**3. Results**

Of 107 trauma patients undergoing general emergency noncardiac surgery, 12 patients were excluded from the study after application of the exclusion criteria. The remaining 95 patients were assigned using the permuted block randomization design in a 1:1 ratio to the standard monitoring group (SMG) or to the entropy-SPI standard monitoring group (ESMG). Of these patients, 11 and 10 subjects, respectively, were excluded from data analysis either because they remained intubated at the end of the procedure or because the length of the procedure was less than 2 h (Figure 1).

**Figure 1.** Data collection flowchart.

Patient characteristics were similar in both groups (SMG, ESMG; Table 1), and no significant difference was found in the preoperative data except for the duration of anesthesia. Due to the heterogeneity of trauma patients and the variety of surgical procedures employed, no significant statistical analysis could be performed given the small sample for each group studied. Regarding comorbidities, the most frequently associated pathologies were represented by cardiovascular disease (arterial hypertension, ischemic cardiomyopathy) and obesity.

The total dose of fentanyl administered to patients was lower in the ESM Group than in the SM Group, with a statistically significant difference between the two groups(*p* < 0.0001). Sevoflurane uptake per hour was significantly lower in the study group than in the control group (*p* < 0.0001) (Table 2). Anesthesia length was approximately 17 min shorter in the

entropy and SPI monitored group than in the standard monitored group (132.52 vs. 150.05 min, *p* = 0.0013). The shorter anesthesia length in the ESM group might be a cofounding factor with regard to the anesthetic volatile consumption.


**Table 1.** Patient characteristics.

\* ASA, American Society of Anesthesiologists. \*\* Categorical data were expressed as number and percentage.

**Table 2.** Comparison of entropy and SPI-guided anesthesia in contrast with standard monitoring-guided anesthesia.


Data were analyzed using the Mann–Whitney test.

In regard to intraoperative fluid management, fewer fluids were used for the ESM Group, and statistically significant results between the two groups were found only for crystalloid (*p* = 0.010). As for the noradrenaline dosage, the ESM Group received a smaller dose of vasopressor in comparison to the SM Group (*p* < 0.0001) (Table 2).

Hemodynamic events are listed in Table 3. Intraoperative hypotension was encountered more frequently in the control group (*p* < 0.0001). No statistically significant differences were noted between the two groups regarding the incidence of other hemodynamic disturbances.

**Table 3.** Comparison of entropy and SPI-guided anesthesia in contrast with standard monitoringguided anesthesia regarding adverse intraoperative hemodynamic events.


Nominal data were compared using Fisher's exact test.

#### *Postoperative Delirium and Cognitive Dysfunction*

Although fewer patients in the intervention group experienced postoperative cognitive dysfunctions episodes in comparison to the control group, the results were not statistically significant (*p* = 0.08). The study showed a statistically significant inverse correlation between fentanyl and the NEECHAM Confusion Scale at 24 h (r = −0.32, *p* = 0.0005) and 48 h (r = −0.46, *p* = 0.0002), sevoflurane and the NEECHAM Confusion Scale at 24 h (r = −0.38, *p* = 0.0014) and 48 h (r = −0.52, *p* = 0.0002), and noradrenaline and POCD events in the first 48 h (r = −0.46, *p* = 0.0013 for the first 24 h respectively, and r = −0.46, *p* = 0.0002

for the next 24 h) (Figure 2). There was no statistically significant correlation between fentanyl, sevoflurane, or noradrenaline and POCD at 72 h (Figure 2).

**Figure 2.** Correlation matrix. The table above shows correlations coefficients between the following variables: Fentanyl (μg), sevoflurane (mL/h), noradrenaline (μg/kg/min) and NEECHAM score at 24 h, 48 h, and 72 h. The colorencodes the sign of correlation between each 2 variables: Blue for positive r values and red for negative r values.

> In order to identify how we couldavoid postoperative cognitive dysfunction, we developed a logistic regression model that used a NEECHAM score higher than 24 points (indicating absence of cognitive dysfunction) at 24 h as a dependent variable. A fourpredictor logistic model was fitted to the data to test the research hypothesis regarding the relationship between the use of entropy and the doses of anesthetic drugs and vasopressor with the advent of postoperative cognitive dysfunctions.

> The logistic regression hadan overall model fit described by a nullmodel-2 Log Likelihood of 74.150 and a full model-2 Log Likelihood of 65.311, with a chi-squared value of 8.840 (*p* = 0.06). The goodness of fit of this regression model was calculated with Cox&Snell (R<sup>2</sup> = 0.19). According to the model, the log of the odds of a patient to develop POCD was negatively related to the dose of fentanyl, sevoflurane, or noradrenaline and positively related toentropy and SPI monitoring (Table 4).


**Table 4.** Logistic regression analysis of 74 patients for POCD appearance.

## **4. Discussion**

The main finding of this study was that entropy and Surgical Pleth Index-guided anesthesia versus standard monitoring may reduce the incidence of postoperative cognitive dysfunction in the first 72 h for patients undergoing general emergency noncardiac surgery. Also, entropy and SPI may offer a protective role in developing postoperative cognitive dysfunctions. The reported incidence varies greatly in the literature [16,17], especially because neuromonitoring anesthesia has been studied less during emergency noncardiac surgery in comparison to elective surgery.

