Abstract
Background
To analyze the effects of different anesthesia depths on perioperative heart rate variability and hemodynamics in middle-aged and elderly patients undergoing general anesthesia, and to provide a basis for clinical application.
Methods
A total of 111 patients with gastric cancer who were treated with epidural anesthesia combined with general anesthesia were selected as the study subjects, and the patients were randomly divided into group A, group B and group C. The bispectral index (BIS) was maintained by adjusting the infusion speed of anesthetics, the BIS of group A was maintained at 50 ~ 59, the BIS of group B was maintained at 40 ~ 49, and the BIS of group C was maintained at 30 ~ 39. The high-frequency power (HFP), low-frequency power (LFP), total power (TP), mean arterial pressure (MAP), heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured before anesthesia induction (T1), immediately after intubation (T2), 3 min after intubation (T3), and 6 min after extubation (T4). The cognitive function of the patients was evaluated before and 48 h after surgery.
Results
The HFP, LFP/HFP, TP, HR, DBP and SBP between the three groups at T1 ~ T3 are significantly difference from each other (P < 0.05). There were significant differences in spontaneous breathing recovery time, eye opening time and extubation time among group A, B and C groups, and group B had the lowest spontaneous breathing recovery time, eye opening time and extubation time (P < 0.05). There was no significant difference in the incidence of adverse reactions during anesthesia between the three groups. The cognitive function score of group B was significantly higher than that of group A and group C (P < 0.05).
Conclusions
BIS maintenance of 40 ~ 49 has little effect on perioperative heart rate variability and hemodynamics in middle-aged and elderly patients undergoing general anesthesia, which is helpful for postoperative recovery.
Keywords: Depth of anesthesia, Geriatric general anesthesia surgery, Perioperative, Heart rate variability, Hemodynamics
Introduction
As the global aging population accelerates, the demand for surgery among the elderly is gradually increasing. Surgery is a common medical intervention; however, middle-aged and elderly patients face relatively higher surgical risks due to the gradual decline in physiological functions, the accumulation of various chronic diseases, and the use of medication [1]. Among these, the stability and adaptability of the cardiovascular system have become important considerations in the perioperative management of middle-aged and elderly patients. Instability in cardiovascular function may lead to adverse events during and after surgery, even posing a threat to the patient’s life [2]. General anesthesia is widely employed in surgeries involving middle-aged and elderly patients; however, the depth of anesthesia may have a significant impact on the cardiovascular stability and hemodynamics of middle-aged and elderly patients during the perioperative period [3].
Heart rate variability (HRV) is a measure of the variations in the length of consecutive heart cycles and is suggested to reflect the modulation of heart rate by the autonomic nervous system [4]. It has been shown to be a valuable tool for assessing the autonomic nervous system’s regulation of cardiovascular function. Previous studies have investigated the effects of anesthesia depth on HRV in various patient populations, including middle-aged and elderly patients [5]. However, there is still a lack of comprehensive understanding of the specific effects of different anesthesia depths on HRV and hemodynamics in middle-aged and elderly patients undergoing general anesthesia.
Control of anesthesia depth can regulate physiological indicators such as heart rate and blood pressure, thereby affecting the stability of cardiovascular function [6]. Therefore, in-depth research on the effects of different anesthesia depths on heart rate variability and hemodynamics during the perioperative period in middle-aged and elderly patients can contribute to optimizing anesthesia management strategies and improving the safety and success rates of surgeries in the elderly. Hence, this study aims to select patients undergoing general anesthesia at our hospital as the research subjects, analyze the impact of different anesthesia depths on heart rate variability and hemodynamics during the perioperative period in middle-aged and elderly patients undergoing general anesthesia, and provide a basis for clinical applications.
Data and methods
Inclusion and exclusion criteria
Inclusion criteria: (1) No contraindications for spinal anesthesia or epidural anesthesia. (2) American Society of Anesthesiologists (ASA) classification I-II. (3) Informed and consenting participants for this study. (4) Middle-aged and elderly patients aged 50 years or above.
