Effect of dexmedetomidine-ropivacaine transversus abdominis plane block on analgesia and cognitive impairment risk in colorectal cancer surgery

Abstract

BACKGROUND

The dexmedetomidine (DEX) plus ropivacaine treatment enables a transversus abdominis plane block (TAPB) of the peripheral nerves in patients undergoing radical resection for colorectal cancer (CRC) that can provide clinical data for improving the postoperative analgesic effect, reducing the risk of cognitive impairment, and decreasing the circulating levels of serum inflammatory factors and stress hormones.

AIM

To assess the impact of DEX plus ropivacaine-enabled TAPB on pain, postoperative cognitive dysfunction (POCD), and inflammatory/stress factors.

METHODS

Our patient cohort was randomly divided into control and observation groups (60/group). The observation group used a DEX plus ropivacaine-enabled TAPB, while the control group employed a ropivacaine-enabled TAPB. The pain score [Visual Analogy Scale (VAS), Montreal Cognitive Assessment (MoCA)], serum inflammatory factor level (C-reactive protein, interleukin-6 and tumor necrosis factor-α), serum stress hormone levels (cortisol and adrenaline) and postoperative adverse reactions were compared between the two groups.

RESULTS

The observation group VAS scores were lower than those of the control group (better analgesic effect, P < 0.05). The MoCA and POCD scores decreased post-surgery in the observation group (P < 0.05). In the elderly, the overall VAS and MoCA scores were significantly reduced compared with the young group. The C-reactive protein, interleukin-6, tumor necrosis factor-α, cortisol and adrenaline levels were lower in the observation group compared with the control group post-surgery (P < 0.05). There was no significant difference in adverse reactions between the two groups post-surgery, but the incidence of adverse reactions in the observation group was still lower. DEX continuously inhibited p65-phosphorylation levels in the nuclear factor κB pathway at multiple time points, and its inhibitory effect became more significant over time.

CONCLUSION

DEX plus ropivacaine-enabled TAPB reduces POCD and inflammatory/stress hormone levels, and significantly improves the postoperative analgesic effect of patients undergoing radical resection for colorectal cancer.

Key Words: Radical resection; Colorectal cancer; Dexmedetomidine; Ropivacaine; Transversus abdominis; Plane block

Core Tip: The dexmedetomidine plus ropivacaine combination for transversus abdominis plane block significantly improves postoperative outcomes in patients undergoing radical resection for colorectal cancer. This treatment enhances pain control, reduces postoperative cognitive dysfunction, and lowers the levels of serum inflammatory markers and stress hormones, such as cortisol and adrenaline. The approach provides a promising strategy for better managing postoperative analgesia and minimizing cognitive decline, particularly in elderly patients. Moreover, it demonstrates a favorable safety profile with fewer adverse reactions compared to traditional analgesic methods, making it a valuable addition to colorectal surgery protocols.

INTRODUCTION

Colorectal cancer (CRC) is one of the common and high-incidence malignant tumors worldwide, and its morbidity and mortality have been increasing in recent years[1]. Radical surgical resection is still the main treatment for CRC, but postoperative pain management and cognitive function protection have always been clinical challenges[2]. Postoperative pain increases the stress response of patients, affects their recovery process, and leads to postoperative cognitive dysfunction (POCD), thus affecting the long-term quality of life of patients. The choice of postoperative analgesia is crucial for postoperative recovery[3,4]. Although traditional opioid drugs play an important role in postoperative analgesia, the adverse reactions related to their use, such as respiratory depression, nausea and vomiting, and addiction problems, highlight an urgent need to find more safe and effective analgesic methods[5]. In recent years, regional nerve block techniques, such as the transversus abdominis plane block (TAPB), have attracted increasing attention owing to their superior analgesic effects and low incidence of adverse reactions[6]. Ropivacaine is a long-acting local anesthetic amide widely used in various types of nerve blocks because of its excellent analgesic effects and low toxicity to the central nervous and cardiovascular systems[7]. Dexmedetomidine (DEX), as a highly selective α2-adrenergic receptor agonist, has multiple effects of sedation, analgesia, anti-anxiety and a certain neuroprotective effect, and its use during and after surgery can significantly reduce the demand for opioids[8,9]. However, the combined use of DEX and ropivacaine to establish a TAPB remains rare, and its effect on postoperative analgesia and cognitive function in patients undergoing radical resection for CRC has not been fully explored[10].

