Effects Of Anesthetic Depth And Dexmedetomidine On Postoperative Delirium And Pain:A Meta-analysis Combined With Randomized Controlled Trial

Objective:The effects of anesthetic depth on postoperative outcomes remains controversial.Therefore,we conducted this systematic review and meta-analysis to evaluate the effects of deep vs.light anesthesia on postoperative cognitive function,pain,recovery from anesthesia,complications,and mortality.Methods:We searched PubMed,EMBASE,and Cochrane CENTRAL databases from inception to January 2022.Randomized controlled trials(RCT)comparing anesthetic depth for postoperative outcomes in adult surgical patients were included.Quality assessments of the included trials were conducted using the Cochrane evaluation tool.We used the RevMan software 5.4,with a random-effect model for data pooling analysis.We used the Begg’s rank correlation test and Egger’s linear regression test with the STATA software for assessing publication bias.For the co-primary outcomes,we performed the trial sequential analysis(TSA)for reliability assessment and utilized the Grading of Recommendations Assessment,Development and Evaluation(GRADE)approach to evaluate the quality of evidence of this study.(1)The co-primary outcomes were the incidence of postoperative delirium(POD)and postoperative pain scores at rest at 0-1 h postoperatively.Delirium was assessed using the confusion assessment method(CAM)from the first day after surgery up to 1 week postoperatively or until discharge.Postoperative pain was assessed using the visual analogue scale(VAS)pain scores,0 point means no pain and 10 points means the most intense pain.(2)We conducted subgroup analyses for delirium according to cardiac or non-cardiac surgery and pain scores at different postoperative time points.(3)The secondary outcomes included postoperative VAS pain scores at 8 h and 24 h postoperatively,intraoperative sufentanil consumption,need for postoperative rescue analgesia,persistent pain during 3-12 months postoperatively,delayed neurocognitive recovery(DNR)during 1-7 days postoperatively,neurocognitive disorder during 1-3 months postoperatively,Mini-mental State Examination(MMSE)scores,time to emergence from anesthesia,time to extubation,orientation recovery time,length of post-anesthesia care unit(PACU)stay,length of intensive care unit(ICU)stay,length of hospital stay,quality of recovery on postoperative day 1 and day 90.Health Survey Short Form score,clinically significant hypotension,postoperative nausea and vomiting(PONV),any major complication,myocardial infarction,sepsis,stroke,wound infection,intraoperative awareness,1-year cancer recurrence,mortality within 30-90 days postoperatively,and 1-year mortality.Results:A total of 26 trials with 10,743 patients were included.Of these,12 trials had a low risk of bias,13 trials had an unclear risk of bias and one had a high risk of bias.The mean difference between deep anesthesia and light anesthesia was 11 to 12 in bispectral index.(1)4 trials(included 1579 patients)reported the incidence of POD,when compared with light anesthesia,deep anesthesia increased the incidence of POD(24.95%vs.15.92%;risk ratio[RR]=1.57,95%confidence interval[CI]=1.28 to 1.91,P<0.0001,I2=0%),with high reliability in TSA and high-quality evidence in GRADE.5 trials(included 505 patients)reported the VAS pain scores at rest at 0-1 h postoperatively.When compared with light anesthesia,deep anesthesia reduced pain scores at rest at 0-1 h postoperatively(weighted mean difference[WMD]=-0.72,95%CI=-1.25 to-0.18,P=0.009,I2=33%)with high reliability in TSA and moderate quality evidence in GRADE.There was no publication bias for the co-primary outcomes.