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. 2024 Sep 6;24:316. doi: 10.1186/s12871-024-02701-8

Index of Consciousness monitoring may effectively predict and prevent circulatory stress induced by endotracheal intubation under general anesthesia: a prospective randomized controlled trial

Shan Cao 1,#, Minhui Kan 1,#, Yitong Jia 1, Chunxiu Wang 2, Tianlong Wang 1,✉
PMCID: PMC11378600  PMID: 39243003

Abstract

Background

The primary objective of anesthesiologists during the induction of anaesthesia is to mitigate the operative stress response resulting from endotracheal intubation. In this prospective, randomized controlled trial, our aim was to assess the feasibility and efficacy of employing Index of Consciousness (IoC, IoC1 and IoC2) monitoring in predicting and mitigating circulatory stress induced by endotracheal intubation for laparoscopic cholecystectomy patients under general anesthesia (GA).

Methods

We enrolled one hundred and twenty patients scheduled for laparoscopic cholecystectomy under GA and randomly allocated them to two groups: IoC monitoring guidance (Group T, n = 60) and bispectral index (BIS) monitoring guidance (Group C, n = 60). The primary endpoints included the heart rate (HR) and mean arterial pressure (MAP) of the patients, as well as the rate of change (ROC) at specific time points during the endotracheal intubation period. Secondary outcomes encompassed the systemic vascular resistance index (SVRI), cardiac output index (CI), stroke volume index (SVI), ROC at specific time points, the incidence of adverse events (AEs), and the induction dosage of remifentanil and propofol during the endotracheal intubation period in both groups.

Results

The mean (SD) HR at 1 min after intubation under IoC monitoring guidance was significantly lower than that under BIS monitoring guidance (76 (16) beats/min vs. 82 (16) beats/min, P = 0.049, respectively). Similarly, the mean (SD) MAP at 1 min after intubation under IoC monitoring guidance was lower than that under BIS monitoring guidance (90 (20) mmHg vs. 98 (19) mmHg, P = 0.031, respectively). At each time point from 1 to 5 min after intubation, the number of cases with HR ROC of less than 10% in Group T was significantly higher than in Group C (P < 0.05). Furthermore, between 1 and 3 min and at 5 min post-intubation, the number of cases with HR ROC between 20 to 30% or 40% in Group T was significantly lower than that in Group C (P < 0.05). At 1 min post-intubation, the number of cases with MAP ROC of less than 10% in Group T was significantly higher than that in Group C (P < 0.05), and the number of cases with MAP ROC between 10 to 20% in Group T was significantly lower than that in Group C (P < 0.01). Patients in Group T exhibited superior hemodynamic stability during the peri-endotracheal intubation period compared to those in Group C. There were no significant differences in the frequencies of AEs between the two groups (P > 0.05).

Conclusion

This promising monitoring technique has the potential to predict the circulatory stress response, thereby reducing the incidence of adverse reactions during the peri-endotracheal intubation period. This technology holds promise for optimizing anesthesia management.

Trail registration

 Chinese Clinical Trail Registry Identifier: ChiCTR2300070237 (20/04/2022).

Keywords: Index of Consciousness, Bispectral index, Endotracheal intubation, Stress response

Background

Both endotracheal intubation and surgical procedures can elicit a stress response due to sympathetic nervous system stimulation during general anesthesia (GA). Research indicates that this activation of sympathetic nervous system is associated with a significant elevation in catecholamine levels, including epinephrine, norepinephrine, and dopamine, resulting in increased blood glucose, blood lactate, and cortisol levels. The magnitude of this response correlates with the intensity of the stimulus [1]. Prior investigations have revealed that endotracheal intubation is linked to substantial hemodynamic fluctuations induced by sympathetic stimulation, leading to rapid increases in heart rate and blood pressure. These changes can elevate myocardial oxygen consumption [2, 3]. The resulting imbalance between myocardial oxygen supply and demand can exacerbate myocardial ischemia, hypoxia events, increase the incidence of acute heart failure and arrhythmias, prolong the postoperative recovery period, and even contribute to perioperative mortality [4]. Additionally, it has been reported that perioperative stressors can cause enduring alterations in cerebral structure and function, associated with postoperative chronic pain, posttraumatic stress disorder, and learning abnormalities [5]. Therefore, vigilant monitoring of the clinical response to noxious stimuli and prompt adjustment of anesthetic drug dosages to attenuate the stress response induced by endotracheal intubation is paramount for anaesthesiologists. Effective anaesthesia depth monitoring aids in providing precise guidance to anaesthesiologists for stress response inhibition during tracheal intubation, thereby maintaining intraoperative hemodynamic stability, reducing narcotic drug requirements, shortening postoperative recovery times, and decreasing the incidence of perioperative adverse events (AEs) [6]. In recent years, the Index of Consciousness (IoC) monitoring has emerged as a tool for assessing intraoperative consciousness levels. IoC is an innovative index derived from a combination of subparameters extracted from EEG spectra and symbolic dynamics using a fuzzy inference system. Previous studies have shown that IoC not only quantifies sedation depth objectively but also reflects the analgesic depth in patients [7]. Furthermore, IoC places emphasis on identifying the critical point of a patient's loss of consciousness during anaesthesia induction, which aids in tailoring patient management accordingly [8]. Currently, IoC monitoring has been successfully employed in intraoperative monitoring for procedures such as ultrasonographic endoscopy, gastroscopic polypectomy, laparoscopic radical resection of colorectal cancer, modified radical mastectomy, laparoscopic hysterectomy, and laparoscopic urological surgery. It has proven to be a reliable indicator for monitoring anaesthetic depth [9–13].