MATERIALS AND METHODS

General data

In this study, we undertook a single-center, randomized controlled trial with a patient cohort comprised of 120 patients who underwent radical resection for CRC at our hospital between January 2022 and March 2024. The patients were randomly divided into an observation and a control group, with 60 patients in each group. The inclusion criteria were as follows: (1) Age between 18 and 75 years old; (2) American Society of Anesthesiologists (ASA) grades I-III; (3) Undergoing radical resection for CRC; and (4) Signed informed consent form. The exclusion criteria were as follows: (1) Patients who were allergic to local anesthetics or DEX; (2) Patients with severe cardiac, hepatic, or renal insufficiency; (3) Patients with preoperative cognitive dysfunction; and (4) Pregnant or lactating women. The observation group consisted of 34 men and 26 women with a mean age of 56.30 ± 11.40 years. The mean body weight was 67.80 ± 10.30 kg. The mean operation time was 143.50 ± 30.20 minutes. There were 20 cases with ASA grade I, 30 cases with ASA grade II and 10 cases with ASA grade III. The control group was made up of 32 men and 28 women with a mean age of 55.90 ± 12.10 years. The mean body weight was 66.40 ± 11.20 kg. The mean operation time was 140.70 ± 28.70 minutes. There were 18 cases with ASA grade I, 32 cases with ASA grade II, and 10 cases with ASA grade III. There were no significant differences in baseline data between the two groups (P > 0.05), indicating that they were comparable.

Methods

The patients in the observation group underwent a DEX-ropivacaine enabled TAPB. All patients were evaluated for standard anesthesia 30 minutes before surgery and midazolam (Jiangsu Hengrui Pharmaceuticals Co., Ltd.) was given intravenously at 0.05 mg/kg. Guidance was conducted by employing an ultrasonography-guided device. The patient was placed in a supine position for a routine disinfection of the operating area. The ultrasonography probe was positioned in the plane of the transverse abdominal muscle. Based on clinical practice guidelines, a solution of 0.5% ropivacaine (AstraZeneca Pharmaceutical Co., Ltd.), 20 mL and 1 μg/kg of DEX (Yangtze River Pharmaceutical Group Co., Ltd.) was prepared. A 22-gauge needle was used to slowly inject this solution under ultrasonographic guidance into the planes of the bilateral transverse abdominal muscles at 10 mL per side. The patient continued to receive intravenous DEX at an initial dose of 0.2-0.5 μg/kg/hour, and the infusion rate was adjusted according to the Visual Analog Scale (VAS) pain score of the patient and sedation. Postoperative analgesia was maintained for 48 hours, during which vital signs such as heart rate, blood pressure and respiratory rate were monitored.

The patients in the control group were administered a ropivacaine-enabled TAPB. All control group patients were evaluated for standard anesthesia 30 minutes before surgery and midazolam (Jiangsu Hengrui Pharmaceuticals Co., Ltd.) was given intravenously at 0.05 mg/kg. Guidance was conducted by employing an ultrasonography-guided device. The patient was placed in a supine position for a routine disinfection of the operating area. The ultrasonography probe was positioned in the plane of the transverse abdominal muscle. Based on the clinical practice guidelines, a 20 mL solution of 0.5% ropivacaine (AstraZeneca Pharmaceutical Co., Ltd.) was prepared. A 22-gauge needle was used to slowly inject this solution under ultrasonographic guidance into the planes of the bilateral transverse abdominal muscles at 10 mL per side. After surgery, the patient received only a single injection of ropivacaine for analgesia instead of continuous drug infusion. Depending on the VAS pain score of the patient, supplemental opioids may have been administered for additional analgesia.