Exclusion criteria: (1) Individuals with symptoms of depression or related mental disorders. (2) Individuals with allergies to relevant medications. (3) Individuals with a history of alcohol or substance dependence for more than six months. (4) History of abuse or dependence on ketamine. (5) Individuals with abnormal coagulation function, liver, or kidney dysfunction, or those with hypertension or diabetes. (6) Individuals with a failed epidural block.
This study has been approved by the Ethics Committee of the First People’s Hospital of Putian City (No. 2023-028). The clinical trial registration information of the present study is ChiCTR2400088433, approved by the Chinese Clinical Trial Registry (https://www.chictr.org.cn/), Registration Date: Aug 19, 2024.
Randomization and blinding
Patients were randomly assigned to one of the three groups (Group A, Group B, and Group C) using a computer-generated randomization sequence. The allocation was concealed in sealed, opaque envelopes until just prior to the induction of anesthesia. Blinding of the anesthesiologists, data collectors, and patients was not feasible due to the nature of the intervention. However, outcome assessors and data analysts were blinded to group allocation to minimize bias.
Methods
All patients underwent epidural anesthesia combined with general anesthesia. Vital signs were monitored, and the bispectral index (BIS) of brain electrical activity was recorded. Anesthesia induction was initiated with sufentanil (Yichang Renfu Pharmaceutical, H20054171, 1 mL:50 µg), and maintenance was achieved with remifentanil (Yichang Renfu Pharmaceutical, H20030197, 1 mg) and intravenous propofol (Guangdong Jiabo Pharmaceutica, H20133248, 10 mg/mL). Before intubation, BIS was maintained at the following levels: 50–59 for Group A, 40–49 for Group B, and 30–39 for Group C, as per the protocol [7]. Medication was stopped at the end of the surgery, and patients were observed for 30 min after recovering consciousness and spontaneous breathing. Postoperative pain management from the same medical team was provided to the three groups of patients.
Observational indices
This study comprehensively compared heart rate variability among the three groups, including low-frequency power (LFP), high-frequency power (HFP), LFP/HFP ratio, and total power (TP) at various time points: before anesthesia induction (T1), immediately after intubation (T2), 3 min after intubation (T3), and 6 min after extubation (T4). Hemodynamic parameters, including mean arterial pressure (MAP), heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP), were compared at T1, T2, T3, and T4. Additionally, adverse reactions during anesthesia and the recovery period, such as time to spontaneous breathing recovery, time to eye opening, extubation time, nausea and vomiting, hypotension, respiratory depression, and agitation, were detailed and compared between groups. Cognitive function was analyzed using the Mini-Mental State Examination (MMSE) scale 48 h before and after surgery.
Sample size calculation
With α = 0.05 and a power of 90%, the sample size for each group in this study is calculated to be 37 cases using the formula for sample size calculation for multiple mean groups.
Statistical methods
Statistical analysis was performed using SPSS 20.0 software. Count data were expressed as percentages, and measurement data were presented as means ± standard deviations. Chi-square tests were used for intergroup differences in count data, and LSD-t tests and variance analysis were employed for intergroup differences in measurement data. A significance level of P < 0.05 indicated statistical significance.
Results
General information comparison
A total of 111 middle-aged and elderly patients with gastric cancer undergoing partial gastrectomy or subtotal gastrectomy at our hospital were selected as the study subjects and divided into Groups A, B, and C. Patients received individualized administrations of sufentanil, remifentanil, and propofol. The dosages were based on the body weight and individual needs, including: (1) Sufentanil: The patients received a total dose of sufentanil ranging from 50 to 100 µg/kg, depending on their body weight and individual requirements for analgesia. (2) Remifentanil: The patients received a continuous infusion of remifentanil at a rate of 0.1–0.3 µg/kg/min, adjusted based on their hemodynamic parameters and depth of anesthesia. (3) Propofol: The patients received a continuous infusion of propofol at a rate of 5–10 mg/kg/h, adjusted to maintain the desired BIS level.
