With the rapid development of surgical technology, the enhancement of intensive care rescue ability, and the popularization of cardiopulmonary resuscitation technology, the number of craniocerebral injury patients surviving after all-out treatment has increased significantly. DoC refers to various states of loss of consciousness caused by severe brain injuries, such as coma, Vegetative state (VS)/ Unresponsive Wakefulness Syndrome (UWS) and Minimally conscious state (MCS).1–3 VS/UWS refers to a state in which the basic reflexes of the brain stem and the sleep-wake cycle are preserved,4 with spontaneous eye opening or stimulated eye-opening, but with unconscious content.3,5 In contrast to VS/UWS, MCS can exhibit residual sensory and partial conscious retention,6–8 such as pain localization, visual object tracking,6 or target gaze,9 but cannot complete compliance activities. The mutual change of the two states also represents a change in the level of consciousness. At present, the gold standard for clinical evaluation of DoC is the Coma Recovery Scale-Revised (CRS-R),10–12 which includes six aspects of auditory, visual, motor, promotor/verbal function, communication, and arousal level. Due to its reliability, it is currently recommended by the mainstream, especially in the identification of VS/ UWS and MCS.13

In treating patients with DoC, the medical community utilizes a variety of approaches, categorized as non-invasive, invasive, and mechanical therapies. Non-invasive treatments include the use of medications to modulate neurotransmitters and electromagnetic stimulation techniques such as oxygen therapy,14,15 music therapy,15–17 stem cell therapy,18,19 amantadine,20,21 etc., have little therapeutic effect.1,22 Invasive treatments focus on deep brain stimulation (DBS),23 SCS, cortical electrical stimulation,24 vagus nerve electrical stimulation,25,26 etc. SCS is currently the recommended treatment method.27–29 SCS represents a promising neuromodulation technique for the treatment of patients with DoC. In SCS, electrodes are implanted into the epidural space at C2–C4, delivering electrical impulses to stimulate the ascending reticular activating system and regulate the awareness circuit.28 Studies have shown that SCS can directly activate the reticular structure and stimulate the thalamus,30,31 or increase the cerebral blood flow in the injured area through the brain stem pathway, improve the levels of neurotransmitters and neuromodulators, and promote the neuroplasticity of the central nervous system.32 Mechanical therapies involve transcranial-focused ultrasound (FUS), which utilizes ultrasound waves to penetrate the skull and affect brain activity.

At present, the depth of sedation under general anesthesia is usually measured by BIS in clinical practice. BIS is a medical technology utilized to monitor the depth of anesthesia by analyzing electroencephalogram (EEG) signals to assess a patient’s response to hypnotic agents. The BIS monitor integrates multiple EEG descriptors into a single, dimensionless value that ranges from 0 to 100, where 0 denotes the resting state of the EEG (inactive) and 100 indicates a fully awake state. The BIS calculation is based on the statistical processing of the EEG signal, which combines the frequency and power spectra of the EEG, the amount of burst suppression, and the degree of EEG synchronization. As the degree of sedation increases, the in-phase coupling within the frequency of the signal increases, and the extent of this coupling represents a coherent pattern. As the amount of hypnotic drug is increased, distinctive changes in biphasic coherence patterns occur, and these patterns serve as markers of the level of sedation. Maintaining BIS within the range of 40–60 in perioperative period is considered to be a more appropriate depth of anesthesia.33 Too deep or too shallow anesthesia will increase perioperative mortality and intraoperative awareness.34,35 Is BIS monitoring helpful for the treatment of DoC patients undergoing SCS implantation under general anesthesia? There are no relevant studies. The purpose of this study was to investigate the effect of BIS monitoring in the perioperative period on the outcome of resuscitation therapy in patients with DoC.

Methods General Information

103 patients with DoC admitted to the Department of Neurosurgery of Peking University International Hospital were collected from 2019.01 to 2021.12. The patient data was collected from the inpatient information system and anesthesia information system (approved by the Ethics Committee of Peking University International Hospital, Ethics number: 2022-KY-0023-01; International registration code: ChiCTR2300069756). Inclusion criteria: ① Age 18–65 years old; ②No central sedative drugs were used 24 hours before anesthesia; ③ No prior history of brain tumor or family psychosis; ④ Tracheotomy. ⑤Frontal lobe was intact. Exclusion criteria: ① single/multiple organ failure; ② Severe coagulation dysfunction; ③ the circulatory system is not stable; ④metal implants in the brain⑤ Lost follow-up. A total of 83 patients were included in the study, divided into the BIS group (n =45) and the non-BIS group (n =38) according to whether BIS was monitored in the perioperative period. The general data of the two groups are shown in Figure 1. and Table 1.

Table 1 Demographic Characteristics of Patients in Both Groups

Figure 1 Flow Chart.

