Effects of Abdominal Wall Blocks on Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Study.

BACKGROUND Postoperative delirium (POD) seriously affects the rapid postoperative recovery of elderly patients. We investigated the effect of abdominal wall blocks on POD in elderly patients undergoing laparoscopic radical resection of colon cancer and underlying mechanisms. MATERIAL AND METHODS A total of 100 patients undergoing laparoscopic radical resection of colon cancer were randomly assigned to group C (control) and group R (regional nerve blocks). In group R, 20 mL of local anesthesia-mixed solution was injected into the bilateral transverse abdominis muscle plane and 10 mL was injected into the bilateral posterior sheath of the rectus abdominis muscle. In group C, the same amount of saline was used for nerve block. The consumption of propofol and remifentanil during surgery was recorded. Levels of serum interleukin (IL)-6 and highly sensitive C-reactive protein (hs-CRP) during surgery were evaluated. The Confusion Assessment Method for the Intensive Care Unit Scale and the Richmond Agitation-Sedation Scale were adopted to evaluate POD. RESULTS The incidence of POD was lower in group R than in group C (P=0.048). The consumption of propofol and remifentanil was significantly reduced in group R, compared with group C (P<0.05). Compared with T0, serum IL-6 and hs-CRP levels in both groups were significantly increased at T1 and T2 (P<0.05). Moreover, serum IL-6 and hs-CRP were lower at T1 and T2 in group R compared with group C (P<0.05). CONCLUSIONS Abdominal wall blocks may alleviate POD in elderly patients undergoing laparoscopic surgery, which may be related to the reduction of anesthetic consumption and inflammatory response.

Background

Postoperative delirium (POD) includes acute changes or fluctuations in conscious state, attention disorders, changes in consciousness level, and confusion and is a common complication in elderly patients after surgery [1,2]. POD increases the difficulty of nursing, affects the quality of life, prolongs the length of hospital stays, and increases social burden [1]. Numerous studies have focused on the prevention and treatment of POD; however, to date, the mechanisms remain unclear.

It has been suggested that the aging of nerve cells, use of anesthetic drugs during surgery, and inflammatory response to surgery are associated with a greater chance of delirium [2-4].

Laparoscopic surgery has been widely used in radical resection of colon cancer owing to its small incision and relatively light trauma; however, POD still occurs in about 50% of patients in laparoscopic abdominal surgery [5]. Radical resection of colon cancer takes a relatively long time and uses a large amount of anesthetic drugs, and the most commonly used anesthetics, propofol and remifentanil, can cause cognitive decline [6,7]. The inflammatory response caused by surgical trauma is also related to POD [8]. Therefore, a method to reduce the amount of anesthetic drugs used intraoperatively and to attenuate the inflammatory response caused by surgery may reduce the incidence of delirium after laparoscopic radical colon cancer surgery.

In recent years, the transversus abdominis plane block (TAPB) and rectus sheath block (RSB) were combined into abdominal wall blocks [9], which have been widely used in abdominal surgery [10-12]. With the increased use of ultrasound, nerve blocks guided by ultrasound have improved the success rate and reduced the risk of puncture to a large extent. TAPB can provide nerve block of the thoracic nerves below T10 on the abdominal wall [13], and RSB can provide a block covering T7 to T12 on the belly-line incision [14]. The analgesic effects of TAPB and RSB during and after abdominal surgery have been widely reported [15-18]. Previous studies have shown that both TAPB and RSB reduce the amount of narcotic drugs used [19-21]. According to previous reports, TAPB could reduce the inflammatory response [22,23] and reduce the incidence of delirium after laparoscopic surgery [24,25]. However, the effect of TAPB combined with RSB on POD after laparoscopic surgery remains unexplored.

This study was designed to investigate whether TAPB combined with RSB could alleviate POD in elderly patients undergoing laparoscopic radical resection of colon cancer and to investigate the underlying mechanisms.

Material and Methods

Patients and Setting

This randomized controlled study was registered in the Chinese Clinical Trial Registry (no. ChiCTR2000040532). All patients signed the informed consent form approved by the Ethics Committee of Cangzhou Central Hospital (reference no.: 2020-028-02). Patients undergoing laparoscopic colorectal cancer radical surgery between December 7, 2020, and March 7, 2021, were enrolled in the study. Inclusion criteria were as follows: (1) age 65 years or older; (2) American Society of Anesthesiologists (ASA) class I–II; and (3) preoperative Mini Mental State Examination (MMSE) score >22.