Group A comprised 37 cases, including 23 males and 14 females, with an age range of 54 to 74 years (67.48 ± 4.19), surgery duration of 132 to 172 min (153.28 ± 8.29), and a body mass index (BMI) of 18 to 26 (21.99 ± 1.32) kg/m2, 17 patients with comorbidities, 17 without comorbidities, 34 with normal cognitive function and 3 with abnormal cognitive function. Group B comprised 37 cases, including 25 males and 12 females, with an age range of 53 to 75 years (67.62 ± 5.32), surgery duration of 130 to 178 min (155.32 ± 12.28), and a BMI of 18 to 27 (22.01 ± 1.7) kg/m2, 16 patients with comorbidities, 18 without comorbidities, 34 with normal cognitive function and 3 with abnormal cognitive function. Group C comprised 37 cases, including 24 males and 13 females, with an age range of 52 to 73 years (66.93 ± 5.25), surgery duration of 131 to 175 min (150.98 ± 12.48), and a BMI of 18 to 26 (22.01 ± 1.29) kg/m2,18 patients with comorbidities, 16 without comorbidities, 35 with normal cognitive function and 2 with abnormal cognitive function. There were no significant differences in the general information among the three groups (P > 0.05), indicating comparability. Details are presented in Table 1.
Table 1.
Comparison of the patient’s general information
| Factors | Group A | Group B | Group C | |
|---|---|---|---|---|
| Sexuality |
Male Female |
23 14 |
25 12 |
24 13 |
| Age (Years) | 67.48 ± 4.19 | 67.62 ± 5.32 | 66.93 ± 5.25 | |
| Time Of Surgery (min) | 153.28 ± 8.29 | 155.32 ± 12.28 | 150.98 ± 12.48 | |
| BMI (kg/m2) | 21.99 ± 1.32 | 22.01 ± 1.70 | 22.01 ± 1.29 | |
| Bispectral Index | 50–59 | 40–49 | 30–39 | |
| Comorbidities |
Yes No |
17 17 |
16 18 |
18 16 |
| Cognitive Function |
Normal Abnormal |
34 3 |
34 3 |
35 2 |
Patient heart rate variability investigation results
There were no statistically significant differences in HFP among the three groups at T1, whereas HFP was significantly differed at T2 to T4 (P < 0.05). There were no significant differences in LFP among the three groups at T1 to T4 (P > 0.05). And the LFP/HFP ratio showed statistically significant differences among the three groups at T2 to T4 (P < 0.05). The TP exhibited no statistically significant differences among the three groups at T1 (P > 0.05), and comparisons between groups at T2 to T4 showed statistically significant differences in TP (P < 0.05). Details are presented in Table 2.
Table 2.
Patient heart rate Variability Investigation results
| Groups | Group A | Group B | Group C | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T1 | T2 | T3 | T4 | T1 | T2 | T3 | T4 | T1 | T2 | T3 | T4 | |
| LFP/ms2 | 1621.03 ± 128.39 | 1761.22 ± 141.28 | 1653.29 ± 137.47 | 1620.37 ± 129.84 | 1713.29 ± 130.92 | 1781.27 ± 128.77 | 1702.19 ± 131.29 | 1653.23 ± 133.20 | 1660.27 ± 127.38 | 1698.98 ± 131.27 | 1654.59 ± 128.57 | 1597.97 ± 131.24 |
| HFP/ms2 | 1133.82 ± 144.38 | 1656.49 ± 172.94a | 1503.48 ± 154.38a | 1468.91 ± 133.29a | 1078.22 ± 143.84 | 1501.28 ± 165.44a | 1321.75 ± 158.48a | 1280.27 ± 154.75a | 1186.85 ± 149.38 | 1935.48 ± 132.18a | 1745.31 ± 129.47a | 1564.05 ± 130.19a |
| LFP/HFP |
1.43± 0.21 |
1.06± 0.19a |
1.10± 0.18a |
1.10± 0.22a |
1.59± 0.18 |
1.19± 0.17a |
1.29± 0.20a |
1.29± 0.21a |
1.40± 0.19 |
0.88± 0.20a |
0.95± 0.19a |
1.02± 0.28a |
| TP/ms2 | 2754.83 ± 231.28 | 3421.28 ± 199.47a | 3148.57 ± 201.36a | 3084.93 ± 217.84a | 2793.18 ± 223.18 | 3279.84 ± 198.38a | 3015.48 ± 204.58a | 2931.28 ± 209.98a | 2799.79 ± 198.33 | 3128.36 ± 214.37a | 2890.23 ± 208.47a | 2767.84 ± 221.17a |
Note a: Statistically significant difference compared to T1 within the same group (P < 0.05)
Patient hemodynamic investigation results
The results of this study revealed statistically significant differences in heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) among the three groups compared to T1 (P < 0.05). Additionally, comparisons between groups at the same time points (T2 to T4) showed statistically significant differences in HR, DBP, and SBP (P < 0.05). Details are presented in Table 3.
