Is the bispectral index monitoring protective against postoperative cognitive decline? A systematic review with meta-analysis.

BACKGROUND: Several studies have suggested that monitoring the depth of anaesthesia might prevent the development of postoperative cognitive decline. We aimed to conduct a meta-analysis to investigate the effects of bispectral index (BIS) monitoring in anaesthesia.
METHODS: We searched in six major electronic databases. Trials were included if they discussed anaesthesia with and without BIS monitoring or low (<50) and high (≥50) BIS levels and which measured the risk of postoperative delirium (POD) and/or postoperative cognitive dysfunction (POCD).
RESULTS: We included fourteen studies in the systematic review, eight of which were eligible for meta-analysis. BIS proved to be protective against POD at 1 day postoperatively in a cohort of 2138 patients (16.1% vs. 22.8% for BIS vs. no BIS groups, respectively; relative risk [RR] 0.71; 95% confidence interval [CI] 0.59 to 0.85, without significant between-study heterogeneity I2 = 0.0%, P = 0.590). The use of BIS was neutral for POCD at 1 week but protective for POCD at 12 weeks (15.8% vs. 18.8% for BIS vs. no BIS groups, respectively; RR = 0.84, CI: 0.66 to 1.08), without significant between-study heterogeneity (I2 = 25.8%, P = 0.260). The neutral association at 1 week proved to be underpowered with trial sequential analysis. In the comparison of low BIS versus high BIS, the incidence of POD at 1 day was similar in the groups.
CONCLUSION: Our findings suggest a protective effect of BIS compared to not using BIS regarding the incidence of POD at 1 day and POCD at 12 weeks. However, limitations of the evidence warrant further investigation to identify those groups of patients by age, comorbid conditions and other individual variables who would benefit the most from the use of BIS monitoring.

Introduction

The disturbance in cognitive brain activity after surgery under general anaesthesia is worrisome. According to the literature, the incidence of cognitive decline after minor or major surgeries ranges from 7 to 29% in the elderly and even reaches 19% in younger patients as well [1-4]. A prominently high incidence was observed after heart surgery (80%) [5].

The aetiology of postoperative cognitive decline is multifactorial [1–4, 6–9]. Considering the causes of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), the predisposing factors are very similar [1, 2, 6, 7]. However, important differences may be found in the pathophysiological background [2, 6]. By definition, POD is an acute deterioration in cognitive function, a disturbance of consciousness. It develops in the early days postoperatively [2, 6, 7, 10, 11]. POCD is one of the adverse effects of anaesthesia which develops in the later postoperative period and manifests as a decline in a patient’s cognitive abilities [2, 6, 7, 10]. Several neuropsychological tests are available to detect changes of cognitive function, although proper test assessment and interpretation are often problematic [2, 8].

Prevention of postoperative cognitive disturbances is a top priority, with one potential tool being the application of bispectral index (BIS) monitoring [2, 6, 7, 9, 12–14]. Previous systematic reviews have yielded discrepant results, although the methods applied in data collection, selection and pooling have been varied and, sometimes, incomplete as well [15-19]. These reviews have left the question open on how BIS monitor-guided anaesthesia influences the incidence of POD and POCD.

Our aim was to compile all available evidence on the effects of BIS on POD and POCD in a systematic review with meta-analysis using two comparisons: general anaesthesia with or without BIS monitoring and anaesthesia with low (BIS values <50) or high (BIS values ≥50) BIS levels.

Materials and methods

Our study is a systematic review with a meta-analysis of randomized controlled trials (RCTs) evaluating the effect of BIS monitoring on patients under general anaesthesia in the prevention of POD and POCD. Our publication adheres to the PRISMA Statement [20].

PICOS and eligibility

The review question was formulated by the PICO framework. We included studies that discuss (Population) adult patients who underwent general anaesthesia (Intervention1 vs. Comparator1) with BIS monitoring vs. without BIS monitoring or (Intervention2 vs. Comparator2) with low vs. high BIS and which measure (Outcome) the risk of POD and/or POCD. (Study design) As regards study design, we included RCTs exclusively.

A BIS value is a number on a spectrum between 0 and 100 without dimension, scaled to correlate with important clinical endpoints and electroencephalographic (EEG) signals under anaesthesia [7, 12–14]. The upper end of the spectrum is the awake state with a typical BIS value near 100 [7, 12]. The lower end (BIS = 0) is defined as an isoelectric EEG record [7, 12]. The optimal BIS range of standard surgical anaesthesia falls between 40 and 60 [7, 12–14]. This range can be divided into low (<50) and high (≥50) BIS levels.

We defined POD as a complete disturbance affecting the integrity of consciousness in the first 1–5 days after surgery, whereas POCD begins days later from 1 week on and may persist for 4–6 weeks or even longer, up to 52 weeks [2–4, 10]. Our primary outcome was POD at 1 day, while secondary outcomes included POD at 2, 3, 4 and 5 days as well as POCD at 1, 12 and 52 weeks.

Search, selection and data extraction

We searched electronic databases including MEDLINE (via PubMed), EMBASE, Cochrane Controlled Register of Trials (CENTRAL), SCOPUS, WHO Global Health Library/Global Index Medicus and Clinical Trial.gov for relevant articles from inception up to 29 April 2019. Human and English-language filters were imposed on the search, where appropriate. Further details of search, selection and data extraction are shown in S1 Appendix. We did not contact the original authors for further information.

Risk of bias (RoB) assessment

We used the Cochrane Risk of Bias Tool to rate risk of bias along critical points in methodology (PH, GV, IP and IT) [21].

Results from the RoB assessment were incorporated into the interpretation of findings but not in statistical analysis (KK). Discrepancies during the assessment were resolved by reaching a consensus.

