Prediction Of Anesthesia Depth And Postoperative Behavior Changing By Neural Activity Of Prefrontal Cortex In Children Under 3 Years Old

Introduction:There are approximately 234 million anesthesia performed each year worldwide,10 million children are under 3 years old among of them.The impairment of neurodevelopment exposed with anesthesia has became a troubling dilemma to pediatric anesthesiologists.Recent studies have shown that multiple anesthetic exposures in early childhood and long duration of anesthesia increased the risk of developmental delay and impair behavior and execution ability^[1-3].The key to improve the safty and quality of pediatric anesthesia in children younger than 3 years old is to conduct anesthesia appropriately and prevent excessive anesthesia exposure.Adjusting the dose of anesthesia based on pharmacokinetics of population and hemodynamics of patients rather than the specific brain activity of the patient,may easily lead to inappropriate depth of anesthesia,which may cause neuroapoptosis and significant behavior changes postoperatively.Neural oscillations in the prefrontal cortex can reflect the individual response to anesthetics.The characteristics of electroencephalogram（EEG）indicate the degrees of unconsciousness.Continuous EEG monitoring provides a non-invasive and real-time method to detect prefrontal cortex activity during anesthesia.Additionally,the response of neural activity to anesthetics is different from that of adults due to the immature of the nervous system in children under 3 years old.It is necessary to determine the responses to anesthesia by using characteristics of EEG conformed to the physiology of children.The aims to this study are to monitor the EEG of the prefrontal cortex,analyze the characteristics of neural oscillations under different anesthesia exposures,observe the postoperative behavioral changes,and explore new methods on monitoring the depth of anesthesia in children under 3 years old.Materials and Methods:The study is divided into three parts and a total of 225 eligible patients were included.Part 1,54 patients aged less than 37 months were included and divided into sevoflurane-inhalation group and Propofol-intravenous group at Sichuan Provincial People’s Hospital from May 2018 to August 2019.Demographic characteristics,vital signs,and adverse events were recorded during the peri-anaesthesia period.EEG in prefrontal cortex was monitored using Sedline EEG machine during anesthesia and emergence.The Peds QL^TM(Pediatric Quality of Life Inventory^TM)scale was used to evaluate the physical,mental and social function scores of patients before anesthesia,one week after anesthesia,and one month after anesthesia.Isoelectric events were obtained from off-line data of EEG.Anesthetic-related variables and Peds QL^TMscores were recorded as well.Part 2,83 patients aged less than 37 months who received general anesthesia with propofol from Sichuan Provincial People’s Hospital between November 2019 and November 2020 were divided into the Target Control Infusion group（TCI）and the Modified Manual Infusion group（TIVA）.The EEG in the prefrontal cortex was monitored during anesthesia and emergence using Sedline EEG machine.The amount of propofol and the EEG data were collected every 10 minutes during the maintenance and recovery period.The EEG data were preprocessed by EEGLAB program in MATLAB.Time-frequency analysis by Chronux program was used to calculate the power and spectral edge frequency of the oscillation in the prefrontal cortex.The correlation between amount of propofol,power of oscillation and spectral edge frequency in the prefrontal cortex were analyzed in pairs at each time point.Part 3,88 children under 37 months old were included,who received total intravenous anesthesia with propofol under Sedline EEG monitoring at Sichuan Provincial People’s Hospital from March 2018 to November 2020.The EEG datas were obtained in a complete and high quality.All the patients were divided into 0-12months old group and 13-36 months old group according to age.The EEG spectrogram based on fast Fourier transform was drawn by MATLAB,and the EEG trajectory was analyzed by combining with power spectrum.The characteristics of neural oscillations under different EEG trajectories were compared and analyzed according to age.The correlation between different trajectories and anesthetic dosage,extubation time and recovery time were analyzed.Results:Part 1,The total incidence of isoelectric events in both groups was 29.6%,15.4%in propofol group,42.9%in sevoflurane group,the incidence of isoelectric events in sevoflurane group was higher than in intravenous group（P=0.0272）.The average number of isoelectric events was 16 times individually,average cumulative time of isoelectric event was 66.50s,accounting for 1.92%of the anesthesia time.The incidence of isoelectric events in the maintenance period during anesthesia was more than that in induction and preincision period（P<0.001）.Maintenance of sevoflurane anesthesia,long duration of anesthesia and low baseline Peds QL^TM scores were related to the incidence of isoelectric events（P=0.0623,P=0.0057,P=0.0234）.Younger age,low body mass index（BMI）,and low baseline Peds QL^TM scores were associated with the length and number of isoelectric events（P=0.0099,P=0.0074,P=0.0272）.The total Peds QL^TM scores of patients with isoelectric events decreased significantly one week and one month postoperatively than baseline（P=0.0003,P=0.0086）,emotional score and cognitive score among them decreased significantly（all P<0.05）.The postoperative Peds QL^TM score decline is related to the preoperative quality of life score.The lower the preoperative Paeds QL^TM score,the more