Exclusion criteria were as follows: (1) impairment in reading or comprehension; (2) coagulation dysfunction, infection, and other regional anesthesia contraindications; (3) heart, liver, kidney, and other vital organ function failure; (4) long-term use of anti-inflammatory drugs or hormone drugs or a history of opioid abuse; (5) hearing or visual impairment; (6) anxiety and depression; (7) mental illness; and (8) alcohol abuse or drug dependence.

Randomization and Masking

Randomization was performed by a researcher not involved in the study who prepared opaque sealed envelopes containing a slip of paper completed with an online tool (http://www.randomization.com) indicating group R (regional nerve blocks) and group C (control). The day before surgery, an anesthesiologist who was not involved in the study visited the patients to check that they agreed to participate in the study. Once confirmed, the envelope was opened to confirm the group allocation. One hour before surgery, the anesthetists were informed of the group allocation. After surgery, a researcher blinded to the group recorded the data for the analysis.

TAPB and RSB

In group R, bilateral TAPB was performed under ultrasonic guidance (Mylab Alpha, Esaote, Italy) after anesthesia induction and before surgery. The surrounding skin of the puncture point was disinfected, and a high-frequency linear array probe was selected (SL1543, 3-3 MHz) using an aseptic probe, which was placed in the vertical axillary front between the crest and costal margin and the external oblique, internal oblique, transverse abdominal, and peritoneal structures. The tip was pierced to the fascia layer between the internal oblique and transverse abdominal muscles using an 18G needle from the inside to the outside plane, the syringe was withdrawn without blood and gas, and then local anesthetics were injected into each side bilaterally. In the second step, a bilateral RSB was performed, with the probe placed between the xiphoid process and the umbilical foramen on the surface of the rectus abdominis; the intraplanar puncture technique was used. In group R, local anesthetics were injected to form a fusiform anechoic area in the posterior sheath of the rectus abdominis, indicating the successful injection of the liquid medicine; the same method was used to implement the RSB on the opposite side (Figure 1). The local anesthetic used was a mixture of 0.25% ropivacaine and 1 μg/kg dexmedetomidine. In addition, a total of 40 mL of mixed local anesthetic was used for bilateral TAPB and 20 mL was used for bilateral RSB in group R, according to a previous study [26]. In group C, the same volume of normal saline was injected in the same positions and in the same way.

Figure 1

Ultrasound images (A) before and (B) after transverse abdominis plane block; (C) before and (D) after rectus sheath block. EOM – external oblique muscle; IOM – internal oblique muscle; TAM – transverse abdominal muscle; LA – local anesthetics; RAM – rectus abdominis muscle. (Adobe Photoshop CS5, Adobe Systems Inc).

Anesthesia Management

After entering the operating room, all patients were monitored with electrocardiography (ECG), noninvasive blood pressure (BP), respiratory rate, body temperature, pulse oxygen saturation (SPO2), end-tidal carbon dioxide partial pressure (PetCO2), and bispectral index. Owing to the need to maintain an internal environmental balance during surgery for elderly patients and the need for postoperative intravenous (i.v.) nutrition, all patients underwent ultrasound-guided right-internal jugular vein catheterization and right-radial artery catheterization before anesthesia induction.

Anesthesia Induction

The induction of anesthesia began with i.v. injection of 2 to 5 μg/kg fentanyl, 0.3 mg/kg etomidate, and 0.2 to 0.3 mg/kg cis-atracurium, which were injected i.v. in sequence. After full action of the muscle relaxants, endotracheal intubation was performed with a video laryngoscope. The respiratory rate of the ventilator was adjusted to 12 to 20 times per min, based on blood gas analysis results. The ratio of inspiratory/expiratory was 1.0: 1.5 to 1: 2, inhalation oxygen concentration was 40%, oxygen flow was 2 L/min, and PetCO2 was maintained 35 to 45 mm Hg (SL2400, Spacelabs, MA, USA).

