Effects of Different Injection Rates of Propofol on Postoperative Cognition in Elderly Patients Undergoing Laparoscopic Inguinal Hernia Repair

Introduction

As the world ages, the number of surgical procedures performed in elderly patients has rapidly increased. POCD is a common complication after anesthesia in elderly patients.¹ POCD is characterized by acute or persistent impairment of attention, concentration, learning, and memory after surgery.² The occurrence of POCD is associated with decreased quality of life, increased the long-term mortality, and significantly increased use of medical resources.^3–5 This prompted us to explore anesthetic interventions that could help reduce the incidence of POCD.

Despite extensive research in recent years, the causes and pathophysiological mechanisms underlying postoperative cognitive decline remain unclear. The underlying mechanism of POCD may involve a combination of surgical, patient, and anesthetic factors.^6,7 Traumatic stimuli after major surgery may activate the release of nuclear factor (NF)-κB and cytokines, thereby impairing the integrity of the blood–brain barrier. Age is an independent risk factor for POCD.^8,9 Intraoperative EEG monitoring in high-risk patients with cognitive impairment can promote early postoperative cognitive recovery.¹⁰ BIS has been widely used in clinical practice as the earliest tool for monitoring the depth of anesthesia. Propofol is a commonly used intravenous anesthetic owing to its rapid onset and recovery time. Studies have shown that BIS is closely related to propofol and can accurately reflect the depth of sedation.^11,12 The maximum EEG effect of propofol in patients increased with increasing rate of propofol injection.¹³ This may also lead to differences in the incidence of burst suppression. However, the incidence and duration of intraoperative EEG burst suppression are associated with early postoperative cognitive decline.^14,15 A dose-dependent decrease in systemic vascular resistance with propofol causes hypotension and cerebral hypoperfusion.^16,17 These factors may affect the early POCD in patients.

In clinical practice, the anesthesiologist can freely choose the rate of anesthesia injection for the patient. However, there is currently no relevant research on the effect of propofol injection rates on the early postoperative cognition in elderly patients. Therefore, we conducted a randomized controlled trial to compare the effect of propofol injection rate on early postoperative cognition in elderly patients undergoing laparoscopic inguinal hernia repair.

Materials and Methods

Study Design and Study Population

The trial was approved by the Ethics Committee of the Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) (Ethics Approval Number: 2021 KY-081 Anhui, China), and was registered in the Chinese Clinical Trial Registry (ChiCTR2000040005) on November 18, 2020. The inclusion criteria were as follows: age 60–90 years, American Society of Anesthesiologists (ASA) physical status II–III, education level sufficient to complete neuropsychological tests, voluntary participation in this study and signed informed consent. The exclusion criteria were obesity (body mass index >28 kg m⁻²), allergy to the anesthetics used, history of cerebrovascular disease in the last 3 months, liver and kidney dysfunction, history of mental illness or taking psychotropic drugs, recent alcohol abuse, language communication difficulties, significant hearing or visual impairment, and preoperative Mini-Mental State Examination score <24. Patients who required more than the standard dose of propofol (2.5 mg kg⁻¹) during anesthesia induction, experienced burst suppression during anesthesia maintenance and declined postoperative follow-up were not included in the final statistical analysis.

Randomization

Elderly patients who underwent laparoscopic inguinal hernia repair in our hospital from May to November 2021 were enrolled in this prospective randomized single-blind clinical trial. The patients were randomly divided into three groups at a 1:1:1 proportion using random number table: Vs-Group (the induction rate of propofol was 30 mg kg⁻¹ h⁻¹); V_M-Group (the induction rate of propofol was 100 mg kg⁻¹ h⁻¹) or V_F-Group (the induction rate of propofol was 300 mg kg⁻¹ h⁻¹). The assigned numbers are wrapped in opaque envelopes that can only be seen by the anesthesiologist in charge of the patient’s anesthesia. Patients, outcome evaluators, and data information analysts were blinded to trial intervention.

