Effects of dexmedetomidine dosage on the short-term cognitive function of elderly patients undergoing cardiac surgery

Background This study aimed to investigate the effects of perioperative dexmedetomidine (DEX) infusion rates on the postoperative short-term cognitive function. Methods A total of 88 patients aged ≥ 60 years who underwent cardiac surgery from January 2022 to November 2022 at the First Affiliated Hospital of The University of Science and Technology of China (USTC) were included. Based on a single-center pilot analysis, patients were divided into two groups according to the rate of intraoperative DEX infusion, which started after tracheal intubation and continued until 1 h before extubation in the cardiac surgery intensive care unit. In Group L (n = 44), the infusion rate was 0.1–0.5 µg/kg/h (low-dose group), whereas in Group H (n = 44), the infusion rate was 0.5–0.9 µg/kg/h (high-dose group). Clinical outcomes were then compared between the groups. The Mini–Mental State Evaluation (abbreviated as MMSE1, MMSE2, MMSE3, and MMSE4) scale was used for the assessment of cognitive function, which was conducted on postoperative Days 2 (T1), 7 (T2), 14 (T3), and 28 (T4), with the score from postoperative Day 2 (MMSE1) considered as the primary observation. Results Patients in Group L had higher MMSE1 scores compared to those in Group H (26.0 [24.0, 27.0] vs. 24.5 [22.0, 26.0], p = 0.046), and there was no significant difference in the scores between the groups at all subsequent time points. Group H exhibited a higher incidence of hypotension and bradycardia compared to Group L (p = 0.044 and p = 0.047, respectively). Conclusions Compared to a high dose (0.5–0.9 µg/kg/h) of DEX infusion, a low-dose (0.1–0.5 µg/kg/h) infusion started after induction of anesthesia and continued until 1 h before extubation improved postoperative cognitive function scores on postoperative Day 2 in patients aged 60 years and older. Trial registration URL: www.chictr.org.cn with registration number ChiCTR2100055093, registered on 31/12/2021.


Background
Postoperative cognitive dysfunction (POCD) is a common complication that typically occurs within 1-3 months after surgery.Factors affecting postoperative cognitive function include patient age [1], cerebral perfusion pressure [2], cerebral microemboli [3], modes of cardiopulmonary bypass [4], systemic inflammatory response [5], preoperative depression [6], use of inhaled anesthesia [7], opioid administration [8], and sleep disturbances [9].Dexmedetomidine (DEX) has been used in open heart surgery; however, its effect on postoperative cognitive function has yielded inconsistent results across different studies.These discrepancies can be attributed to differences in the objects being compared, cognitive assessment tools, and the infusion dose of DEX [10][11][12].The optimal DEX infusion rate during cardiac surgery remains unknown.In a meta-analysis, Duan et al. [13] found that if the occurrence of delirium was the only primary endpoint, an optimal strategy might involve a loading dose ranging from 0 to 0.5 µg/ kg, followed by a maintenance dose of 0.2 µg/kg/h.However, this conclusion is not universally applicable owing to the differences in research subjects, administration methods, and timing of drug delivery in clinical practice.Furthermore, it is difficult to inject DEX at a certain fixed dose.Therefore, it is more realistic to find the optimal range of DEX infusion rates to reduce POCD without side effects.According to the infusion rates of DEX listed in the previous anesthesia records from cardiac surgeries in our hospital, we found that the typical DEX infusion rate ranged between 0.1 and 0.9 µg/kg/h.After discussion with a statistician, we divided the DEX infusion rates into two groups with equally wide ranges: 0.1-0.5 µg/kg/h, classified as the low-dose group, and 0.5-0.9µg/kg/h, classified as the high-dose group.The dosing strategy for DEX is tailored for each patient by the attending anesthesiologist based on their clinical experience, personal preference, and the patient's condition.Given the significance of preventing cognitive impairment in elderly patients, a keen emphasis is placed on this aspect.The minimental state examination (MMSE) serves as a widely employed tool for evaluating cognitive function, and, in our study, the MMSE score on postoperative day 2 was designated as the primary study index.Our study did not focus on whether perioperative infusion of DEX reduces postoperative cognitive impairment.Instead, the main objective of this study was to compare the effects of different intraoperative DEX infusion doses on the cognitive function of elderly patients undergoing cardiopulmonary bypass (CPB) cardiac surgery.A secondary objective was to assess the impact of different perioperative DEX infusion doses on other complications and safety outcomes.