Maintenance of Anesthesia

The bispectral index was used to maintain the depth of anesthesia, and total i.v. anesthesia of propofol and remifentanil was administered immediately after endotracheal intubation. During anesthesia, the concentrations of propofol and remifentanil were adjusted according to the changes in BP and heart rate (HR) of the patients, as well as the intensity of surgical stimulations. Cis-atracurium was administered intermittently to maintain muscle relaxation. The bispectral index was maintained at 40 to 60 in both groups during anesthesia. Vasoactive drugs were used to maintain the BP fluctuation range within 20% of the baseline value. When BP was low, 1 to 2 mg dopamine/10 to 20 μg norepinephrine were administered as an i.v. injection. When HR <50 times/min, atropine 0.5 to 1 mg was administered. Anesthesia was discontinued at the end of surgery, and the endotracheal catheter was removed when the patient regained consciousness and the tidal volume reached 8 mL/kg, while the hemodynamic parameters were stable.

Postoperative Analgesia

All patients received pump-controlled i.v. analgesia (0.15 μg/kg sufentanil was diluted with normal saline to 100 mL) after surgery. The background infusion was 2 mL/h, the patient-controlled infusion was 0.5 mL/h, and the locking time was 15 min. When the visual analog score (VAS) was greater than 3, flurbiprofen 50 mg was administered for remedial analgesia.

Baseline Assessment

Basic information of the 100 patients, including sex, age, height, weight, years of education (education ≥9 years), ASA, and heavy alcohol consumption (>20 g/day for women or >40 g/day for men), was collected. A history of diseases, including hypertension, diabetes mellitus, coronary heart disease, and smoking history, was also collected.

Collection of Blood Samples

At 0 min before anesthesia induction (T0), 1 h after the beginning of surgery (T1), and at the end of surgery (T2), 3 mL of blood was collected with a tube of aseptic ethylene diamine tetraacetic acid. The blood was then centrifuged at 3000×g for 15 min to collect serum, which was stored at −80°C for use. The level of serum interleukin (IL)-6 (lot: 131161131210, code: EK0410, Boster Biological Technology Co, Wuhan, China) was evaluated by enzyme-linked immunosorbent assay, according to the manufacturer’s instructions. Highly sensitive C-reactive protein (hs-CRP) (lot: 201110, code: CH0402311, Maccura Biotechnology, China) was evaluated by the latex immunoturbidimetric method, according to the manufacturer’s instructions.

Assessment of POD

POD was evaluated by a highly trained, double-blind investigator who assessed patients using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) [27] and the Richmond Agitation-Sedation Scale (RASS) [2] for the first 7 days following surgery. The investigators were followed up twice a day at an interval of 12 h the day after surgery, for 7 consecutive days. The criteria for assessment of delirium were as follows: (1) an acute change or fluctuation in the state of consciousness; (2) attention disorder; (3) changes in consciousness level (RASS not equal to 0); and (4) confusion. The condition of (1)+(2)+(3)/(1)+(2)+(4) proved that delirium existed. When POD occurred, 5 mg haloperidol was administered i.v.

Statistical Analyses

The sample size was calculated using the online sample size calculation tool (http://powerandsamplesize.com/Calculators/). The alpha level and power were set to 0.05 and 0.8, respectively. According to previous pilot tests [28,29], the incidence of the primary outcome was 30%. After calculation, an average of 47 patients was required in each group. Considering the shedding rate of 5%, 103 patients were selected for inclusion in the study. SPSS (version 21.0; IBM Corp, Armonk, NY, USA) was used for the statistical analysis of all data. Measurement data with a normal distribution were expressed as mean±SD, and the t test was used for comparison between groups. Non-normally distributed data were represented as median±quartile, and comparisons between groups were performed using the rank-sum test. Categorical variables were compared using the chi-squared test or Fisher’s exact test. Two-way repeated measures analysis of variance was used for repeated measurements. Statistical significance was set at P<0.05.

Results

Basic Information of Patients and Surgical Results

A total of 103 patients who were scheduled for laparoscopic radical resection for colon cancer were enrolled in the study. Three patients were excluded because of a history of hearing impairment and failure to cooperate (n=2 [1.9%]) or mental disorders (n=1 [0.97%]). The remaining patients were randomized into groups C and R (Figure 2).

Figure 2

Flow diagram of the study. (Adobe Photoshop CS5, Adobe Systems Inc).