In this study, IoC was employed to monitor the depth of sedation and analgesia in patients and to guide anaesthetic dosages. The study's objective was to determine whether IoC monitoring is beneficial in mitigating the stress response and maintaining hemodynamic stability during tracheal intubation in laparoscopic cholecystectomy patients under GA. Our aim was to enhance the quality of anaesthesia and optimise anaesthesia management.

Methods

Study design and settings

This study was a prospective, randomized controlled trial with patient blinding. Randomization was achieved using computer-generated lists in a 1:1 ratio. All patients signed informed consent before enrollment and were blinded to their group assignment. Our study obtained approval from the Ethics Committee of Xuanwu Hospital, Capital Medical University (23, 02, 2022, Approval Number: LYS [2022]032), and was registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn/), with registration number ChiCTR2300070237 (Date: 20,04,2022).

Patients

From January 2022 to March 2023, we enrolled 120 patients scheduled to undergo elective laparoscopic cholecystectomy under GA at Xuanwu Hospital, Capital Medical University. Written informed consent was obtained from all individual participants included in the study. Inclusion criteria were as follows: (1) Age between 18 and 60 years; (2) American Society of Anesthesiologists (ASA) class I or II; (3) Total intravenous anaesthesia; (4) No contraindications to the medications used in this study. Exclusion criteria included: (1) Severe hypertension, coronary heart disease, diabetes, or significant organ dysfunction and other chronic medical conditions; (2) Coagulation dysfunction or severe heart, liver, and kidney dysfunction; (3) Cerebrovascular disease or neuropsychiatric disease; (4) Long-term administration of sedative and analgesic drugs; (5) Contraindications to general anaesthesia intubation; (6) Allergies to the drugs used in the study. Elimination criteria were applied for: (1) Changes in anaesthetic medications; (2) Alterations in the surgical procedure; (3) Patients experiencing severe adverse reactions during the operation.

Anesthesia

Patients in both groups were routinely monitored for electrocardiogram (ECG), heart rate (HR), non-invasive blood pressure (NIBP), mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), and LiDCOrapid haemodynamic parameters including systemic vascular resistance index (SVRI), cardiac output index (CI) and stroke volume index (SVI) by the noninvasive LiDCOrapid hemodynamic analyzer (HM 81–01 Hemodynamic Monitor, LiDCO Ltd, London, UK) [14, 15]. The group T received IoC1 and IoC2 monitoring (Angel-6000A Multiparameter Anesthesia Monitor, Shenzhen Weihaokang Medical Technology CO., Ltd, Guangdong, China) and the group C received routine BIS monitoring (BIS VISTA, Covidien llc, Wyoming, USA).

All patients underwent an 8-h fasting period and refrained from drinking for 2 h before their scheduled surgeries. Upon admission to the operating room, a peripheral intravenous line was inserted into the right upper extremity of each patient, and oxygen was administered via a face mask prior to the induction of anaesthesia. In the IoC monitoring group (Group T), patients received an initial dose of 2 mg/kg of propofol, 1 μg/kg of remifentanil [16, 17], and 0.6 mg/kg of rocuronium for induction. Subsequently, the amounts of propofol and remifentanil administered were adjusted gradually based on the IoC1 and IoC2 values. If IoC1 exceeded 60 and persisted for over 1 min, a bolus dose of 0.5 mg/kg of propofol was administered. Similarly, if IoC2 exceeded 50 and persisted for over 1 min, a bolus dose of 0.5 μg/kg of remifentanil was infused. The defined target range for IoC was IoC1 between 40 and 60 and IoC2 between 30 and 50 [18]. Endotracheal intubation was performed immediately following the induction of anaesthesia using a visual laryngoscope. In the BIS monitoring group (Group C), patients were induced with 2 mg/kg of propofol, 1.5 μg/kg of remifentanil [16, 17, 19, 20], and 0.6 mg/kg of rocuronium. Subsequently, the propofol dosage was adjusted gradually based on the BIS values. If the BIS exceeded 60 and persisted for over 1 min, a bolus dose of 0.5 mg/kg of propofol was administered until the BIS values fell within the defined intubation range of 40 to 60 [21]. Endotracheal intubation was then performed using a visual laryngoscope.

Heart rate (HR), mean arterial pressure (MAP), systemic vascular resistance index (SVRI), cardiac output index (CI), and stroke volume index (SVI) were recorded in both groups on the day before surgery, before the induction of anaesthesia, immediately before intubation (T0), immediately after intubation (T1), and at 1 min (T2), 2 min (T3), 3 min (T4), 4 min (T5), and 5 min (T6) after intubation. In Group T, IoC values were recorded during the endotracheal intubation period under GA, while in Group C, BIS values were recorded. The occurrence of AEs during the endotracheal intubation, such as tachycardia, bradycardia, cough, hypertension, and hypotension, was also documented.

Tachycardia was defined as HR exceeding 100 beats per minute, while bradycardia was defined as HR less than 60 beats per minute. Hypertension was defined as systolic pressure equal to or greater than 140 mmHg and/or diastolic pressure equal to or greater than 90 mmHg [22]. Hypotension was defined as a decrease in systolic pressure of more than 20% from the baseline blood pressure [23].

Outcomes

The primary outcomes of this study included HR, MAP of patients, and the rate of change (ROC) at each time point during the peri-endotracheal intubation period. Secondary outcomes included CI, SVI, SVRI, ROC at each time point, frequencies of AEs, and the induction dosages of remifentanil and propofol during the peri-endotracheal intubation period under GA in both groups.

Sample size calculation

Based on the preliminary experimental results regarding the primary outcome, HR, the calculation of the proportion of HR rate change exceeding 30% at the T2 time point was undertaken. Utilizing the sample size calculation formula for comparing two independent sample rates, each group's sample size was determined to be 57 cases, employing PASS 15 version software. Factoring in a 10% failure rate, a total of 125 patients were included in the study.