Study population and stratification
This trial was approved by the institutional review board of the First Hospital of the University of Science and Technology of China and registered at the Chinese Clinical Trial Registry with registration number ChiCTR2100055093(31/12/2021).
Out of 111 elderly patients who underwent cardiac surgery and received DEX infusion, 11 were excluded, 12 withdrew, and 88 were included in the study (Fig. 1).The patients were divided into two groups: Group L (n = 44), in which patients received a low-rate infusion of DEX at 0.1-0.5 µg/kg/h and Group H (n = 44), in which patients received a high-rate infusion of DEX at 0.5-0.9µg/kg/h.The inclusion criteria were as follows: (1) having undergone cardiac surgery (valve or aortic root surgery) between January 2022 and November 2022; (2) age between 60 and 75 years; and (3) DEX infusion rate of 0.1-0.5 µg/ kg/h or 0.5-0.9µg/kg/h, continued until 1 h before postoperative extubation in the cardiac surgery intensive care unit (CSICU).The exclusion criteria were as follows: (1) preoperative disagreement or refusal to participate in the study; (2) pre-existing history of mental illness; (3) baseline MMSE (MMSE 0 ) score ≤ 20; and (4) ejection fraction ≤ 50% after admission.The withdrawal criteria were as follows: (1) perioperative use of DEX that was not within the scope of the defined group parameters or the use of a loading dose; (2) a second admittance to CSICU; (3) incomplete postoperative follow-up data; (4) failure in patient data analysis; (5) Dex infusion for more than 36 h; and (6) III° atrioventricular block during Dex infusion.
All patients underwent cardiac surgery following standard anesthesia and CPB protocols and were routinely admitted to the CSICU for postoperative management.The types of surgery were categorized into valve surgery and aortic root surgery.Valve surgery included procedures such as isolated mitral, tricuspid, and aortic valve surgery; combined mitral and tricuspid valve surgery; and combined mitral and aortic valve surgery.Aortic root surgery included procedures such as Bentall surgery, Wheat surgery, and David surgery.
We collected and analyzed data related to age; sex; body mass index (BMI); MMSE 0 (recorded on preoperative Day 1 [T 0 ]); educational level (specifically, those with < 5 years of education); history of hypertension and diabetes; type and duration of surgery; preoperative ejection fraction (EF); hemoglobin level; benzodiazepine use; doses of sufentanil, propofol, and penehyclidine; and duration of DEX infusion (Table 1).

Data collection
We recorded and collected relevant preoperative and intraoperative baseline data, as described above.The data also included various outcome indicators, such as MMSE score on postoperative Day 2 (MMSE 1 ), Day 7 (MMSE 2 ), Day 14 (MMSE 3 ), and Day 28 (MMSE 4 ); instances of intraoperative hypotension; duration of initial intubation; length of CSICU stay; incidence of postoperative delirium (POD); occurrence of myocardial infarction and stroke; length of hospital stay; and hospitalization-related mortality.

Primary outcome measures
Our primary outcome was short-term cognitive function.We used the MMSE score recorded on postoperative Day 2 as the primary observation endpoint.Assessments were conducted in the CSICU or the cardiac surgery ward on this day.During inpatient evaluation, patients were assessed face-to-face by the researchers, whereas for outof-hospital evaluations, the MMSE scale evaluations were conducted through WeChat video visits, combined with a patient self-help model.Uniform assessment forms were used for both in-hospital and out-of-hospital evaluations.

