| 【Background】Coma is a compelling neurological condition where spontaneous eye opening is absent and the patient cannot be awakened by external stimuli[1].Comatose patients require massive medical resources from the society and cause tremendous economical and mental stress to their families.The prognosis evaluation in coma is essential for the medical decision-making,budget control,and resource allocation.Therefore,it is very important and necessary to investigate the outcomes of coma,and especially the prognostic factors related to consciousness recovery.Conventional evaluation of brain function in comatose patients was based on clinical presentations,physical signs,and coma scales,which were quite subjective and of low accuracy.As the development of science and computer technology,PET and MRI were used to evaluate the brain function of comatose patients.However,these examinations are of limited availability in patients with severe brain injury.Therefore,to explore for a new and accurate evaluation tool with high availability for brain function in comatose patients has been a clinical challenge needed to be solved promptly.Electroencephalography（EEG）is a bedside real-time monitoring method which possesses a great advantage in the prognosis evaluation of comatose patients.Elements of sleep EEG often reflect the integrity and functionality of certain brain regions involved in consciousness,such as the cerebral cortex,thalamocortical circuits,and brainstem nuclei[2-5].It makes sense that the sleep EEG pattern is related to the level of consciousness in severely brain-damaged patients and the appearance of sleep elements,e.g.spindle activity,strongly indicates a good prognosis in comatose patients[6-8].However,few studies have investigated the association between sleep EEG patterns and the possibility of patients with coma regaining consciousness.Thus,we plan to explore the value of electrophysiological sleep cycle in evaluating brain function and predicting the outcomes of coma with a larger sample size.The lack of sleep-wake cycle is another important characteristic of comatose patients.Lately,several studies have focused on the sleep-wake cycle and circadian rhythm in patients with DOC[9-13].An important characteristic of comatose patients was the absence of a behavioural sleep-wake cycle,which is regulated by circadian chemicals,including melatonin and Orexin[14-16]Melatonin and Orexin are endogenous substances contributing to the regulation of sleep-wake cycles[17],and they will change with circadian rhythmicity.[18,19].Recent research found that circadian integrity of melatonin was related to prognosis in patients with brain injury[20,21].However,circadian characteristics of serum melatonin and Orexin in patients with coma and their prognostic value for recovery of consciousness within one month have not yet been studied.Therefore,this study monitored the sleep status of comatose patients using polysomnography monitoring（PSG）,and combined sleep EEG patterns with erum melatonin and orexin levels in order to provide an objective and accurate method to determine the possibility of consciousness restoration in comatose patients.【Objectives】1.To investigate the prescense and charistaristics of EEG sleep elements in patients at the acute stage of coma and to examine the association of sleep EEG pattern with the recovery of consciousness in patients with coma.2.To explore the changing rhythm pattern of circadian biomarkers melatonin and Orexin-A in the serum of patients with acute coma and the potential relationship between serum circadian biomarker and the recovery of consciousness in patients with coma.【Methods】1.This was a prospective observational study conducted in the Neuro-Intensive Care Unit（N-ICU）at Xijing Hospital,China,a tertiary academic hospital.Seventy-five patients with coma from July 2016 to January 2018 were enrolled.Patients with a GCS score of 8 or less and with coma for three days or more were eligible for inclusion.2.Baseline characteristics on enrolment were collected.Each patient was continuously recorded for at least 24 hours in N-ICU with a bedside PSG system from 8a.m.on the next day of N-ICU admission.We measured serum levels of melatonin and Orexin-A at 8 a.m.,2 p.m.,8 p.m.,and 2 a.m.successively during the 24-h PSG recording.We modified Valente’s Grade[22]of sleep EEG pattern.According to the mVG,the sleep EEG patterns of each patient were classified.3.All patients were followed for 1 month after entry into the study.Recovery of consciousness within one month of enrolment was used as the primary outcome.Patients were classified into a conscious group（recovered consciousness）and