Effect of Dexmedetomidine-Assisted Intravenous Inhalation Combined Anesthesia on Cerebral Oxygen Metabolism and Serum Th1/Th2 Level in Elderly Colorectal Cancer Patients

Objective To observe the effect of dexmedetomidine-assisted intravenous inhalation combined anesthesia on cerebral oxygen metabolism and serum Th1/Th2 levels in elderly patients with colorectal cancer. Method From April 2018 to May 2020,100 elderly patients undergoing elective laparoscopic radical resection of colorectal cancer were prospectively selected and randomly divided into observation group and control group. Before induction of anesthesia, the loading dose of dexmedetomidine was given at 0.5 μg/kg, and the infusion time was 15 min. After tracheal intubation, 0.4 μg/kg/h dexmedetomidine was continuously pumped, and the infusion was stopped 40 min before the end of the operation. In the control group, the same amount of 0.9% sodium chloride was injected intravenously in the same way. 30 min before induction of anesthesia (T0), immediately before induction of anesthesia (T1), immediately after tracheal intubation (T2), 40 min before operation (T3), and immediately after operation (T4), record the blood oxygen content of the artery and internal jugular vein Difference (D(a-jv)O2), brain oxygen uptake rate (COER%), brain oxygen saturation (rSO2) mean. VAS scale, Ramsay scale, MoCA scale were taken at 6, 12, 24, and 48 h postoperatively to evaluate analgesia, sedation, and cognitive function. And monitor the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), myelin basic protein (MBP), neuron-specific enolase (NSE) and S100β. The occurrence of restlessness and adverse reactions during the recovery period of the two groups were compared. Result The levels of D(a-jv)O2, COER%, and rSO2 in the control group and observation group were higher than the preoperative basic values at T2, T3, and T4 (P < 0.05); The levels of D(a-jv)O2, COER%, and rSO2 in the observation group were lower than those in the control group at T2, T3, and T4 (P < 0.05). The VAS score and Ramsay score of the observation group were lower than those of the control group at 6, 12, 24, and 48 h after surgery, while the MoCA score was higher than that of the control group (P < 0.05). In addition, the serum IFN-γ, MBP, NSE and S100β levels of the observation group were lower than those of the control group (P < 0.05), and the ratio of IFN-γ/IL-4 was higher than that of the control group (P < 0.05). The overall incidence of adverse reactions in the observation group was lower than that in the control group [32.0% (16/50) vs. 12.0% (6/50), P < 0.05]. Conclusion Dexmedetomidine-assisted combined intravenous and inhalation anesthesia is beneficial to reduce perioperative cerebral oxygen metabolism and improve postoperative immunosuppression in elderly patients with colorectal cancer. It has a certain protective effect on nerve injury after operation, thus improving the cognitive function of patients and reducing the occurrence of adverse reactions.


INTRODUCTION
Colorectal cancer is one of the high-risk gastrointestinal malignant tumors, and more than 50% of patients die, ranking the third in malignant tumor deaths. Laparoscopic radical surgery is the main treatment of colorectal cancer, which greatly reduces the surgical trauma and ensures the smooth progress of postoperative rehabilitation. However, laparoscopic surgery establishes artificial pneumoperitoneum, and a large amount of CO 2 enters the peripheral blood circulation through the peritoneum, which affects brain metabolism and leads to nerve damage. Elderly patients have decreased body function and organ reserve function, and they are more likely to suffer from acute lung injury and postoperative cognitive dysfunction when receiving surgical treatment. Elderly patients are prone to cognitive dysfunction or delirium after surgery, and the selection of anesthetic methods and drugs is an important factors affecting the injury of brain neurons (1). Dexmedetomidine is an α2 receptor high-affinity agonist, especially for the α2A receptor located in the locus coeruleus nucleus in the brain, which has high selectivity. By inhibiting the release of sympathetic nerve excitatory transmitters and the upward transmission of peripheral pain signals, Produce sedation and analgesia (2). In addition, dexmedetomidine has a certain affinity for imidazoline I1 receptors located in brain stem and hippocampus, which inhibits the release of catecholamine and excitotoxic amino acids, reduces the sensitivity of neurons to glutamic acid, and thus plays a role in brain protection (3). At present, dexmedetomidine has been used in neurosurgery, thoracic surgery, cardiology surgery, pediatric surgery and other operations, but there are still few studies in the operation of abdominal tumor patients. Malignant tumor patients generally have disorders of immune system. Surgery and anesthesia may further inhibit the cellular immune function of the body, thus affecting the prognosis of patients (4). Dexmedetomidine is a commonly used auxiliary anesthetic in surgery, which has the effects of central nervous protection and cardiopulmonary function protection. This study was designed to observe the effects of dexmedetomidine combined with intravenous inhalation anesthesia on brain oxygen metabolism and serum Th1/Th2 levels in elderly patients with colorectal cancer, aiming to provide certain evidencebased evidence and reference for the clinical application of dexmedetomidine.

