Assessing the use of the Index of Consciousness (IoC) as a monitoring tool for the sedative effects of ciprofol during general anesthesia induction: a prospective observational study

Abstract

Background

We investigated the consistency and accuracy of the Index of Consciousness (IoC) and the Bispectral Index (BIS) in monitoring the sedative effect of ciprofol during the induction of general anesthesia. There is extensive literature that reports good consistency and correlations between the IoC1 and the BIS in reflecting the sedation levels induced by propofol and sevoflurane but not by ciprofol.

Objective

The aim was to compare the consistency and accuracy of the IoC and BIS in monitoring the sedative effect of ciprofol during the induction of general anesthesia.

Methods

We conducted a prospective observational study. A total of 130 patients aged 18 to 65 years who underwent noncardiac or noncranial elective surgery under general anesthesia were included. All patients were diligently monitored for both the BIS and IoC. IoC1 and BIS values were recorded at eight specific time points (T1 to T8) during the induction of general anesthesia. Bland‒Altman analysis was conducted to assess the consistency between the IoC1 and BIS, including the calculation of mean differences and 95% limits of agreement (LOAs). Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive accuracy of the IoC1 for loss of responsiveness.

Results

The mean difference in the BIS and IoC1 values from T1 to T8 between the two measurement methods was − 0.4308 (95% LOA ranging from − 19.47 to 18.61). There was no significant difference between the IoC1 and BIS (P = 0.6664). The areas under the curve (AUCs) for the IoC1 and BIS in predicting loss of responsiveness were 0.9821 (95% CI 0.9741 to 0.9900) and 0.9855 (95% CI 0.9789 to 0.9922), respectively. The optimal threshold values were 91.5 (sensitivity 94.6%, specificity 96.0%) and 82.5 (sensitivity 99.2%, specificity 93.7%).

Conclusion

The IoC1 is highly consistent with the BIS in the assessment of the sedative effects of ciprofol during general anesthesia induction. The IoC is effective in monitoring the sedative effects of ciprofol when responsiveness disappears. The IoC is an effective monitoring tool for monitoring the sedative effects of ciprofol-induced general anesthesia.

Trial registration

ChiCTR2400086320.

Introduction

Ciprofol, as a novel anesthetic agent, is increasingly used in clinical settings for various procedures, including endoscopic procedures, sedation in the intensive care unit (ICU), and general anesthesia induction (Zhong et al. 2023; Liu et al. 2023; Luo et al. 2022; Wang et al. 2022; Chen et al. 2022). However, current clinical research on ciprofol is still at an early stage. The induction of general anesthesia is a critical phase that is affected by various confounding factors. In addition to the influence of sedative drugs, the level of anesthesia can be influenced by pain caused by laryngoscope placement and tracheal intubation, as well as the analgesic effects induced by opioids. The BIS is an accurate and sensitive objective index used to evaluate the state of consciousness, and it is widely recognized as the “gold standard” for monitoring the level of anesthesia. However, this index can assess only the level of sedation and neglects the level of analgesia. Simultaneous monitoring of sedation and analgesia indicators would enable a more objective assessment of the sedative effect of ciprofol during anesthesia induction while also guiding the application of analgesic drugs. The index of consciousness (IoC) is an emerging indicator that effectively measures both the level of sedation and the intensity of analgesia. While the IoC1 assesses the sedation level, the IoC2 reflects the intensity of the painful stimulus. Previous studies have demonstrated good consistency and correlation between the IoC1 and BIS in reflecting the sedation levels induced by propofol and sevoflurane (Huo et al. 2024; Jensen et al. 2008). Nevertheless, the consistency of the IoC and BIS in monitoring the sedative effects of ciprofol has not been assessed. This is an important marker for assessing the accuracy of the IOC in monitoring the sedative effects of ciprofol. In this study, we hypothesized that IoC could be a good assessment of the sedative effects of ciprofol, and we verified this by assessing the consistency of IoC1 with BIS.

Methods

Research ethics

This was a prospective observational study. The study was approved by the Medical Ethics Committee of the Characteristic Medical Center of the Chinese People’s Armed Police Force (PAP) (approval number: 2023–0017) and was registered in the Chinese Clinical Trial Registry (06/28/2024; Registration number: ChiCTR2400086320). Patients were voluntarily enrolled in this study and provided written informed consent.

Study design

Patients scheduled for elective surgeries requiring general anesthesia between July 2023 and February 2024, including procedures such as thyroidectomy and intestinal, urological, gynecological, and orthopedic surgeries, were included. The inclusion criteria were patients classified as ASA I–II, aged 18 to 65 years, and with a body mass index (BMI) ranging from 18 to 28 kg/m².

