ml(-1) min(-1) and with a targeted concentration of 2 mu g ml(-1). During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, untilthey did no longer respond to loud verbal commands, until loss of thecorneal reflex and until the appearance of burst suppression patternsin the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysedwith NON-MEM(R) by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO(2) was analysed every 6 min. Results. The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75+/-0.221 min(-1)), small volumes of distribution (Vc=7.7+/-3.41; Vdss=92+/-221) and relatively short half-lives (t(1/2 alpha)=1.5+/-0.6 min; t(1/2 beta)=27+/-5 min; t(1/2 gamma)=184+/-32 min) (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7+/-1.3 min (mean+/-SD), reaction to verbal contact was lost after 10.4+/-1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9+/-2.8. During recovery, the corneal reflex reappeared 9.4+/-2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2+/-4.3 min and full orientation was regained after 34.7+/-6.2 min. During the second cycle all signs disappeared faster and were regained later (Table 3). The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance (Fig. 2). The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P < 0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about24% (P < 0.05) (Fig. 3 and 4). Oxygen saturation remained stable withvalues between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO(2) analyses was 41 mmHg with a range of 25-60 mmHg. Theonly serious undesirable effect was a seizure during awakening in onevolunteer which coincided with polyspike waves in his raw-EEG recordings (Fig. 5). Conclusions. Eltanolone proved to be a potent hypnotic. With regard to haemodynamics and respiration it caused relatively modest reactions. The quantification of the concentration-effect relationship revealed a time lag between serum concentration and corresponding effect that seems to exceed the effect-hysteresis of thiopentone and propofol. This hysteresis restricts the control of the substance, if the effect has to be changed rapidly, and leads to a delayed recovery. Together with its possible proconvulsant properties and increased reports of urticaria this meanwhile led to the cessation of the clinical investigations with eltanolone.

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Documento generato il 27/10/20 alle ore 04:40:37