[Induction of anesthesia using the new intravenous steroid anesthetic eltanolone (pregnanolone). Dose determination and pharmacodynamics].
Since the 1940s several preclinical investigations have demonstrated the anaesthetic activity of a series of structurally related pregnanes without notable endocrine action. One of the most active of these is pregnanolone (3-alpha-hydroxy-5-beta-pregnane-20-one), which is a naturally occurring metabolite of progesterone. Pregnanolone is not soluble in water, which has prevented its use for clinical research. In 1987, however, a stable oil-in-water emulsion of eltanolone that could be used for i.v. administration in man was introduced by KABI Pharmacia, Stockholm, Sweden. METHODS. In an open study the dose of eltanolone that induces anaesthesia in 50% of the patients (AD50) was estimated according to the "up and down method" of Dixon and Massey. Respiratory and cardiovascular effects were evaluated as well as the reliability of eltanolone emulsion. The study was conducted in accordance with the Declaration of Helsinki and started after the approval of the local Medical Ethics Review Committee. In all, 31 patients of ASA risk categories I and II (male or female with non child-bearing potential) were included in the study after written informed consent had been obtained. All patients were premedicated with 5 mg midazolam i.m. about 30 min before the injection of eltanolone. Eltanolone emulsion was given i.v., usually on the back of the hand, over 20 s. In connection with the injection of eltanolone every patient was asked whether he or she felt any pain or discomfort at the injection site. As suggested by results in volunteers in a previous study the starting dose was 0.5 mg/kg body weight. Cessation of counting and loss of eyelash reflex were used as indicators of efficacy in the induction of anaesthesia. If these criteria were achieved within 120 s after the start of injection (responder) the dose for the next patient was decreased by 15%, if not (non-responder), the next patient received the same dose plus 15% (up to 1.01 mg/kg body weight). Heart rate and oxygen saturation were recorded continuously (Sirecust 404; Nellcor) from 1 min before to 10 min after the start of injection, and blood pressure was measured noninvasively 1 min before induction and then at 1, 2, 3, 5, 8 and 10 min from the start of the eltanolone injection (Sirecust 888). If oxygen saturation fell to 85% oxygen was applied by way of the face mask and the patients were ventilated if necessary. Respiratory disturbances, time to and duration of apnoea were recorded, as were involuntary movements or increase in muscle tone. Usually intubation was carried out at the end of the 10-min observation period using thiopentone, vecuronium and suxamethonium. If a patient did not fall asleep or awoke prematurely, intubation was performed in the same way and from this point pharmacodynamic parameters were no longer evaluated for the study. RESULTS. The AD50 was 0.33 mg/kg body weight, and the 95% confidence interval, 0.30-0.36 mg/kg body weight. The eltanolone dose varied from 0.25 to 0.5 mg/kg body weight. Induction was successful in 17 (of 31) patients according to the eyelash reflex as criterion and in 28 according to cessation of counting. Above 0.38 mg/kg body weight efficacy variables were achieved in all patients, while below 0.29 mg/kg body weight eyelash reflex was not lost in any patient. The mean time to loss of consciousness (cessation of counting) in the responder group was 48 +/- 12 s after the start of injection and loss of eyelash reflex was recorded after 94 +/- 13 s. In the nonresponder group eyelash reflex persisted over 120 s in all patients and counting stopped on average after 72 +/- 23 s. Three patients in this group also did not stop counting (dose: 0.29 mg/kg body weight). Blood pressure remained stable in all patients but 1 throughout the observation period. In 1 patient there was an alarming rise in blood pressure from 160/90 mmHg before to 200/100 mmHg 3 min after the injection.(ABSTRACT TRUNCATED AT 400 WORDS)
Hering
W
W
Institut für Anaesthesiologie, Universität Erlangen Nürnberg.
Biburger
G
G
Rügheimer
E
E
D000293:Adolescent; D000328:Adult; D000771:Anesthesia, Intravenous; D004655:Emulsions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology*
D004655:Emulsions; D011280:Pregnanolone
Narkoseeinleitung mit dem neuen intravenösen Steroidanästhetikum Eltanolon (Pregnanolon). Dosisfindung und Pharmakodynamik.