Outcome indicators

The outcome indicators were as followed: (1) Postoperative pain: Postoperative pain was evaluated by a VAS. The pain scores were evaluated at 2 hours, 6 hours, 12 hours, 24 hours and 48 hours after surgery. The patients marked their extent of perceived pain on a 10 cm straight line, from “no pain” to “the severest pain”; (2) POCD was assessed using the Montreal Cognitive Assessment (MoCA). The MoCA score ranges from 0 to 30 points, and the patient is deemed normal if the score is 26 points or above, while a MoCA score < 26 indicates cognitive dysfunction. MoCA assessments were performed on the day before surgery, and the 1^st, 3^rd, and 7^th day after surgery. MoCA covers eight aspects, namely, attention, memory, executive function, language ability, visual and spatial ability, abstract thinking, computational ability, and directional ability. Each item was scored, and the total score was calculated; (3) Serum levels of inflammatory factors: These factors include C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). On the day before surgery, and 6 hours, 24 hours, and 48 hours after surgery, 2 mL of venous blood was collected from patients and placed into ethylenediaminetetraacetic acid (EDTA) anticoagulation tubes. Blood samples were centrifuged at 3,000 rpm for 10 min. The test was performed using an enzyme-linked immunosorbent assay using a Thermo Fisher Scientific kit; (4) Serum levels of stress hormones: These hormones include cortisol (Cor) and adrenaline (AD). On the day before surgery, and 6 hours, 24 hours, and 48 hours after surgery, 2 mL of venous blood was collected from patients and placed into ethylenediaminetetraacetic acid anticoagulation tubes. Blood samples were centrifuged at 3000 rpm for 10 minutes. The assay was conducted using a Thermo Fisher Scientific enzyme-linked immunosorbent assay kit; (5) Adverse reactions: The adverse reactions after surgery include nausea, vomiting, headache, hypotension, and local numbness. Adverse reactions were recorded at 6 hours, 24 hours, and 48 hours after surgery; and (6) Nuclear factor κB (NF-κB) activity detection: We detected p65 (key protein in the NF-κB pathway) phosphorylation levels by immunoblotting. Total cellular protein was extracted, and the protein concentration was quantified by using the bicinchoninic acid Protein Assay Kit (Thermo Fisher Scientific, Cat No. 23225). A 100 μg protein sample from each patient was size-separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Bio Rad, Mini PROTEAN Tetra Cell) and transferred to a polyvinylidene fluoride membrane (Millipore, Cat No. IPVH00010). After the membrane was blocked to prevent the non-specific binding of antibodies, it was exposed to either an antibody against p-NF-κB p65 (Cell Signaling Technology, Cat No. 3033S, dilution: 1:1000) or β-actin (Internal control cell protein, Cell Signaling Technology, Cat No. 4970S, dilution: 1:5000). The antibody-binding signals were acquired and quantified by employing Enhanced Chemiluminescence imaging (Bio Rad, Clarity Western ECL Substrate).

Statistical analysis

SPSS 26.0 software was used for statistical analysis. Measurement data were expressed as mean ± SD, and inter-group comparison was examined by independent sample t-test. Enumeration data were expressed as percentages, and inter-group comparisons were performed using the χ²-test and analysis of variance. Statistical significance was set at P < 0.05.

RESULTS

Postoperative pain

The postoperative pain scores of patients in the observation group were significantly lower than those of the control group when measured at various postoperative time points, and both the young and elderly groups showed similar trends. The pain score values of the observation group measured within 2 to 48 hours after surgery were significantly lower than those of the control group (P < 0.05), indicating the effectiveness of the treatment in reducing postoperative pain (Table 1).

Table 1 Comparison of Visual Analogy Scale levels among different groups after surgery, n = 30 for each group.

Time point	Youth control group	Youth observation group	Elderly control group	Elderly observation group	t	P value
2 hours post-surgery	4.35 ± 0.87	3.55 ± 0.74	4.15 ± 0.85	3.45 ± 0.70	2.581	0.012
6 hours post-surgery	3.75 ± 0.82	2.85 ± 0.68	3.55 ± 0.80	2.75 ± 0.65	3.511	0.001
12 hours post-surgery	3.30 ± 0.75	2.60 ± 0.64	3.10 ± 0.78	2.50 ± 0.59	4.256	< 0.001
24 hours post-surgery	2.90 ± 0.70	2.20 ± 0.60	2.80 ± 0.73	2.05 ± 0.57	4.341	< 0.001
48 hours post-surgery	2.60 ± 0.65	2.00 ± 0.59	2.40 ± 0.66	1.90 ± 0.58	3.731	0.003

P < 0.05 indicated significant difference.