Patient Characteristics

The patients included into this final cohort were all Han Chinese, and the general characteristics of the entire cohort of patients included age (71.28±4.967 years), sex (female, 49 [49%]), body mass index (BMI) (23.74±3.146 kg/m2), ASA score (65 [65%]), education ≥9 years (17 [17%]), heavy alcohol consumption (25 [25%]), smoking (21 [21%]), history of diabetes mellitus (15 [15%]), hypertension (44 [44%]), and coronary heart disease (15 [15%]). The characteristics of the patients in the 2 groups are summarized in Table 1 (details in Supplementary Table 1).

Table 1

Clinical characteristics of patients.

Characteristics	Entire (n=100)	Group C (n=50)	Group R (n=50)	P
Age (years, mean [SD])	71.28±4.967	72.06±5.266	70.50±4.568	0.117
Sex (Female [%])	49 (49)	24 (48)	25 (50)	0.841
Weight (kg, mean [SD])	64.81±11.430	66.18±12.104	63.44±10.660	0.233
BMI (kg/m2, mean [SD])	23.74±3.146	23.99±3.540	23.49±2.710	0.434
ASA (I, %)	65 (65)	32 (64)	33 (66)	0.834
Education ≥9 years (n [%])	17 (17)	8 (16)	9 (18)	0.790
Hypertension (n [%])	44 (44)	24 (48)	20 (40)	0.546
Diabetes mellitus (n [%])	15 (15)	8 (16)	7 (14)	0.779
Coronary heart disease (n [%])	15 (15)	7 (14)	8 (16)	0.779
Smoking (n [%])	21 (21)	10 (20)	11 (22)	0.806
Heavy alcohol consumption (n [%])	25 (25)	12 (24)	13 (26)	0.817

BMI – body mass index; ASA – American Society of Anesthesiologists; C – control; R, regional nerve blocks.

Intraoperative Measurements and Postoperative Assessments

There were no statistically significant differences in infusion volume, blood loss, urine output, surgical duration, and anesthesia time between the 2 groups (Table 2). For the postoperative assessments, there were no statistical differences in length of stay and VAS scores between the 2 groups (Table 2).

Table 2

Intraoperative and postoperative variables.

Characteristics	Entire (n=100)	Group C (n=50)	Group R (n=50)	P
Infusion volume (mL, mean [SD])	2011±441	2018±427	2004±458	0.875
Blood loss (mL, mean [SD])	356±91	367±86	345±96	0.230
Urine volume (mL, mean [SD])	325±80	334±79.8	317±80.1	0.277
Surgical duration (min, mean [SD])	223.8±48.3	230.3±48.7	217.3±47.5	0.180
Anesthesia time (min, mean [SD])	246±46.96	251.1±47.5	240.9±46.3	0.280
Length of stays [days, mean (SD])	17.23±2.36	17.10±2.33	17.36±2.41	0.585
VAS scores (points, mean [SD])	1.93±0.71	1.92±0.70	1.94±0.74	0.889
Numbers of analgesic pump compression (times, mean [SD])	12.09±8.95	5.62±3.26	18.56±8.11	<0.001

C – control; R – regional nerve blocks; VAS – Visual Analog Score.

Compared with group C, the intraoperative dosage of propofol (t=2.864, P=0.005) and remifentanil (t=0.301, P=0.001) in group R were significantly lower (Table 3; Supplementary Table 1).

Table 3

The incidence of postoperative delirium and intraoperative dosage of propofol and remifentanil (n=50).

Group	C	R	P
Incidence of delirium, n (%)	15 (30)	6 (12)*	0.027
Propofol (mg)	1114±263	973±230*	0.005
Remifentanil (μg)	3304±802	2784±713*	0.001

C – control; R – regional nerve blocks.

Represents P<0.05 between 2 groups.

Compared with group C, the number of analgesic pump compressions in group R was significantly lower within 24 h after surgery (t=10.465, P<0.001) (Table 2; Supplementary Table 1).

Serum IL-6 and hs-CRP Levels

Compared with T0, the levels of serum IL-6 were significantly increased at T1 and T2 in group R and group C (F [1.762, 86.356]=1343.072, P<0.001; Table 4). Compared with T0, the levels of hs-CRP were significantly increased at T1 and T2 in group R and group C (F [2, 98]=26585.179, P<0.001; Table 4).

Table 4

Serum interleukin-6 and high-sensitive C-reactive protein levels (n=50).

