The study was a single-center, prospective, physiological trial. This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (KY2023 − 182-03). According to the Declaration of Helsinki, written informed consent was obtained from all patients or their legal representatives. The study was registered at ClinicalTrials.gov (NCT06287138), https://clinicaltrials.gov/study/NCT06287138.

Patients were consecutively recruited from December 2023 to February 2024. The inclusion criteria were critically ill adults with endotracheal intubation who received mechanical ventilation in pressure support mode after surgery under general anesthesia, and the patients were expected to receive sedation for a target of Richmond Agitation and Sedation Scale (RASS) score of −2 to +1. The exclusion criteria included age less than 18 years; body mass index (BMI) less than 18 or greater than 30 kg/m²; pregnancy or lactation; brain stem tumors, myasthenia gravis, or neuromuscular diseases; acute severe neurological disorder or any other condition interfering with RASS assessment; systolic blood pressure (SBP) less than 90 mmHg after appropriate fluid resuscitation; heart rate (HR) less than 50 beats per minute or second- or third-degree atrioventricular block without a pacemaker; contraindications or allergies to any study medications; acute hepatitis or serious hepatic dysfunction (Child-Pugh class C); chronic kidney disease with glomerular filtration rate less than 60 mL/min/1.73m².

During the intervention period, when the patient’s baseline sedation level had reached a RASS score ≥ −2, cipepofol was given and initiated at 0.3 mg/kg/h, which dose was increased by 0.1 mg/kg/h every 30 min, until the maximal dose of 0.8 mg/kg/h, the titration method for cipepofol is described in Figure 2A. The predefined discontinuation criterion of the study was the maximal dose of cipepofol at 0.8 mg/kg/h, RASS score ≤ −4, respiratory rate < 8 breaths/min (20), or pulse oxygen saturation (SpO₂) < 90% (21), whichever comes the first. RASS score (22, 23) was assessed before starting the infusion and 30 min after each increase in cipepofol rate, or more often if a fluctuation in the level of sedation was observed. The reason for discontinuation and the final rates given for each patient were recorded. The protocol stipulated a maximum infusion rate of 0.8 mg/kg/h for cipepofol, if the target RASS score was not reached, the patient would be excluded and sedatives would be given at the discretion of treating physicians.

Remifentanil was infused for analgesia before cipepofol administration, which dose was started at 0.01 μg/kg/min and adjusted to achieve a Critical-care Pain Observation Tool (CPOT) score of 0 to 1 (24). Because enrolled patients in our study suffered from major painful stimuli, including surgical wounds, and stimuli from endotracheal tubes and artificial ventilation. Experimental and clinical studies have suggested that pain influences respiration in some ways (25). To balance the bias caused by pain at baseline, we performed the goal-directed minimization of the analgesics to rule out pain-induced changes in breathing patterns, respiratory drive, and inspiratory effort. In our clinical treatment, we adhered to the eCASH concept that emphasizes early comfort using analgesia, and remifentanil is arguably one of the most commonly used opioids for acute pain in our unit, so we have chosen remifentanil to balance the pain levels at baseline.

Baseline data collection includes demographic data (age, sex, BMI), history of hypertension, information about the surgery (duration of surgery, American Society of Anesthesiologists physical status classification system (ASA) score, emergency surgery or elective surgery), illness severity (baseline Acute Physiology and Chronic Health Evaluation-II (APACHE-II) and Sequential Organ Failure Assessment (SOFA) score on the day of enrollment), Glasgow coma scale (GCS)-(Eye, Verbal, Motor) score after waking up from general anesthesia, time from ICU admission to inclusion, site of tracheal (oral or nasal), ventilator parameter settings [pressure support (PS) levels, positive end-expiratory pressure (PEEP), fraction of inspired oxygenation (FiO₂)], the maintenance infusion rate of remifentanil, baseline arterial blood gas analysis.