Table 3.
Patient hemodynamic investigation results
| Groups | Group A | Group B | Group C | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T1 | T2 | T3 | T4 | T1 | T2 | T3 | T4 | T1 | T2 | T3 | T4 | |
| HR/time/min | 70.42 ± 5.48 |
122.21± 11.29a |
138.98± 12.01a |
119.37± 13.28a |
69.74 ± 8.48 |
114.38± 9.01a |
126.05± 10.37a |
110.32± 11.22a |
72.38 ± 13.28 |
99.01± 16.47a |
114.32± 17.21a |
102.19± 16.43a |
| DBP/mmHg | 83.51 ± 5.86 |
88.20± 6.92a |
91.53± 7.01a |
95.33± 6.59a |
85.01 ± 9.83 |
90.31± 10.20a |
93.84± 11.32a |
97.38± 12.19a |
85.61 ± 9.87 |
90.97± 10.27a |
95.48± 11.43a |
99.85± 12.10a |
| SBP/mmHg | 114.38 ± 11.47 |
166.85± 12.43a |
150.38± 10.94a |
141.29± 11.32a |
117.05 ± 10.84 |
154.48± 13.28a |
141.28± 12.19a |
129.02± 13.23a |
118.03 ± 9.38 |
140.12± 10.22a |
124.78± 11.21a |
118.92± 9.78a |
Note a: Statistically significant difference compared to T1 within the same group (P < 0.05)
Patient anesthesia safety investigation results
The results of this study revealed significant differences in the time to spontaneous breathing recovery, time to eye opening, and extubation time among Groups A, B, and C. Specifically, Group B had the shortest time for spontaneous breathing recovery, eye opening, and extubation, and these differences were statistically significant (P < 0.05). Details are presented in Table 4.
Table 4.
Patient Anesthesia Safety Investigation results
| Groups | Cases | Time to Spontaneous Breathing Recovery/min | Time to Eye Opening/min | Extubation Time/min |
|---|---|---|---|---|
| Group A | 74 | 8.31 ± 1.02 | 10.31 ± 0.77 | 19.32 ± 0.76 |
| Group B | 74 | 7.68 ± 0.89a | 9.68 ± 0.76a | 18.55 ± 0.81a |
| Group C | 74 | 8.42 ± 1.16 | 10.44 ± 0.89 | 19.29 ± 0.77 |
Note a: Significantly different from Groups A and C (P < 0.05)
Patient adverse reactions during anesthesia investigation results
The results of this study indicated that there were no significant differences in the incidence of adverse reactions during anesthesia among the three groups (P > 0.05). Details are presented in Table 5.
Table 5.
Patient adverse reactions during Anesthesia Investigation results
| Groups | Nausea and Vomiting | Hypotension | Respiratory Depression | Agitation |
|---|---|---|---|---|
| Group A | 2 (5.4%) | 1(2.7%) | 1(2.7%) | 2(5.4%) |
| Group B | 4(10.8%) | 3 (8.1%) | 0 (0%) | 1(2.7%) |
| Group C | 2(5.4%) | 0 (0%) | 1(2.7%) | 1(2.7%) |
Patient cognitive function investigation results
The results of this study indicated that there were no significant differences in cognitive function among the three groups before surgery (P > 0.05). However, after surgery, patients in Group B had significantly higher cognitive function scores compared to Groups A and C, and this difference was statistically significant (P < 0.05). Details are presented in Table 6.
Table 6.