Quality of evidence

We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to rate the quality of evidence on each outcome (ZS) [22].

Statistical analysis

The statistical analysis was performed using Stata 15 SE (Stata Corp) by an expert statistician (NG). We calculated pooled relative risks (RRs) with 95% confidence intervals (CIs) for POD and POCD [23]. The analysis was done according to the timing of neuropsychological test measurements (that is, POD at 1, 2 and 5 days and POCD at 1 and 12 weeks). We only performed statistical analysis if at least two RCTs per group were available. Since the settings of the studies do not match exactly, we applied the random effect model with the DerSimonian–Laird estimation [24]. I2 and chi2 tests were used to quantify statistical heterogeneity and obtain P-values, respectively; P < 0.100 indicated a significant heterogeneity [24]. To evaluate the effect of the individual studies on the pooled estimate, sensitivity analysis was conducted by omitting studies one by one from the analysis if at least three studies were available per analysis. Trial sequential analysis (TSA) was used to quantify the statistical reliability of data if the condition of the tests were met [25].

Since the number of studies included in the analysis was low, publication bias could not be checked either using graphical tools (e.g. funnel plots) or tests (e.g. Egger’s test).

Study protocol and protocol deviations

The protocol for this study was registered in PROSPERO a priori under registration number CRD42018092981, protocol deviations are described in S1 Appendix.

Results

Identification and characteristics of the studies

Fig 1 shows the flow chart of our meta-analysis. In total, we identified 1653 records through database searches and one record through other sources; 1408 of which were screened for eligibility after removing duplicates. A total of 1386 ineligible studies were eliminated after browsing titles. Twenty-two studies were removed based on abstract screening. Finally, fourteen studies were included in the systematic review [26-39] eight of which [29–33, 36–38] were qualified to be in the meta-analysis (for reasons, see Fig 1).

Fig 1

Flow chart of study selection.

The characteristics of the studies included and those excluded on full-text assessment are summarised in Table 1 [26-39] and S1 Table [40-47], respectively.

Table 1

Characteristics of the studies included.

Author (year, country)	Recruitment period	Study design	Population, Intervention and Comparator	Cognitive test	Outcome, follow-up
Wong et al. (2002, Canada)[26]	Not stated	RCT	Elderly (≥65 years) with isoflurane-fentanyl anaesthesia undergoing elective orthopaedic surgery, BIS-guided (50–60) (n = 34) vs. no BIS-guided (n = 34)	MMSE, TDT, DSST	POD (at 1–3 days)
Farag et al. (2006, USA)[27]	Not stated	RCT	Adults (≥50 years) with isoflurane-fentanyl anaesthesia undergoing spine, abdominal, and pelvic surgery, low BIS (30–40) (n = 36) vs. high BIS (50–60) (n = 38)	MMSE, PSI, WMI, VMI	POCD (at 4–6 weeks)
Sadek et al.(2010, Egypt)[28]	Not stated	RCT	Elderly (≥60 years) with desflurane anaesthesia undergoing elective spine surgery, BIS-guided (50–55) (n = 20) vs. MAC-guided (n = 20)	MMSE	POD (at 1–3 days)
Sieber et al.(2010, USA)[29]	2005–2008	RCT	Elderly (≥65 years) with spinal anaesthesia or propofol sedation undergoing hip fracture repair, low BIS (<50) (n = 57) vs. high BIS (>80) (n = 57)	MMSE, CAM	POD (at 1–2 days)
An et al.(2011, China)[30]	Not stated	RCT	Adults (28–65 years) with propofol-remifentanil anaesthesia undergoing receive microvascular decompression, low BIS (30–40) (n = 46) vs. high BIS (55–65) (n = 50)	Mental control, Visional rational, PAVL, DSST, TMT (A), DSF, DSB, Pegboard favoured/no favoured hand	POD (at 5 days)
Ballard et al. (2012, UK)[31]	2007–2009	RCT	Elderly (≥60 years) with general anaesthesia undergoing elective orthopaedic or abdominal surgery, BIS-used (n = 192) vs. no BIS-used (n = 138)	MMSE, VRT, TMT	POCD (at 1, 12, and 52 weeks)
Chan et al.(2013, Hong-Kong)[32]	2007–2009	RCT	Elderly (≥60 years) with general anaesthesia undergoing elective major surgery, BIS-guided (40–60) (n = 462) vs. no BIS-guided (n = 459)	MMSE, CFQ, VFT,CAVLT, CTT	POD (at 1 day),POCD (at 1 and 12 weeks)
Radtke et al.(2013, Germany)[33]	2009–2010	RCT	Elderly (≥60 years) with general anaesthesia undergoing general, abdominal, thoracic, vascular, orthopaedic, otorhinolaryngological, oral and maxillofacial, gynaecological, and urologic surgery, BIS-guided (40–60) (n = 575) vs. no BIS-guided (n = 580)	MMSE	POD (at 1 day),POCD (at 1 and 12 weeks)
Altun et al.(2015, Turkey)[34]	Not stated	RCT	Adult (18–40 years) women with sevoflurane or desflurane or regional anaesthesia undergoing Caesarean section, BIS-used (sevoflurane / n = 25, desflurane / n = 25) vs. no BIS-used (n = 25)	MMSE, TDT, CDT	POD (at 1 day)
Shu et al.(2015, China)[35]	2012–2014	RCT	Young and middle-aged women with sevoflurane-remifentanil anaesthesia undergoing gynaecologic laparoscopic operation, low BIS (30–40 and 40–50) (n = 64 and n = 64) vs. high BIS (50–60) (n = 64)	MMSE, TMT	POD (at 1 day)
Hou et al.(2018, China)[36]	Not stated	RCT	Elderly (≥60 years) with sevoflurane-fentanyl anaesthesia undergoing elective total knee arthroplasty, low BIS (40–50) (n = 33) vs. high BIS (55–65) (n = 33)	MoCA	POD (at 1 day)
Zhou et al.(2018, China)[37]	2014–2016	RCT	Elderly (65–75 years) with general anaesthesia undergoing surgery for resection of colon carcinoma, BIS-guided (40–60)(n = 41) vs. no BIS-guided (n = 40)	MMSE, ANT	POD (at 1–5 days)
Sieber et al.(2018, USA)[38]	2011–2016	RCT	Elderly (≥65 years) with spinal anaesthesia or propofol sedation undergoing hip fracture repair, low BIS (n = 100) vs. high BIS (n = 100)	MMSE	POD (at 1–5 days)
Quan et al.(2019, China)[39]	2014–2016	RCT	Elderly (≥60 years) with total intravenous anaesthesia undergoing abdominal surgery, low BIS (40–50) (n = 60) vs. high BIS (50–60) (n = 60)	MMSE, CAM, ANT, Mental control, Visional rational, PAVL, DSST, TMT (A), DSF, DSB, Pegboard favoured/no favoured hand	POCD (at 1 and 12 weeks)