Anesthesia and Perioperative Care

None of the patients had received premedication. After entering the operating room, routine continuous monitoring was performed (Mindray, Shenzhen, China), including blood pressure, electrocardiography, pulse oxygen saturation (SpO₂), and bispectral index (BIS Covidien IIC, USA). The direction of electroencephalogram electrode sticking was determined by tossing a coin. Before anesthesia, the peripheral veins of the upper extremities were opened and balanced crystalloid solutions (5–7 mL kg⁻¹) were infused at a rate of 5–7 mL kg⁻¹ h⁻¹ until anesthesia induction. Anesthesia was induced after preoxygenation for at least 3 minutes. Anesthesia induction with propofol was accomplished by an anesthesiologist responsible for the patient’s anesthesia using a microinfusion pump. Propofol was stopped when BIS value dropped to 60. If the dose of propofol exceeds 2.5 mL kg⁻¹ and BIS value is still greater than 60, propofol was stopped. Within 2 min, if BIS value did not decrease but increased, additional propofol of 0.5 mg kg⁻¹ time⁻¹ was administered for remediation until the BIS value was ≤60. Then, sufentanil 0.4 µg kg⁻¹ and rocuronium 0.6 mL kg⁻¹ were administered. Endotracheal intubation and mechanical ventilation were performed after muscle relaxation was satisfactory. and BIS value was less than 50. During the operation, the end-tidal carbon dioxide pressure (P_etCO₂) was maintained at 35–45 mmHg.

Intraoperative anesthesia was maintained with propofol 4–8 mL kg⁻¹ h⁻¹, remifentanil 0.1–0.3 μg kg⁻¹ min⁻¹ continuous intravenous pumping. BIS value was maintained between 40 and 60. At the end of pneumoperitoneum, all anesthetics were stopped and all patients in all three groups were given intravenous flurbiprofen axetil 100 mg and ondansetron 4 mg and then sent to the post-anesthesia unit (PACU). The tracheal tube was removed after spontaneous breathing resumed. If the Steward score (mainly from the degree of consciousness, respiratory tract patency, and limb activity of the three indicators; each index is 0–2 points, with the highest score of 6 points) is greater than 4, patients can be sent back to the ward. During the postoperative period, flurbiprofen axetil (50 mg) was given intravenously when the VAS score was above 3.

Perioperative heart rate (HR) was maintained at 50–100 beats min⁻¹; If HR < 50 beats min⁻¹, atropine (0.3–0.5 mg) was administered; If HR > 100 beats min⁻¹, esmolol (0.3–0.6 mg kg⁻¹) is given. If systolic blood pressure increases or decreases by 10% from baseline, nicardipine (5–10 μg kg⁻¹) and norepinephrine (0.1–0.2 μg kg⁻¹ min⁻¹) are given. Ephedrine (3–6 mg) should be given if blood pressure and heart rate are low. Intraoperative midazolam, dexmedetomidine, and inhalation anesthetics were avoided, and there were no restrictions on the use of muscle relaxants and vasoactive drugs. As propofol is widely used in clinical practice, this study did not establish a clinical data safety monitor.

Data Collection

The main outcome measure of this study was the incidence of early POCD in the three groups of patients. We simultaneously collected data at the following time points: the time from propofol injection to the declining of BIS value, the time for BIS value dropped to 60, the induction dose of propofol, the BIS-min and the incidence of burst suppression during induction of anesthesia, the number of patients with hypotension, anesthesia and surgery duration, and duration of hospitalization. In this study, burst suppression was defined if the burst suppression ratio (SR) was greater than zero and was observed 15 minutes after induction of anesthesia. The mean arterial pressure (MAP) and heart rate (HR) were recorded at baseline, 5 minutes after anesthesia induction, 5 min after surgery begin and 5 min after surgery end. Blood samples were collected at baseline, 5 min after anesthesia induction, 30 min and 24 h after surgery to determine the concentrations of interleukin (IL)-6, IL-10, S100β, and tumor necrosis factor (TNF)-α.

Cognitive Function Measurement

Cognitive function was assessed by a trained investigator on the day before surgery and on the first and seventh days after surgery. Cognitive tests were performed in a quiet room with only the patient and the investigator. The same investigator performed the tests for each patient. The researchers were unaware of the patient grouping. We used the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess changes in cognitive function in elderly patients. These two scales were chosen for practical reasons owing to their relative simplicity, short time consumption, high patient compliance, and members of the research group were familiar with the MMSE and MoCA. A patient was considered to have POCD if the scores on both scales decreased by 1 SD (standard deviation) from the preoperative level.