POCD

The MoCA scores of the observation group were significantly higher than those of the control group at various postoperative time points, and both the young and elderly groups showed similar trends. The MoCA scores of the observation group were significantly higher than those of the control group on postoperative days 1, 3 and 7 (P < 0.05), indicating that the treatment effectively improved postoperative cognitive function (Table 2).

Table 2 Comparison of postoperative Montreal Cognitive Assessment scores among different groups, n = 30 for each group.

Time point	Youth control group	Youth observation group	Elderly control group	Elderly observation group	t	P value
1 day before surgery	27.80 ± 1.08	27.75 ± 1.12	27.40 ± 1.22	27.25 ± 1.06	0.521	0.611
1 day post-surgery	25.20 ± 1.54	23.10 ± 1.60	24.20 ± 1.49	22.00 ± 1.69	3.437	0.002
3 days post-surgery	25.40 ± 1.43	23.80 ± 1.58	24.80 ± 1.40	23.10 ± 1.60	2.983	0.007
7 days post-surgery	26.20 ± 1.30	24.60 ± 1.45	25.80 ± 1.38	24.40 ± 1.56	3.205	0.003

P < 0.05 indicated significant difference.

Serum levels of inflammatory factors

The serum levels of IL-6, TNF-α, and CRP in patients of the observation group were significantly lower than those of the control group at 6 hours, 24 hours and 48 hours after surgery. The F values of time main effect, group main effect and interaction showed significant differences. In particular, the F value and P value of group main effect and interaction further verify the advantage of using a combination of DEX and ropivacaine in reducing postoperative inflammatory response (Table 3).

Table 3 Comparison of serum inflammatory factor levels between two groups.

Time point	Group	IL-6 (pg/mL)	TNF-α (pg/mL)	CRP (mg/L)
1 day before surgery	Observation	12.45 ± 3.15	8.73 ± 2.22	3.45 ± 1.02
	Control	12.39 ± 3.09	8.69 ± 2.18	3.42 ± 0.98
6 hours after surgery	Observation	26.78 ± 5.32	16.45 ± 3.47	7.89 ± 2.15
	Control	35.12 ± 6.48	22.67 ± 4.56	10.34 ± 2.87
24 hours after surgery	Observation	18.65 ± 4.08	12.34 ± 2.98	5.23 ± 1.65
	Control	25.78 ± 5.21	17.89 ± 3.84	7.68 ± 2.12
48 hours after surgery	Observation	14.32 ± 3.67	10.12 ± 2.45	4.12 ± 1.34
	Control	19.65 ± 4.35	13.78 ± 3.12	5.89 ± 1.78
Time main effect F value		87.452	92.678	79.345
Time main effect P value		< 0.001	< 0.001	< 0.001
Group main effect F value		36.541	41.763	34.217
Group main effect P value		< 0.001	< 0.001	< 0.001
Interaction F value		9.328	10.456	8.974
Interaction P value		< 0.001	< 0.001	< 0.001

P < 0.05 indicated significant difference. IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; CRP: C-reactive protein.

Serum levels of stress hormone

The serum levels of Cor and AD in patients of the observation group were significantly lower than those of the control group at 6 hours, 24 hours and 48 hours after surgery, and the differences were statistically significant (P < 0.001) (Table 4).

Table 4 Comparison of serum stress hormone levels between two groups.

Time point	Group	Cor (nmol/L)	t	P value	AD (ng/mL)	t	P value
1 day before surgery	Observation	295.45 ± 36.25	-0.118	0.906	15.23 ± 3.45	-0.344	0.731
	Control	296.23 ± 35.78			15.45 ± 3.56
6 hours after surgery	Observation	450.32 ± 40.12	-7.973	< 0.001	25.32 ± 4.67	-6.096	< 0.001
	Control	512.67 ± 45.34			30.78 ± 5.12
24 hours after surgery	Observation	395.65 ± 38.78	-6.949	< 0.001	22.45 ± 4.12	-6.671	< 0.001
	Control	445.89 ± 40.56			27.89 ± 4.78
48 hours after surgery	Observation	320.45 ± 35.34	-5.198	< 0.001	18.45 ± 3.67	-4.653	< 0.001
	Control	355.67 ± 38.78			21.67 ± 3.89

P < 0.05 indicated significant difference. Cor: Cortisol; AD: Adrenaline.