The Clinical Data Selected
From April 2018 to May 2020,100 elderly patients who underwent elective laparoscopic radical resection of colorectal cancer in the First Affiliated Hospital of Hunan Normal University were taken as the overall research object. Combined with clinical manifestations, related imaging manifestations and pathological first-stage biopsy, rectal cancer was diagnosed. Inclusion criteria: age 60-85 years old; Indications for laparoscopic radical resection of rectal cancer; American society of anesthesiologists (ASA) (5) grade I-II; There is no obvious contraindication to anesthesia. Exclusion criteria: those who have a history of neurological or mental illness; People with a history of drug allergy or long-term alcoholism; Those who took anticoagulants, sedatives, antidepressants, non-steroidal anti-inflammatory drugs or hormone drugs 3 months before operation; Eliminate those whose blood loss during the operation is > 20% of the basal blood volume; Those with intractable hypotension or anaphylactic shock. With the approval of the ethics committee of this hospital and the informed consent of the patients, 100 patients were divided into control group and observation group according to equal-length random sampling method with the approval of the ethics committee of the hospital and the informed consent of the patients. Comparing the age, gender composition, weight, body mass index (BMI), ASA classification, and cancer type of the two groups of patients, the difference was not statistically significant (P > 0.05) and was comparable. As shown in Table 1.

Methods of Anesthesia
Routine fasting and drinking before operation lasted 6-8 h. After entering the room, open the venous channel to monitor the electrocardiogram, mean artery pressure (MAP), heart rate (HR), pulse oxygen saturation (SpO 2 ), and bispectral index (BIS). Patients in the observation group were given dexmedetomidine (Jiangsu Hengrui Pharmaceutical Co., Ltd., specification: 2 mL: 200 µg, batch number 190423BP) loading dose of 0.5 µg/kg before induction of anesthesia, and the infusion time was 20 min. After tracheal intubation, dexmedetomidine was continuously pumped at 0.4 µg/kg/h (prepared with normal saline to 4 µg/mL) until 40 min before the end of the operation. Patients in the control group were given an equal volume of 0.9% sodium chloride injection intravenously in the same way General anesthesia induction: intravenous infusion of propofol (1.5-2 mg/kg), after the patient's consciousness disappears, slow intravenous bolus of midazolam (0.02 mg/kg) and sufentanil citrate (2.0-3.5 µg/kg), etomidate (0.2 mg/kg) and cis-atracurium benzenesulfonate (0.1-0.2 mg/kg), the patients were subjected to sequential induction of general anesthesia; After the muscle relaxation takes effect, perform tracheal intubation, connect to anesthesia machine for mechanical ventilation, tidal volume 6-8 mL/kg, frequency 12-15 times/min, continuous inhalation of sevoflurane 1%-2%, target-controlled infusion C Poofol (4-10 mg/kg/h) was used for anesthesia maintenance, intermittent intravenous injection of cis-atracurium to relax the muscles. BIS is maintained between 40 and 60. Connect the intravenous analgesic pump after the operation. Patient controlled intravenous analgesia (PCIA) was used, dexmedetomidine (0.5 g/kg) + sufentanil (0.8 g/kg) was used, and normal saline was diluted into 100 ml solution. The dose is 1 mL, and the lock time is 15 min.