RCT: randomised controlled trial; BIS: bispectral index; MAC: Minimal Alveolar Concentration; MMSE: Mini Mental State Examination; TDT: Trieger Dot Test; DSST: Digit Symbol Substitution Test; PSI: Parenting Stress Inventory; WMI: Working Memory Index; VMI: Visual Motor Integration Test; CAM: Confusion Assessment Method; PAVL: Paired Associate Verbal Learning; TMT: Trail Making Test; DSF: Digit Span Forward; DSB: Digit Span Backward; VRT: Vigilance Reaction Time; CFQ: Cognitive Failure Questionnaire; VFT: Verbal Fluency Test; CAVLT: Chinese Auditory Verbal Learning; CTT: Color Trial Test; CDT: Clock Drawing Test; MoCA: Montreal Cognitive Assessment; ANT: Attention Network Test; POD: postoperative delirium; POCD: postoperative cognitive dysfunction.

Conclusions from studies included in the systematic review are summarised in Table 2 [26-39] with detailed results presented in S2 and S3 Tables.

Table 2

Summary of the conclusions of the studies included.

Comparison	Outcome	Follow-up	Conclusion regarding the effect of intervention
			Protective	Risk	Neutral
BIS vs. no BIS	POD	at 1 day	Sadek[28], Chan[32], Radtke[33], Zhou[37]		Wong[26], Altun[34]
		at 2–3 days	Zhou[37]		Wong[26], Sadek[28]
		at 5 days	Zhou[37]
	POCD	at 1 week	Ballard[31], Chan[32], Radtke[33]
		at 12 weeks	Ballard[31], Chan[32]		Radtke[33]
		at 52 weeks	Ballard[31]
low (<50) BIS vs. high BIS (≥50) level	POD	at 1 day	Shu[35]	Sieber[29], Hou[36]	Sieber[38]
		at 2 days		Sieber[29]	Sieber[38]
		at 3–4 days			Sieber[38]
		at 5 days	An[30]		Sieber[38]
	POCD	at 1 week	Quan[39]
		at 4–6 weeks	Farag[27]
		at 12 weeks			Quan[39]

BIS: bispectral index; POD: postoperative delirium; POCD: postoperative cognitive dysfunction

The Summary of findings table provides a brief synopsis of the analyses (Table 3).

Table 3

Summary of findings table.

P: patients who underwent general anaesthesia, I: BIS monitoring, C: no BIS monitoring, O: postoperative cognitive performance (POD and POCD)
Outcomes	Illustrative comparative risk		Relative effect (95% CI)	No. of participants (studies)	Quality of evidence (GRADE)
	BIS monitoring	no BIS monitoring
POD at 1 day (raw data)	16.1 per 100 patients	22.8 per 100 patients	RR: 0.71 (0.59–0.85)	2138 (3)	●●○○1low
POCD at 1 week (raw data)	15.8 per 100 patients	18.8 per 100 patients	RR: 0.84 (0.66–1.08)	1985 (3)	●○○○2 very low
POCD at 12 weeks(raw data)	6.4 per 100 patients	9.1 per 100 patients	RR: 0.71 (0.53–0.96)	2047 (3)	●○○○3 very low
POCD at 52 weeks (raw data)	3.7 per 100 patients	12.5 per 100 patients	RR: 0.32 (0.04–2.72)	59 (1)	●○○○4 very low
P: patients who underwent general anaesthesia, I: low level of BIS, C: high level of BIS, O: postoperative cognitive performance (POD and POCD)
Outcomes	Illustrative comparative risk		Relative effect (95% CI)	No. of participants (studies)	Quality of evidence (GRADE)
	low level of BIS	high level of BIS
POD at 1 day (raw data)	26.2 per 100 patients	20.1 per 100 patients	RR: 1.92 (0.39–9.33)	259 (2)	●○○○5 very low
POCD at 1 week (raw data)	19.2 per 100 patients	10.3 per 100 patients	RR: 0.52 (0.27–1.00)	105 (1)	●○○○6 very low
POCD at 12 weeks (raw data)	39.6 per 100 patients	14.6 per 100 patients	RR: 0.73 (0.22–2.41)	83 (1)	●○○○7 very low
POCD at 52 weeks	no data	no data	no data

1downgraded one level for risk of bias and one level for indirectness;

2downgraded two levels for risk of bias and one level for imprecision;

3downgraded two levels for risk of bias and one level for indirectness;

4dowgraded one level for risk of bias and two levels for imprecision;

5downgraded two levels for risk of bias, two levels for imprecision and one level for indirectness;

6downgraded one level for risk of bias and two levels for imprecision;

7downgraded one level for risk of bias, two levels for imprecision and one level for indirectness.