Cognitive test scales included the following: (1) the MMSE scale, which is the most commonly used rapid screening tool for clinical cognitive dysfunction, with a high sensitivity of 88% and specificity of 86% for clinical screening.^18–20 Because of its ease of completion and reliability, it remains valuable for tracking postoperative cognitive changes. This scale evaluates cognitive function in the following five parts: orientation, memory, attention, calculation, recall, and language. The higher the score, the better is the cognitive performance. (2) the MoCA Scale is a sensitive and widely used screening assessment test for detecting mild cognitive impairment, with a sensitivity and specificity of 90% and 87%, respectively.^21,22 The cognitive function of the patients was assessed mainly by visuospatial and executive function, naming, memory, attention, calculation, language, abstraction, delayed recall, and orientation. For patients with a high school education and below and a total score of less than 30, the scale score adds one more point to the total score.

Enzyme-Linked Immunosorbent Assay

Blood samples were collected before anesthesia induction, 5 min after anesthesia induction, 30 min and 24 h after surgery to determine the plasma concentrations of IL-6, IL-10, S-100β, and TNFα. Blood samples were centrifuged at 3000g for 15 min at 4°C, and the centrifuged serum was stored at −80°C until analysis. The serum concentrations of IL-6, IL-10, S-100β, and TNFα were analyzed using an ELISA kit (Jianglai, Shanghai, China) according to the manufacturer’s instructions.

Sample Size and Statistical Analysis

The primary outcome of this study was the incidence of POCD. We calculated the number of patients required for each group based on the cognitive scores of the first 15 patients (5 patients in each group) recorded in the pre-experiment. In this small sample, cognitive scores decreased by 2.3 ± 3.8 (mean ± SD) immediately after surgery in the immediate postoperative period. We hypothesized that cognitive scores would not decline in the slow injection group compared with the rapid injection anesthesia group. Therefore, assuming a mean difference in groups of 2.3 and a pooled standard deviation of 3.8. Set bilateral α=0.05, 1-β=0.85. According to PASS 15.0, the sample size in each group was 50. Considering the 20% loss to follow-up rate, the final sample size in this study was 60 patients per group.

IBM SPSS Statistics software (version 25.0) was used for data analysis. Numerical variables are expressed as mean ± SD or median [IQR]. The differences among the groups were analyzed using a one-way ANOVA test or Kruskal–Wallis test, as appropriate. Categorical variables were presented as frequencies (percentages), and X² or Fisher’s exact test was used for analysis. Repeated measures ANOVA was used to compare different time points within the groups. Univariate logistic regression analysis was used as the first step to identify the possible prognostic factors for POCD. Variables with P < 0.05 in these analyses were included in the multivariate regression analysis to exclude the influence of confounding factors. Multicollinearity among independent variables was evaluated using the variance inflation factor (VIF). The Hosmer–Lemeshow test was used to test the goodness of fit of the model. The accuracy of the model was estimated by analyzing the area under the ROC curve. Statistical significance was set at P < 0.05.

Results

A total of 180 patients were enrolled in this study. Among these patients, two patients in the V_S group were excluded, one of whom required additional propofol beyond the prescribed maximum dose and the other was lost to follow-up. In the V_M and V_F groups, one patient each refused postoperative follow-up. None of the three groups experienced burst suppression during the maintenance period of anesthesia. Thus, 58 patients in the V_S group, 59 patients in the V_M group and 59 patients in the V_F group completed the study according to the protocol, and finally included in the data analysis (Figure 1). The baseline characteristics of patients in the experimental group are shown in Table 1. No statistically significant differences were observed among the three groups.

Table 1 Basic Characteristics

Figure 1 Consolidated standards of reporting trial diagram.

There were no statistically significant differences in the incidence of POCD in the three groups of patients at 1 day (8.6% VS 11.9% VS 16.9%; P = 0.389, Table 2) and 7 days after surgery (3.4% VS 5.1% VS 8.5%; P = 0.493). With the increase in anesthesia injection rate, the induction time of patients were significantly shortened [224 (203–249) seconds (s) vs 116 (104–135) s vs 73 (61–89) s, P < 0.001, Table 3), the induction doses of propofol [11.2 (10.4–13.7) mL vs 14.1 (12.1–15.4) mL vs 16 (14.5–17.8) mL, P < 0.001], and the maximum EEG effect of propofol [47 (42–51) vs 44 (35–47) vs 42 (37–46), P < 0.001] and the incidence of burst suppression during anesthesia induction [7 patients (12.1%) vs 11 patients (18.6%) vs 18 patients (30.5%), P < 0.001] were significantly increased. Similarly, rapid induction is not conducive to the stability of perioperative hemodynamics and increases the incidence of hypotension [15 patients (25.9%) vs 25 patients (42.4%) vs 39 patients (66.1%), P < 0.001], Table 3) in patients.

