Comparison of Postoperative Neurocognitive Function in Older Adult Patients with and without Diabetes Mellitus

Introduction: Delayed neurocognitive recovery (DNR; neurocognitive disorder up to 30 days postoperative) and postoperative neurocognitive disorders (POCD; neurocognitive disorder 1–12 months postoperative) occur frequently after surgery, with diabetes mellitus (DM) suggested to contribute to this. This was a single-center prospective cohort study. The main aim of this study was to investigate the role of DM and preoperative hemoglobin A1c (HbA1c) in the development of POCDs after noncardiac surgery. Methods: Older adult patients ≥65 years of age scheduled for elective surgery were recruited. The Modified Telephone Interview for Cognitive Status questionnaire (TICS-M), a test of global cognitive functioning, was administered to determine cognition. Preoperative, 30-day postoperative, and 6-month postoperative cognition were compared for patients with and without DM. Cognitive decline was subdivided into mild (1 to 2 standard deviations below controls) and major (≥2 standard deviations below controls) DNR or POCD. Preoperative HbA1c levels were correlated with TICS-M scores. Results: We analyzed 102 patients [median (IQR [range]) age 72.0 (5 [68–74])]), who were divided into patients with DM (80 patients [78%]) and patients without DM (22 patients [22%]). Baseline cognitive function was similar for both groups. Repeated measures ANOVA showed that mean DM patient TICS-M scores decreased 30 days postoperative (F(2, 200) = 4.0, p = 0.02), with subsequent recovery 6-month postoperative, compared to stable TICS-M scores in non-DM patients. There were significantly more DM patients with DNR than non-DM patients (n = 11 [50%] vs. n = 14 [17.5%]; p = 0.031). There were no between-group differences in mild or major POCD. Higher preoperative HbA1c levels were significantly correlated with decreased 30-day Δcognition scores (F(1, 54) = 9.4, p = 0.003) with an R2 of 0.149 (β −0.45, 95% confidence interval: −0.735 to −0.154). Conclusions: Older adult patients with DM undergoing surgery have an increased risk of DNR compared to older adult non-DM patients, but no increased risk of POCD. In DM patients, higher preoperative HbA1c levels were associated with an increased risk of DNR.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Delayed neurocognitive recovery (DNR) and postoperative neurocognitive disorders (POCD) occur frequently after surgery [1, 2] and are described as an objectively measurable decline in cognitive function at varying intervals after anesthesia and surgery [2, 3]. DNR is a cognitive decline from baseline after surgery with either a maintained or impaired capacity for activities of daily living (ADL) up to 30 days postoperative [2]. POCD is longer persisting DNR (between 1 and 12 months postoperative) [2]. They can subsequently be divided into mild (reliable change index of 1 to 2: maintained ADL and symptoms roughly equivalent to mild cognitive impairment (MCI)) or major (reliable change index of ≥2: impaired ADL and symptoms roughly equivalent to dementia). Increasing age, lower educational level, and frailty are all associated with higher incidences of DNR and POCD [3, 4], which in turn are associated with an increased length of hospitalization and institutionalization (approximately one and a half times as long compared to patients without POCD), as well as an increased risk of premature death (hazard ratio of 1.63) [5, 6]. However, perhaps due to a lack of uniform diagnostic criteria [7, 8], substantial variation exists in reported incidences of DNR and POCD [3, 5, 9]. A recent systematic review found a pooled incidence in noncardiac surgery of 11.7% 3 months postoperative [10].