Statistical analysis

All data were analyzed using SPSS 23.0 (IBM, Armonk, NY, USA). Quantitative data were evaluated for normality and homogeneity of variance and were presented as mean ± standard deviation when they exhibited normal distribution. Comparison of data between the two groups was performed using independent sample T-tests. Data at different time points within the same group were analyzed using one-way ANOVA with repeated measures. Categorical data were expressed using the number of cases or n (%), and comparisons between the two groups were performed using the chi-square test. A P < 0.05 was considered statistically significant.

Results

Among the 125 patients initially assessed for eligibility, five patients were not meet the inclusion criteria. Consequently, the remaining 120 patients were randomly and equally distributed between the two groups (Fig. 1).

Fig. 1.

Fig. 1

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CONSORT diagram of patient recruitment

The baseline characteristics of the patients

The baseline characteristics of the patients are presented in Table 1. There were no significant differences between the two groups in terms of demographic characteristics, hemodynamic indices recorded on the day before surgery, or surgical data (all P > 0.05).

Table 1.

Baseline characteristics of the study patients. Values are mean (SD), number/number

Variables Group C (n = 60) Group T (n = 60) P value
Demographics
 Age, years 44 (10) 44 (11) 0.800
 Height, m 1.66 (0.09) 1.66 (0.15) 0.974
 Weight, kg 69.28 (13.1) 73.23 (13.4) 0.105
 BMI, kg.m−2 25.12 (3.70) 27.63 (12.43) 0.136
 Gender, male/female 23/37 31/29 0.142
 ASA, I/II 34/26 33/27 0.854
Hemodynamic indexes on the day before surgery
 HR, beats.min−1 68 (9) 70 (10) 0.291
 MAP, mmHg 91 (11) 93 (10) 0.241
 SVRI, dyn.s.m2.cm−5 2404 (498) 2417 (558) 0.893
 CI, l.min−1.m−2 3.1 (0.6) 3.2 (0.7) 0.528
 SVI, ml.m−2 44 (7) 43 (7) 0.473
Data related to surgery
 Duration of anesthesia, min 76 (19) 75 (18) 0.734
 Duration of Operation, min 47 (15) 47 (15) 0.605
 Blood loss, ml 10 (4) 9 (4) 0.842
 Infusion volume, ml 620 (159) 636 (173) 0.412
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Abbreviations: BMI Body Mass Index, ASA American Society of Anesthesisologists, HR heart rate, MAP mean arterial pressure, SVRI systemic vascular resistance index, CI cardiac output index, SVI stroke volume index

Hemodynamic indexes at different time points between the two groups

Hemodynamic indices at different time points are detailed in Table 2 and illustrated in Fig. 2. Except for the T2 time point, there were no significant differences in HR and MAP between the two groups at each time point (P > 0.05). At the T2 time point, HR and MAP in Group T were significantly lower than those in Group C (P < 0.05). However, there were no significant differences in SVRI, CI, and SVI between the two groups at different time points during peri-tracheal intubation under GA (P > 0.05).

Table 2.

Hemodynamic indexes at different time points between the two groups. Values are mean (SD)

BI T0 T1 T2 T3 T4 T5 T6
HR, beats.min−1
 Group T (n = 60) 75 (11) 64 (10) 69 (15) 76 (16)# 75 (15) 73 (15) 71 (14) 70 (14)
 Group C (n = 60) 78 (12) 66 (12) 71 (14) 82 (16) 79 (15) 76 (14) 74 (14) 74 (13)
 P value 0.155 0.559 0.354 0.049 0.134 0.167 0.281 0.191
MAP, mmHg
 Group T (n = 60) 103 (13) 81 (16) 85 (19) 90 (20)# 88 (19) 85 (17) 84 (17) 82 (18)
 Group C (n = 60) 102 (15) 87 (17) 91 (17) 98 (19) 93 (18) 89 (18) 87 (17) 87 (17)
 P value 0.859 0.085 0.070 0.031 0.140 0.192 0.279 0.123
SVRI, dyn.s.m2.cm−5
 Group T (n = 60) 2542 (691) 2752 (1338) 2719 (1191) 2703 (1344) 2612 (1275) 2701 (1433) 2673 (1120) 2667 (1273)
 Group C (n = 60) 2573 (675) 2886 (994) 2946 (1859) 2893 (1408) 2800 (1719) 2923 (2339) 2655 (1233) 2580 (898)
 P value 0.808 0.535 0.313 0.451 0.498 0.532 0.934 0.668
CI, l.min−1.m−2
 Group T (n = 60) 3.2 (0.8) 2.5 (0.8) 2.5 (0.9) 2.8 (1.0) 2.8 (1.0) 2.7 (1.0) 2.6 (0.9) 2.6 (0.9)
 Group C (n = 60) 3.3 (1.0) 2.5 (0.8) 2.5 (0.8) 2.8 (1.0) 2.9 (1.0) 2.7 (1.0) 2.7 (1.0) 2.8 (0.9)
 P value 0.499 0.817 0.830 0.654 0.654 0.897 0.546 0.283
SVI, ml.m−2
 Group T (n = 60) 42 (10) 38 (12) 38 (11) 37 (10) 37 (10) 37 (11) 37 (11) 37 (12)
 Group C (n = 60) 42 (9) 37 (10) 36 (10) 37 (10) 37 (11) 36 (11) 37 (12) 38 (11)
 P value 0.800 0.544 0.432 0.866 0.937 0.756 0.913 0.822
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Compared with group C, # P < 0.05

Abbreviation: BI before induction

Fig. 2.