The exclusion criteria were the presence of severe cardiovascular or cerebrovascular diseases, challenges with airway management, an allergy or intolerance to ciprofol, soybean allergy, and chronic use of sedatives or antidepressants.

Anesthesia methods

Patients were instructed to fast for 6 h and orally consume liquids 2 h prior to surgery and received a phencyclidine hydrochloride (1 mg) injection 30 min before the surgical procedure. Venous access was established in an upper extremity when the patient arrived in the operating room. Sodium lactate Ringer’s injection was administered at a rate of 10 ml/kg/h. Vital signs, including pulse oxygen saturation (SpO₂), electrocardiogram (ECG) results, invasive arterial pressure, and heart rate (HR), were continuously monitored. The patient’s forehead was cleaned with saline, and once dry, BIS or IoC electrodes were affixed to either the left or right side, with electrode placement randomized by coin tossing. The BIS and IOC monitors were subsequently connected. Prior to anesthesia induction, patients were preoxygenated with a face mask at a flow rate of 5 L/min for 5 min. Sufentanil (0.3 μg/kg) was then slowly intravenously administered. Two minutes later, ciprofol (0.4 mg/kg) was administered intravenously over 30 s. Rocuronium (0.6 mg/kg) was administered intravenously until the patient became unresponsive (which was defined as a Modified Observer Assessment of Alertness/Sedation (MOAA/S) scale score ≤ 1 point), followed by tracheal intubation 90 s later. The respiratory parameters were subsequently adjusted, and the inspired oxygen concentration was set to 60%. Following successful anesthesia induction, a continuous intravenous infusion of propofol and remifentanil was initiated to maintain anesthesia. Patients were followed up on the first and second postoperative days to record the occurrence of intraoperative awareness. (MOAA/S scale: 6 points given for being fully awake and responding normally to normal name calling; 5 points given for being drowsy during induction but responding normally to normal name calling; 4 points given for having a delayed response to normal name calling; 3 points given for having a response to repeated loud name calling; 2 points given for responding only to tapping on the body; 1 point given for having no response to tapping on the body; and 0 points given for having no response to injurious stimuli).

Adverse events management protocol

Hypotension was defined as mean blood pressure (MBP) < 65 mmHg or decreased by ≥ 30% of the baseline MBP (Song et al. 2023), and patients with hypotension were treated with intravenous ephedrine (6 mg) or methoxamine (1 mg). Bradycardia was defined as a heart rate (HR) below 50 beats/min (Zhou et al. 2024), if it lasted over 30 s, was treated with intravenous atropine (0.5 mg).

Observational indices

We recorded IoC1, IoC2, and BIS values for participants at eight specific time points: awake state (T1); after sufentanil injection but before ciprofol injection (T2); at the time of loss of consciousness following ciprofol injection (T3); 90 s after rocuronium injection and before tracheal intubation (T4); and at 1 min (T5), 4 min (T6), 7 min (T7), and 10 min (T8) after tracheal intubation.

Statistical methods

We applied MedCalc statistical software version 23.0.8 to calculate the sample size. The total number of cases required for Bland–Altman analysis was estimated using the data of 30 patients in the preliminary experiment. The significance level was set at α = 0.05, β = 0.05, mean difference between the two methods = 0.13, σ = 7.48, and maximum allowed difference between methods equal to 19.52. Based on these parameters, the required sample size was 114 patients, and 130 patients were included to accommodate potential dropouts.

Statistical analyses were performed via SPSS version 27.0 and GraphPad version 8.0 software. Continuous data with a normal distribution are presented as the means ± standard deviations, with paired t tests employed for within-group comparisons. Bland‒Altman analysis was used to assess consistency between the IoC1 and BIS by determining the mean difference and 95% limits of agreement (LOAs). Receiver operating characteristic (ROC) curves were generated to evaluate the predictive accuracy of the IoC1 for loss of responsiveness. P < 0.05 was considered statistically significant.

Results

A total of 136 patients were initially included, and 6 were excluded from the trial because of poor monitoring signals, resulting in the inclusion of 130 patients, including 59 males and 71 females, with a mean age of 45.09 ± 12.57 years, a mean BMI of 24.07 ± 3.56 kg/m², and an ASA classification of class I (76 patients) or class II (54 patients).

The variations in the IoC1 and BIS values at specific points (T1–T8) are shown in Fig. 1. Most of the data had values greater than 40, and the mean values fluctuated from 40 to 60 at T4–T8 for both indices (Fig. 1A). The changes in IoC2 values at time points T1–T8 are depicted in Fig. 2, with the means values oscillating between 30 and 50 during T4–T8 (Fig. 1B).