Growing evidence suggests that impaired glucose metabolism and diabetes mellitus (DM) [4] are associated with DNR and POCD [11], although the underlying pathophysiology remains largely unknown. Possible mechanisms include autonomic dysfunction [12], perioperative hypotension [13], stress-induced hyperglycemic neurotoxicity [11, 14], temporary states of hypoglycemia caused by antihyperglycemic treatment [4] and preexisting vascular damage [15]. In addition, chronic hyperglycemia, as measured by high levels of glycated hemoglobin A1c (HbA1c), is associated with cognitive dysfunction in both patients with DM and patients without DM [16, 17]. The exact mechanisms by which DM and elevated HbA1c levels cause impaired cognition are not yet fully understood. Higher HbA1c levels (in patients with and without DM) have been associated with a range of health problems including cardiovascular disease [18], mortality [19, 20], and carotid artery plaques [21], in addition to its association with impaired cognition. It is possible that the vascular pathology associated with prolonged elevated glucose levels may affect cognition [22]. Furthermore, glucose and insulin can directly affect brain structure and function [23]. Metabolites of glucose such as polyols can accumulate, which may cause cerebral problems through the formation of AGEs, nonenzymatic glycation of myelin or oxidative damage/stress [24]. Whether the development of DNR and POCD in patients with impaired glucose metabolism or DM is related to preexisting cognitive dysfunction or to surgical procedures and anesthesia remains to be determined [8].

The roles of cardiac surgery and major noncardiac surgery (based on the Cardiac Risk Stratification for Noncardiac Surgical Procedures [25]) in the development of DNR and POCD have been widely established [3, 9]; however, no research into DNR and POCD risk for DM patients undergoing minor or moderate risk noncardiac surgery has been performed [4]. The main aim of this study was to investigate the role of DM and preoperative HbA1c in the development of POCDs. We conducted a study to determine the risk of developing DNR (30 days postoperative) and/or POCD (6 months postoperative) in older adult DM patients without preselecting subgroups, thus mainly including patients undergoing minor and moderate noncardiac surgery. We hypothesized that DNR and POCD in older adult DM patients depend on decreased preoperative cognitive function and that their courses would differ between older adult patients with and without DM.

Materials and MethodsStudy Design, Study Population, and Inclusion Criteria

This study was a single-center observational prospective cohort study. Subjects were recruited among patients visiting the outpatient clinic of the Department of Anesthesiology of the Amsterdam University Medical Center (UMC), Location Academic Medical Center (AMC) in Amsterdam for preoperative assessment preceding elective surgery. Patients were included in the study between February 2019 and July 2020. All patients aged 65 years or older were screened for eligibility. We included patients without previously diagnosed cognitive impairment (i.e., deficient neuropsychological test performance on at least one test performed by either a general practitioner, geriatrician, psychologist, or neurologist) who were scheduled for elective surgery. Exclusion criteria were planned multiple procedures requiring anesthesia during the follow-up period, a language barrier hindering informed consent or a recent (i.e., within the last 12 months) cerebrovascular event.

Measurements

If the eligibility criteria were met and written informed consent was provided, the Dutch version of the Modified Telephone Interview for Cognitive Status (TICS-M) [26] and the Geriatric 8 (G8) questionnaire [27] were administered over the telephone, at latest on the day before surgery. DNR (i.e., 30-day postoperative cognitive decline from baseline) was considered mild when the TICS-M score decreased by a reliable change index of 1 to 2, and was considered major when the TICS-M score decreased by a reliable change index of ≥2. The same applied to POCD (i.e., 6 months of postoperative cognitive decline from baseline), which was considered mild when the TICS-M score decreased by a reliable change index of 1 to 2, and was considered major when the TICS-M score decreased by a reliable change index of ≥2. The reliable change index is a psychometric expression for the extent to which an individual difference between pre- and post-measurement scores represents a clinically relevant change [28]. The TICS-M is modelled after the Mini-Mental State Examination (MMSE) and is a test of global cognitive functioning [29, 30]. It has the added benefit of being administered by telephone. It consists of 12 items and a maximum score of 50 points can be reached. The established threshold score for MCI is ≤33 points [31], and the established threshold score for dementia is ≤27 points [32]. The TICS-M has relatively little ceiling [33] or practice effects [34] and it takes around 10 min to administer the test [26].

The G8 questionnaire was developed to identify frailty in elderly patients in oncology. It’s an easy-to-use screening tool and consists of eight short questions. It is derived from the Comprehensive Geriatric Assessment (CGA), which is an extensive, multidimensional, multidisciplinary approach to thoroughly evaluate, among others, the medical needs of geriatric patients [35]. The maximum score of the G8 questionnaire is 17 points, with 14 points or lower indicating frailty.