Fig. 2

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Changes in hemodynamic indexex during endotracheal intubation under GA in group T (red line) and Group C (black line). Changes in HR in two groups (A). Changes in MAP in two groups (B). Changes in SVRI in two groups (C). Changes in CI in two groups (D). Changes in SVI in two groups (E). #: Comparisons at the same time point between the two groups. *: Comparisons between T0 and each time point after intubation in the same group. Date were expressed as mean ± SD (n = 60) compared by the independent sample T test and one-way ANOVA with repeated measures. Statistically significant difference from the previous measurement: #P < 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Abbreviations: BI before induction, GA general anesthesia

Figure 2 illustrates the analysis of data at various time points within each group. In comparison to T0, group T displayed increased heart rate (HR) at T2, T3, and T4 (T2: P < 0.001; T3: P < 0.01; T4: P < 0.05). In contrast, group C exhibited an elevated HR from T2 to T6 (T2, T3: P < 0.0001; T4: P < 0.001; T5, T6: P < 0.05) when compared to T0 (Fig. 2A). However, there was no statistically significant difference in mean arterial pressure (MAP) at any time point following intubation in group T (P > 0.05). At the T2 time point, MAP was significantly higher in group C compared to group T (P < 0.05) (Fig. 2B). Regarding cardiac index (CI), group T displayed a significant increase at T2 and T3 (T2, T3: P < 0.01), while group C exhibited a noticeable increase at T2, T3, and T6 (T2, T3: P < 0.01; T6: P < 0.05) when compared to T0 (Fig. 2D). However, there were no statistically significant differences in systemic vascular resistance index (SVRI) and stroke volume index (SVI) at any time point after intubation in either group (Fig. 2C, E). Notably, group T demonstrated a more stable overall trend in changes in each hemodynamic index, while group C displayed significant fluctuations.

Rates of change (ROC) of hemodynamic indexes at each time point between the two groups

Table 3 presents the number of cases with ROC in HR less than 10% at each time point from T2 to T6. In group T, the number of cases with HR ROC less than 10% was significantly higher than in group C at all these time points, with statistical significance (P < 0.05). Additionally, at the T2 time point, group T had significantly fewer cases with HR ROC between 20 and 40% than group C (P < 0.01). At T3, group T had significantly more cases with HR ROC between 10 and 20% compared to group C (P < 0.01). At T3, T4, and T6, group T had significantly fewer cases with HR ROC between 20 and 30% than group C (T3: P < 0.001; T4, T6: P < 0.05). At T2, group T had significantly more cases with MAP ROC less than 10% compared to group C (P < 0.05), while the number of cases with MAP ROC between 10 and 20% was significantly lower in group T than in group C (P < 0.01). At T1, group T had significantly more cases with SVRI ROC between 10 and 20% than group C (P < 0.05), and at T3 and T4, group T had significantly more cases with SVRI ROC less than 10% than group C (P < 0.05). At T5 and T6, group T had significantly fewer cases with CI ROC between 20 and 30% compared to group C (P < 0.05). However, there were no significant differences in SVI values between the two groups at different time points during tracheal intubation under general anaesthesia (P > 0.05).

Table 3.

Rates of change (ROC) of hemodynamic indexes at each time point between the two groups. Values are number (proportion)