BIS: bispectral index; CI: confidence interval; RR: relative risk; POD: postoperative delirium; POCD: postoperative cognitive dysfunction.

RoB

Although selective reporting was scarce, most items did not meet the criteria for low RoB; these include random sequence generation, allocation concealment and blinding. Three out of fourteen studies were considered to be at high risk in terms of incomplete data reporting. RoB of the included RCTs is summarised in Figs 2 and 3.

Fig 2

Risk of bias table.

RCT: randomised controlled trial; "+": low risk of bias; "?": unclear risk of bias; "−": high risk of bias.

Fig 3

Risk of bias graph.

BIS vs. no BIS: POD

We included three [32, 33, 37] studies in the meta-analysis on POD (Fig 4). Based on pooled data from 2138 cases, the use of BIS did prevent POD 1 day after surgery (16.1% vs. 22.8% for BIS vs. no BIS groups, respectively; RR = 0.71, CI: 0.59 to 0.85 for BIS vs. no BIS comparison), without significant between-study heterogeneity (I2 = 0.0%, P = 0.590) [32, 33, 37].

Fig 4

Risk of POD at 1 day with BIS vs. without BIS monitoring.

POD: postoperative delirium; BIS: bispectral index; RR: relative risk; Cl: confidence interval.

Two studies [28, 37] based on data from 121 patients showed that the use of BIS did seem to prevent POD within 1–5 days after surgery. In contrast, findings from two studies [26, 34] involving 135 patients showed a neutral effect of the use of BIS monitoring.

BIS vs. no BIS: POCD

We included three [31-33] studies in the meta-analysis on POCD (Fig 5). Based on pooled data from 1985 cases, the use of BIS did not prevent POCD 1 week after surgery (15.8% vs. 18.8% for BIS vs. no BIS groups, respectively; RR = 0.84, CI: 0.66 to 1.08 for BIS vs. no BIS comparison), without significant between-study heterogeneity (I2 = 25.8%, P = 0.260) [31-33]. The neutral association calculated from the data from 1985 cases proved to be underpowered (indicated by TSA) and therefore insufficient to draw a final conclusion (Fig 6). Based on the pooled data from 2047 cases, the use of BIS did prevent POCD 12 weeks after surgery (6.4% vs. 9.1% for BIS vs. no BIS groups, respectively; RR = 0.71, CI: 0.53 to 0.96 for BIS vs. no BIS comparison), again, without significant between-study heterogeneity (I2 = 0.0%, P = 0.969) [31-33]. Only one study [31] involving 60 patients in groups reported data of POCD 52 weeks after surgery (3.7% vs. 12.5% for BIS vs. no BIS groups, respectively; P = 0.36), indicating no benefit of the intervention.

Fig 5

Risk of POCD at 1 and 12 weeks with BIS vs. without BIS monitoring.

POCD: postoperative cognitive dysfunction; BIS: bispectral index; RR: relative risk; Cl: confidence interval.

Fig 6

Trial sequential analysis of data in the BIS vs. no BIS monitoring anaesthesia comparison for the outcome of POCD.

Trial sequential analysis (TSA) is a random effect-based meta-analytical model to estimate the "required information size"; in other words, the required meta-analytical sample size allowing us to draw a confident conclusion. Each dot on the Z-curve represents a new piece of information, the results of a new randomised study (a total of three studies were used in our case). If the Z-curve crosses the futility boundary, the intervention has no significant effect on the outcome and the results are unlikely to change if further studies are added. If the Z-curve, crosses the significance boundaries, the intervention has a significant effect on the outcome. In our case, neither the conventional significance boundary nor trial sequential significance boundary was crossed by the cumulative Z-curve indicating that the meta-analytical sample size (1985 patients) is insufficient to draw a confident conclusion: further studies are needed until the "required information size" (6461 patients) is reached. BIS: bispectral index; POCD: postoperative cognitive dysfunction.

Two studies [31, 32] with multiple cognitive tests and 154 cases reported a preventive effect of BIS POCD at 1, 12 and 52 weeks.

S2 Table summarises the results of studies reporting on the BIS vs. no BIS comparison for POD and POCD.

Low BIS vs. high BIS: POD

We included four [29, 30, 36, 38] studies in the meta-analysis on POD. Data were available in two studies for POD at 1 day [36, 38], POD at 2 days [29, 37] and POD at 5 days [30, 38]. As demonstrated in Fig 7, low BIS did not change the risk of POD at 1 and 5 days, while high BIS proved to be favourable at 2 days (RR = 1.91, CI: 1.13 to 3.22 for the low BIS vs. high BIS comparison), without significant between-study heterogeneity (I2 = 0.0%, P = 0.589).

Fig 7

Risk of POD at 1, 2 and 5 days with low BIS vs. high BIS monitoring.

POD: postoperative delirium; BIS: bispectral index; RR: relative risk; Cl: confidence interval.

One study [29] involving 114 patients reported no significant difference in Mini Mental State Examination (MMSE) between groups for POD at 2 days (20.0 ± 9.3 in the low BIS group vs. 23.1 ± 5.5 in the high BIS group; P = 0.08). Another study [35] involving 192 patients attributed a protective effect to low BIS for POD at 1 day P = 0.006 for MMSE scores and P = 0.01 for TMT (Trail Making Test) scores.