Adverse reactions

Six hours after surgery, the incidence of nausea, vomiting, headache, hypotension, and local numbness in patients of the observation group were 5.00%, 3.33%, 1.67%, 6.67%, and 3.33%, respectively, and were lower than those in the control group (P > 0.05). At 24 hours and 48 hours after surgery, the incidence of adverse reactions decreased further, with the highest incidence rate in the observation group not exceeding 3.33% (Table 5).

Table 5 Comparison of adverse reactions between two groups, n (%).

Time point	Group	Nausea	Vomit	Headache	Hypotension	Local numbness	χ2	P value
6 hours after surgery	Observation	3 (5.00)	2/3.33	1 (1.67)	4 (6.67)	2 (3.33)	1.087	0.9
	Control	4 (6.67)	3/5.00	2 (3.33)	5 (8.33)	3 (5.00)
24 hours after surgery	Observation	2 (3.33)	1/1.67	0	2 (3.33)	1 (1.67)	2.066	0.733
	Control	3 (5.00)	2/3.33	1 (1.67)	3 (5.00)	2 (3.33)
48 hours after surgery	Observation	1 (1.67)	1/1.67	0	1 (1.67)	1 (1.67)	1.667	0.798
	Control	2 (3.33)	2/3.33	1 (1.67)	2 (3.33)	2 (3.33)

P < 0.05 indicated significant difference.

NF-κB activity status

The p65 phosphorylation level in patients of the observation group was significantly lower than that in the control group at each time point (P < 0.001). The p65 phosphorylation level in patients of the observation group decreased gradually with the passage of time. An F value of 24.539 and a P value of < 0.001 indicate significant differences between the groups and suggest that DEX effectively inhibits the activity of the NF-κB pathway (Table 6).

Table 6 Comparison of nuclear factor κB activity levels between two groups after surgery.

Group	24 hours phosphorylated p65 level (relative value)	48 hours phosphorylated p65 level (relative value)	72 hours phosphorylated p65 level (relative value)	96 hours phosphorylated p65 level (relative value)	120 hours phosphorylated p65 level (relative value)	F value	P value
Control group	1.05 ± 0.12	1.25 ± 0.15	1.40 ± 0.18	1.50 ± 0.20	1.60 ± 0.22
Observation group	0.75 ± 0.10	0.55 ± 0.08	0.45 ± 0.07	0.35 ± 0.06	0.30 ± 0.05	24.539	< 0.001
P value	0.02	0.001	< 0.001	< 0.001	< 0.001

P < 0.05 indicated significant difference.