	Group	T0	T1	T2
IL-6 (μg/mL)	C	42.83±1.899	63.45±1.964#	79.21±1.668#
	R	43.16±1.755	54.79±2.094*#	63.61±2.116*#
Hs-CRP (mg/L)	C	0.92±0.183	19.47±0.671#	28.09±0.596#
	R	0.90±0.157	10.40±0.540*#	15.59±0.448*#

C – control; R – regional nerve blocks; IL-6 – interleukin-6; hs-CRP – highly sensitive C-reaction protein; T0 – 0 min before anesthesia induction; T1 – 1 h after beginning of surgery; T2 – the end of surgery. Compared with corresponding group C,

P<0.05. Compared with T0,

P<0.05.

However, the levels of serum IL-6 (t=21.316, P<0.001 for T1; t=40.937, P<0.001 for T2) and hs-CRP (t=74.434, P<0.001 for T1; t=118.598, P<0.001 for T2) were lower in group R than in group C at T1 and T2 (Table 4; details in Supplementary Table 2).

Incidence of POD

On postoperative day 1, there were 5 cases (10%) of POD in group R and 12 cases (24%) in group C. On postoperative day 2, there was 1 new case of POD in group R and 3 new cases in group C; there were no new cases during the remaining 5 days. In total, there were 6 cases of POD in group R (12%) and 15 cases of POD in group C (30%). The incidence of POD was significantly lower in group R than in group C (P=0.048) by the Fisher’s exact 2-sided test (Table 3; Supplementary Table 1).

Discussion

In this study, our data preliminarily suggested that TAPB combined with RSB could alleviate the incidence of POD in elderly patients undergoing laparoscopic radical resection for colon cancer. In addition, both anesthetic consumption and inflammatory factors, such as IL-6 and hs-CRP, were reduced.

The incidence of POD has been reported to be 12.4% to 48.7% in elderly patients undergoing surgery [30]. In our study, the incidence of POD was 21%, which is consistent with previous reports. Clinical risk factors for POD include the advanced age of patients, anesthetic drugs, and inflammation caused by surgical trauma [31-33]. Therefore, methods that can reduce the amount of anesthetic during surgery and attenuate the inflammatory response caused by surgery may reduce the incidence of POD.

Laparoscopic radical resection of colon cancer takes a relatively long time, which causes the use of large amounts of narcotic drugs and a peripheral inflammatory response. Peripheral injurious stimuli are released into the central nervous system, leading to POD. General anesthesia, as a traditional anesthetic method in laparoscopic radical resection of colon cancer, can inhibit the response of the limbic system and hypothalamic projection system to stress, but it cannot prevent the release of harmful stimuli from the peripheral to the central nervous system.

TAPB, a nerve block technique, is often used in combination with general anesthesia to reduce the stress response and perioperative opioid use [22,23,34]. It is simple and safe to inject local anesthetic liquid into the fascial space between the internal oblique and transverse abdominis. RSB is a simple and easy method for treating abdominal nerve block. Local anesthetics are injected into the rectus sheath to block the branches of the T7 to T12 nerves in the abdominal wall [14], which can be used for anesthesia and postoperative analgesia in a midline abdominal incision and to significantly reduce the intraoperative amount of opioids used [35]. Our data suggest that TAPB combined with RSB can not only reduce the intraoperative opioid dosage but can also reduce the postoperative dosage, which is consistent with previous studies [36,37] and may be related to alleviating postoperative hyperalgesia with a preemptive nerve block [38].

Inflammation is one of the most discussed causes of POD [2,39]. Inflammatory cytokines, including IL-6 and hs-CRP, released during surgery and anesthesia, are closely related to the occurrence and development of POD [40,41]. To explore the mechanism of POD, we selected these 2 indicators. IL-6 is the initiator of the inflammatory response in the body, which can trigger the downstream inflammatory cascade response, induce the release of other inflammatory factors, and eventually lead to neuronal damage of neurons [42]. Hs-CRP is an acute response protein, which is synthesized by liver cells and released into the blood, and serum hs-CRP levels in healthy people are very low. However, when the body shows an inflammatory response caused by bacterial infection or tissue damage, serum hs-CRP can rise rapidly, and the condition will decline after improvement. It can also lead to the impairment of neuronal function and cognitive function of patients by mediating the related inflammation and oxidative stress response [43].