Fig. 1

A Comparison of IoC1 and BIS changes at specific time points during T1–T8. ^aP < 0.05 versus T1. ^bP < 0.05 versus T2. ^cP < 0.05 versus T3. ^dP < 0.05 versus T4. ^eP < 0.05 versus T5. ^fP < 0.05 versus T6. B Change of IoC2 at specific time points during T1–T8. ^aP < 0.05 versus T1. ^bP < 0.05 versus T2. ^cP < 0.05 versus T3. ^dP < 0.05 versus T4. ^eP < 0.05 versus T5. ^fP < 0.05 versus T6. The various time points during anesthetic induction are defined as awake state (T1), after sufentanil injection but before ciprofol injection (T2), at the time of loss of responsiveness following ciprofol injection (T3), 90 s after rocuronium injection but before tracheal intubation (T4), at 1 min (T5), 4 min (T6), 7 min (T7), and 10 min (T8) after tracheal intubation

Fig. 2

Bland–Altman analysis of the consistency between BIS and IoC1 during the anesthetic induction with ciprofol

Bland‒Altman analysis revealed that the mean difference in the BIS and IoC1 values was − 0.4308 (95% LOA ranging from − 19.47 to 18.61). There was no significant difference between the two measurements (P = 0.6664) (Fig. 2).

The areas under the curve (AUCs) for the IoC1 and BIS, which indicate the ability to predict loss of responsiveness, were 0.9821 (95% CI 0.9741 to 0.9900) and 0.9855 (95% CI 0.9789 to 0.9922), respectively. The optimal threshold values were 91.5 (sensitivity 94.6%, specificity 96.0%) and 82.5 (sensitivity 99.2%, specificity 93.7%) (Fig. 3). These findings suggest that the IoC1 can be used to assess loss of responsiveness accurately.

Fig. 3

ROC curve analysis for predicting the loss of consciousness using IoC1 and BIS

No patient developed hypotension or bradycardia during the induction of anesthesia. No instances of intraoperative awareness were reported during the postoperative follow-up period.

Discussion

This study demonstrated that the IoC1 is strongly consistent with the BIS in monitoring sedation levels during ciprofol-induced general anesthesia, confirming the effectiveness of the IoC1 in monitoring the sedative effects of ciprofol when responsiveness disappears.

Compared with that in propofol, the active ingredient in ciprofol, HSK3486, an isopropylphenol derivative, has a significantly greater affinity for the GABAA receptor. Ciprofol is 4–5 times stronger than traditional propofol (Liao et al. 2022; Bian et al. 2021; Qin et al. 2017). Compared with propofol, ciprofol has advantages, such as stable hemodynamics and a reduced incidence of injection pain (Chen et al. 2022; Zhu et al. 2023). With the increasing use of ciprofol, a deeper understanding of its role in sedation is needed. Effective monitoring of the sedation level is essential for evaluating the effectiveness of anesthetics and could inform the adjustment of anesthetic drug dosages (Xuan and Xu 2022). There is a range of methods for monitoring anesthesia levels, including the BIS, E-Entropy, Narcotrend, AEP, PSI, and IoC (Scheeren et al. 2019). The BIS, endorsed by the U.S. FDA, has emerged as the “gold standard” due to its prevalence in clinical practice. While the BIS demonstrates efficacy in monitoring ciprofol-induced sedation, the reporting of alternative methods for assessing sedation levels with the use of ciprofol is very rare. A more comprehensive assessment of ciprofol using a wider variety of monitoring methods is essential. The IoC is an emerging monitoring approach that includes the IoC1 and IoC2, which reflect the sedation level and analgesia level, respectively.

The IoC can influence not only the sedation level but also the analgesia level on the basis of its electrophysiologic mechanism during detection. The BIS and IoC monitors are both based on EEGs, and the collected EEG numerical values are converted into indices through different calculation methods. The BIS is based on EEG bispectral analysis that integrates multiple EEG parameters into a single index, and this single index quantifies only sedative effects. During unresponsiveness, the EEG amplitude is positively correlated with injury alertness, and the IoC is based on this principle. EEG signaling components are separated, recorded, and partitioned by symbolic dynamics, and finally, two indices are calculated, the IoC1 and IoC2, which reflect both the sedation level and the analgesia level. This is the greatest advantage of the IoC over the BIS (Melia et al. 2017).