Time point Rates of change Group C (n = 60) Group T (n = 60) P value
HR
    T1 ROC < 10% 43 (71.7%) 44 (73.3%) 0.838
10% ≤ ROC < 20% 7 (11.7%) 10 (16.7%) 0.432
20% ≤ ROC < 30% 4 (6.7%) 2 (3.3%) 0.402
ROC ≥ 30% 6 (10.0%) 4 (6.7%) 0.509
    T2 ROC < 10% 11 (18.3%) 25 (41.7%)## 0.005
10% ≤ ROC < 20% 13 (21.7%) 15 (25.0%) 0.666
20% ≤ ROC < 40% 28 (45.8%) 13 (24.6%)## 0.004
ROC ≥ 40% 28 (45.8%) 7 (11.7%) 0.783
    T3 ROC < 10% 14 (23.3%) 26 (37.1%)# 0.020
10% ≤ ROC < 20% 17 (28.3%) 34 (48.6%)## 0.002
20% ≤ ROC < 30% 14 (23.3%) 0 (0.0%)### 0.000
ROC ≥ 30% 15 (25.0%) 10 (14.3%) 0.261
    T4 ROC < 10% 18 (30.0%) 34 (56.7%)## 0.003
10% ≤ ROC < 20% 19 (31.7%) 14 (23.3%) 0.307
20% ≤ ROC < 30% 15 (25.0%) 5 (8.3%)# 0.014
ROC ≥ 30% 8 (13.3%) 7 (11.7%) 0.783
    T5 ROC < 10% 22 (36.7%) 36 (60.0%)# 0.011
10% ≤ ROC < 20% 21 (35.0%) 10 (16.7%)# 0.022
20% ≤ ROC < 30% 11 (18.3%) 8 (13.3%) 0.453
ROC ≥ 30% 6 (10.0%) 6 (10.0%) 1.000
    T6 ROC < 10% 25 (41.7%) 36 (60.0%)# 0.045
10% ≤ ROC < 20% 18 (30.0%) 14 (23.3%) 0.409
20% ≤ ROC < 30% 11 (18.3%) 3 (5.0%)# 0.023
ROC ≥ 30% 6 (10.0%) 7 (11.7%) 0.769
MAP
    T1 ROC < 10% 46 (76.7%) 44 (73.3%) 0.673
10% ≤ ROC < 20% 6 (10.0%) 10 (16.7%) 0.283
20% ≤ ROC < 30% 7 (11.7%) 2 (3.3%) 0.083
ROC ≥ 30% 1 (1.7%) 4 (6.7%) 0.171
    T2 ROC < 10% 27 (45.0%) 39 (65.0%)# 0.028
10% ≤ ROC < 20% 17 (28.3%) 4 (6.7%)## 0.002
20% ≤ ROC < 30% 6 (10.0%) 9 (15.0%) 0.408
ROC ≥ 30% 10 (16.7%) 8 (13.3%) 0.609
    T3 ROC < 10% 37 (61.7%) 38 (63.3%) 0.850
10% ≤ ROC < 20% 14 (23.3%) 11 (18.3%) 0.500
20% ≤ ROC < 30% 2 (3.3%) 4 (6.7%) 0.402
ROC ≥ 30% 7 (11.7%) 7 (11.7%) 1.000
    T4 ROC < 10% 41 (68.3%) 42 (70.0%) 0.843
10% ≤ ROC < 20% 10 (16.7%) 9 (15.0%) 0.803
20% ≤ ROC < 30% 5 (8.3%) 3 (5.0%) 0.464
ROC ≥ 30% 4 (6.7%) 6 (10.0%) 0.509
    T5 ROC < 10% 49 (81.7%) 43 (71.7%) 0.195
10% ≤ ROC < 20% 4 (6.7%) 9 (15.0%) 0.142
20% ≤ ROC < 30% 4 (6.7%) 3 (5.0%) 0.697
ROC ≥ 30% 3 (5.0%) 5 (8.3%) 0.464
    T6 ROC < 10% 49 (81.7%) 46 (76.7%) 0.500
10% ≤ ROC < 20% 10 (10.0%) 8 (13.3%) 0.570
20% ≤ ROC < 30% 2 (3.3%) 3 (5.0%) 0.648
ROC ≥ 30% 3 (5.0%) 3 (5.0%) 1.000
SVRI
    T1 ROC < 0% 36 (60.0%) 32 (53.3%) 0.461
0% ≤ ROC < 10% 19 (31.7%) 18 (30.0%) 0.843
10% ≤ ROC < 20% 0 (0.0%) 6 (10.0%)# 0.012
20% ≤ ROC < 30% 1 (1.7%) 2 (3.3%) 0.559
ROC ≥ 30% 4 (6.7%) 2 (3.3%) 0.402
    T2 ROC < 0% 40 (66.7%) 35 (58.3%) 0.346
0% ≤ ROC < 10% 9 (15.0%) 14 (23.3%) 0.246
10% ≤ ROC < 20% 5 (8.3%) 5 (8.3%) 1.000
20% ≤ ROC < 30% 0 (0.0%) 3 (5.0%) 0.079
ROC ≥ 30% 6 (10.0%) 3 (5.0%) 0.298
    T3 ROC < 0% 46 (76.7%) 39 (65.0%) 0.160
0% ≤ ROC < 10% 3 (5.0%) 12 (20.0%)# 0.013
10% ≤ ROC < 20% 7 (11.7%) 4 (6.7%) 0.343
20% ≤ ROC < 30% 0 (0.0%) 2 (3.3%) 0.154
ROC ≥ 30% 4 (6.7%) 3 (5.0%) 0.697
    T4 ROC < 0% 43 (71.7%) 36 (60.0%) 0.178
0% ≤ ROC < 10% 6 (10.0%) 14 (23.3%)# 0.050
10% ≤ ROC < 20% 4 (6.7%) 4 (6.7%) 1.000
20% ≤ ROC < 30% 4 (6.7%) 3 (5.0%) 0.697
ROC ≥ 30% 3 (5.0%) 3 (5.0%) 1.000
    T5 ROC < 0% 45 (75.0%) 43 (71.7%) 0.680
0% ≤ ROC < 10% 7 (11.7%) 8 (13.3%) 0.783
10% ≤ ROC < 20% 5 (8.3%) 7 (11.7%) 0.543
20% ≤ ROC < 30% 1 (1.7%) 1 (1.7%) 1.000
ROC ≥ 30% 2 (3.3%) 1 (1.7%) 0.559
    T6 ROC < 0% 42 (70.0%) 40 (66.7%) 0.695
0% ≤ ROC < 10% 6 (10.0%) 12 (20.0%) 0.125
10% ≤ ROC < 20% 6 (10.0%) 6 (10.0%) 1.000
20% ≤ ROC < 30% 3 (5.0%) 1 (1.7%) 0.309
ROC ≥ 30% 3 (5.0%) 1 (1.7%) 0.309
CI
    T1 ROC < 0% 15 (25.0%) 15 (25.0%) 1.000
0% ≤ ROC < 10% 35 (58.3%) 30 (50.0%) 0.360
10% ≤ ROC < 20% 3 (5.0%) 7 (11.7%) 0.186
20% ≤ ROC < 30% 1 (1.7%) 4 (6.7%) 0.171
ROC ≥ 30% 6 (10.0%) 4 (6.7%) 0.509
    T2 ROC < 0% 12 (20.0%) 11 (18.3%) 0.817
0% ≤ ROC < 10% 16 (26.7%) 24 (40.0%) 0.121
10% ≤ ROC < 20% 8 (13.3%) 5 (8.3%) 0.378
20% ≤ ROC < 30% 6 (10.0%) 6 (10.0%) 1.000
ROC ≥ 30% 18 (30.0%) 14 (23.3%) 0.409
    T3 ROC < 0% 13 (21.7%) 12 (20.0%) 0.822
0% ≤ ROC < 10% 13 (21.7%) 20 (33.3%) 0.152
10% ≤ ROC < 20% 6 (10.0%) 6 (10.0%) 1.000
20% ≤ ROC < 30% 10 (16.7%) 10 (16.7%) 1.000
ROC ≥ 30% 18 (30.0%) 12 (20.0%) 0.206
    T4 ROC < 0% 18 (30.0%) 15 (25.0%) 0.540
0% ≤ ROC < 10% 13 (21.7%) 19 (31.7%) 0.215
10% ≤ ROC < 20% 8 (13.3%) 8 (13.3%) 1.000
20% ≤ ROC < 30% 8 (13.3%) 8 (13.3%) 1.000
ROC ≥ 30% 13 (21.7%) 8 (13.3%) 0.487
    T5 ROC < 0% 14 (23.3%) 18 (30.0%) 0.409
0% ≤ ROC < 10% 18 (30.0%) 20 (33.3%) 0.695
10% ≤ ROC < 20% 8 (13.3%) 12 (20.0%) 0.327
20% ≤ ROC < 30% 9 (15.0%) 2 (3.3%)# 0.027
ROC ≥ 30% 11 (18.3%) 8 (13.3%) 0.453
    T6 ROC < 0% 13 (21.7%) 16 (26.7%) 0.522
0% ≤ ROC < 10% 18 (30.0%) 24 (40.0%) 0.251
10% ≤ ROC < 20% 7 (11.7%) 9 (15.0%) 0.591
20% ≤ ROC < 30% 9 (15.0%) 2 (3.3%)# 0.027
ROC ≥ 30% 13 (21.7%) 9 (15.0%) 0.215
SVI
    T1 ROC < 0% 26 (43.3%) 28 (46.7%) 0.714
0% ≤ ROC < 10% 28 (46.7%) 24 (40.0%) 0.416
10% ≤ ROC < 20% 3 (5.0%) 4 (6.7%) 0.697
20% ≤ ROC < 30% 2 (3.3%) 3 (5.0%) 0.648
ROC ≥ 30% 1 (1.7%) 1 (1.7%) 1.000
    T2 ROC < 0% 32 (53.3%) 28 (46.7%) 0.465
0% ≤ ROC < 10% 15 (25.0%) 20 (33.3%) 0.315
10% ≤ ROC < 20% 5 (8.3%) 8 (13.3%) 0.378
20% ≤ ROC < 30% 5 (8.3%) 1(1.7%) 0.094
ROC ≥ 30% 3 (5.0%) 3 (5.0%) 1.000
    T3 ROC < 0% 32 (53.3%) 30 (50.0%) 0.715
0% ≤ ROC < 10% 14 (23.3%) 19 (31.7%) 0.307
10% ≤ ROC < 20% 6 (10.0%) 5 (8.3%) 0.752
20% ≤ ROC < 30% 3 (5.0%) 3 (5.0%) 1.000
ROC ≥ 30% 5 (8.3%) 3 (5.0%) 0.464
    T4 ROC < 0% 34 (56.7%) 33 (55.0%) 0.854
0% ≤ ROC < 10% 14 (23.3%) 18 (30.0%) 0.409
10% ≤ ROC < 20% 6 (10.0%) 4 (6.7%) 0.509
20% ≤ ROC < 30% 3 (5.0%) 2 (3.3%) 0.648
ROC ≥ 30% 3 (5.0%) 3 (5.0%) 1.000
    T5 ROC < 0% 31 (51.7%) 33 (55.0%) 0.714
0% ≤ ROC < 10% 14 (23.3%) 16 (26.7%) 0.673
10% ≤ ROC < 20% 7 (11.7%) 6 (10.0%) 0.769
20% ≤ ROC < 30% 5 (8.3%) 3 (5.0%) 0.464
ROC ≥ 30% 3 (5.0%) 2 (3.3%) 0.648
    T6 ROC < 0% 28 (46.7%) 32 (53.3%) 0.465
0% ≤ ROC < 10% 15 (25.0%) 15 (25.0%) 1.000
10% ≤ ROC < 20% 8 (13.3%) 7 (11.7%) 0.783
20% ≤ ROC < 30% 4 (6.7%) 4 (6.7%) 1.000
ROC ≥ 30% 5 (8.3%) 2 (3.3%) 0.243
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Compared with group C, #P < 0.05, ##P < 0.01, ###P < 0.001