Our data showed that TAPB and RSB, when performed preoperatively, can reduce the levels of IL-6 and hs-CRP, which is basically consistent with the results of previous studies [22,44]. Preemptive analgesia has been reported to reduce the inflammatory response caused by surgery [45]. Preemptive nerve block can effectively relieve surgical stress and inflammation and exert an immunomodulatory effect [46]. Preemptive nerve block analgesia is different from postoperative opioid administration.

There were several limitations to our study. First, although our data preliminarily indicated that TAPB combined with RSB could reduce the incidence of delirium after laparoscopic radical resection of colon cancer, the result of Fisher’s exact probability test, P=0.048, is considered to be on the margin of a statistically significant difference. The reason for this result may be (1) the sample size was relatively small; future studies with a larger sample size are needed to verify the results, and (2) the mechanism of POD is very complex. Nerve block only blocks muscles and nerves in the abdominal wall. Oxidative stress caused by intra-abdominal surgery and slagging vessels is still the cause of POD, which can be studied in subsequent experiments. Although the P value obtained is on the edge of statistical significance, it is undeniable that the results are still statistically significantly different, and this study is still valuable. Second, only CAM-ICU was selected to evaluate POD, and multiple scales should be used for evaluation. Third, the observation time was short, so we could extend the observation time in subsequent studies to observe the long-term effects of TAPB combined with RSB on patients’ cognitive function.

Conclusions

Our data preliminarily showed treatment with TAPB and RSB can reduce the incidence of POD in patients undergoing laparoscopic radical colon cancer surgery. The mechanism may be related to the reduction of anesthetic consumption and the inflammatory response.

Supplementary Table 1

Original clinical data and intraoperative and postoperative variables of patients.

CAM-ICU (POD3)	CAM-ICU (POD4)	CAM-ICU (POD5)	CAM-ICU (POD6)	CAM-ICU (POD7)	VAS scores	The number of analgesic pump compressions	Sufentanil consumption 24 h following surgery
0	0	0	0	0	1	12	60.75
0	0	0	0	0	2	30	51.975
1	0	0	0	0	2	15	49.95
0	0	0	0	0	3	16	54.6
0	0	0	0	0	2	14	51.15
0	0	0	0	0	1	8	35.1
0	0	0	0	0	3	26	54.9
0	0	0	0	0	2	32	62.4
0	0	0	0	0	2	18	40.185
0	0	0	0	0	3	29	51.5625
0	0	0	0	0	3	9	55.125
0	0	0	0	0	1	8	66.3
1	0	0	0	0	1	20	45.24
0	0	0	0	0	2	22	57.525
1	1	1	0	0	1	18	55.575
0	0	0	0	0	3	16	58.8
0	0	0	0	0	1	33	91.9125
0	0	0	0	0	2	20	69.6
1	1	0	0	0	2	40	71.4
1	1	0	0	0	1	10	38.955
0	0	0	0	0	3	11	56.175
0	0	0	0	0	3	19	43.125
0	0	0	0	0	2	36	47.52
0	0	0	0	0	2	20	67.86
1	1	1	0	0	1	18	55.575
0	0	0	0	0	1	16	72.24
0	0	0	0	0	2	8	60.84
1	1	1	0	0	1	10	55.65
0	0	0	0	0	2	11	48.15
0	0	0	0	0	3	10	43.725
1	1	1	1	0	3	22	70.8
0	0	0	0	0	2	20	37.41
0	0	0	0	0	2	18	68.4
1	1	1	0	0	2	28	44.64
0	0	0	0	0	2	17	67.8
1	1	1	1	0	1	11	56.9775
0	0	0	0	0	2	23	71.4
0	0	0	0	0	3	20	71.34
0	0	0	0	0	2	19	56.0625
1	0	0	0	0	1	30	56.7
0	0	0	0	0	1	32	72
0	0	0	0	0	2	21	52.65
1	1	0	0	0	3	16	50.4
0	0	0	0	0	3	21	57.0375
0	0	0	0	0	2	7	54.075
0	0	0	0	0	2	9	55.125
0	0	0	0	0	2	10	67.575
0	0	0	0	0	1	17	50.85
0	0	0	0	0	1	10	47.7
0	0	0	0	0	2	22	57.525
0	0	0	0	0	2	3	48.2625
0	0	0	0	0	3	5	49.2375
0	0	0	0	0	2	6	38.25
1	1	1	0	0	2	10	63.6
0	0	0	0	0	2	8	39
0	0	0	0	0	1	2	57.33
0	0	0	0	0	3	9	55.125
0	0	0	0	0	3	8	50.7
0	0	0	0	0	2	5	45.45
0	0	0	0	0	3	11	36.1125
0	0	0	0	0	1	10	63.6
0	0	0	0	0	1	4	53.25
0	0	0	0	0	2	3	41.58
0	0	0	0	0	2	5	68.175
0	0	0	0	0	2	2	50.715
0	0	0	0	0	2	9	59.0625
0	0	0	0	0	3	3	43.8075
0	0	0	0	0	2	7	46.35
0	0	0	0	0	3	8	66.3
0	0	0	0	0	1	2	33.075
0	0	0	0	0	1	10	55.65
0	0	0	0	0	2	11	58.5825
0	0	0	0	0	3	6	49.725
0	0	0	0	0	2	5	41.6625
0	0	0	0	0	2	1	47.2875
1	0	0	0	0	2	2	51.45
0	0	0	0	0	1	8	42.9
0	0	0	0	0	1	3	59.4
0	0	0	0	0	1	7	47.895
0	0	0	0	0	1	9	66.9375
0	0	0	0	0	2	10	47.7
0	0	0	0	0	2	6	38.25
0	0	0	0	0	2	5	38.6325
0	0	0	0	0	3	5	51.51
1	1	0	0	0	2	4	41.25
0	0	0	0	0	1	1	45.105
0	0	0	0	0	2	2	47.775
0	0	0	0	0	2	9	43.3125
0	0	0	0	0	2	6	45.9
0	0	0	0	0	3	0	46.8
1	1	1	0	0	3	0	36
0	0	0	0	0	2	6	45.9
0	0	0	0	0	2	11	44.1375
0	0	0	0	0	2	12	44.55
0	0	0	0	0	1	4	37.5
0	0	0	0	0	1	5	53.025
0	0	0	0	0	1	5	46.965
0	0	0	0	0	2	2	44.1
0	0	0	0	0	1	1	47.2875
0	0	0	0	0	2	5	42.42