The target range for the IoC1 during deep sedation is 40–60, and that for the IoC2 is 30–50, indicating optimal sedation and analgesia levels (Sadrawi et al. 2015; Wu et al. 2016). Induction of general anesthesia may trigger dramatic hemodynamic fluctuations, thereby increasing the risk of cardiovascular and cerebrovascular accidents (Smilowitz and Berger 2020). Utilizing the IoC1 and IoC2 in tandem facilitates more holistic monitoring of sedation and analgesia during ciprofol induction. Previous studies have confirmed the efficacy of applying the IoC to monitor the IoC1 and IoC2 simultaneously to guide the use of general anesthesia medications. Wang T et al. reported that the integrated application of the IoC1 and IoC2 for elderly patients undergoing laparoscopic surgery could decrease the propofol and opioid dosages and reduce stress responses, which include increased blood glucose and lactic acid levels, thereby reducing complications and accelerating patient recovery (Qi et al. 2021). Another study indicated that in elderly patients undergoing thoracoscopic lobectomy, dual monitoring of the IoC1 and IoC2 can curtail remifentanil and vasoactive drug usage, thereby stabilizing hemodynamics (Ma et al. 2023). Therefore, it is necessary to determine the accuracy of the IoC in monitoring the level of sedation with ciprofol.

The findings of this study indicated significant alterations in both the BIS and IoC1 values at T2 (after sufentanil injection but before ciprofol injection) and T3 (after ciprofol injection when the patient lost consciousness), demonstrating that the IoC1 could track sedation changes in a timely manner. Figure 1A clearly shows that the IoC1 and BIS values fluctuated within 40–60 from T4 to T8, suggesting comparable efficacy of the IoC1 in monitoring sedation levels during ciprofol-induced general anesthesia. The study findings further demonstrate that IoC2 is sensitive to tracking variations in the analgesic response, in conjunction with sedation, across various time points, and the mean values were in the range of 30–50 at t4–t8 time points. This suggests that IoC2 responds to the analgesic levels of ciprofol-induced complex sedation.

To objectively evaluate the consistency between the IoC1 and BIS during ciprofol induction, this study utilized the Bland‒Altman test for statistical analysis. Bland‒Altman analysis graphically represents the agreement between two measurement methods, indicating good consistency when the majority of data points are within the 95% confidence interval and when the maximum difference is deemed clinically acceptable. Bland‒Altman plots revealed that the majority of the data points in this study were within this interval and the maximum difference, which is deemed clinically acceptable, with no significant difference between the two measurements. These findings confirmed the strong consistency between the IoC1 and BIS in monitoring sedation levels during the induction of general anesthesia by ciprofol.

This study assessed the accuracy of the IoC1 in assessing loss of responsiveness by using an ROC curve. The closer the ROC curve is to the upper left corner, the more correct the test is, and the area under the ROC curve (AUC) is between 0.5 and 1. The closer the curve is to 1, the better the effectiveness of the diagnosis and treatment, and an AUC of 0.9 or greater has a high degree of correctness. The results demonstrated that the AUC for the IoC1 and BIS in monitoring at the time of loss of responsiveness exceeded 0.98, indicating high predictive accuracy of the IoC1 for loss of responsiveness.

Previous studies on the IoC1 and BIS have focused on monitoring the consistency of the sedative effects of propofol and sevoflurane. Jensen EW et al. reported a good correlation between the IoC and BIS during ultrasonographic endoscopy with propofol and remifentanil (Jensen et al. 2008). Revuelta M et al. applied both the IoC1 and BIS during sevoflurane induction in patients undergoing cardiac bypass surgery, and the indices performed equally well during the induction phase and were able to satisfactorily predict the level of consciousness of the patients (Revuelta et al. 2008). These findings are similar to the results of this study. Our study confirms the consistency and accuracy of the IoC and BIS in monitoring the sedative effect of ciprofol during the induction of general anesthesia, provides additional monitoring methods for the clinical use of ciprofol, and lays a stronger foundation for better clinical use of ciprofol.

There are still some shortcomings in this study. First, the study was limited to the induction phase of general anesthesia. The accuracy of the IoC for monitoring the maintenance and awakening phases of ciprofol anesthesia has not been studied. Second, the sample size for this study was not very large. These findings need to be confirmed by more studies in the future.

Overall, this study demonstrated that the IoC1 is strongly consistent with the BIS in monitoring sedation levels during ciprofol-induced general anesthesia, confirming the effectiveness of the IoC1 in monitoring the sedative effects of ciprofol when responsiveness disappears. The IoC is an effective tool for monitoring the sedative effects of ciprofol-induced general anesthesia.