For decades, etomidate has stood out among other hypnotic agents for its remarkable hemodynamic stability and minimal respiratory depression [1]. However, etomidate-induced adrenocortical suppression has been proved to increase morbidity and mortality, especially in critically ill patients [2, 3], and these concerns have greatly limited its use. Thus, there is still an urgent clinical need for a general intravenous anesthetic with a beneficial cardiovascular and respiratory profile like etomidate, but with no or minimal adrenocortical suppression.

Methoxyethyl etomidate hydrochloride (ET-26) is one of the novel etomidate analogues designed and synthesized by the Laboratory of Anesthesia & Critical Care Medicine of West China Hospital, Sichuan University. It differs from other etomidate analogues by a modification of the ester side chain instead of replacement to keep its metabolite to etomidate acid, thus minimizing or eliminating its adrenocortical inhibition [4, 5]. The major structural change in the ET-26 molecule compared to etomidate is presented in Fig. 1. Preclinical studies conducted in beagle dogs and rats have demonstrated that ET-26 has very favourable pharmacological advantages, including rapid-onset with short-lasting sedative-hypnotic effects, superior myocardial performance, stable hemodynamic, minimal respiratory depression, and virtually no adrenocortical suppression [4]. In a phase I, single-centre clinical trial on healthy volunteers, ET-26 exhibited an excellent safety profile and tolerability up to a single-administration dose of 2.8 mg/kg. A bolus dose of ET-26 0.8 mg/kg was found to have a comparable sedative-hypnotic effect and slight cortisol inhibition versus etomidate. These superior anesthetic advantages and non-suppression of adrenal function have quickly promoted ET-26 into clinical practice for anesthesia induction in surgical patients. Here, we present our latest clinical research findings on ET-26.

Fig. 1
figure 1

The transformation of ET-26’s molecular structure compared with etomidate and an overview of the design in clinical research phases for testing the efficacy and safety of ET-26

Full size image

A phase II clinical trial was conducted from June 30, 2022 through February 3, 2023. This study was approved by the Clinical Trial Ethics Committee of West China Hospital, Sichuan University and registered on National Medical Products Administration (registration number, CTR20221102) and Chinese Clinical Trial Register (registration number, ChiCTR2400083190).

The phase IIa part of the study was designed as a single-centre, non-randomized, single-blind, positive control, dose-exploration study to find optimal dosage of ET-26 for the safety and effective induction of anesthesia. Patients 18–65 years of age, with a body mass index between 18 and 30 kg/m2, ASA physical status 1–2 and scheduled for an elective surgery (without cardiothoracic and neurosurgical surgery) longer than 0.5 h were included. Etomidate at 0.3 mg/kg was used for the positive control group according to current practice. The optimal dosage was determined on the basis of the success rate of anaesthesia induction following the sequential design and up-and-down method. A total of 34 patients were enrolled with 10 in the 0.3 mg/kg etomidate group, 10 in the 0.8 mg/kg ET-26 group, 10 in the 0.6 mg/kg ET-26 group, 2 in the 0.5 mg/kg ET-26 group and 2 in the 0.4 mg/kg ET-26 group. Loss of consciousness (LOC) maintained for more than four minutes was defined as successful induction. LOC was assessed by both the loss of eyelash reflex and no response to verbal. All patients in the 0.3 mg/kg etomidate group showed LOC within one min after administration and achieved for a 100% induction success rate. For ET-26, 100% induction success was achieved in both the 0.6 mg/kg and 0.8 mg/kg dose groups, but in the 0.4 mg/kg and 0.5 mg/kg dose groups, further exploration was terminated at the second patients because the doses did not produce anesthesia effect that could maintain LOC. Based on the results, we choose 0.8 mg/kg ET-26 as the recommended dosage for preferred depth of anesthesia with a higher proportion of bispectral index values maintained between 40 and 60 during the post-administration observation period and only mild adrenocortical inhibition compared with etomidate. For the purpose of preliminarily confirming the efficacy and safety of ET-26 at a dosage of 0.8 mg/kg, the phase IIb clinical trial was designed as a single-blind, multicentre randomized controlled study. Eighty patients were randomly allocated to either the etomidate group (0.3 mg/kg) or the ET-26 group (0.8 mg/kg). The trial was conducted at five centres in China, including the First Affiliated Hospital of Peking University, the Shenzhen People's Hospital, the First Affiliated Hospital of Zhengzhou University and the Second Xiangya Hospital of Central South University. The successful induction of anesthesia was defined as the achievement of a MOAA/S score ≤ 1 and the completion of tracheal intubation within seven minutes after administration. Both groups achieved a successful induction rate of 100%. Most importantly, ET-26 presented promising advantages in causing only a slight and transitory adrenocortical suppression and a rapid adrenocortical recovery profile within 24 h in the surgical patients. No myoclonus was observed in any patient, as the anesthetic was used in combination with pre-administration of midazolam and sufentanil, as clinical routine. A lower incidence of nausea and vomiting were also observed in the ET-26 group than in the etomidate group. No AEs of grade ≥ 3 or SAEs were reported. To the best of our knowledge, this phase II clinical trial was the first study of etomidate analogues for anesthesia induction in surgical patients, and ET-26 showed highly promising potential.

Based on the preliminary findings from Phase II clinical studies, we concluded that the satisfactory sedative-hypnotic properties and minimal adrenocortical suppression profile of ET-26 warranted further investigation. The phase III clinical trial was designed to involve a larger sample size to verify the efficacy and safety of ET-26 for induction in patients undergoing elective surgery. It was designed as a multicentre, randomized, double-blinded, and double-simulation study, with a total of 270 subjects planned to be enrolled. The study was initiated in October 2023 and being carried out at nine centres in China. The overview of the study design and research process is displayed in Fig. 1. We expect that ET-26 will prove to be a promising, effective and safe etomidate analogue for clinical application.