Relevant demographic data and medical history including preoperative medication use were obtained from patient records. American Society of Anesthesiology (ASA) physical status [36], International Standard Classification of Education (ISCED 2011) levels [37], and preoperative laboratory test results (HbA1c, sodium and creatinine) were obtained, together with type of surgery, perioperative anesthetic data, length of hospital stay, and the number of postoperative days at home up to 30 days after surgery (DAH30) [38].

Outcome

We aimed to investigate the role of DM and preoperative HbA1c in the development of DNR and POCD. We hypothesized that DNR and POCD in DM patients depend mainly on decreased preoperative cognitive function. As the primary outcome measure, we therefore determined pre- and postoperative cognitive status by assessing intra- and intergroup differences in baseline cognitive function and the changes in cognition scores between older adult DM and non-DM patients, as measured by the TICS-M scores preoperatively and at 30 ± 3 days and 180 ± 7 days postoperatively.

Since only one Dutch version of the TICS-M is currently available, the occurrence of a practice effect was expected. To control for this, the mean practice score (mean retest score – mean baseline score) was subtracted from the individual’s subsequent scores [39].

Delta (Δ = difference between two scores, expressed as a percentage change from baseline) TICS-M scores and reliable change index Z-scores were calculated and compared for the different time points for both groups. Furthermore, we correlated HbA1c levels with both ΔTICS-M scores for all patients together and also for older adult DM and non-DM patients separately.

As secondary outcomes between group differences in baseline characteristics including ASA physical status, ISCED levels, G8 scores, preoperative laboratory test results, and surgical risk stratification [25] were determined for patients with and without DM. Intraoperative anesthesia and surgical data (e.g., intraoperative hypotension, defined as a mean arterial pressure <65 mm Hg) and postoperative outcomes (i.e., length of hospital stay and DAH30) were compared between groups and between-group differences were determined. The number of older adult patients scoring above the MCI threshold preoperatively, but subsequently scoring below the threshold after surgery, was compared for DM and non-DM.

Sample Size

Before the start of this study, no data on the utility of the TICS-M questionnaire for the assessment of DNR or POCD in older adult patients undergoing noncardiac surgery was present. Furthermore, no previous studies were performed in which DNR or POCD in patients with and without DM was the primary outcome measure; consequently, measures of variability for our primary outcome measure were not available. Therefore, we aimed for a convenient sample size of 100 patients. Examining data from a recent systematic review regarding DM and POCD [4], this would mean approximately 20–25% of patients would have a diagnosis of DM. In a two-sided Z-test for two means, a study with a group 1 sample size (n1) of 47 and a group 2 sample size (n2) of 47 would achieve >90% power at the 5% significance level when the difference in the sample means under the alternative hypothesis is 6.7% [40] and the group 1 and group 2 standard deviations (SD) are 10 and 10, respectively.

Statistical Methods

Baseline characteristics of included patients and patients lost to follow-up were assessed and compared. Included patients were divided into two groups: patients with and without DM. Pairwise comparisons were performed for all preoperative and surgical characteristics, laboratory and functional tests, and postoperative outcomes. In case of normally distributed data the Student’s t test was performed, and data are expressed as means with SD. In non-normally distributed data, either the Mann-Whitney U or χ2 test was performed depending on the type of variable, and data are expressed as medians with interquartile ranges (IQR [range]). Normality was assessed using the Shapiro-Wilk test and by visualizing and inspecting the data.

Repeated measures ANOVA’s were performed to assess any differences between group means of TICS-M scores. Z-scores were calculated and compared between groups. Exploratory multivariable linear regression was performed to assess the role of DM on postoperative TICS-M scores corrected for possible confounding (i.e., correction for the level of education, creatinine levels, surgical risk stratification, cardiac surgery, sex, age, body mass index [BMI], duration of surgery, and a medical history of hypertension or stroke) and beta coefficients and the associated 95% confidence intervals (CIs) are reported. Linear regression was used to predict changes in TICS-M and ΔTICS-M based on preoperative HbA1c levels. All statistical analyses were performed using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA) [41].