Low BIS vs. high BIS: POCD

Only one study [39] involving 120 patients presented data on POCD at 1 week. Results from groups were significantly different for POCD at 1 week (19.2% in the low BIS group vs. 39.6% in the high BIS group; P = 0.032) and were similar at 12 weeks (10.3% in the low BIS group vs. 14.6% in the high BIS group; P = 0.558).

Two studies [27, 39] involving 154 patients reported similar results on POCD at 1 [27] and 4–6 weeks [39] after surgery. These studies demonstrated a protective effect of lower BIS on POCD. Only one study [39] reported no significant difference between the effects of different BIS levels at 12 weeks.

S3 Table illustrates the results of postoperative cognitive performance tests for the low BIS vs. high BIS comparison.

Sensitivity analysis

Results for POD at 1 day and POCD at 1 week remained unchanged if any studies were removed from the analysis. However, we lost significance if we removed the Chan et al. study from the analysis on POCD at 12 weeks (probably due to the lack of statistical power).

Discussion

Appropriate brain function monitoring (electroencephalogram monitoring and depth of anaesthesia) would be important to ensure personalised, patient-specific anaesthesia. Theoretically, the application of BIS monitoring could reduce the incidence of prolonged recovery and delayed return of normal cognitive abilities (i.e., orientation and other cognitive functions). A quick and safe postoperative cognitive recovery, such as the avoidance of POD, is of critical importance for patient safety, reduction, and prevention of postoperative complications, early mobilisation and discharge and cost-effectiveness of surgery [2, 6, 7, 9]. POCD starts from the end of the first postoperative week and may persist for weeks to months [2, 11]. POCD impairs quality of life and reduces the Quality-Adjusted life-year (QALY) [11].

Several trials have been conducted to date to evaluate the benefit of BIS monitoring under anaesthesia to prevent POD and POCD (Table 2); however, they have yielded discrepant conclusions (Table 3). Our aim was to summarise the true benefits of BIS monitoring by conducting a meta-analysis with a systematic review.

Our findings provide low quality of evidence that the use of BIS monitoring was superior to not using BIS for POD at 1 day and for POCD at 12 weeks (very low quality of evidence). However, the beneficial effects remained undetected for POCD at 1 week, although the analysis was underpowered (see TSA in Fig 6). (very low quality of evidence) (Table 3). In addition, low BIS seems to be protective against POD at 2 days and maybe against POCD at 1 week (very low grade of evidence for both) (Fig 7, Table 3).

Three previous meta-analyses [15-17] and two systematic reviews [18, 19] have investigated the association between the depth of anaesthesia and cognitive impairment. Lu et al. [15] compared low BIS and high BIS groups in four studies and concluded that the depth of anaesthesia did not correlate with the risk of POCD, but deep anaesthesia carried a significantly increased risk of POD. In their meta-analysis, the number of eligible studies was relatively low and the merged results on the outcomes were inconsistent. Oliveira et al. [16] demonstrated that BIS monitoring is favourable for POD and POCD at 1 month, as opposed to POCD at 1 week. However, in the latter case, data collection might be compromised since neither event numbers nor total number of patients included in analyses match that reported by the original Chan et al. article for POCD [30]. When pooling dichotomous and continuous outcomes, Mackenzie et al. [17] found that electroencephalogram-guided anaesthesia was associated with a reduction in POD incidence. Luo and Zou reported similar results as Mackenzie [17] on the association of BIS- and AEP-controlled anaesthesia with POD. Furthermore, a significant association was found with regard to the reduction of long-term cognitive decline. They identified significant heterogeneity across studies but ORs were similar for cardiac and no-cardiac surgeries [18]. Orena et al. concluded based on their research and currently available data that the use of intraoperative anaesthesia depth monitor is recommended during lighter sedation. Furthermore, the prudent use of premedications was also highlighted [19]. Contrasting these studies, we separated dichotomous and continuous data in the analysis, complemented the list of included studies with new ones and used TSA to decide whether not observing a difference between groups can be attributed to the size of the sample (beta-type error) or to a true association.

Strengths and limitations

(1) This is the first comprehensive assessment to discuss the effect of BIS monitoring on both POD and POCD with rigorous evidence synthesis (as seen in Table 3). In our study, data were shorted to the time of sampling. (2) The main strength of this study is that we included RCTs exclusively [26, 39]. (3) We conducted a comprehensive search with rigorous selection and RoB assessment (Figs 2 and 3). (4) Our main comparisons included a homogenous data set; therefore, confounding factors are unlikely to bias our results (see the I2 and chi2 tests results). This contrasts with the fact that the measurement of cognitive performance is based due to the lack of uniform, comprehensive and ecologically valid tests.

Besides the strengths, the evidence acquired is limited for a number of reasons (Table 3). (1) Although there are many publications, study protocols and data reporting are discrepant and incomplete (e.g. tests handled as continuous variables), thereby impeding statistical analysis. (2) There were mild differences in the definition of POD and POCD across studies, especially in the execution of postoperative cognitive measurements, although this discrepancy did not cause statistical heterogeneity in most analyses. (3) Publication bias could not be assessed due to the low number of eligible studies included. (4) For the same reason, subgroup analyses would be inconclusive. (5) Statistical heterogeneity occurred in some analyses, a result which might be explained by clinical heterogeneity (e.g. indications and types of surgery) and methodological heterogeneity (e.g. perioperative medications). However, previous studies [42, 43, 47] have suggested that certain intraoperative anaesthetic agents (e.g. propofol or volatile gases) may not affect POD and POCD; therefore, they are unlikely to distort our results. (6) Despite the high number of patients included, TSA on the BIS vs. no BIS comparison for POCD at 1 week indicated that neither the conventional significance boundary nor the trial sequential significance boundary was crossed by the cumulative Z-curve (Fig 6). The required sample size would thus be 6461 patients to draw a final conclusion, whereas our meta-analysis of three RCTs included only 1985 cases. (7) It is possible that the neutral association identified in the comparison of low BIS vs. high BIS regarding POD at 1 day is the consequence of beta-type error (Fig 7), which, unfortunately, could not be tested because the conditions of TSA were not met in this case.