Table 2 Incidence of Postoperative Cognitive Decline in Patients Who Received Different Injection Rate of General Anesthetics

Table 3 Variables During Induction of Anesthesia

We also conducted a statistical analysis of perioperative hemodynamic in the three groups of patients. We found that mean arterial pressure (F = 0.823, P = 0.441) and heart rate (F = 0.753, P = 0.472) of patients with three anesthesia injection rates were not statistically significant (Figure 2). We planned to take blood samples were collected from all enrolled patients. However, some patients refused to draw blood or missed some points in the blood sample, and some samples showed hemolysis. Therefore, for each biomarker, 38–73 patients had a complete set of blood samples available for the analysis. Although these blood indicators (IL-6, IL-10, S100-β, and TNFα) had time-dependent changes, there were no differences in these indicators between patients with and without POCD at various times (Figure 3).

Figure 2 Comparison of MAP and HR at different time points in the three groups. (A) MAP at different time points in the three groups; (B) HR at different time points in the three groups.

Figure 3 Comparison of S-100β, IL-6, IL-10 and TNFα between patients with or without POCD. (A) S-100β concentration between patients with or without POCD; (B) IL-6 concentration between patients with or without POCD; (C) IL-10 concentration between patients with or without POCD; (D) TNFα concentration between patients with or without POCD.

Prognostic Factors for POCD

Univariate logistic regression analysis showed that the risk factors for POCD included age, cardiopathy, cerebral infarction, ASA physical status classification, educational level, preoperative MMSE and MoCA scores, and the duration of hospitalization (Supplementary Table 1). With increasing age, history of previous cerebral infarction and cardiopathy, ASA of Anesthesiologists physical status classification III, and a long hospitalization time, the incidence of POCD after surgery increased. Higher preoperative MMSE and MoCA scores and a higher educational level were associated with a lower incidence of POCD.

Variables such as age, cerebral infarction, and education level have also been reported as risk factors for POCD in previous studies.^9,23,24 In this study’s univariate logistic regression analysis, the P value was also <0.05. Therefore, we selected variables with P < 0.05 in this analysis to be included in multiple regression analysis to correct for the effects of confounding factors. Multicollinearity between independent variables was evaluated using the variance inflation factor (VIF). We found that the VIFs were all less than 2.1 (1.034–2.069), indicating less collinearity between predictors in the regression analysis. The Hosmer–Lemeshow test method was used to test the goodness of fit of the model. The results showed P = 0.813, indicating that our model predictions matched the observed data well. The models were identified by analyzing the area under the curve. The area under the curve for our model was 0.833 (95% CI, 0.733–0.934). Finally, we found that age (OR, 1.11; 95% CI, 1.01–1.23; P = 0.043) and duration of hospitalization (OR, 1.71; 95% CI, 1.29–2.27; P < 0.001, Table 4) were risk factors for POCD.

Table 4 Multiple Logistic Regression Analysis of Potential Risk Factors for Postoperative Cognitive Decline

Discussion

We observed no correlation between the injection rate of propofol and the incidence of early postoperative cognitive decline. However, with the decrease in the induction rate of propofol, the incidence of burst suppression and the induction dose of propofol decreased significantly, and the hemodynamics of patients became more stable.

In this study, with the increase in the propofol injection rate, the time to anesthesia was significantly shortened, but the induction dose of propofol was significantly increased. Of course, the dosage was all within the reasonable range of the recommended dosage.²⁵ Studies have shown that owing to the special physicochemical properties of propofol, “biological phase delay” is a rate-limiting process that regulates the concentration of propofol at its action site.²⁶ A slower infusion rate can easily reach the necessary concentration at the action site. Therefore, the total induction dose was lower than that required for rapid injection. This finding implies that a higher infusion rate may result in excess propofol, which is the price for achieving the rapid induction of propofol. During anesthesia induction with propofol at 300 mg kg⁻¹ h⁻¹, we stopped the infusion of lactated Ringer’s solution to avoid drug reflux. Previous studies have shown that the infusion rate of the equilibrium solution had no effect on the induction time, propofol dosage, and plasma propofol concentration.²⁷