Methods and Monitoring of Anesthesia

ECG, pulse oxygen saturation (SPO2), invasive arterial blood pressure, end-tidal carbon dioxide (EtCO2), body temperature, and intermittent blood gas analysis. BIS (Covidien. (2014). BIS VISTA, Mansfield, U.S.A) Group: Clean the patient’s facial skin to remove sweat and grease to ensure the conductivity of the electrode pads. Place the specialized BIS monitoring electrode pads on the patient’s forehead, about 5 cm above the root of the nose, in the temple area (between the eye canthus and hairline), and directly above the eyebrow ridge parallel to it. After confirming the position of the electrode pads, press firmly for 5 seconds to enhance contact with the skin. Connect the monitoring device lead, and the routine monitoring interval is 15 seconds (BIS value between 40 and 60 is generally considered an appropriate anesthesia depth). The anesthesia machine is connected to the tracheotomy tube. Propofol 1mg/kg, Sufentanil 0.4μg/kg, and Rocuronium 0.8mg/kg were used for induction under general anesthesia. After induction, the ventilation mode was changed to mechanical ventilation, the respiratory rate was 10~12 times /min, the tidal volume was 8 ~ 10mL/kg, and EtCO2 was maintained between 35 ~ 45mmHg. Anesthetic maintenance: Propofol 2 ~ 3mg/kg·h, Remifentanil 0.1 ~ 0.2ug/kg·min. The depth of anesthesia in the BIS group was maintained between 40–60, and the depth of anesthesia in the non-BIS group was adjusted by the anesthesiologist according to clinical experience. After the operation, the patient was given 200mg of Sugammadex sodium for antagonism. When the patient recovered from spontaneous breathing and inhaled air for more than 10 minutes, the SPO2 > 90% then was transferred to the rehabilitation department for further treatment.

Surgical Methods and CRS-R Scale Evaluation

SCS implantation surgery were performed by the same senior neurosurgeon. In the prone position, the T6-T7 space was identified by X-ray as the puncture point, and the puncture needle was inserted into the skin at an Angle of about 30 degrees. After the tip of the needle reached the epidural space, the stimulation electrode was delivered to the level of the C2 vertebral body with the assistance of an X-ray, the electrical impedance of the electrode was tested, and the electrode lead was fixed after the puncture needle met the requirements. After the operation, the patients was transferred to the rehabilitation department of our hospital for awakening treatment and regular follow-up. All patients’ CRS-R scores were performed by the same neurosurgeon (qualified for CRS-R assessment).

Data Collection and Analysis

Data was collected from the inpatient information system and anesthesia information system of Peking University International Hospital. Data such as gender, age, height, weight, etiology, course of disease, anesthesia time and operation time were collected. CRS-R (preoperative), CRS-R (24h), and CRS-R (3m) scores and improvements in consciousness were collected. Awareness improvement criteria: Patients classified as VS/ UWS at the start of the study had their awareness improvement rise to MCS−, MCS+, or EMCS; patients classified as MCS− at the start of the study had their awareness improvement rise to MCS+ or EMCS at the start of the study. If the clinical diagnosis at the end of treatment did not improve compared to the start of the study, the clinical outcome was classified as invalid, as shown in Table 2.

Table 2 CRS-R Rating Scale

Statistical Processing

SPSS 26.0 statistical software was used for data analysis. The measurement data conforming to normal distribution were expressed as mean ± standard or median (Interquartile Range). Paired T-test or Wilcoxon test was performed. The count data were presented as [example (%)]. Fisher test and Mann–Whitney U-test were used to compare the differences between groups. Multivariate Logistic regression analysis was used, and the improvement of consciousness was included in the multivariate Logistic regression analysis model as the dependent variable. Anesthetic duration time, Propofol, and Remifentanil were included. CRS-R score at three moments: CRS-R(preoperative), CRS-R(24h), CRS-R(3m); Disease event: cause, course of disease and damaged brain area: temporal lobe, parietal lobe, frontal lobe, basal ganglia, thalamus, brainstem, occipital lobe and pontine as independent variables. P < 0.05 was statistically significant.

Results

Comparison of general data between the two groups showed no statistical significance (P > 0.05), as shown in Table 1.

There was no statistical significance in the composition ratio of consciousness level during preoperative, 24h after surgery and 3m after surgery between the two groups (P > 0.05); The CRS-R(3m) of the BIS group was higher than that of the non-BIS group, and the difference was statistically significant (P < 0.05). The improvement of consciousness level 3 months after surgery was better than a preoperative period, and the difference was statistically significant (P < 0.05). The score of CRS-R(3m) was higher than that of CRS-R(preoperative), and the difference was statistically significant (P < 0.05). There was no significant difference between CRS-R(24h) and CRS-R(preoperative) (P > 0.05). See Table 3.