Conclusion

BIS monitoring might have a protective effect against POD at 1 day and POCD at 12 weeks compared to not using BIS while low BIS seems to be favourable regarding the incidence of POD at 2 days and POCD at 1 week. Considering the grade of evidence, these findings call for further investigation to identify those patients by age, comorbid conditions, mental status, type of surgery and anaesthesia and by other individual variables who would benefit the most from the use of BIS or other entropy monitoring as well as to establish the optimal BIS value during anaesthesia.

Characteristics of the studies excluded.

(DOCX)

Click here for additional data file.

Parameters for the BIS vs. no BIS comparison for the results of postoperative cognitive performance to establish the diagnosis of POD and POCD.

(XLSX)

Click here for additional data file.

Parameters for the low BIS vs. high BIS comparison for the results of postoperative cognitive performance to establish the diagnosis of POD and POCD.

(XLSX)

Click here for additional data file.

Methodological details.

(DOCX)

Click here for additional data file.

PRISMA checklist.

(DOC)

Click here for additional data file.

11 Dec 2019

PONE-D-19-29094

Is the bispectral index monitoring protective against postoperative cognitive decline? A systematic review with meta-analysis

PLOS ONE

Dear Dr.László Lujber

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I would appreciate if you pay a careful attention to the reviewers' comments in your reply.

We would appreciate receiving your revised manuscript by Jan 25 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Ehab Farag, MD FRCA FASA

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We noticed this systematic review may have potential overlap with your study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166333/

Please consider introducing it in the References and adequately discussing it in the present submission.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

'This study was supported by an Economic Development and Innovation Operative Program Grant (GINOP 2.3.2-15-2016-00048) and an Institutional Developments for Enhancing Intelligent Specialization Grant (EFOP-3.6.2-16-2017-0006) from the National Research, Development and Innovation Office.'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

'The author(s) received no specific funding for this work.'

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now

Please state what role the funders took in the study.  If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

c. Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for submitting the article. It combined information form multiple studies according to the PRISMA Statement and had an updated information since previous metanalysis . There were some issues I wanted to clarify/change:

Abstract.

Ln 47 – Results: We included fourteen studies in the systematic review, eight of which were eligible 48 for meta-analysis. Explain why 6 of them were not included

Ln 49: add the word ’groups’, after “no BIS’

Ln 91-93: consider clarifying abbreviations, reconstruct the sentence and clarify: BIS vs no BIS, then patients with BIS were divided in two groups…

Ln 145: why P<0.1 was chosen?

Ln 166-168: Specify in general terms why 6 studies were not included in metanalysis

Ln 171: Table2 is the same as Table S1. Also you should mention Table 3 Please revise table numbers and comments.

Ln 196: What did other contrasted studies, which included 135 patients, show?

Ln 227-228: where results significantly different with P=0.032, and if they were different, why it was not mentioned in the conclusion?

Reviewer #2: The authors are to be commended for a rigorous attempt to answer 2 questions...does BIS monitoring affect the development of POD or POCD and if the occurrence of a high or low BIS number affects the development of these complications. In an analysis of 1985 patients the conclusions drawn suggest that BIS monitoring is protective of POD on day 1 and protective of POCD at week 12. The level of BIS, high or low did not make a difference in the anlaysis. However, I do not believe that these conclusions can be drawn based on several factors that are not identified; age must be considered, type of anesthetic used, duration of anesthesia, type of surgery preoperative condition, preemptive measures against POD, postoperative complications such as pneumonia, infection or fever, and importantly, what if any measures were taken based on BIS monitoring. For example, if the BIS was low, was the degree of sedation reduced?

Several other studies have looked at BIS monitoring. Orena et al concluded that:

“Use of a depth of anesthesia monitor and lighter sedation had the strongest evidence in reduction of POD. Perioperative dexmedetomidine, ketamine, dexamethasone, and antipsychotic administration may reduce the risk of POD” .(Orena EF et al The role of anesthesia in the prevention of postoperative delirium: a systematic review Minerva Anestesiol. 2016;82(6):669-83.) Other measures were probably also effective

Choi et al developed a screening tool that “successfully identified patients at a high risk of POD at admission. The POD prevention project was feasible to implement, effective in preventing delirium, and improved knowledge regarding delirium among the medical staff” (Choi et al . Impact of a delirium prevention project among older hospitalized patients who underwent orthopedic surgery: a retrospective cohort study BMC Geriatr. 2019 Oct 26;19(1):289. doi: 10.1186/s12877-019-1303-z. The emphasis here was on geriatric patients.

Lee et al also noted that POD is a risk factor for later dementia and following a metanalysis concluded that, “POD after hip surgery is a risk factor for incident dementia. Early identification of cognitive function should be needed after surgery and appropriate prevention and treatment for dementia will be required, especially in cases with POD.” Lee SJ, et al Postoperative delirium after hip surgery is a potential risk factor for incident dementia: A systematic review and meta-analysis of prospective studies. Arch Gerontol Geriatr. 2019 Nov 11;87:103977. doi: 10.1016/j.archger.2019.103977. [Epub ahead of print]. Preoperative recognition of dementia should be made and appropriate measures taken such as medication adjustment.

Specific to this manuscript are the following:

1. All the requirements of PLOS One have been met with the exception of the conclusions drawn

2. The paper could be shortened by eliminating explanations of studies not considered relevant. In general it could be simplified.