In our study, the increase in propofol injection rate was associated with a decrease in BIS value, which was consistent with previous studies.^28,29 The incidence of burst suppression during induction of anesthesia in patients increased significantly with an increase in anesthesia injection rate. However, no correlation was found between burst suppression during induction of anesthesia and early postoperative cognitive decline in regression analysis. This suggests that further attention should be paid to the maintenance phase of anesthesia. A recently published multicenter clinical study also found that the occurrence and duration of intraoperative burst suppression were associated with POCD.^14,30 This is why we excluded patients with intraoperative burst suppression in order to accurately observe the effects of different induction rates of propofol on burst suppression during induction and postoperative cognition. Previous studies have suggested that intraoperative hypotension is a risk factor for postoperative cognitive dysfunction.^31,32 Therefore, in this study, we took immediate intervention measures for hypotension that appeared during the induction to avoid its influence on the study results. We found that the number of patients requiring vasoactive drugs increased with injection rate. This also prompts us to choose a slower rate of anesthesia induction (at least 30 mg kg⁻¹ h⁻¹) to stabilize the hemodynamics of patients in clinical practice.

Univariate logistic regression analysis showed that age, coronary heart disease, cerebral infarction, ASA physical status classification, education level, preoperative MMSE and MOCA scores were predictors of POCD, which were similar to those previously reported.^9,23,33,34, However, only age and duration of hospitalization were found to be independent risk factors for POCD in multivariate regression analysis. This indicated that the incidence of POCD increased with age and the duration of hospitalization increased, similar to the finding reported previously.^33,34 This may be because with the increase in age, the functions of various organs in the body of elderly patients tend to degenerate, the reserve capacity decreases, and the ability to withstand trauma such as surgery and anesthesia decreases.³⁵ The pharmacodynamics and pharmacokinetics of elderly patients may be decreased, making them more sensitive to drugs. At the same time, advanced age can reduce brain weight and volume, reduce cell bodies and myelin sheath fibers, synaptic density and DNA repair capacity of multiple brain regions (such as the hippocampus), which is not conducive to memory formation and indirectly contributes to postoperative cognitive decline in elderly patients.³⁶

To further explore the role of neuroinflammation in the pathogenesis of POCD, we assessed the levels of S-100β, IL-6, IL-10 and TNFα according to previous studies. However, there was no significant difference between the groups. In a recent multicenter study, the serum levels of IL-6, ascertain endothelial growth factor, intercellular adhesion molecule, transforming growth factor-β1, C3α, and advanced glycation were detected. Finally, it was only found that higher blood interleukin-6 concentration after surgical incision was an independent risk factor for delayed neurocognitive recovery.³⁷ This suggests that only selected cytokines are induced to change. The cytokines included in this study are limited, which may be the reason why we did not observe differences.

In this study, we adjusted the drugs under BIS monitoring rather than the modified observer’s assessment of alertness/sedation (MOAA/S) score. BIS is superior to MOAA/S in simplicity and provides a more continuous measurement.³⁸ Although there may be some delayed effect of BIS. According to literature reports, there is currently no monitoring tool that can monitor or predict patients’ conscious response in real time. However, BIS is the monitoring tool with the least delay effect among these monitoring tools.³⁹ In addition, BIS can more accurately reflect the depth of sedation of propofol compared with other anesthetics.¹¹ BIS best detected suppressed periods, and BIS monitors might be preferable for older patients with increased sensitivity to anaesthesia.⁴⁰ At the same time, we also look forward to the emergence of more real-time anesthesia depth monitoring tools to facilitate the management of clinical anesthesia.

The present study still has several limitations. First, this study was a single-center study, and the data only came from one study center, which needs further multi-center study to verify the results. Secondly, since most of the patients with inguinal hernia are elderly men, it remains to be further studied whether the results of this study can be generalized in elderly women. Finally, we did not include normal patients as control group, but we disrupted the order of cognitive correlation scales, which may mitigate the learning effects of repeated testing to some extent.

Conclusion

For elderly patients undergoing laparoscopic inguinal hernia repair, lowering the injection rate of propofol (such as 30 mg kg⁻¹ h⁻¹) cannot decrease the incidence of early POCD, but reduces induction dose of propofol and use of vasoactive drugs, making the patient’s hemodynamics more stable. For the induction of propofol anesthesia in elderly patients, slow induction (at least 30 mg kg⁻¹ h⁻¹) is recommended.