(2)For the outcome of POD,deep anesthesia was associated with a higher incidence of POD after non-cardiac surgery(RR=1.54.95%CI=1.26 to 1.89.P<0.0001,I2=0%)and cardiac surgery(RR=8.20,95%CI=1.07 to 62.6,P=0.04)compared with light anesthesia,without significant subgroup differences.For the outcome of VAS pain scores,the VAS pain scores at rest(WMD=-0.69.95%CI=-0.97 to-0.40.P<0.0001.I2=31%)and on movement(WMD=-0.78,95%CI=-1.26 to-0.30,P=0.002,I2=43%)during 24 h postoperatively were significantly lower in the deep anesthesia group than that in the light anesthesia group,without significant subgroup differences.(3)The deep anesthesia group had lower VAS pain scores at rest at 8 h(WMD=-1.16,95%CI=-1.74 to-0.57,P=0.0001,I2=0%)and 24 h postoperatively(WMD=-0.50,95%CI=-0.94 to-0.06,P=0.03,I2=52%)and on movement at 8 h postoperatively(WMD=-1.25,95%CI=-1.88 to-0.61,P=0.0001,I2=0%).The deep anesthesia group had prolonged time to emergence from anesthesia(WMD=3.65 min,95%CI=1.94-5.36 min,P<0.0001,12=90%),time to extubation(WMD=3.64 min,95%CI=1.39-5.90 min,P=0.002,12=89%),orientation recovery time(WMD=4.51 min,95%CI=1.61-7.40 min,P=0.002,I2=88%),length of PACU stay(WMD=5.85 min,95%CI=2.30-9.41 min,P=0.001,I2=83%)and length of hospital stay(WMD=1 day,95%CI=0.14-1.86 days,P=0.02,I2=94%).There were no between-group differences in other cognitive outcomes,pain outcomes,complications and mortality.Conclusion:For the adult surgical patients undergoing surgical procedures,deep anesthesia reduced early postoperative pain but increased the incidence of postoperative delirium.However,due to the limited RCTs included,more studies should be conducted to prove the outcomes of our meta-analysis in the next step.Objective:Postoperative delirium(POD)is a common complication after anesthesia and surgery.In previous studies,the effect of dexmedetomidine(DEX)infusion on POD remains controversial.Furthermore,the results of part Ⅰ(meta-analysis)showed that light anesthesia reduced the incidence of POD.The aim of part Ⅱ was to assess the feasibility of using DEX vs normal saline placebo during deep anesthesia or light anesthesia and to explore the effects of DEX and anesthetic depth on POD among older patients undergoing major noncardiac surgery.Methods:This is a randomized,placebo controlled,2*2 factorial designed(based on categorical variable as primary outcome)clinical trial.A total of 120 patients aged 60 years or older undergoing major non cardiac surgery were enrolled in this study.Patients were randomized to one of four groups with a 1:1:1:1 ratio,including DEX-light group,DEX-deep group,placebo-light group and placebo-deep group.DEX was infused at 0.5 μg/kg/h intraoperatively from skin incision to the beginning of skin closure,and normal saline placebo was infused with the same rate as DEX.Anesthetic depth was monitored using the bispectral index(BIS),with the target of 40 for deep anesthesia and 55 for light anesthesia.(1)The primary feasibility endpoint was achieving the BIS targets throughout>70%of surgery duration.(2)The primary efficacy outcome was the incidence of POD during the first 7 days postoperatively or until discharge.The POD was assessed by 3-minute Confusion Assessment Method or 3-minute Confusion Assessment Method for Intensive Care Unit.(3)The secondary outcomes included days with POD.VAS pain scores at rest and on cough at 24 and 48 h postoperatively,fentanyl consumption within 0-24 h and 24-48 h postoperatively,hypotension and bradycardia,postoperative nausea and vomiting(PONV),non-delirium complications,postoperative hospital stay,30-day Telephone Interview of Cognition Status(TICS)-10 scores,and 30-day mortality.