In our research, we found a substantial reduction in anesthesia duration in the entropy and Surgical PlethIndexmonitored group than in the standard monitored group (132.52 vs. 150.05 min, *p* = 0.0013). The shorter anesthesia length in the ESM Group might be a confounding factor with regard to the anesthetic volatile consumption. In our study, we observed significantly lower sevoflurane doses in the ESM Group. Previous studies demonstrated that neuromonitoring may lead to a less 'roller-coaster'-like anesthesia [18] and less fluctuation from a defined target than the clinical estimation of anesthetic depth only [19]. Hor et al. conducted a randomized controlled trial in order to assess sevoflurane uptake in patients undergoing major surgery andfounda significant reduction in sevoflurane uptake with the use of entropy, in addition to a faster extubation [20]. Fedorow et al. highlighted that using neuromonitoring in order totitrateanesthetic agents may avoid an unnecessary increase in anesthesialevels and possible neurotoxic effects, especially in high-risk patients [21]. Our data sugges<sup>t</sup> that anesthetic agents may represent a risk factor for developing POCD in the first 48 h. This finding is consistent with previouslypublished studies. According to Micha et al., sevoflurane has a negative influence on short-termcognition [22].

Another pharmacological factor, fentanyl, can be considered a causal factor for the presence of POCD, and we have identified significant dose reduction in the entropy-SPI monitored group in comparison to the standard monitored group. In our study, we identified that fentanyl may represent a risk factor for developing POCD in the first 48 h, but the results cannot be extended topatients who develop POCD in the next 24 h. Although the incidence of cognitive disorders is highly dependent on the type of surgery and general anesthesia managemen<sup>t</sup> [23,24], opioid treatment remains very influential in POCD occurrence [25].

Emergency surgery is usually closely related to hemodynamic instability. Thus, another favorable trend for the entropy-SPI studied group is represented by fewer hypotensive eventsin the intervention group and by the significantly decreased demand for vasopressor. Intraoperative hypotension was encountered more frequently in the control group (*p* < 0.0001). It is well known that, in addition to uncontrolled anesthetic exposure, another important factor that may increase the risk of developing POCD is represented by blood pressure fluctuation [26,27]. As Wu et al. investigated in a randomized controlled trial, this

may be related to sevoflurane consumption [28]. However, we must keep in mind that, in trauma settings, other important factors may contribute to hemodynamic alteration (type of injury, intravascular volemic status, volemic resuscitation, response to tissue injury, tissue perfusion, etc.) [29]. Our findings highlight that noradrenaline may contribute to cognitive impairment in the first 48 h after surgery. Although vasopressors are a cornerstone for treating refractory hypovolemic shock, they may also exhibit negative side effects with harmful repercussion on cerebral perfusion [30,31].

In our study, the majority of patients experiencedthe following comorbidities: Cardiovascular disease (arterial hypertension, ischemic cardiomyopathy) and obesity. Current data do not support the hypothesis that these comorbidities are potential cofounders for developing postoperative cognitive dysfunctions [32,33].

## **5. Limits**

Although in the intervention group, fewer patients experienced postoperative cognitive dysfunctions episodes in comparison to the control group, the results were not statistically significant (*p* < 0.08). We consider that one of the main drawbacks of the study was the inability to control all ofthe risk factors that contribute to the development cognitive disorders.

Another study limitation is the consequence of not being to further evaluate postoperative cognitive disorders after 72 h because the majority of patients were discharged from ICU. We also considered that, after 72 h, other factors may interfere with cognitive function and mislead POCD screening.

Due to the fact that neuromonitoring anesthesia and nociception have been studied less frequentlyduring emergency noncardiac surgery in comparison to elective surgery, the available papers do not allow us to entirely compare the magnitude of our findings with the previous published data.

The present research included a small number of patients in each group. In order to establish future relevant knowledge for improving patients' cognitive outcome, we con-sider it imperative to recruit a higher number of patients.

## **6. Conclusions**

The present study was designed to reflect routine clinical practice in emergency settings. It is difficult to isolate one perioperative risk factor for POCD in studies even when excluding individual factors. Despite the extensive research conducted in recent years onthe subject, the causes and pathophysiological mechanismsresponsible for postoperative cognitive decline remain unclear. Entropy and SPI monitoring during anesthesia may play an important role in diminishing the risk ofdeveloping immediate postoperative cognitive dysfunctions after emergency surgery. Also, sevoflurane, fentanyl, and noradrenaline may be closely associated with POCD occurrence in the first 48 h. In order to confirm our hypothesis, we considered that our study required a higher number of patientsto be enrolled. Building upon the data found inour research, we sugges<sup>t</sup> monitoring intraoperative anesthetic depth using entropy and nociception through the SurgicalPlethIndex (SPI) in patients with pre-existing cognitive impairment in order to investigate postoperative cognitive dysfunction in future research.

**Author Contributions:** Conceptualization, A.-M.C., C.C., M. ¸T. and I.M.G.; Data curation, A.-M.C., C.C., M. ¸T., A.E.B. and D.M.I.; Formal analysis, A.E.B.; Investigation, A.-M.C., C.C., M. ¸T., A.E.B. and D.M.I.; Methodology, A.-M.C., C.C., M. ¸T. and I.M.G.; Project administration, A.-M.C. and I.M.G.; Resources, C.C. and I.M.G.; Software, A.E.B. and D.M.I.; Supervision, D.M.I. and I.M.G.; Validation, A.-M.C., C.C., M. ¸T. and A.E.B.; Visualization, I.M.G.; Writing—original draft, A.-M.C., C.C., M. ¸T., A.E.B., D.M.I. and I.M.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This prospective randomized study was carried out in the Anaesthesia and Intensive Care Clinic, Clinical Emergency Hospital of Bucharest, between August 2018 and January 2019. All the procedures performed during this study were in accordance with the Dec-laration of Helsinki. The study was approved by the Research Ethical Committee of our hospital (registration number 2100/2021).

**Informed Consent Statement:** All the patients provided written informed consent.

**Data Availability Statement:** No data were reported.

**Conflicts of Interest:** The authors declare no conflict of interest.