3. Any reasons suggested for why neither low nor high BIS values impacted POD at day 1 (In contradiction to other studies)?

4. Lines 91-93 are confusing: l1 vs C1…is that the same as I1 vs Chi1 ?

5. Please reconcile the statements “narcotics do not affect POD and POCD” and “deep anesthesia may”?

6. Of the 14 authors, only one appears to be an anesthesiologist. Given that anesthesia has been implicated in POD and POCD, more impute should be provided from this specialty.

7. The authors note that 6461 patients would be required for a final conclusion and given that only 1/3 are included in this analysis, then even a suggested association with BIS monitoring and POD or POCD may not be warranted. Certainly, more detailed and larger studies looking at many more factors are necessary. Given that some decades ago something akin to mass hysteria arose insisting that BIS monitoring should be the standard of care. Medico legal implications resulted. Subsequent studies have disapproved this insistence. Until more is understood about the development especially of POCD in the elderly, universal BIS monitoring should not be even considered as essential. It may be a tool, but there are too many unanswered questions. And there are other entropy monitors.

.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: elizabeth frost

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: BIS paper .docx

Click here for additional data file.

25 Jan 2020

Ehab Farag MD FRCA FASA 22 January 2020

Academic Editor

PLOS ONE

Dear Academic Editor,

Enclosed please find our revised manuscript entitled “Bispectral index monitoring under general anaesthesia is protective against postoperative delirium and postoperative cognitive dysfunction: A systematic review with meta-analysis”. We greatly appreciate the complimentary comments and suggestions made by You and the Reviewers and thank you for being thorough and for providing us with detailed feedback. We have amended the manuscript as per the recommendations. Based on the reviewers comments we rearranged the sequence of some content. All comments by You and the reviewers were addressed point-by-point to our best knowledge.

As recommended, we removed funding sources from the paper and discussed (and cited) the relevant summary publications mentioned in the letter.

The authors of this manuscript are: Tímea Bocskai, Márton Kovács, Zsolt Szakács, Noémi Gede, Péter Hegyi, Gábor Varga, István Pap, István Tóth, Péter Révész, István Szanyi, Adrienne Németh, Imre Gerlinger, Kázmér Karádi, László Lujber. All authors have reviewed and approved the final revised version of the manuscript.

Registration number: PONE-D-19-29094.

We hope that our revised manuscript meets the high standards of the Journal and that it is now acceptable for publication.

Thank you for giving us this opportunity. We look forward to hearing from you.

Sincerely,

Tímea Bocskai MD PhD

Response to the Reviewers’ comments

Changes are highlighted with the ‘track changes’ function of Microsoft Word.

(Revised Manuscript with Track Changes)

Responses to Reviewer #1

Reviewer #1 Thank you for submitting the article. It combined information form multiple studies according to the PRISMA Statement and had an updated information since previous meta-analysis. There were some issues I wanted to clarify/change:

[Comments from the authors] We would like to thank Reviewer #1 for his/her excellent comments, which have significantly improved the quality of our manuscript.

Abstract

Question Nº 1: Ln 47: Results: We included fourteen studies in the systematic review, eight of which were eligible 48 for meta-analysis. Explain why 6 of them were not included.

[Reply] Thank you for the comment. We added the reasons for exclusion to Fig 1.

[Change in the manuscript] Fig 1

Question Nº 2: Ln 49: add the word ’groups’, after “no BIS’

[Reply] Done.

[Change in the manuscript] Abstract Ln 54

Material and methods

Question Nº 1: Ln 91-93: consider clarifying abbreviations, reconstruct the sentence and clarify: BIS vs no BIS, then patients with BIS were divided in two groups…

[Reply] Thank you for comment. All related abbreviations are clarified in the introduction section, and, to ease the understanding, we spelt out the elements of the PICO framework in this section. In addition, we re-arranged the position of these elements within the paragraph; therefore, PICO elements directly precede the corresponding information in the current version of the manuscript.

[Change in the manuscript] Material and methods Ln 98-102

Question Nº 2: Ln 145: why P<0.1 was chosen

[Reply] Thank you for this comment. The cut-off was chosen as per the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2011. The cut-off deviates from the usual 0.05 to reduce the chance of beta-type error.

https://handbook-5-1.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm

[Change in the manuscript] References [21]

Results

Question Nº 1: Ln 166-168: Specify in general terms why 6 studies were not included in metanalysis.

[Reply] Thank you for the comment. We added the reasons for exclusion to the Fig 1.

[Change in the manuscript] Results Ln 178 and Fig 1

Question Nº 2: Ln 171: Table2 is the same as Table S1. Also you should mention Table 3 Please revise table numbers and comments.

[Reply] We maximally agree with this comment. Indeed, we wrongly inserted the tables in the manuscript before submission. We re-checked all tables and figures and amended the errors. Please find the corrected tables.

[Change in the manuscript] Results Pg 12-15 (Table 2 and 3) and Supplementary (Table S1)

Question Nº 3: Ln 196: What did other contrasted studies, which included 135 patients, show?

[Reply] They found neutral associations. We added it to the corresponding sentence.

[Change in the manuscript] Results Ln 214-216

Question Nº 4: Ln 227-228: Where results significantly different with P=0.032, and if they were different, why it was not mentioned in the conclusion?

[Reply] Thank you for the comment. We complemented the discussion and the conclusion and reported this piece of evidence as well.

