Hering W, Biburger G, Rügheimer E
Institut für Anaesthesiologie, Universität Erlangen Nürnberg.
Anaesthesist. 1993 Feb;42(2):74-80.
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)
自20世纪40年代以来，多项临床前研究已证实一系列结构相关的孕烷具有麻醉活性，且无明显内分泌作用。其中活性最强的一种是孕烷醇酮（3-α-羟基-5-β-孕烷-20-酮），它是孕酮的一种天然代谢产物。孕烷醇酮不溶于水，这阻碍了其用于临床研究。然而，1987年，瑞典斯德哥尔摩的卡比制药公司推出了一种可用于人体静脉注射的艾司氯胺酮稳定水包油乳剂。方法：在一项开放性研究中，根据迪克森和梅西的“上下法”估算能使50%患者产生麻醉效果的艾司氯胺酮剂量（AD50）。评估了呼吸和心血管效应以及艾司氯胺酮乳剂的可靠性。该研究遵循《赫尔辛基宣言》，并在当地医学伦理审查委员会批准后开始。总共31例美国麻醉医师协会（ASA）风险分级为I级和II级的患者（无生育潜力的男性或女性）在获得书面知情同意后被纳入研究。所有患者在注射艾司氯胺酮前约30分钟肌肉注射5毫克咪达唑仑进行术前用药。艾司氯胺酮乳剂通过静脉注射，通常在手背，注射时间为20秒。在注射艾司氯胺酮时，询问每位患者在注射部位是否感到疼痛或不适。根据先前一项志愿者研究的结果，起始剂量为0.5毫克/千克体重。停止计数和睫毛反射消失被用作麻醉诱导效果的指标。如果在注射开始后120秒内达到这些标准（有反应者），下一位患者的剂量减少15%，如果未达到（无反应者），下一位患者接受相同剂量加15%（最高至(1.01)毫克/千克体重）。从注射开始前1分钟到注射后10分钟连续记录心率和血氧饱和度（Sirecust 404；Nellcor），并在诱导前1分钟以及从艾司氯胺酮注射开始后的1、2、3、5、8和10分钟无创测量血压（Sirecust 888）。如果血氧饱和度降至85%，通过面罩给予氧气，必要时对患者进行通气。记录呼吸紊乱、呼吸暂停时间和持续时间，以及不自主运动或肌张力增加情况。通常在10分钟观察期结束时使用硫喷妥钠、维库溴铵和琥珀酰胆碱进行插管。如果患者未入睡或过早醒来，以相同方式进行插管，从此时起不再评估该研究的药效学参数。结果：AD50为0.33毫克/千克体重，95%置信区间为0.30 - 0.36毫克/千克体重。艾司氯胺酮剂量在0.25至0.5毫克/千克体重之间。以睫毛反射为标准，31例患者中有17例诱导成功，以停止计数为标准则有28例成功。体重超过0.38毫克/千克时，所有患者均达到疗效变量标准，而体重低于0.29毫克/千克时，无患者睫毛反射消失。有反应者组意识丧失（停止计数）的平均时间为注射开始后48 ± 12秒，睫毛反射消失记录在94 ± 13秒后。在无反应者组中，所有患者的睫毛反射持续超过120秒，计数平均在72 ± 23秒后停止。该组中有3例患者计数也未停止（剂量：0.29毫克/千克体重）。在整个观察期内，除1例患者外，所有患者血压均保持稳定。1例患者血压从注射前的160/90毫米汞柱急剧升至注射后3分钟的200/100毫米汞柱。（摘要截断于400字）