ResultsStudy Cohort and Patient Characteristics

A total of 175 patients provided informed consent. Thirteen were excluded for reasons that are listed in Figure 1 and 162 patients entered the study. One hundred and two patients completed the study while 60 did not complete the follow-up (shown in Fig. 1), partly due to the global COVID-19 crisis that took place during the study.

Fig. 1./WebMaterial/ShowPic/1435297

Baseline characteristics of patients lost to follow-up were not different from those patients who completed the study (shown in online suppl. Table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000524886). Median age of patients who completed the study was 72.0 (5 [68–74]) years, 49 (48%) were female, and 22 (22%) had DM. Of the DM patients, 2 (9%) used no antidiabetic medication, 10 (45%) used only metformin, 3 (14%) used only sulfonylureas, 2 (9%) combined metformin and sulfonylureas, 3 (14%) combined metformin and insulin, 2 (9%) combined sulfonylureas and insulin and 1 (5%) combined metformin, sulfonylureas, and insulin. Baseline characteristics, surgical characteristics, and postoperative outcomes are listed in Table 1 and online supplementary Table 2.

Table 1.

Between group differences preoperative and surgical characteristics for patients with and without DM

/WebMaterial/ShowPic/1435301

As expected, there was a statistically significant difference in mean (SD) HbA1c between DM patients (54.0 ± 8.0 mmol/mol) and non-DM patients (37.8 ± 3.9 mmol/mol; t[19.3] = −7.9; p = <0.001) (shown in Table 1). Apart from BMI (29.2 ± 5.1 kg/m2 vs. 26.5 ± 4.1 kg/m2, p = 0.01), ASA classification (p = <0.001), and preoperative creatinine [93 (28 [81–112]) μmol/L vs. 81.0 (31 [71–100]) μmol/L; p = 0.018], no other differences in baseline characteristics for DM patients and non-DM patients were observed. Notably, no differences in preoperative cognitive function, educational level, or frailty were observed (shown in Table 1).

Primary Outcome

Mean (SD) preoperative TICS-M questionnaire scores were comparable between older adult DM and non-DM patients (36.2 [5.2] vs. 35.3 [3.6], p = 0.443). The mean (SD) 30-day postoperative TICS-M score decreased from 36.2 (5.2) to 34.2 (6.2) in the DM patient group (−5.3%), while the 30-day postoperative TICS-M score in the non-DM patient group increased with 1.7% from 35.3 (3.6) to 35.9 (4.2) (Tables 1, 2). The mean (SD) 6-month postoperative TICS-M score then increased to 35 (6.1) in the DM patient group (+3.1% compared to the 30-day postoperative TICS-M score), and the score remained stable for the non-DM patient group (35.6 [4.2], a −0.1% decrease compared to the 30-day postoperative TICS-M score). No significant differences were found for 6-month postoperative TICS-M scores between DM and non-DM patients, however there was a significant difference in mean (SD) preoperative versus 30-day postoperative ΔTICS-M score for DM patients (−5.3% ± 13.8%) compared to non-DM patients (1.7% ± 8.1%; t[25.1] = 2.3; p = 0.031) (shown in Fig. 2a, b; Table 2).

Table 2.

Between group differences in postoperative outcomes for patients with and without DM

/WebMaterial/ShowPic/1435299Fig. 2.

ΔTICS-M scores preoperative – 30 days postoperative (a) and preoperative – 6 months postoperative (b) for patients with and without DM. Box and whisker plots represent lower extreme, lower quartile, median, upper quartile, and upper extreme. Blue color represents patients without DM (n = 80). Red color represents patients with DM (n = 22). *Significant at the level of p ≤ 0.05.