NO – progressive number; R – regional nerve block group; C – control group; BMI – body mass index; ASA – American Society of Anesthesiologists; DM – diabetes mellitus; CAM-ICU – Confusion Assessment Method for the Intensive Care Unit Scale.

Supplementary Table 2

The original data of interleukin-6 and highly sensitive C-reactive protein levels at different time points.

RIL-6 (T0)	RIL-6 (T1)	RIL-6 (T2)	CIL-6 (T0)	CIL-6 (T1)	CIL-6 (T2)	RCRPT0	RCRPT1	RCRPT2	CCRPT0	CCRPT1	CCRPT2
40.243	52.044	60.587	42.778	66.467	81.784	0.8	11	15.4	0.9	18.6	27.1
42.128	55.066	63.093	42.094	67.589	77.187	0.7	10.2	16.4	1.1	19.5	28.7
42.098	55	63.157	47.068	66.487	81.576	1	10.5	15.3	1.2	19.6	27.9
45.87	56.375	65.908	46.958	65.159	80.498	0.8	10.6	16.1	0.7	18.7	28.3
44.651	55.687	64.764	43.185	64.586	77.062	1	10.1	15.9	0.9	19.8	28.6
46.714	52.183	60.773	40.942	61.059	78.367	0.9	9.8	15.3	0.7	20.1	27.5
44.189	58.196	66.993	41.129	62.719	79.569	0.6	9.9	15.9	0.9	18.2	27.9
44.537	55.387	64.155	40.684	62.698	78.416	1	11.2	16.4	0.6	19.6	27.2
42.732	54.084	62.199	41.963	61.098	76.087	0.8	9.6	15.7	0.9	18.7	28.4
43.622	53.695	63.885	43.054	63.759	79.198	0.9	9.5	15.2	0.6	19.4	27.3
43.086	51.245	60.176	41.826	61.755	77.669	0.7	10.2	15.4	1.1	18.5	27.6
41.892	52.078	62.065	40.079	60.293	76.546	1.2	11.2	16.4	0.8	18.9	28.1
45.091	50.968	60.459	44.467	65.394	80.287	0.8	10.5	15.7	0.9	20.2	28.6
43.127	51.189	61.562	41.256	62.137	79.512	1.2	10.8	15.2	1.2	19.9	28.9
42.811	54.989	63.742	41.897	62.786	78.064	0.9	10.6	14.9	1	20	28.5
45.292	56.019	65.487	43.908	64.189	80.416	0.7	10.2	15.3	0.7	19.8	27.6
40.037	54.774	63.188	44.023	63.387	80.626	0.8	9.9	14.9	0.9	20.4	28.2
41.272	52.476	61.476	40.905	61.476	78.381	1	10	15.6	1.1	20.7	28.3
43.024	56.098	65.365	41.287	62.587	79.022	1.2	10.4	15.2	0.6	19.8	28.7
41.382	53.595	62.853	40.128	62.158	78.458	0.7	10	15.7	1.2	18.6	27.2
46.052	57.588	65.852	43.587	63.675	81.198	1	9.3	14.9	0.8	19.5	28.4
43.096	54.87	62.165	40.344	61.769	78.639	0.9	9.8	15	1.1	19.2	27.8
42.483	55.768	64.917	42.785	63.586	80.906	1.1	11.3	16	0.7	19.5	28.5