Secondary outcome measures
The secondary outcomes for this study included the incidence of POD, intraoperative hypotension and bradycardia, length of hospital stay, and in-hospital mortality.The CSICU of our unit has a routine protocol for POD evaluation.To differentiate from the residual effects of anesthesia, delirium screening was started 24 h after cardiac surgery and performed twice a day.The Confusion Assessment Method Intensive Care Unit (CAM-ICU) scale was used to assess delirium every 12 h, specifically at 9:30 and 21:30.When a patient was discharged from the CSICU to the ward, the CAM was used to assess delirium every 12 h until postoperative Day 5.If delirium was not resolved by this day, the evaluation continued until discharge.The incidence of POD was defined as the percentage of patients who developed delirium during their hospitalization.Intraoperative hypotension was defined as systolic blood pressure below 80 mmHg lasting for at least 1 min or instances where the systolic blood pressure dipped below 80 mmHg at least twice.Intraoperative bradycardia was defined as a heart rate ≤ 60 beats/min.Myocardial infarction was defined as an increase in troponin I by more than 10 ng/mL during the postoperative CSICU and ward stays, along with higher than normal CK-MB, total CK exceeding 10%, and a new Q wave in the ECG lead in two or more consecutive measurements.Postoperative stroke was identified when its diagnosis was confirmed by a neurologist during postoperative CSICU and ward monitoring.CSICU duration was defined as the time of the patient's stay in the CSICU, calculated in hours.Hospital stay was defined as the time from registration of patient admission to their discharge.Inhospital mortality was calculated as the ratio of deaths from CSICU admission to discharge relative to the total number of patients in the study group.

Sample size calculation
This study aimed to compare the differences in the MMSE scores on postoperative Day 2 between the two study groups.Studies by Shaefi et al. [14] and Saczynski et al. [15] showed that the MMSE score on postoperative Day 2 is the lowest point, with the minimum clinically significant difference being 2 points after surgery.The pre-test results of 12 patients using low-dose infusion showed a mean and standard deviation of 24.4 ± 2.6 for the postoperative Day 2 MMSE scores.Assuming a difference test of the usage rate with a 5% two-tailed type I error rate (α = 0.05) and a test efficiency of 90%, the sample size was calculated using PASS 15.0 software, requiring 37 patients in each group.Considering a dropout rate of approximately 20%, a sample size of 46 patients per group was planned.

Statistical methods
Normally distributed continuous variables were described using mean ± standard deviation, non-normally distributed continuous variables were described as median (interquartile range), and categorical variables were described using percentages.

Baseline data and intraoperative parameters
The results of our patients are presented in Table 1.
No statistically significant differences were observed between the two groups for the most analyzed indicators.

Effects of different rates of DEX infusion on patient outcomes
Among the elderly patients included in this study, the MMSE 1 score was lower in Group H compared to Group L after cardiac surgery (p = 0.046).No significant differences were observed between the MMSE 2 , MMSE 3 , and MMSE 4 scores between the two groups.Group L showed lower incidences of both hypotension (p = 0.044) and bradycardia compared to Group H (p = 0.047).No statistically significant differences were observed in other secondary indicators between the two groups (Table 2).
The MMSE score of both the groups decreased from the preoperative time point (T 0 ) to postoperative Day 2 (T 1 ; p < 0.001) and then increased on postoperative Day 3 (T 2 ; p < 0.001).However, scores between T 2 , T 3 , and T 4 remained consistent in their respective groups.These results can be seen in Tables 3 and 4, and Fig. 2.