non-conscious group（those who did not regain consciousness）.The conscious group included patients who restored consciousness without entering chronic DOC,MCS-,MCS+,and emergence MCS.The non-conscious group included UWS and death（All the patients that passed away did not regain consciousness before their death）.4.Baseline characteristics were compared using Student’s t-test,Mann-Whitney U test and χ2 test.Spearman’s coefficient was calculated to detect the correlation of mVG and classification of consciousness recovery.The association between mVG and recovery of consciousness within one month was determined using multivariate logistic regression.Repeated measures analysis of variance（ANOVA）with post-hoc SNK was conducted to determine the variation of serum melatonin and Orexin-A at four time points.【Results】1.We enrolled 75 patients and analysed 70 patients due to four patients lost in follow-up and one with unanalysable EEG data.Within one month of enrolment,34patients regained consciousness,and 36 patients were non-conscious.There was no significant difference in demographic and baseline clinical characteristics between the two groups including age,sex,level of S-100,time from coma onset to PSG,CV of melatonin and Orexin-A.Patients included in this study suffered coma due to hypoxic,encephalitis,stroke,trauma,and other.Patients in the conscious and non-conscious groups had significantly different proportions of etiologies（P=0.005）.The consciousness restoration rates in coma due different etiologies were:encephalitis,trauma,stroke,other,and hypoxic.Patients in the conscious and non-conscious groups had significantly different proportions of aetiologies（P=0.005）.Significantly more patients in the non-conscious group had slow or absent pupillary reflex（P=0.003）and corneal reflex（P=0.002）.Non-conscious patients had a significantly lower Glasgow coma scale-motor response（GCS-M）（P=0.035）and Full Outline of Unresponsiveness（FOUR）scale（P=0.002）and significantly higher Acute Physiology and Chronic Health Evaluation Ⅱ（APACHE Ⅱ）score（P<0.001）.Serum NSE level in the non-conscious group was significantly higher than that in the conscious group（P<0.001）。2.The time from onset of coma to PSG was 6（3-9）days in the conscious group and it was 4.5（3-9.75）days in the non-conscious group（P=0.376）.According to the mVG of the sleep EEG,the PSG patterns of the patients were categorized into five grades.Spearman rank correlation revealed a significant association between mVG and patients’recovery of consciousness（P=0.000018,Spearman rank correlation test,Spearman coefficient=0.489）.3.There was no significant difference between the serum levels of melatonin at the four time points（P=0.656,F[3,198]=0.539）.A significant difference was not detected between the melatonin level of the conscious group and non-conscious group（P=0.391,F[1,66]=0.391）.There was no significant difference between the serum levels of Orexin-A at the four time points（P=0.111,F[2.6,178.6]=0.111）.A significant difference in the Orexin-A level was also not detected between the conscious group and non-conscious group（P=0.848,F[1,68]=0.391）.4.Univariate regression analysis shows that there is a significant difference regarding hypoxic aetiology（OR=0.078,95%CI[0.016–0.377],P=0.001）,presence of pupillary（OR=0.078,95%CI[0.016–0.377],P=0.001）and corneal reflexes（OR=0.172,95%CI[0.054–0.546],P=0.003）on admission,baseline FOUR score（OR=1.309,95%CI[1.095–1.564],P=0.003）,APACHE Ⅱ score（OR=0.859,95%CI[0.776–0.950],P=0.003）,NSE（OR=0.032,95%CI[0.964–0.998],P=0.032）,and mVG（OR=2.605,95%CI[1.509–4.497],P=0.001）between the conscious and non-conscious group.Multivariate logistic regression analysis showed that hypoxic aetiology（OR=0.178,95%CI[0.033–0.974],P=0.047）,APACHE Ⅱ score（OR=0.874,95%CI[0.782–0.978],P=0.019）and mVG（OR=2.247,95%CI[1.238–4.080],P=0.008）were independently associated with the recovery of consciousness within one month.【Conclusions】1.Our study confirmed the existence of sleep EEG patten in patients with coma.Patients with more structured pattern of sleep EEG elements are more likely to have better consciousness recovery.2.The circadian rhythm of serum melatonin and Orexin-A was not detected in patients both regained consciousness and not recovered consciousness.Significant difference was also not detected between patients who recovered consciouseness and patients who didn’t regain consciousness.3.Multivariate analysis revealed that hypoxic aetiology,baseline APACHE Ⅱ score,and the sleep EEG pattern of the comatose.patients were independently associated with recovery of consciousness within one month. |
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