During the intervention period, all patients were connected to a ventilator (Dräger Evita Infinity V500, Drägerwerk Verwaltungs AG, Germany) in pressure support mode. PS level was adjusted to obtain a tidal volume (VT) between 6 and 8 mL/kg of ideal body weight and a respiratory rate (RR) lower than 30 breaths/min; PEEP and FiO₂ were adjusted to obtain arterial partial pressure of oxygen (PaO₂) values higher than 90 mmHg. Respiratory parameters include breathing patterns [RR, VT, and minute ventilation (V_min)], respiratory drive [airway occlusion pressure at 100 msec (P_0.1)] (26), and inspiratory effort [pressure muscle index (PMI) (27) and expiratory occlusion pressure (P_occ) (28)] were obtained from the ventilator. Ten consecutive respiratory cycles were averaged to determine RR, TV, and V_min. P_0.1, PMI, and P_occ were evaluated in triplicate at 20-s intervals and the average values were reported, respectively.

Cardiorespiratory parameters including [SBP and diastolic blood pressure (DBP), MAP, HR, SpO₂, and end-tidal carbon dioxide (ETCO₂)] were monitored continuously with Mindray monitor (BeneVision N17). ETCO₂ will be monitored continuously using a sidestream device, and the airway adapter will be placed at the end of the endotracheal tube (DRYLINE^™ II Water Trap, Adult).

Before starting the infusion and 30 ± 5 min after each increase in the infusion rate of cipepofol, respiratory variables, cardiorespiratory variables, and RASS scores were recorded and stored on a dedicated personal computer for further analysis. Adverse events were recorded which included bradycardia (HR < 50 beats/min); hypotension (SBP < 90 mmHg after appropriate intravenous volume replacement); apnea (respiratory rate < 8 breaths/min) or hypoxemia (SpO₂ < 90%).

The primary outcome was the change from baseline in respiratory variables (RR, VT, V_min, P_0.1, PMI, P_occ) at 30 min after continuous infusion of cipepofol at 0.3 mg/kg/h.

The secondary outcomes were: (1) changes in respiratory variables (RR, VT, V_min, P_0.1, PMI, P_occ) at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h; (2) changes in cardiorespiratory variables (SBP, DBP, MAP, HR, SpO₂, EtCO₂) at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h; (3) changes in RASS scores at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h.

Categorical variables were described as numbers (percentages). Continuous variables were described as mean ± standard deviation (SD) and medians with interquartile range [IQR]. For primary outcome analysis, the normal data was analyzed using a paired t-test, and the non-normally distributed data was analyzed with Wilcoxon signed ranks test. For secondary outcome analysis, the changes in respiratory variables, cardiorespiratory variables, and RASS scores at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h were analyzed with a linear mixed effects model, where the dose was considered as the fixed effect, the subject as the random effect and baseline as the covariate.

As patients reached the rate of 0.8 mg/kg/h was small (only 5 patients), we performed a post hoc analysis to analyze the changes in respiratory variables, cardiorespiratory variables, and RASS scores as the infusion rate of cipepofol increasing from 0.3 to 0.7 mg/kg/h, with methods similarly to those secondary outcomes. In addition, we conducted a post hoc analysis to illustrate the changing trend in respiratory variables, cardiorespiratory variables, and RASS scores at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h with data from five patients who reached the rate of 0.8 mg/kg/h. A p-value of <0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics V.26.0 and GraphPad Prism V.9.0 statistical software.

The clinical characteristics of the patients are presented in Table 1. We enrolled 20 patients whose main diagnoses were intracranial tumors and the main causes for ICU admission were intracranial tumor resections. Remifentanil was used to relieve the pain and discomfort at baseline, whose median infusion rate for CPOT 0 to 1 was 0.01 μg/kg/min.