Discussion
In our study, the high-dose group (0.5-0.9 µg/kg/h) showed a trend of relatively weaker neuroprotective effect compared to the low-dose group (0.1-0.5 µg/kg/h) on postoperative Day 2 (p = 0.046).However, animal studies by Zhou et al. [16] and Ma et al. [17] indicated that the neuroprotective effect of DEX is dose-dependent, with higher doses providing stronger neuroprotective effects.Zhang et al. [12] performed a prospective study on the effect of different doses of DEX on POCD in elderly patients, in which 80 patients undergoing laparoscopic colorectal cancer surgery were divided into four groups (n = 20), namely, control, D 1 , D 2 , and D 3 .While the control group received a loading dose of 0.5 µg/kg DEX, the D 1 , D 2 , and D 3 groups received maintenance doses of 0.2 µg/kg/h, 0.5 µg/kg/h, and 0.8 µg/kg/h of  DEX, respectively.The results showed that the high dose (0.8 µg/kg/h) afforded better neuroprotective effects compared to the low dose (0.20 µg/kg/h; p < 0.05).This difference may be attributed to the different durations of DEX intervention between the two studies.While Zhang et al. 's study included a short-term intervention of less than 3 h, our study had an overall median DEX infusion time of 19.0 (14.0, 24.8) hours for both groups.Another reason for the difference may be the increased incidence of hypotension in the high-dose group compared to the low-dose group in this study (p = 0.044).As documented in the literature, intraoperative hypotension may increase early cognitive dysfunction [18], diminishing the neuroprotective benefits in the high-dose group on postoperative Day 2. There was no difference in MMSE scores between the two groups at other time points (T 2 , T 3 , and T 4 ).As shown in Fig. 2, the MMSE score at T 1 was the lowest, but it returned to the baseline level at T 2 , T 3 , and T 4 .These data indicate that there was a transient decrease in MMSE scores on postoperative Day 2, which then returned to preoperative levels by postoperative Day 7 in both groups.
Moreover, this study showed that Group H had a slightly higher incidence of intraoperative hypotension (p = 0.044) and bradycardia (p = 0.047) compared to Group L. The anti-sympathetic effect (resulting in decreased blood pressure and slowed heart rate) was observed when DEX plasma concentrations were in the range of 0-0.7 ng/mL in Ebert et al. 's study [19], which showed that this anti-sympathetic effect could be amplified in a dose-dependent manner with the DEX infusion.Other secondary observations, including time to initial intubation, instances of myocardial infarction, stroke, duration of CSICU stay, and hospital mortality, did not significantly differ between the groups.
Our study has several limitations that should be considered.First, the p-value for the comparison of MMSE 1  scores between the two groups on postoperative Day 2 was close to 0.5, rendering the evidence less convincing.Second, because this was a small single-center study, the limited sample size and the single study population limit the generalizability of the results.Third, the study only compared two different infusion dose groups without a blank control group; hence, our results cannot be simply attributed to a direct increase or decrease in postoperative cognitive function in our sample.Fourth, although the content of the in-hospital and out-of-hospital cognitive function assessments was similar, differences in the assessment methods may influence the results of the study.

Conclusions
In patients aged 60 and older, a low-dose perioperative infusion of DEX (0.1-0.5 µg/kg/h) may offer better cognitive protection on postoperative Day 2 compared to a high-dose infusion (0.5-0.9 µg/kg/h).Additionally, to reduce the incidence of bradycardia and hypotension, a low-dose (0.1-0.5 µg/kg/h) DEX infusion during the perioperative period may be a better option.

Table 4 Fig. 2
Fig. 2 MMSE of patients at different time points during the study period.MMSE values are reported separately for the low-dose group (red dots) versus the high-dose group (black squares), and data are expressed as medians (interquartile spacing).MMSE, Mini-Mental State Examination; T 0 , on preoperative 1 day; T 1 , on postoperative 2 days; T 2 , on postoperative 7 days; T 3 , on postoperative 14 days; T 4 , on postoperative 28 days

Table 1
Baseline clinical characteristics and intraoperative variables of Group L and Group H Data are shown as the mean ± standard deviation, number (percent), or median (interquartile range) as appropriate.# Fisher's exact test BMI Body mass index, MMSE 0 baseline Mini-Mental State Evaluation, ASA American Statistical Association, EF Ejection fraction, CAS Carotid artery stenosis, CPB Cardiopulmonary bypass, DEX Dexmedetomidine

Table 2
Postoperative outcomes in Group L and Group H Data are shown as the mean ± standard deviation, number (percent), or median (interquartile range) as appropriate.# Fisher's exact test MMSE Mini-Mental State Evaluation, T 1 on postoperative 2 days, T 2 on postoperative 7 days, T 3 on postoperative 14 days, T 4 on postoperative 28 days, POD postoperative delirium, CSICU cardiosurgery intensive care unit

Table 3
Comparison MMSE of adjacent time points within the group L Data are shown as the median (interquartile range) as appropriate.*P <0.05,compared with the preoperative timepoint (T 0 ) ,**P <0.05, compared with the postoperative 2 days (T 1 ) MMSE Mini-Mental State Evaluation, T 0 the preoperative timepoint, T 1 on postoperative 2 days, T 2 on postoperative 7 days, T 3 on postoperative 14 days, T 4 on postoperative 28 days