Table 3 Comparison of Preoperative Diagnosis, Outcome, and CRS-R Score Between the Two Groups

Before surgery, there was no statistical significance in CRS-R score in 6 aspects between the two groups (P > 0.05); 24h after surgery, the auditory CRS-R score of the BIS group was higher than that of the non-BIS group, the difference was statistically significant (P < 0.05), and the other aspects were not statistically significant (P > 0.05). 3 months after surgery, there was no statistical significance in CRS-R score in 6 aspects between the two groups (P > 0.05), (Figure 2 A-C)

Figure 2 Comparison of auditory in CRS-R before surgery (A), 24h after surgery (B), and 3 months after surgery (C). As shown in Fig A, there was no statistically significant difference between the two groups in preoperative auditory scores (X2=0.929, P =0.338). Fig B, the auditory score of the two groups 24 hours after surgery was compared. The auditory score of the BIS group was higher than that of the non-BIS group, and the difference was statistically significant (X2=8.787, P =0.004). The comparison of hearing scores 3 months after surgery between the two groups showed no statistical significance (X2=2.078, P =0.153).

Logistic regression analysis of consciousness improvement and multiple factors during operation

Events related to anesthesia: duration of anesthesia, Propofol, Remifentanil; CRS-R score at three moments: CRS-R(preoperative), CRS-R(24h), CRS-R(3m); Events of the disease itself: cause of disease, course of disease and damaged brain area: The temporal lobe, parietal lobe, frontal lobe, basal ganglia, thalamus, brainstem, occipital lobe and Pontus were taken as independent variables, and the improvement of consciousness as dependent variables were included in the multivariate Logistic regression analysis model. Through regression analysis, the thalamus was considered to be an independent influencing factor for the improvement of consciousness, while the other independent variables were not high-risk factors for the improvement of consciousness (P > 0.05), as shown in Table 4.

Table 4 Multivariate Logistic Regression Analysis of Consciousness Improvement

Adverse Outcome

In 83 patients with DoC, we followed up to 3 months after operation. The consciousness of 1 patient in the BIS group decreased from the original MCS− to VS/ UWS; In the BIS group, 2 patients died on the 46th and 69th postoperative days.In the non-BIS group, 2 patients died during SCS stimulation and on the 81st day after surgery, respectively. The causes of death were pulmonary infection and systemic multiple organ failure.

Discussion

It is very difficult for current medical technology to improve the consciousness of DoC patients, and studies have pointed out that SCS plays a certain role in improving the consciousness of DoC patients.21 The SCS procedure entails the implantation of neurostimulation electrodes within the high cervical spinal canal of the patient, whereby pulsed electrical currents are applied to stimulate the spinal nerves. This stimulation increases cerebral blood flow and activates the ascending reticular activating system, thereby improving brain circulation, exciting the cerebral cortex, and promoting the patient’s return to consciousness.22 The surgical procedure is minimally invasive and does not damage any of the patient’s neural tissues. The surgeon performs SCS with the patient in a prone position and braking, and general anesthesia is the only option. Whether general anesthesia drugs have an effect on the recovery of consciousness in patients with DoC, and whether the depth of anesthesia monitoring is helpful to the recovery of consciousness in such patients are the main purposes of this study (SCS).

By measuring the frequency and power of electroencephalogram and processing them with digital standard, the comprehensive monitoring index BIS of anesthesia depth was obtained. BIS is a relatively objective indicator to evaluate sedation level,29 and it can evaluate cortical electrical inhibition or excitation30 and guide anesthetic administration, which can reduce the occurrence of adverse reactions.31 However, at present, BIS is mainly used for patients with unconscious disorders in clinical practice, and there are few relevant studies about whether BIS can accurately monitor the sedation depth of DoC patients. Xue et al32 found that BIS could judge the cerebral ischemia and hypoxia status of patients with craniocerebral injury and assess the prognosis, and some experiments suggested that the use of BIS monitoring in general anesthesia of DoC patients might be useful for patients.29,33 In this study, we found that there was no significant difference in the value of CRS-R (24h) compared with that before surgery, indicating that the short-term effect of anesthetic drugs had little impact on patients with DoC. Because BIS can be more accurate in monitoring the depth of anesthesia, effectively control the state of anesthesia, avoid excessive sedation, and reduce the impact on brain function, it may help promote nerve remodeling and functional recovery of patients in the rehabilitation process. In this study, compared with the CRS-R (3m) score and CRS-R (preoperative) score, the score of the BIS group increased significantly, which was exactly in line with the role of BIS monitoring. However, the proper BIS value of patients with DoC under general anesthesia and its exact effect on the improvement of consciousness need to be verified by larger samples and increased long-term follow-up.