[Change in the manuscript] Ln 280-281 and Ln 342-344

Responses to Reviewer #2

Reviewer #2: General comment: The authors are to be commended for a rigorous attempt to answer 2 questions...does BIS monitoring affect the development of POD or POCD and if the occurrence of a high or low BIS number affects the development of these complications. In an analysis of 1985 patients the conclusions drawn suggest that BIS monitoring is protective of POD on day 1 and protective of POCD at week 12. The level of BIS, high or low did not make a difference in the anlaysis. However, I do not believe that these conclusions can be drawn based on several factors that are not identified; age must be considered, type of anesthetic used, duration of anesthesia, type of surgery preoperative condition, preemptive measures against POD, postoperative complications such as pneumonia, infection or fever, and importantly, what if any measures were taken based on BIS monitoring. For example, if the BIS was low, was the degree of sedation reduced?

Several other studies have looked at BIS monitoring. Orena et al concluded that:

“Use of a depth of anesthesia monitor and lighter sedation had the strongest evidence in reduction of POD. Perioperative dexmedetomidine, ketamine, dexamethasone, and antipsychotic administration may reduce the risk of POD”. (Orena EF et al The role of anesthesia in the prevention of postoperative delirium: a systematic review Minerva Anestesiol. 2016;82(6):669-83.) Other measures were probably also effective.

Choi et al developed a screening tool that “successfully identified patients at a high risk of POD at admission. The POD prevention project was feasible to implement, effective in preventing delirium, and improved knowledge regarding delirium among the medical staff” (Choi et al . Impact of a delirium prevention project among older hospitalized patients who underwent orthopedic surgery: a retrospective cohort study BMC Geriatr. 2019 Oct 26;19(1):289. doi: 10.1186/s12877-019-1303-z. The emphasis here was on geriatric patients.

Lee et al also noted that POD is a risk factor for later dementia and following a metanalysis concluded that, “POD after hip surgery is a risk factor for incident dementia. Early identification of cognitive function should be needed after surgery and appropriate prevention and treatment for dementia will be required, especially in cases with POD.” Lee SJ, et al Postoperative delirium after hip surgery is a potential risk factor for incident dementia: A systematic review and meta-analysis of prospective studies. Arch Gerontol Geriatr. 2019 Nov 11;87:103977. doi: 10.1016/j.archger.2019.103977. [Epub ahead of print]. Preoperative recognition of dementia should be made and appropriate measures taken such as medication adjustment.

[Comments from the authors] We would like to thank Reviewer #1 for her excellent comments, which have significantly improved the quality of our manuscript. We entirely agree with your comments and strove to modify the conclusion accordingly.

Question Nº 1: All the requirements of PLOS One have been met with the exception of the conclusions drawn

[Reply] Thank you for the comment. We have revised the evidence and reconsidered the conclusions accordingly. Please, indicate if further fine-tuning is required.

[Change in the manuscript] Discussion and Conclusion

Question Nº 2: The paper could be shortened by eliminating explanations of studies not considered relevant. In general it could be simplified.

[Reply] To ease the understanding of the paper, we simplified the methods section by relocating sections not essential for the understanding to the appendix. Only studies meeting our eligibility criteria are detailed in the results section but to allow the readers a quick summary of the process, the findings and grade of evidence are summarized in Tables 2 and 3. Unfortunately, as Reviewer #1 pointed to it correctly, we wrongly inserted the tables in the manuscript, which was amended in the current version. We hope that these changes made the paper easier to read but we are open to further simplifications if needed.

[Change in the manuscript] Material and methods

Question Nº 3: Any reasons suggested for why neither low nor high BIS values impacted POD at day 1 (In contradiction to other studies)?

[Reply] Thank you for the thought-provoking question. We consulted a statistician on this issue and concluded that the neutral association might be the consequence of beta-type error (TSA could not be executed in this case due to technical reasons). We used the random-effect model in the analyses to overcome the differences in the settings of the studies included, which is accompanied by the widening of the confidence intervals (in other words, results are considered less precise to reduce the risk of establishing false positive associations). In addition, the neutral effect detected by Sieber et al. was taken into account in the analysis when calculating the final estimate. We indicated this as a limitation in the manuscript.

[Change in the manuscript] Results Ln 235-240 and Discussion 276-281

Question Nº 4: Lines 91-93 are confusing: l1 vs C1…is that the same as I1 vs Chi1 ?

[Reply] Thank you for this comment. We spelt out the abbreviation to prevent any misunderstanding from occurring.

[Change in the manuscript] Material and Methods Ln 97-100

Question Nº 5: Please reconcile the statements “narcotics do not affect POD and POCD” and “deep anesthesia may”?

[Reply] Thank you for this comment. The wording has been clarified according to the references cited.

[Change in the manuscript] Discussion Ln 325-327

Question Nº 6: Of the 14 authors, only one appears to be an anesthesiologist. Given that anesthesia has been implicated in POD and POCD, more impute should be provided from this specialty.

[Reply] Thank you for this comment. We invited two expert anesthesiologists for reviewing the manuscript and considered their opinion as well when revising the manuscript. Please, find their opinion attached. Unfortunately, in our opinion, this contribution did not meet the ICMJE authorship policy; therefore, we indicated their contribution within the acknowledgements.

[Change in the manuscript] Additional file, Response to Reviewer (opinion of independent reviewers)

Question Nº 7:

[Reply] We maximally agree with this comment and rephrased the conclusion accordingly.

[Change in the manuscript] Discussion and Conclusion

29 Jan 2020

Is the bispectral index monitoring protective against postoperative cognitive decline? A systematic review with meta-analysis

PONE-D-19-29094R1

Dear Dr. László Lujber

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Ehab Farag, MD FRCA FASA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

5 Feb 2020

PONE-D-19-29094R1

Is the bispectral index monitoring protective against postoperative cognitive decline? A systematic review with meta-analysis

Dear Dr. Lujber:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Ehab Farag

Academic Editor

PLOS ONE