Observation Indicators
Cerebral Oxygen Metabolism Postoperative Analgesia, Sedation Effect and Early Postoperative Cognitive Function At 6, 12, 24, and 48 h after surgery, the visual analog scale (VAS) method was used to evaluate the analgesic effect. VAS scoring criteria: 0 point means no pain, 10 points means the most pain, < 3 points means good analgesia, and ≥5 points means poor analgesic effect. Ramsay score was used to evaluate the sedative effect. The total Ramsay score was 6 points. The higher the score was, the higher the degree of sedation would be. Montreal Cognitive Assessment (MoCA) score was also recorded. The MoCA scale included visual space and executive function, naming, memory, attention, language, abstraction, delayed memory and orientation, with a full score of 30. A lower score indicated lower cognitive function, < 26 indicated abnormal.

Postoperative Laboratory Index Monitoring
Serum samples were collected at the preoperative basic value and immediately after the operation, 6, 12, 24, and 48 h after the operation, and the ELISA kit was used to monitor interferon-γ (IFN-γ) and interleukin-4 (interleukin-4, IL-4), myelin basic protein (MBP), neuron-specific enolase (NSE), S100β content. The kit used was purchased from Shanghai Kanglang Biotechnology Co., Ltd.

Adverse Reactions
The incidence of restlessness, dizziness, nausea and vomiting, and respiratory depression in the two groups of patients during the recovery period was counted within 48 h after the operation.

Statistical Processing
Using SPSS19.0 statistical software, measurement data are expressed as mean ± standard deviation (x ±s), using repeated measures analysis of variance for intra-group comparison, and comparison between groups using LSD-t test; The count data is expressed as a percentage or rate (%), and the χ 2 test is performed. P < 0.05 indicates that the difference is statistically significant.

Comparison of Surgical Conditions Between the Two Groups
There was no significant difference in anesthesia induction time, operation time, anesthesia maintenance time, fluid replacement, blood loss during operation, directional recovery time, extubation time and observation time in PACU after anesthesia (P > 0.05). As shown in Table 2.  and rSO 2 of the observation group were lower than those of the control group at T 2 , T 3 , and T 4 (P < 0.05). zThere was a statistical difference in the trend of changes in the levels of D (a−jv) O 2 , COER%, and rSO 2 between the two groups of patients (F = 38.757, 12.605, 9.374, P < 0.05). As shown in Figure 1.

Comparison of Postoperative Analgesia, Sedation Effects and Cognitive Function Between the Two Groups
The analysis of variance with repeated measures design was used to compare the VAS score, Ramsay score, and MoCA score at each time point of 6, 12, 24, and 48 h after the operation of the two groups. 1. VAS score, Ramsay score, and MoCA score were statistically different at different time points (F = 12.351, 5.462, 8.291, P < 0.05). 2. There was a statistical difference between the observation group and the control group in VAS score, Ramsay score, and MoCA score (F = 21.358, 27.642, 13.058, P < 0.05). The observation group had VAS score and Ramsay score at 6, 12, 24, 48 h were lower than the control group, while the MoCA score was higher than the control group (P < 0.05). 3. There was a statistical difference in the trend of VAS score, Ramsay score, and MoCA score between the two groups (F = 42.637, 27.814, 29.854, P < 0.05). As shown in Figure 2.

Comparison of Laboratory Indicators Between the Two Groups
The analysis of variance with repeated measures design was used to compare the serum IFN-and ILIL-4els and IFNγ/IL -4 ratios of the two groups of patients before the operation, immediately after the operation, and at each time point of 6, 12, 24, and 48 h after the operation. The serum IFN-γ levels, MBP and S100β levels of the observation group were lower than those of the control group immediately after the operation and at 6, 12, 24, and 48 h after the operation (P < 0.05). At the same time, IFN-γ The ratio of /IL-4 was higher than that of the control group (P < 0.05). Serum NSE levels in the observation group were lower than those in the control group at 6, 12, 24, and 48 h after surgery (P < 0.05). In addition, there was no significant difference in serum IL-4 levels between the two groups of patients (F = 1.734, P = 0.325). 3. There were statistical differences in the changes of serum IFNγ levels, IFN-γ/IL-4 ratio, serum MBP, NSE and S100β levels between the two groups (F = 43.218, 786.454, 118.379, 72.361, 28.504, P < 0.05), while the comparison of the trend of changes in serum IL-4 levels between the two groups of patients, the difference was not statistically significant (F = 0.927, P = 0.564). As shown in Figure 3.