Hearing is the primary way to distinguish cognitive abilities in patients with DoC, such as UWS, MCS, or cognitive-motor dissociation (cognitive-motor dissociation).35 Some studies have observed an increase in brain response after significant stimulation of DoC patients, especially in the auditory system, with significant improvements in brain sensitivity36–38 and brain function.12,13,39 The study of Boly et al40,41 also proved that the auditory system is highly sensitive to changes at the level of consciousness. Heine et al42 compared the activation of the auditory cortex with the conscious state of the patient in the clinic and proposed that the retention of the auditory cortex might be an indicator of the retention of consciousness. The above studies all indicate the correlation between hearing and consciousness. Propofol is a commonly used general anesthetic drug, and its mechanism of action is to inhibit the excitability of the central nervous system by enhancing the inhibitory effect of the neurotransmitter gamma-aminobutyrate (GABA).34 If the sedation depth is too deep, propofol may excessively inhibit the activity of the nervous system, including the brain’s ability to perceive and process external stimuli, including the auditory system. We found that the hearing score in the CRS-R (24h) rating scale in the BIS group was higher than that in the non-BIS group. The author believes that BIS monitoring can reduce the dosage of propofol and reduce its inhibition on the auditory system, which seems to have certain benefits for the short-term hearing and cognitive function improvement of DoC patients.

The thalamus and thalamic neural network are the relay stations for cortical nerve command delivery and upward transmission of sensory neurons,43 and are part of the upwelling tegmental activation system of the midbrain, so the thalamic network system is a key structure for maintaining arousal.44 In this study, it was found that the less thalamus involved in cranial injury, the better the awakening effect 3 months after surgery, indicating that the thalamus plays a key role in the neural correlation theory of consciousness from the perspective of neuroanatomy and functional neural brain network.45–47 Dolce et al48 found that thalamic injury was common in VS/UWS patients, and neuronal death in the thalamus was also the most common pathological outcome.49 The relative preservation of corticothalamic connections in MCS patients may play an important role in supporting residual consciousness50 and cognitive function.19 Even in the most severe multifocal brain injuries associated with permanent VS/UWS, large-scale neural electrical activity has been demonstrated in the thalamic network system, which provides a physiological basis for arousal therapy in such patients.51 Zhang et al52 proposed that the functional connectivity between the thalamus and the whole brain could be used as an imaging marker to evaluate the prognosis of patients with DoC, as well as an indicator to evaluate the potential conscious function of the remaining brain network. Therefore, the less thalamus involved in craniocerebral injury, the better the effect of 3-month awakening therapy.

This study is retrospective. Whether BIS can truly reflect the anesthesia status of patients with DoC needs further investigation and confirmation. Keeping BIS between 40–60 is a more appropriate depth for surgical anesthesia for normal people, but for patients with DoC, the appropriate depth should be further explored. In the future, we will improve the clinical trial design and conduct prospective controlled studies with large samples and extended follow-up time to enhance the credibility of the research results.

There are some limitations to this paper. First, due to the retrospective research design, this somewhat limits our ability to make inferences about causality. Second, the sample size of the study was relatively small, which may affect the generalizability of the findings. In addition, the applicability of the BIS monitoring technique in a population of patients with DoC and the determination of the optimal depth of anesthesia needs to be further validated by additional studies. Furthermore, only a 3-month follow-up was conducted in this study, which limits our understanding of long-term effects. Finally, because the data came from only a single center, there may have been a selection bias, which may also have had some impact on the results of the study. Nonetheless, our study provides valuable preliminary findings and points the way for future research.

In conclusion, maintaining BIS between 40–60 during SCS implantation in patients with DoC may help increase the hearing score of patients 24 hours after awakening therapy.

Data Sharing Statement

The data and materials used and/or analyzed in the current study are available from the corresponding author upon reasonable request. Written informed consent was obtained from the individual(s) and/or the legal guardian/next of kin of minor(s) for the publication of any potentially identifiable images or data included in this article.

Ethics Approval and Consent to Participate

The study adhered to the principles outlined in the Declaration of Helsinki and obtained an exemption from informed consent.

Approval for the study was obtained from the institutional review committee of Peking University International Hospital (Approval No.: 2022-KY-0023-01).

Confidentiality Statement

This study is committed to maintaining the strictest standards of patient data confidentiality. All patient records will be accessed and reviewed in a secure environment, with access limited to study personnel who require it for research purposes. Data will be de-identified to remove all personal identifiers, ensuring that the information cannot be linked back to individual patients. Any data storage and transmission will adhere to the highest security protocols to prevent unauthorized access or disclosure. The findings of the study will be reported in an aggregate form that does not reveal any individual patient’s information.

Registration

International registration code: ChiCTR2300069756.

Acknowledgment

The authors thank Prof. Xiangyang Guo and Jianghong He for their support in data collection during the research.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Funding source: STI2030-Major Projects+2021ZD0204300.

Disclosure

The authors declare no competing commercial or financial interests that could be considered a potential conflict of interest in conducting this study.

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