/WebMaterial/ShowPic/1435295

There were significantly more DM patients with DNR than non-DM patients (n = 11 [50%] vs. n = 14 [17.5%]; p = 0.031). There was also significantly more major DNR in patients with DM than in non-DM-patients (n = 4 [18.2%] vs. n = 2 [2.5%]; p = 0.006). There were no between group differences in mild or major POCD (shown in Table 2). Mean TICS-M scores differed significantly between time points (F(2, 200) = 4.0, p = 0.02) in DM patients compared to non-DM patients (shown in Fig. 3).

Fig. 3.

TICS-M scores over time for patients with and without DM. Blue line represents patients without DM (n = 80). Red line represents patients with DM (n = 22).

/WebMaterial/ShowPic/1435293

Preoperative HbA1c levels were negatively correlated with preoperative versus 30-day postoperative ΔTICS-M scores (F(1, 54) = 9.4, p = 0.003) with an R2 of 0.149 (regression coefficient −0.45, 95% CI: −0.735 to −0.154) (shown in online suppl. Fig. 1.1), meaning that every 1 mmol/mol increase in HbA1c is associated with a 0.45% decrease in ΔTICS-M.

Baseline TICS-M scores and 6-month ΔTICS-M scores showed no relationship with preoperative HbA1C levels. Similarly, when only the HbA1c levels of non-DM patients were correlated with preoperative versus 30-day postoperative ΔTICS-M score, no relationship was found (F(1, 37) = 6.0, p = 0.727), with an R2 of 0.003 (regression coefficient 0.103, 95% CI: −0.490 to 0.697) (shown in online suppl. Fig. 1.2).

Secondary Outcomes

In univariable analysis, DM (p = 0.01) was associated with 30-day postoperative ΔTICS-M scores (F(11, 78) = 2.27, p = 0.018, R2 = 0.243). This was confirmed in multivariable analysis correcting for DM, level of education, creatinine levels, surgical risk stratification, cardiac surgery, sex, age, BMI, duration of surgery, and a medical history of hypertension or stroke. No other significant associations were found (shown in online suppl. Table 3).

Five (23%) DM patients who preoperatively scored above the MCI threshold decreased below this threshold after surgery, compared to 6 (8%) non-DM patients (p = 0.022). Four out of 5 DM patients returned to a non-MCI status after 6 months versus 5 out of 6 non-DM patients. Preoperative G8 questionnaire scores were comparable between groups (p = 0.066), although significantly more DM patients considered their health status to be worse than people of the same age, compared with non-DM patients (p = 0.031). No between-group differences were observed for intraoperative hypotension (p = 0.419). The antidiabetic medication used by the DM patients did not affect the ΔTICS-M values. Metformin use: p = 0.138 for 30-day postoperative ΔTICS-M score, p = 0.172 for 6-month postoperative ΔTICS-M score; sulfonylureas use: p = 0.209 for 30-day postoperative ΔTICS-M score, p = 0.576 for 6-month postoperative ΔTICS-M score; insulin use: p = 0.442 for 30-day postoperative ΔTICS-M score, p = 0.943 for 6-month postoperative ΔTICS-M score.

Discussion

In this prospective cohort study, we aimed to investigate the role of DM and preoperative HbA1c in the development of DNR and POCD, and we hypothesized that DNR and POCD in DM patients depend mainly on decreased preoperative cognitive function. We show that, in the absence of cognitive impairment before surgery, patients with DM undergoing surgery had an increased risk of (major) DNR but not POCD as compared to non-DM patients, despite similar preoperative cognitive function. While higher preoperative HbA1c levels were not associated with preoperative cognitive status, they were associated with an increased risk of DNR. After 6 months, the cognition of DM patients improved, and no significant difference was detectable. HbA1c levels of patients without DM were not associated with POCDs. Thus, in older adult patients with DM, there is an increased risk of postoperative neurocognitive impairment after 30 days but not after 6 months, and the higher the HbA1c of a DM patient, the higher the risk.