Abbreviation: ROC rate of change

Dosage of propofol and remifentanil between the two groups

The dosage of propofol did not exhibit a significant difference between the two groups during the endotracheal intubation period under GA (P > 0.05). However, the dosage of remifentanil was significantly higher in group T compared to group C (P < 0.01) (Table 4).

Table 4.

Comparisons of dosage of propofol and remifentanil between the two groups. Values are mean (SD)

Medicine Group C (n = 60) Group T (n = 60) P value
Propofol, mg 142 (29) 157 (26) 0.129
Remifentanil, μg 105 (20) 137 (45)##  < 0.01
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Compared with group C, ##P < 0.01

Adverse events (AEs) between the two groups

There were no statistically significant differences in the frequencies of AEs during endotracheal intubation, including tachycardia, bradycardia, cough, hypertension, and hypotension, between the two groups (P > 0.05). However, it is noteworthy that the frequencies of tachycardia and hypertension in group C were higher than those in group T (Table 5).

Table 5.

Frequencies of adverse events between the two groups. Values are number (proportion)

Item Group C (n = 60) Group T (n = 60) P value
Tachycardia 10 (16.7%) 7 (11.7%) 0.432
Bradycardia 7 (11.7%) 10 (16.7%) 0.432
Cough 1 (1.7%) 0 (0.0%) 0.315
Hypertension 13 (21.7%) 9 (15.0%) 0.345
Hypotension 5 (8.3%) 7 (11.7%) 0.543
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Electroencephalogram (EEG) parameters values

The heatmap in Fig. 3 depicts the values of EEG parameters during endotracheal intubation in both groups. From T0 to T3, the BIS values in group C largely remained within the predefined range of 40 to 60 suitable for general anaesthesia. However, from T4 to T6, the BIS values in some patients in group C increased, possibly due to propofol metabolism, surpassing the suitable range for general anaesthesia (Fig. 3A). Conversely, at each time point from T0 to T6, the IoC1 values in group T consistently fell within the set range of 40 to 60 suitable for general anaesthesia. Similarly, from T0 to T3, the IoC2 values in group T generally remained within the predefined range of 30 to 50 suitable for general anaesthesia. Yet, from T4 to T6, the IoC2 values in some patients in group T increased, possibly due to remifentanil metabolism, exceeding the suitable range for general anaesthesia (Fig. 3B).