susceptible to anesthesia（P=0.0234）.Part 2,83 eligible patients were enrolled and divided into TCI group and TIVA group.The mean dose of propofol was 11.3±7.3 mg·kg^-1·h^-1 for 0-12 months and12.5±7.4 mg·kg^-1·h^-1 for 13-36 months in the TCI group.10.7±2.1 mg·kg^-1·h^-1 for0-12 months,11.8±2.1 mg·kg^-1·h^-1 for 13-36 months in the TIVA group.There was no statistical difference on propofol dose at each time point during maintenance between the two groups.The average plasma concentration of the TCI group during the maintenance was 3.03μg.ml^-1.All infusion regimen could meet the requirements of surgical anesthesia and effectively reduce isoelectric events with incidence of 3.6%in all patients.The frontal EEG of the two groups mainly showed changes inδ,θ,αandβoscillations during the maintenance and recovery of anesthesia.During the maintenance of propofol,the frontal EEG of infants mainly showed the changes ofδ,β,αandθoscillations,and the power ratios ofδandθoscillations of infants were higher than those of 13-36m children,while the power ratio ofαoscillations of infants was significantly lower than that of 3-36m children.The power ratio ofβoscillation was significantly higher thanαoscillation,while the patient age grew close to 2 years old.After drug withdrawal,the power ratio ofδoscillations decreased briefly,βoscillations increased first and then decreased,αoscillations decreased gradually,θoscillations had little change.In 13-36 m children,the power ratio ofδandθoscillations gradually increased,while those ofαandβoscillations gradually decreased.The SEF95 during maintenance and recovery in infants were lower than those in 13-36 m children.The SEF95 in maintenance was lower than that in emergence.Part 3,The frontal spectrum of 88 children under 3 years old mainly showedδdominate slow-wave anesthesia（dd SWA）trajectory,sd SWA and n SWA respectively or in combination during the maintenance of propofol.There was only one trajectory of dd SWA in the maintenance of anesthesia in infants 0-3 months.The amount of propofol in dd SWA and sd SWA in all children was higher than that in n SWA trajectory（P=0.0168,P<0.0001）.Theθoscillation power was lowest in dd SWA trajectory and highest in Emergence trajectory（P<0.0001）.Theαoscillation power appeared the lowest in the emergence trajectory compared with other trajectories（P<0.0001）.Total power decreased from dd SWA,sd SWA,n SWA to Emergence successively,while 95%Spectral edge frequency（SEF95）increased inversely（P<0.0001,P<0.0001）.There was no significant correlation between the type of spectral EEG trajectory,the amount of propofol,the duration time of anesthesia,extubation time and recovery time.Conclusion:Isoelectric events are common during maintenance of general anesthesia in children under 3 years old.Sevoflurane maintenenance,long duration time of anesthesia and low baseline Paeds QL^TMscores are high risk factors for Isoelectric events.Furthermore,young age,low BMI value and low baseline Paeds QL^TM scores exacerbate the severity of Isoelectric events.The incidence of isoelectric events revealed that excessive anesthesia can cause short-term postoperative neurological impairment,which is manifested as a decline in the quality of life in one week and one month after surgery,especially on cognitive and emotional functions.Patients with poorer physical development,physical status,cognitive,behavioral and social functions preoperatively are more likely to suffer impairment by anesthesia.Stimulating propofol plasma concentration of 3μg·m L^-1in children under 3 years old,combined with regional block or opioid analgesic effectively can maintain the anesthesia depth between deep and light,which conclude Morse infusion model,Paedfusor model of target control infusion and modified manually infusion solution.The characteristics of prefrontal cortex are composed of mainlyδoscillations,followed byθoscillations,and very fewαandβoscillations during maintenance of the infusion solutions.In age 4-6 months,αandβoscillations begin to appear,andβoscillations are slightly more thanαoscillations.Theαoscillations increased gradually in children aged 1-3 years,andαandβoscillations show coherent,which constituted a slow wave anesthesia dominated by spindle oscillations.Prefrontal cortex spectral EEG trajectory combined with 95%spectral edge frequency（SEF95）can be used to determine the changes of neural activity and reveal different anesthesia depths during the maintenance of propofol in children above 4months.The changes ofθoscillations in prefrontal cortex might be an indicator to predict anesthesia state in infants 0-3 months.The dd SWA trajectory is close to deep anesthesia,sd SWA trajectory is close to light anesthesia,n SWA trajectory stands for sedation,and isoelectric events suggest excessive anesthesia.Both dd SWA and dd SWA+sd SWA trajectories can provide surgical anesthesia.sd SWA trajectory is suitable for light anesthesia,and n SWA trajectory should be avoided as far as possible during anesthesia maintenance.EEG trajectories are not sensitive to the prediction of awakening.SEF95 is a sensitive indicator reflecting the frontal neural activity during the anesthesia maintenance.It can indicate the changes in the distribution of neural oscillations induced by propofol in real time,but it cannot reflect the changes in the power of neural oscillations.SEF95 combined with the total power of prefrontal EEG can be used to distinguish between deep anesthesia and sleep status in emergence.SEF95 is low while the total power is high in deep anesthesia,reversely in emergence.Therefore,monitoring EEG of prefrontal cortex in children under 3 years old can predict the depth of anesthesia and avoid excessive anesthesia.