DISCUSSION

Our present findings revealed that the VAS pain scores of the observation group at each time point post-surgery were significantly lower than those of the control group (P < 0.05). Some researchers have pointed out that DEX-enabled TAPB can significantly reduce the postoperative pain score[11]. DEX, as an α2- adrenergic receptor agonist, can prolong analgesic time and reduce pain intensity by enhancing the effect of local anesthetics[12]. This mechanism is related to the DEX-mediated inhibition of norepinephrine released by neurons, thereby reducing pain transmission[13]. DEX can further enhance the analgesic effect by inhibiting the release of glutamic acid from presynaptic nerve endings in the spinal dorsal horn[14]. Our present results showed that the postoperative MoCA scores of the observation group were significantly higher than those of the control group (P < 0.05), suggesting that DEX combined with ropivacaine helped to reduce the incidence of POCD. Studies have shown that DEX has a neuroprotective effect, which can reduce the inflammatory response during and after surgery, thus protecting cognitive function. DEX protects brain function by activating the α2-adrenergic receptor, reducing the release of norepinephrine, and reducing the excitability of neurons and the neuroinflammatory response[15]. DEX can also reduce cognitive dysfunction by reducing oxidative stress and improving cerebral blood flow[16]. Regarding serum levels of inflammatory factors, the results of this study showed that the IL-6, TNF-α, and CRP serum levels of patients in the observation group were significantly lower than those in the control group at each time point post-surgery (P < 0.05). These findings are consistent with previous studies. DEX reduces the release of inflammatory mediators and the postoperative inflammatory response by inhibiting the NF-κB signaling pathway. DEX also reduces postoperative pain and cognitive dysfunction by reducing the production and release of inflammatory factors[17]. The anti-inflammatory effect of DEX may also be related to its efficacy in reducing oxidative stress and improving microcirculation, thereby reducing postoperative inflammatory response[18]. The incidence of postoperative adverse reactions in the observation group was lower than that in the control group, which may be related to analgesic mechanisms. The observation group may have been managed by adopting milder analgesic methods, such as reducing the use of opioids, in order to reduce side effects such as nausea and vomiting. In addition, the regimen in the observation group may have been more sensitive to postoperative hemodynamic stability and minimizing the occurrence of hypotension. Additionally, the incidence of local numbness was relatively low, which may be related to the faster recovery of nerve sensitivity. Overall, patients in the observation group exhibited mild postoperative adverse reactions, indicating that their analgesic regimen may be more beneficial for postoperative recovery and patient comfort while ensuring analgesic efficacy. Our data revealed that the p65 phosphorylation level in the observation group was significantly lower than that in the control group at all time points and displayed a continuous downward trend, indicating that DEX can effectively inhibit the activity of the NF-κB signaling pathway. The NF-κB pathway plays a key role in inflammation regulation, and a lowering of its activity helps to alleviate the inflammatory response. Our present study suggests that DEX treatment may reduce the postoperative inflammatory response by inhibiting the NF-κB pathway, providing experimental evidence for its application in perioperative management.

Serum levels of stress hormones (Cor and AD) are important indicators for evaluating the postoperative stress response. Our present results showed that the serum levels of Cor and AD for patients in the observation group were significantly lower than those in the control group at 6 hours, 24 hours and 48 hours after surgery (P < 0.05), indicating that DEX could effectively reduce the postoperative stress response. DEX inhibits the overexcitation of the sympathetic nervous system by exciting the α2-adrenergic receptor, thereby reducing the postoperative stress response[19]. Previous studies have pointed out that DEX treatment can reduce the postoperative stress response by reducing sympathetic nerve activity and increasing parasympathetic nerve activity[20]. DEX treatment also reduces postoperative pain and promotes postoperative recovery by reducing the release of stress hormones during surgery. With respect to adverse reactions, there was no significant difference in the incidence of adverse reactions at 6 hours, 24 hours and 48 hours after surgery between the observation and the control groups (P > 0.05), and all incidence values were reduced. This indicates that the use of DEX combined with ropivacaine for establishing a TAPB does not significantly increase the risk of adverse reactions while it improves the analgesic effects. Consistent with previous studies, DEX treatment was found to be safe and effective at a reasonable dose[21]. DEX can exert its analgesic and sedative effects at low doses after surgery without causing significant cardiovascular adverse reactions[22]. The results of this study indicate that DEX can effectively reduce postoperative inflammatory and stress responses by inhibiting the NF-κB pathway and lowering stress hormone levels. However, the DEX-specific mechanism of action in molecular terms still needs further exploration, and future research can further analyze the regulatory effects of DEX on the release of inflammatory factors, activation of immune cells, and related signaling pathways. In addition, the optimal dosage and administration regimen for the combination of DEX and ropivacaine are not clear yet. Further research is warranted on the effects of different dosage combinations on postoperative analgesic efficacy and safety, in order to optimize perioperative management and improve clinical application value.

CONCLUSION

In summary, the use of DEX combined with ropivacaine for establishing a TAPB can significantly improve the postoperative analgesic effect on patients undergoing radical resection for CRC, reduce the occurrence of POCD, reduce the serum levels of inflammatory factors and stress hormones, and does not increase the risk of adverse reactions, while demonstrating high clinical promotion value.