43.078	56.816	65.544	44.887	65.198	77.144	0.9	10.6	15.8	0.9	19.3	28.1
41.745	54.818	62.911	43.143	61.598	77.083	0.7	10.5	15.7	1.2	20.3	27.8
42.563	55.729	63.377	41.209	61.786	76.276	0.9	10.4	15.6	1.1	20.6	28.5
46.984	58.731	67.366	42.675	62.625	76.387	1.1	11.1	16.5	1	19.8	29.6
45.069	56.936	65.095	40.112	60.276	76.377	0.7	10.3	15.4	1.1	20.9	28.3
41.553	54.597	62.158	45.352	64.772	80.067	0.9	10.8	16.2	0.6	19.2	27.3
42.238	53.187	62.366	40.449	60.587	78.007	1.1	9.9	15	0.8	19.8	27.8
40.059	52.098	61.048	41.156	60.665	78.765	1	10.1	15.5	0.9	19.6	28
41.559	54.389	62.639	45.293	65.722	81.585	0.9	11.2	16	0.8	18.3	26.9
43.386	53.476	61.566	41.221	61.447	78.845	1	10.4	15.2	0.7	18.9	27.1
41.288	55.477	64.106	42.026	61.098	78.622	0.9	10.3	15.5	1.1	18.4	27.8
44.086	56.498	65.018	43.458	62.581	79.589	0.8	9.6	15.1	0.7	18.6	28.1
42.675	54.098	63.109	42.067	62.765	80.476	0.9	9.4	15.5	1	18.9	27.5
42.906	55.489	64.487	45.194	64.324	77.254	1	10.5	15.6	0.9	19.2	28.4
44.586	55.863	68.076	42.817	63.162	79.821	1.1	11	16.2	1.3	18.8	27.6
44.795	56.498	65.736	45.557	65.663	81.912	0.6	10.9	15.3	0.9	19.9	28.2
40.569	52.199	61.709	43.078	64.049	79.768	0.9	10.6	15.6	1	19.6	28.7
42.897	54.619	62.159	41.176	62.753	79.874	0.8	9.9	15	0.8	20.1	28.5
44.697	55.784	63.228	44.529	65.185	80.834	0.8	9.6	16.1	0.8	19.8	28.6
40.959	52.209	60.159	45.519	65.055	77.896	1	10.5	16.3	1	19.2	28.4
41.494	54.289	63.756	40.175	61.209	79.558	1.1	11.4	15.8	0.9	20.6	29.6
41.278	51.387	60.873	46.667	66.871	81.843	0.9	10.7	16.1	1.2	19.4	28.9
45.127	57.591	66.954	44.118	65.398	80.377	1	10.9	15.2	0.8	18.9	27.8
42.471	54.096	62.698	42.778	63.128	79.598	1.1	11.2	15.7	1	19.2	28.3
44.685	55.739	64.885	42.572	64.584	80.675	0.9	10.1	15.1	0.9	19.6	27.8
44.79	59.166	68.356	43.989	65.487	80.812	0.8	10.6	15.2	1	20.3	28.1
45.162	58.925	66.284	44.099	67.508	81.445	0.6	10.8	15.6	1.1	18.9	27.7

T0 – 0 min before anesthesia induction; T1 – 1 h after the beginning of surgery; T2 – at the end of surgery; IL-6 – interleukin-6; hs-CRP – highly sensitive C-reaction protein.