Comparison of Postoperative Adverse Reactions Between the Two Groups
All patients successfully completed the tracheal intubation, and no coughing or body odor movement occurred. The total incidence of adverse reactions (including restlessness in convalescence) in the control group and observation group was 32.0% (16/50) and 12.0% (6/50), respectively. The difference was statistically significant after the χ 2 test (χ 2 = 5.828, P = 0.016), the overall incidence of adverse reactions in the observation group was slightly lower than that in the control group. As shown in Figure 4.

DISCUSSION
Postoperative cognitive dysfunction (POCD) refers to symptoms such as mental confusion, degeneration of mental function, and decreased social ability within a few days or months after surgery Old age is the risk factor that is closely related to POCD disease Scholars such as Czyz-Szypenbejl (8) found that the incidence of POCD in elderly patients over 60 years old within 7 days was about 17 ∼ 56%, and with the increase of age, the incidence of POCD increased. The incidence of POCD in elderly patients is higher than that of patients aged 60 to 69, and the proportion of patients with long-term persistent POCD has also increased greatly, and some patients may even progress to Alzheimer's disease. It is speculated that the principle lies in the degenerative changes in the brain structure and function of the elderly, the aging of neuronal nuclei, the increase in apoptosis rate, the decrease in neurotransmitter secretion, the deterioration of brain glucose metabolism and neural signal transmission functions, which makes the elderly population The brain is more susceptible to damage from anesthetics (9).
Besides age, anesthesia methods and narcotic drugs are also important factors that affect postoperative cognitive function. According to a multi-center study conducted by Wang Dongting and other scholars (10), 400 elderly patients who were to  undergo radical resection of colorectal cancer were followed up and observed. MoCA score is a common cognitive function screening tool, which is used as an auxiliary diagnostic method for POCD disease. The results showed that the incidence of POCD was about 15.6 %, and the duration of anesthesia and the proportion of general anesthesia are independent risk factors for the occurrence of POCD. In this study, the enrolled patients with colorectal cancer all used propofol-sevoflurane intravenous inhalation combined with general anesthesia. Propofol is a highly fat-soluble intravenous anesthetic. Its sedative mechanism and enhancement of γ-amino Butyrate A receptor activity, which in turn enhances the inhibitory postsynaptic current, is related (11). Gamma-aminobutyric acid receptor activity can lead to longterm potentiation (LTP) that inhibits the excitatory transmission of pyramidal neurons in the hippocampal CA 1 region, and then affect the learning and cognitive functions of patients (12). In addition, scholars such as Alkire MT (13) confirmed that inhalational anesthetics, such as sevoflurane and sevoflurane at the relative minimum alveolar concentration, within 24 h, the memory loss of nitrous oxide is more serious, but it is compared with other inhaled anesthetics. Sexual anesthetics, sevoflurane is metabolized quickly and has little effect on the nervous system, but it still cannot avoid the damage to the cognitive function of elderly patients after surgery.
Dexmedetomidine is an α 2 adrenergic receptor agonist with high selectivity and specificity. By inhibiting the activity of sympathetic nerves and the secretion of stress hormones such as cortisol and catecholamine, it can reduce the damage to hippocampus, thus reducing the influence of anesthetics on the early postoperative cognitive function of elderly patients (14). In this study, patients in the observation group were given dexmedetomidine-assisted intravenous inhalation combined anesthesia, and the postoperative VAS score and Ramsay score were significantly lower than those of the control group, indicating that dexmedetomidine-assisted combined intravenous inhalation anesthesia has good analgesia and sedation. In addition, the postoperative MoCA score of the observation group was higher than that of the control group, and the levels of D (a−jv) O 2 , COER%, and rSO 2 were lower than those of the control group. D (a−jv) O 2 , COER%, and rSO 2 reflect brain oxygen