Patient cognitive function investigation results
| Groups | preoperative | postoperative |
|---|---|---|
| Group A | 29.83 ± 1.34 | 26.86 ± 1.14 |
| Group B | 29.78 ± 1.09 | 28.74 ± 1.02a |
| Group C | 29.82 ± 1.21 | 27.91 ± 0.98 |
Note a: Significantly different from Groups A and C (P < 0.05)
Discussion
In the present study, we found that maintaining a lower anesthesia depth (BIS 40–49) in middle-aged and elderly patients undergoing general anesthesia can have positive effects on perioperative heart rate variability and hemodynamics. Significant differences were observed in heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) among the three groups with different BIS at various time points. This has important clinical implications as it provides guidance for anesthesia management. By choosing an appropriate anesthesia depth within this range, healthcare professionals can optimize postoperative recovery and enhance cognitive function in patients. Additionally, the study highlights that patient maintained at this anesthesia depth range exhibit faster spontaneous breathing recovery, shorter eye-opening time, and quicker extubation time, without an increase in the incidence of adverse reactions. In summary, these findings support the clinical practice of maintaining an anesthesia depth of 40–49 to improve patient outcomes, promote faster recovery, and minimize complications during the perioperative period.
With the increasing prevalence of general anesthesia surgeries in middle-aged and elderly patients, the fragility of their physiological state and their distinct responses to anesthesia compared to younger patients make anesthesia management for the elderly a more cautious and individualized process [8]. Previous study highlighted that anesthesia depth is a crucial parameter in the management of general anesthesia, which directly impacts the safety of surgery and the postoperative recovery of patients [9]. Compared to younger patients, the gradual decline in organ functions in middle-aged and elderly patients is characterized by reduced cardiovascular tolerance, decreased organ sensitivity, and slower drug metabolism [10]. This makes middle-aged and elderly patients more susceptible to cardiovascular events and complications such as postoperative cognitive dysfunction during general anesthesia surgeries. Besides, there are significant variability in the tolerance of elderly patients to anesthesia, necessitating more specific research to determine the optimal range of anesthesia depth for them [11]. Thus, exploring the effects of different anesthesia depths during the perioperative period in middle-aged and elderly patients undergoing general anesthesia is needed, with the goal of providing scientific evidence for anesthesia management in the elderly [12] and clinical guidance for selection of appropriate anesthesia depth [13].
Anesthesia depth is usually assessed through monitoring of heart rate, electroencephalogram (BIS index), arterial blood gas analysis, blood pressure, and other indicators [14]. Heart rate variability (HRV) refers to the irregularity of the heartbeat at different time intervals, serving as a crucial indicator for evaluating the function of the autonomic nervous system [15]. HRV reflects the extent of influence from the sympathetic and parasympathetic nervous systems on the heart’s pacemaker, providing valuable information for assessing cardiovascular system function, stress levels, and psychological states during surgery [16]. Due to physiological changes, the HRV of middle-aged and elderly patients may exhibit characteristics different from those of younger patients, and the impact of anesthesia depth on HRV in middle-aged and elderly patients has not been extensively studied [17]. Hemodynamic parameters, such as cardiac output and cardiac index, are important indicators for evaluating the circulatory status of patients. Aging of the cardiovascular system and the decline in organ function in middle-aged and elderly patients may lead to changes in hemodynamic parameters [18]. Therefore, a more in-depth study is needed to understand the specific mechanisms and extent of the influence of anesthesia depth on the hemodynamics of middle-aged and elderly patients [19].
Previous studies have assessed anesthesia depth during osteotomy, but few investigations have compared anesthesia outcomes using these indexes in middle-aged and elderly patients under different Bispectral Index (BIS) levels [20]. Here, we retrospectively analyzed the clinical data from 111 patients with gastric cancer who were treated with epidural anesthesia combined with general anesthesia in the present study. Our results showed that in elderly surgical patients, adjusting the infusion rate of anesthetics to maintain different levels of BIS at different levels (Group A: 50–59, Group B: 40–49, Group C: 30–39) significantly impacted heart rate, diastolic blood pressure, systolic blood pressure, spontaneous breathing recovery time, awakening time, extubation time, and postoperative cognitive function. Within 30 min after surgery, all three groups exhibited statistically significant differences in heart rate and blood pressure, indicating varied effects on the cardiovascular system in the early post-anesthesia period. Furthermore, at postoperative observation points (T1 ~ T3), statistically significant differences in heart rate, diastolic blood pressure, and systolic blood pressure were observed among the groups, suggesting prolonged influence of BIS levels on the postoperative cardiovascular system. Group B, maintaining a lower BIS level, demonstrated the fastest recovery of spontaneous breathing, consciousness, and extubation time. Additionally, postoperative cognitive function scores for Group B patients were also significantly higher than those for Groups A and C, further emphasizing the impact of BIS levels on postoperative cognitive function. This may be attributed to maintaining a lower BIS level to induce the lighter depth of anesthesia, which induces faster recovery of physiological functions, reduced usages of sedative drugs, alleviation of central nervous system suppression, and consequently lowering the risk of postoperative cognitive dysfunction.