Fig. 3.

Fig. 3

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The heatmap of EEG parameters values during endotracheal intubation in two groups. The heatmap of BIS values (n = 60) at each time point in group C (A). The heatmap of IoC values (n = 60) at each time point in group T (B). The illustration of heatmap (C). Red area: IoC or BIS value was higher than the preset value of general anesthesia; green area: IoC or BIS value was within the set value of general anesthesia (IoC1:40 ~ 60, IoC2:30 ~ 50, BIS: 40 ~ 60); blue area: IoC or BIS value was lower than the set value of general anesthesia. Abbreviations: BI before induction

Discussion

In this single-center randomized clinical trial involving patients undergoing elective laparoscopic cholecystectomy, it was observed that HR and MAP of patients in group T were significantly lower than those in group C at 1 min after intubation. Moreover, the number of cases exhibiting ROCs of HR and MAP less than 10% at each time point after intubation in group T exceeded those in group C. All hemodynamic indices in group T demonstrated better stability compared to group C during the peri-endotracheal intubation period. These findings suggest that IoC offers distinct advantages over traditional anesthesia monitoring methods in assessing patient consciousness levels and guiding the administration of intraoperative anesthetic drugs.

During endotracheal intubation, the use of a laryngoscope blade and endotracheal tube generates significant stimulation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, resulting in hemodynamic fluctuations such as elevated HR and BP. These responses have been linked to perioperative myocardial ischemia, cardiac failure, cerebral hemorrhage, and other adverse events [24–26]. Consequently, the inhibition of the stress response during endotracheal intubation and the maintenance of stable hemodynamics represents the primary objectives of intubation under general anesthesia. To address this challenge effectively, the implementation of a reliable monitoring system capable of promptly recognizing intraoperative stimulation and providing precise guidance for the administration of anesthetic agents to maintain stable hemodynamics is of paramount importance.

In recent years, the quest for optimal strategies in monitoring depth of anesthesia and analgesia has stirred considerable debate and anticipation [27]. Previous studies have confirmed that nociception monitors improve the detection of a shift in the nociception and antinociception balance during anesthesia, guiding perioperative analgesic management which is beneficial to patients’ prognoses [28]. BIS was previously heralded as the most precise tool for monitoring sedation depth during anesthesia. Nevertheless, it has been reported that BIS primarily reflects the sedative impact of substances such as propofol, etomidate, and inhalant anesthetics on the cerebral cortex, with insufficient capacity to monitor the analgesic effect [29]. Furthermore, the accuracy of BIS is susceptible to variations in anesthetic agents and patient age [30, 31]. In contrast, IoC monitoring not only provides an objective assessment of patients' consciousness levels but also captures their response to noxious stimuli, a capability absent in BIS monitoring [7]. IoC relies on a fundamental principle of deriving an index through fuzzy inference, employing a set of spectral parameters and non-linear data extracted from the EEG using symbolic dynamics methodology. These three parameters collectively define IoC1, which in turn serves as the foundation for IoC2, with IoC1 predominantly reflecting the depth of sedation and IoC2 primarily indicating the level of analgesia [32]. Clinical recommendations suggest maintaining IoC1 within the range of 40 to 60 and IoC2 within 30 to 50 for patients under GA [33]. In line with previous research [34, 35], our study demonstrated that the T group achieved greater hemodynamic stability and a lower incidence of tachycardia and hypertension during the peri-endotracheal intubation period.

Our findings unveil the potential of IoC monitoring-guided anesthesia induction medication in effectively mitigating the stress response triggered by endotracheal intubation. This innovative monitoring technique offers the prospect of precise anesthesia management and the implementation of individualized anti-stress measures tailored to different patients. To our knowledge, this marks the first study to evaluate the efficacy of IoC monitoring in attenuating the stress response induced by tracheal intubation while maintaining perioperative hemodynamic stability in patients undergoing elective laparoscopic cholecystectomy under GA. In our investigation, we evaluated the ROC in HR and MAP as indicators of the stress response following tracheal intubation. HR and BP are the most commonly employed and easily measurable hemodynamic parameters in clinical practice, serving as sensitive indicators of the body's indirect response to stress [36]. Our results indicate that patients in group T exhibited significantly lower HR and MAP than those in group C at 1 min after intubation (Table 2). Additionally, the number of cases in group T with an ROC of HR and MAP less than 10% at each time point following intubation exceeded that in group C (Table 3). While statistical differences in HR and MAP between the two groups were observed only at the T2 time point, the overall trend suggests that group T displayed a more stable pattern compared to group C (Fig. 2A, B). This implies that IoC-guided adjustment of intravenous anesthetic dosages during the peri-endotracheal intubation period under GA can lead to superior hemodynamic stability.

Studies have demonstrated a strong correlation between the IoC sedation index (IoC1) and BIS. In our study, there was no significant difference in the dosage of propofol between the two groups (Table 4), consistent with prior research [11]. However, the dosage of remifentanil in group T was notably higher than that in group C (Table 4). Remifentanil, a fast-acting opioid, effectively mitigates the stress response triggered by tracheal intubation and surgical stimulation [37]. It is essential to note that an excessive administration of remifentanil may elevate the risk of arterial hypotension [2]. IoC monitoring offers precise guidance to anesthesiologists, enabling them to objectively adjust narcotic drug dosages, meet individualized analgesic requirements, and minimize the cardiovascular stress response associated with endotracheal intubation.