Half of DM patients had minor or major DNR and they were more than twice as likely to experience a decrease in their 30-day postoperative TICS-M score than non-DM patients. This is a higher percentage than the 26% higher probability reported in the systematic review with meta-analysis by Feinkohl et al. [4]. This may be due to the fact that, in their review, only subgroups of other studies were used. Also, the included studies used many different definitions of POCDs, which were not always in line with the currently leading definitions [2]. As a result, there were some studies that only studied the major forms of DNR and POCD, which means that the true incidence is probably significantly higher. It is also possible that the DM patients in this study had more DM associated conditions such as autonomic dysfunction [12] or preexisting vascular damage [15], which are thought to contribute to DNR in DM.

In our study, both older adult DM and non-DM patients returned to their baseline cognition at 6 months after surgery. Previous research has shown that surgery can also contribute to cognitive decline in the long term [8]. DM patients in our study scored one point lower on the TICS-M 6 months after surgery than they did preoperatively, which could signal the beginning of a possible subsequent deterioration. Alternatively, a few patients just need more than 6 months for full recovery. Possibly, a preoperative decline in the cognitive trajectory was already occurring in the DM patients [8]. Indeed, having DM [42] or higher HbA1c [43] for a long time is associated with a long-term reduction in cognition.

Higher preoperative HbA1c levels were correlated with worse 30-day cognitive function after surgery, which is in line with a previous study examining this relationship [44]. However, there was no correlation between levels of HbA1c and DNR after surgery in patients without DM. Thus, pathophysiological changes associated with DM might play an important role in the development of POCD in this group. High levels of HbA1c in patients with DM may also be associated with vascular damage and/or diabetic neuropathy, and this in turn is a risk factor for intraoperative hypotension [12]. Recent findings from the Neurovision study [40], which identified MRI evidence of silent stroke in 7% of older adults after major surgery (many of whom developed POCD), raised the hypothesis that this may have been attributable to intraoperative hypotension. In our study, we observed no between-group differences for intraoperative hypotension, which is in line with a recent systematic review [45].

All HbA1c levels of non-DM patients from our study fell into normal ranges, with the highest being 48 mmol/mol, so our study population did not include people with prediabetes. Previous research has linked 6 months of cognitive decline with high HbA1c values in patients without DM [17], but no data were available on HbA1c levels in patients without DM and the incidence of DNR or POCD.

Our primary hypothesis that DNR and POCD in DM patients depend on decreased preoperative cognitive function was not confirmed. Baseline cognition was comparable between both groups of patients, and mean preoperative scores were above the threshold for MCI [31] or dementia [32]. Almost a quarter of DM patients decreased below the MCI threshold 30 days after surgery compared to non-DM patients. Except for 2 patients (one with DM and one without), all patients returned to a non-MCI status after 6 months. This implies that cognition in patients with DM is more affected by surgery and anesthesia when compared to non-DM patients, which is in line with previous research showing a higher incidence of postoperative cognitive impairment in DM patients [4]. This might be related to DM-associated conditions such as autonomic dysfunction [12] or preexisting vascular damage [15], but could also be due to the accumulation of glucose metabolites with concurrent AGEs formation, nonenzymatic myelin glycation, oxidative damage/stress [24], or an altered brain structure or function in DM patients [23].

In this study, we found no association between the types of antidiabetic medication and the development of DNR or POCD. This is an interesting finding because several antidiabetic medications, including metformin [46], sulfonylureas [47, 48], and insulin [49], have been described as neuroprotective. However, our study was not designed to detect such an association and therefore no conclusions should be drawn from the fact that we did not demonstrate an association.

Over 80% of the surgeries performed in our cohort were minor or moderate noncardiac surgeries and type of surgery, and their risk stratifications were comparable between groups. Even when correcting for many possible confounders, there was still significant DNR in patients with DM. All previous research was conducted in patients either undergoing major noncardiac surgery or undergoing cardiac surgery. We show here, that patients with DM experience more DNR regardless of the type of surgery. Clarifying the potential role of the surgical procedure and associated risk factors for DNR and POCD in patients with DM is important to enable a reliable risk assessment prior to surgery, to tailor prehabilitation and post-surgery clinical care and to form hypotheses on the mechanisms contributing to DNR and POCD.