The titration method of cipepofol is described in Figure 2A. An initial infusion rate of cipepofol at 0.3 mg/kg/h was completed in all patients, and all patients achieved the RASS score −2 to +1. Compared with baseline values where no sedation was used, the common features of changes in main respiratory variables evaluated 30 min after infusion of cipepofol at 0.3 mg/kg/h were: a profound initial reduction in tidal volume (median 390.9, IQR [356.6–511.0] vs. 451.6 [393.5–565.9], p = 0.002), a non-significant change in respiratory rate (mean 16.7 ± SD 2.7 vs. 16.2 ± 3.4, p = 0.465), and that the change in minute ventilation was not significant (7.2 ± 1.8 vs. 7.5 ± 1.9, p = 0.154). For respiratory drive and inspiratory effort, there were significant reductions in P_0.1 (1.4 [1.0–2.7] vs. 1.7 [1.0–3.1], p = 0.020), PMI (2.1 [1.3–2.7] vs. 2.1 [1.7–4.3], p = 0.019) and P_occ (7.2 [6.1–10.6] vs. 9.4 [6.4–12.9], p = 0.007) (Table 2; Figure 3).

Due to the obvious heterogeneity in individual sensitivity to cipepofol, there was a significant difference in the final infusion rates reached. The number of patients decreased with increasing cipepofol infusion rates, with oversedation (RASS ≤ −4) being the primary cause for discontinuation. Reasons for discontinuation and final given rates are described in Figure 2B.

The changes in respiratory variables, cardiorespiratory variables, and RASS scores at infusion rates of cipepofol from 0.3 to 0.8 mg/kg/h are shown in Table 3 and Figure 4. VT decreased further from the lower to the higher infusion rate (p = 0.002), with RR increasing significantly as the infusion rate increased (p = 0.001), and V_min did not change significantly (p = 0.430). Respiratory drive and inspiratory effort, measured by P_0.1 (p = 0.172), PMI (p = 0.135), and P_occ (p = 0.100) showed no significant changes with increasing infusion rate. Regarding cardiorespiratory variables, there were no significant changes in SBP (p = 0.273) and DBP (p = 0.067) at higher infusion rates. However, there was a significant but small reduction in MAP (p = 0.036) and an increase in HR (p = 0.019) at higher infusion rates of cipepofol. ETCO₂ (p = 0.050) showed slight changes, and SpO₂ (p = 0.645) fluctuated around baseline values, consistently remaining above 96%. As the cipepofol dose increased, there was a corresponding increase in sedation depth, reflected by a decrease in RASS scores (p < 0.001), despite notable heterogeneity among individuals.

Due to only five patients reaching the final infusion rate of 0.8 mg/kg/h, we conducted a post hoc analysis to analyze changes in respiratory variables, cardiorespiratory variables, and RASS scores as the cipepofol infusion rate increased from 0.3 to 0.7 mg/kg/h (Figure 5). The observed trends in all measured variables were similar to those when data at 0.8 mg/kg/h were included except for HR. In post hoc analysis, there was no significant difference in HR with increasing infusion rate of cipepofol from 0.3–0.7 mg/kg/h (p = 0.179).

Then, the changing trend of respiratory variables, cardiorespiratory variables, and RASS scores for 5 patients who reached the maximum infusion rate of 0.8 mg/kg/h were displayed in Figure 6. The primary characteristics included a decrease in VT, an increase in RR, and no significant change in V_min, P_0.1, PMI, and P_occ as the infusion rate increased. The RASS scores decreased significantly and cardiorespiratory variables did not change significantly.

First, we performed goal-directed minimization of the analgesics with remifentanil, which may confound the effect of cipepofol on respiration. Under similar circumstances, to explore the effects of propofol on respiration, Liu L et al. maintained a continuous infusion of analgesics during the study period (39). Moreover, we titrated the infusion rate of remifentanil for CPOT 0–1. After achieving the goal, the remifentanil infusion rate would not be changed throughout the study period. Nevertheless, we were unable to remove the possible effect of baseline analgesia. Second, the study was single-center with a small sample size, and all enrolled patients were neurological surgery patients, which restricted the generalization of our conclusions to all patients. Lastly, the accuracy of non-invasive respiratory drive and inspiratory drive indices, including P_0.1, PMI, and P_occ may be questioned. Although invasive measures using esophageal pressure are more accurate, they are technically challenging and not widely available. Our findings in this area should be considered hypothesis-generating and warrant further validation.