Furthermore, maintaining a lower BIS level in middle-aged and elderly patients undergoing general anesthesia has several beneficial effects. Firstly, it leads to more favorable postoperative heart rate and blood pressure, reducing cardiovascular disruptions and enhancing cardiovascular stability in the early postoperative period. Secondly, it accelerates the recovery of spontaneous breathing, awakening time, and extubation time, facilitating rapid restoration of postoperative physiological function. Additionally, maintaining a lower BIS level helps mitigate suppression of the central nervous system, reducing the risk of postoperative cognitive dysfunction and promoting better maintenance of cognitive function during the postoperative period. In practical clinical work, doctors can flexibly adjust the infusion rate of propofol based on the specific conditions and surgical needs of patients to achieve a more personalized anesthesia depth, thereby maximizing the safety of surgery and postoperative recovery [21]. Remifentanil and remifentanil are consistent with the typical characteristics of opioid (e.g.lowering blood pressure and heart rate) to achieve optimal analgesic and safety effects. intravenous propofol pharmacokinetics have the characteristics of rapid elimination and maintain a good correlation with blood concentration changes [22]. Moreover, for middle-aged and elderly patients, especially those with potential cognitive risks, maintaining a lower BIS level may be a more cautious and effective choice, helping to reduce the risk of postoperative cognitive dysfunction.
It is important to note that this study has some limitations. Firstly, the sample size was relatively small, which may limit the generalizability of the findings. Secondly, the study did not investigate long-term outcomes, such as postoperative complications or long-term cognitive function. Future research should address these limitations and explore the long-term effects of different anesthesia depths on middle-aged and elderly patients.
In conclusion, maintaining a lower anesthesia depth (BIS 40–49) in middle-aged and elderly patients undergoing general anesthesia can have positive effects on perioperative heart rate variability and hemodynamics. This approach may lead to better cardiovascular stability, faster recovery of physiological functions, and improved cognitive function in the postoperative period. Choosing the right anesthesia depth ensures the safe conduct of surgery, reduces the perception of pain during the operation, shortens the recovery period, and lowers the incidence of postoperative complications. Further research is needed to validate these findings and explore their long-term effects on patient outcomes.
Acknowledgements
Not applicable.
Abbreviations
- ASA
American Society of Anesthesiologists
- BMI
Body Mass Index
- BIS
Bispectral Index
- LFP
Low-frequency Power
- HFP
High-frequency Power
- TP
Total Power
- MAP
Mean Arterial Pressure
- HR
Heart Rate
- DBP
Diastolic Blood Pressure
- SBP
Systolic Blood Pressure
- MMSE
Mini-Mental State Examination
- HRV
Heart Rate Variability
Author contributions
Conception and design of the study: Changbi Zhou, Xiaoping Huang, and Shurong Li; Investigation and methodology: Changbi Zhou, Xiaoping Huang, Zhifang Zhuo, Qinghua Wu, Minjian Liu, and Shurong Li; acquisition and analysis of data: Changbi Zhou, Xiaoping Huang, and Shurong Li; drafting the manuscript: Changbi Zhou; supervision of the study and reviewing the manuscript: Shurong Li.
Funding
The present study was not supported by any fundings.
Data availability
The data involved in the present study can be provided under reasonable request.
Declarations
Ethics approval and consent to participate
Protocol of the present study was approved by the Ethic Committee of The First Hospital of Putian City (No. 2023-028). Participate consent was obtained from all participants. Informed consent was obtained from all subjects.
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.
Changbi Zhou and Xiaoping Huang contributed equally to this work.
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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 data involved in the present study can be provided under reasonable request.