This is the first study that specifically studied the role of DM and preoperative metabolic status in the development of DNR and POCD. Furthermore, this is the first time the role of preoperative HbA1c levels of patients without DM in the development of DNR and POCD has been studied. To date, the TICS-M has not been specifically validated for the detection of DNR or POCD, but this is also true of all other tests, such as the MMSE [50], the Montreal Cognitive Assessment (MoCA) [51], and even specific neuropsychological tests in test batteries.

A limitation of our study is the large number of patients who could not be reached to take one of the two postoperative TICS-M questionnaires. This study was conducted during the global COVID-19 crisis, which made it difficult to contact every patient within the predetermined maximum time intervals. However, baseline characteristics were compared, and no differences were found between patients who completed the study and those lost to follow-up. It is important to note that since only 22 patients with a diagnosis of DM were included in the study, this increases the likelihood of type II errors given this relatively small sample size.

Another limitation was the use of a single cognitive test for cognitive measurement. To date, neuropsychological assessment (NPA) is still the gold standard to determine DNR and POCD, yet precise tests are not specifically validated [2]. As NPA is not feasible in daily practice, we chose the TICS-M, which is an easy-to-administer test over the telephone and is thought to detect early cognitive impairment more adequately than the MMSE [31, 33]. However, because there is only one Dutch version available, we needed to adjust for the observed practice effect by taking the test at different time points. Nevertheless, a clear difference in scores was observed between our two groups, which was in line with previous data [4]. Furthermore, the scores in non-DM patients were stable across all assessments, indicating a high test-retest reliability of the TICS-M.

Future studies should focus on the pathophysiological principles underlying DNR and POCD in patients with DM, and the findings from this study need to be confirmed in a larger multicenter study. Furthermore, it seems worth investigating whether lowering HbA1c levels before surgery might have positive effects on postoperative cognition. Also, there is a need for an easy and rapidly administrable cognitive test that is properly validated and sensitive enough to measure subtle changes in cognition. This would greatly benefit the comparability between studies. Lastly, it is recommended to have the first follow-up measurement ≥30 days after surgery, as to minimize possible confounding by surgical aspects or hospitalization [2].

To summarize, our study showed that DM and higher preoperative HbA1c levels in DM increase the risk of DNR, but not POCD, independent of preoperative cognitive function. HbA1c levels in older adult patients without DM showed no relationship with POCDs.

Statement of Ethics

The study was approved by the Local Medical Ethics Committee of the Amsterdam University Medical Centers (UMC), location Academic Medical Center (AMC) (METC AMC, The Netherlands; METC number W19_044 # 19.067). Written informed consent was obtained from all patients before start of the study. The study was performed according to the Declaration of Helsinki [52]. The trial was registered with trialregister.nl, number NL7530 [53]. Performance, recording, analysis, and reporting was done according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for reporting observational studies [54].

Conflict of Interest Statement

The authors declare no conflict of interest regarding the submitted work. Outside the submitted manuscript, Markus W. Holl­mann served as executive section editor of pharmacology for anesthesia and analgesia and as section editor of anesthesiology for the journal of clinical medicine, he received speakers fees from CSL Behring and Eurocept BV.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Mark L. van Zuylen, Robert van Wilpe, Hanna C. Willems, Gert J. Geurtsen, Abraham H. Hulst, and Jeroen Hermanides designed the study. Mark L. van Zuylen, Robert van Wilpe, and Jeroen Hermanides performed the research. Mark L. van Zuylen, Robert van Wilpe, Hanna C. Willems, Gert J. Geurtsen, J. Hans DeVries, and Jeroen Hermanides assisted in reviewing the results. Mark L. van Zuylen, Robert van Wilpe, and Jeroen Hermanides wrote the manuscript. All the authors critically evaluated the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available but are available from the corresponding author (Mark L. van Zuylen) upon reasonable request.

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