Konzentrationswirkungsbeziehung, Hämodynamik und Respiration nach Infusion des Steroidanästhetikums Eltanolon bei gesunden Probanden

Zusammenfassung

In der vorliegenden Untersuchung wurden bei 12 jungen gesunden männlichen Probanden langsam linear ansteigende Blutspiegel mit Hilfe computergesteuerter Perfusorpumpen in jeweils zwei aufeinanderfolgenden Infusionszyklen generiert. Der Endpunkt der Infusion war durch das Auftreten von Burst-Suppression-Mustern im EEG festgelegt. Zur Beurteilung des hypnotischen Effekts wurden die Zeitpunkte erfaßt, zu denen die Probanden einschliefen resp. wieder aufwachten und zu denen die Reaktion auf Ansprache sowie der Kornealreflex ausfiel resp. wiederkam. Parallel wurden regelmäßig arterielle Serumkonzentrationen von Eltanolon bestimmt, der Blutdruck kontinuierlich arteriell gemessen und die Herzfrequenz durchgehend aufgezeichnet. Die Spontanatmung wurde pulsoximetrisch, kapnometrisch als auch klinisch beurteilt. Im Vergleich zur Bolusgabe und venöser Analytik zeigte sich eine höhere Clearance, ein niedrigeres zentrales Verteilungsvolumen, und ein niedrigeres Verteilungsvolumen im Fließgleichgewicht. Klinisch zeigte sich eine gute hypnotische Wirkung, die bei der langsamen Infusionsgeschwindigkeit nach ca. 19 min im ersten und 15 min im zweiten Zyklus zu Burst-Suppression-Mustern im EEG führte. Die Serumkonzentrationen bei Verlust einer Reaktion waren deutlich höher als bei der Wiederkehr. Hierin drückte sich eine Effekthysterese aus, die stärker ausgeprägt zu sein schien als bei anderen bekannten Hypnotika. Die hämodynamischen und respiratorischen Veränderungen fielen vergleichsweise moderat aus. Es kam zu einem dokumentierten Krampfanfall, der zusammen mit anderen Berichten über Krampfanfälle und gehäufte Meldungen von Urtikaria zur Einstellung der klinischen Prüfung von Eltanolon geführt hat.

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 arterial blood 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 0.075 μg ml⁻¹ min⁻¹ and with a targeted concentration of 2 μg 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, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in 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 analysed with NONMEM^® 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 pCO₂ was analysed every 6 min.

Results. The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75±0.22 l min^–1), small volumes of distribution (Vc=7.7±3.4 l; Vdss=92±22 l) and relatively short half-lives (t_1/2α =1.5±0.6 min; t_1/2β=27±5 min; t_1/2γ=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 15 min 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 about 24% (P<0.05) (Fig. 3 and 4). Oxygen saturation remained stable with values between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO₂ analyses was 41 mmHg with a range of 25–60 mmHg. The only serious undesirable effect was a seizure during awakening in one volunteer 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.