The patients’ cardiac function parameters including SVR, CO, SV, SVI, CI and SVRI could influence patients’ myocardial contractility as well as the left ventricular end-diastolic volume. And the drastic change of these parameters may be associated with myocardial injury or perioperative cardiac complications [38]. Stress responses prompt the heightened release of catecholamines, leading to peripheral vasoconstriction, increased myocardial contractility, elevated HR, and heightened myocardial oxygen consumption. Consequently, SVR, CO, and SV experience a surge, potentially culminating in adverse outcomes such as myocardial ischemia and heart failure [15, 39, 40]. In our study, no significant disparities were observed in SVRI, CI, and SVI between the two groups at each time point during the peri-endotracheal intubation period under general anesthesia (Tables 2 and 3). At the T2 time point, the HR and MAP of the T group were significantly lower than those of the C group, but there were no significant differences in SVRI, CI, and SVI between the two groups (Table 2). There may be no significant difference because of the small sample size, or SVRI, CI and SVI affected by many factors were not more sensitive than HR and BP in terms of stress response [41–46]. The objects of our study were adult patients with ASA I and II, with high cardiovascular compensative capacity. For elderly patients or patients with circulatory system diseases such as hypertension and coronary heart disease, whether there are significant differences in cardiac function parameters between the two groups needs further study. However, overarching trends indicated that the amplitude of fluctuations in group T was lower than that in group C (Fig. 2C, D and E). This signifies those patients in group T maintained more stable hemodynamics, and medication induction guided by IoC monitoring exhibited superior ability in counteracting sympathetic overactivity, reducing catecholamine production, and attenuating the stress response to endotracheal intubation, as compared to the induction of general anesthesia guided by BIS monitoring.

Several previous studies have demonstrated that IoC monitoring can predict and mitigate negative outcomes related to nociceptive stimuli during GA. Wu et al.'s investigation found that patients undergoing unilateral modified radical mastectomy under IoC guidance experienced reduced AEs compared to the control group [12]. Qi et al.'s study also indicated that IoC monitoring was associated with a decreased incidence of postoperative cognitive dysfunction (POCD) and an accelerated postoperative recovery [13]. Additionally, a double-blind randomized controlled clinical trial reported that multimodal analgesia guided by IoC monitoring could reduce intraoperative opioid administration while maintaining a comparable level of intraoperative analgesia and improving patient prognosis [47]. In our study, there were no statistically significant differences in the frequencies of AEs between the two groups. However, the incidence of tachycardia and hypertension in group T was lower than that in group C (Table 5). This finding further supports that medication guidance based on IoC monitoring can help patients achieve a more appropriate stress response state, maintain stable circulation, and not increase the frequency of AEs during the peri-endotracheal intubation period under general anesthesia. In conclusion, whether IoC monitoring can further reduce the frequencies of AEs requires further investigation through prospective large-sample experiments.

Limitations

The limitation of this study lies in its small sample size, and the absence of biochemical indicators of the stress response, such as cortisol and catecholamines, and only adult patients aged 18–60 without serious systemic disease were included. In addition, studies have shown that different anesthetic agents induce burst suppression in the electroencephalogram (EEG) at very deep levels of general anesthesia [48, 49]. Due to the limited technical equipment, the BIS instrument used in the research did not recorded the burst suppression ratio (BSR) information, so the BSR value was not recorded in both groups. Subsequent studies could expand the sample size, include the elderly paitients over 60 years old, incorporate biochemica, and applied BSR indices to further investigate the impact of IoC-guided medication on the stress response during endotracheal intubation under general anesthesia in all age groups, and provide more comprehensive guidance for anesthesia management.

Conclusions

Compared to the standard administration of anesthesia induction medication based on BIS monitoring, IoC monitoring could maintain more favorable haemodynamic stability and obtain the administration of induction medication to individual patients aged 18–60 undergoing laparoscopic cholecystectomy. Furthermore, this promising monitoring technique has the potential to predict circulatory stress responses and reduce the incidence of adverse events during the peri-endotracheal intubation period, offering valuable prospects for optimizing anesthesia management. Prospective multicenter trials with large sample sizes and extended follow-up periods are essential to further validate the clinical effectiveness of IoC monitoring.

Acknowledgements

The authors thank the anaesthetists and nursing staff of the Xuanwu Hospital, Capital Medical University for their support and cooperation during this study. This study contains work performed by Shan Cao in fulfillment of her M.M. thesis at Capital Medical University, Beijing, China. All data in deidentified form and custom-generated code are available upon reasonable request from the corresponding author.

Abbreviations

IoC

Index of Consciousness

GA

General anesthesia

BIS

Bispectral index

HR

Heart rate

BP

Blood pressure

MAP

Mean arterial pressure

SVRI

Systemic vascular resistance index

CI

Cardiac output index

SVI

Stroke volume index

ROC

Rate of change

AEs

Adverse events

ASA

American Society of Anesthesiologists

BI

Before induction

EEG

Electroencephalogram

BSR

Burst suppression ratio

Authors’ contributions

SC, MK, CW and TW made substantial contributions to conception and design; SC and MK have been involved in acquisition, analysis and interpretation of data; SC, MK and YJ made substantial contributions to manuscript preparation, editing and review; SC, MK and YJ made contributions to English language editing; TW have given final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SC and MK contributed equally to this paper and are co-first authors. TW is responsible as corresponding author. All authors reviewed, edited, and approved the final version for submission.

Funding

This study is based on Post-subsidy funds for National Clinical Research Center, Ministry of Science and Technology of China (Tianlong Wang: 303–01-001–0272-03), and Huizhi Rencai (3-002-04-03 Huizhi).

Availability of data and materials

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Approval was granted by the the Ethics Committee of Xuanwu Hospital, Capital Medical University (23, 02, 2022, Approval Number: LYS [2022]032), and was registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn/), with registration number ChiCTR2300070237 (Date:20,04,2022). This study was performed in line with the principles of the Declaration of Helsinki. Written informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Shan Cao and Minhui Kan contributed equally to this work and share first authorship.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

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