(4)The perioperative non-outcomes included BIS values,anesthetic usage.intraoperative volume therapy,duration of surgery,time to extubation,length of post-anesthesia care unit(PACU)stays,and intensive care unit(ICU)admission.SPSS 25.0 software was used for statistical analyses.Logistic regression model was established with POD incidence as dependent variable to analyze the interaction between DEX and anesthetic depth.Time to delirium data were analyzed using the log-rank test and Kaplan-Meier curves.The effects of DEX or anesthetic depth on primary or secondary outcomes were analyzed using Mann Whitney sum test,chi-square test,or Fisher exact test depending on the data type.The effects of four groups on outcomes were analyzed using ANOVA,Kruskal-Wallis rank sum test,or Chi-square test depending on the data type.For the outcomes with significant statistical differences among 4 groups,we also conducted multiple comparisons with setting placebo-deep group as reference,and P values were adjusted using Dunn’s multiple tests.Results:A total of 120 patients were randomized,of whom 2 patients withdrew at their request,118 patients were included the final analysis,including 30 patients in DEX-light group,29 patients in DEX-deep group,30 patients in placebo-light group,and 29 patients in placebo-deep group.(1)The perioperative BIS values had significant differences among the 4 groups(P<0.0001).The total dose of intraoperative propofol had significant differences among the 4 groups(P=0.020).The 4 group were similar in terms of other perioperative data.(2)84.7%(100/120)of patients achieved the BIS targets throughout>70%of surgery duration.The complete rate was 86.7%(26/30),93.1%(27/29),80.0%(24/30)and 79.3%(23/29)in the DEX-light group,DEX-deep group,placebo-light group and placebo-deep group,and there was no significant difference among the 4 groups(P=0.417).(3)There was no significant interaction between DEX and anesthetic depth(P=0.466),thus,we independently analyzed the DEX option and anesthetic depth option.When compared with placebo,DEX infusion reduced the incidence of POD(11.9%vs 27.1%,OR[95%CI]=0.362[0.144,0.932],RD=-15.25%,RD[95%CI]=-15.25%[-30.87%,-0.36%],P=0.037),and survival analysis showed that the DEX had decreased the time to POD than placebo(HR[95%CI]=0.40[0.17,0.93],P=0.034).The light anesthesia and deep anesthesia had no significant difference in POD(15%vs.24.1%,OR[95%CI]=0.555[0.235,1.329],RD[95%CI]=-9.14%[-24.42%,6.46%],P=0.210),and survival analysis showed that the time to POD had no significant difference between light and deep anesthesia(HR[95%CI]=0.58[0.25,1.38],P=0.295).(4)For secondary outcomes(DEX vs placebo),DEX infusion reduced VAS pain scores at rest at 48 h postoperatively,when compared with placebo(1 vs 2,WMD[95%CI]=-1[-1,0],P=0.022).The difference between DEX and placebo on other secondary outcomes were not statistically significant.(5)For secondary outcomes(light anesthesia vs deep anesthesia),there were no significant between-group differences in all secondary outcomes.(6)In the analysis of 4 groups,the incidence of POD was 6.7%,17.2%,23.3%and 31.1%in the DEX-light group,DEX-deep group,placebo-light group and placebo-deep group,and there was no significant difference among the 4 groups(P=0.113).Survival analysis showed that the time to POD had no significant difference among the 4 groups(P=0.111).There were significant differences in the VAS pain scores at 48 h postoperatively at rest(P=0.045)and on cough(P=0.047)among the 4 groups.Using placebo-deep group as reference,the DEX-deep group had a lower VAS pain scores at 48 h postoperatively at rest(0 vs 2,WMD[95%CI]=-2[-2,0],adjusted P=0.016)and on cough(2 vs 4.WMD[95%CI]=-2[-3,0].adjusted P=0.019)with Dunn’s method to adjust the significance level.There were no significant differences in other secondary outcomes among the 4 groups.Conclusion:Among older patients undergoing non cardiac surgery,using DEX vs normal saline placebo during deep anesthesia or light anesthesia is feasible.Furthermore,the use of dexmedetomidine was protective against POD,and anesthetic depth itself did not influence POD.