Ameliorative effects of parecoxib in combination with ultrasound-guided paravertebral block ( UGPB ) on stress and inflammatory responses following thoracoscopic surgery

Purpose: To investigate the ameliorative effects of parecoxib combined with ultrasound-guided paravertebral block (UGPB) on stress and inflammatory responses after thoracoscopic surgery. Methods: Forty thoracoscopic surgery patients were randomized into placebo (control) and parecoxib groups. Parecoxib was administered pre-operation, 24 h and 48 h after operation. Arterial blood was collected, and endotoxin (ET), thromboxane A2 (TXA2), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels were measured. Opioid dosage, infusion volume, blood loss, operation time, visual analogue scale (VAS) score at 24 h and 48 h, and hospitalization period were recorded. Results: No significant differences were observed in age, sex, height, body weight, opioid dosage, surgery time, blood loss, or infusion volume between groups. VAS scores in the parecoxib group were significantly lower than the control group after 24 and 48 h. The hospitalization period of the parecoxib group was significantly shorter than the control group. Plasma levels of ET, TXA2, IL-6 and TNF-α in the parecoxib group were lower than the control group after 24 h; however, there was no significant difference after 48 h. Conclusion: Parecoxib, combined with UGPB, effectively relieves thoracoscopic pain, stress, and inflammatory responses of patients after thoracoscopic surgery. This treatment would improve the postoperative quality of life of lung cancer patients.

Parecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a second generation of cyclooxygenase-2 (COX-2) inhibitor.It mediates antipyretic, anti-inflammatory and analgesic effects by selectively inhibiting COX-2 activity and the production of prostaglandins and thromboxane A2 (TXA2) [8].In this study, patients undergoing thoracoscopic surgery were enrolled to evaluate the ameliorative effects of parecoxib, in combination with ultrasound-guided paravertebral block (UGPB) against pain, stress response, and inflammation after thoracoscopic surgery.These studies may provide a basis for the use of parecoxib in post-operative analgesia.

EXPERIMENTAL Subjects
In the present study, thoracoscopic surgery patients were selected from March 2016 to March 2017 in the Department of Anesthesiology of Yantaishan Hospital (Yantai, China).All patients underwent general anesthesia combined with UGPB.The experimental protocols were carried out in accordance with the declaration of Helsinki [9], and approved by the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong University (Ji'nan, China) (no.2015-hu35-1).

Experimental protocol
All patients underwent the perioperative management model according to the concept of enhanced recovery after surgery (ERAS): no drinking 2 h before surgery, no urine catheter, no pre-operative drug administration, and standard preoperative preparation and anesthesia process.
UGPB was performed before general anesthesia by administering 20 mL ropivacaine (0.5%) between the T4 and T8 vertebrae.The anesthesia plane was determined 10 min after blocking.All enrolled patients were randomly divided into two groups: placebo (control group, n = 20) and parecoxib (experimental, n = 20).Before operation, patients were intravenously administered parecoxib (40 mg) or placebo (normal saline), which was administered once again 24 h after surgery.

Determination of ET, TXA2, IL-6 and TNF-α in arterial blood
Arterial blood samples were collected before operation (T0), 24h after operation (T1) and 48 h after operation (T2).The blood was centrifuged at 3500 rpm for 15 min at 4 °C.The plasma was then collected and stored at -80°C.The levels of endotoxin (ET), thromboxane A2 (TXA2), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in arterial blood were measured using commercial ELISA kits following the manufacturer's instructions.The opioid (fentanyl) dosage, infusion volume, blood loss, operation time, visual analog scale (VAS) score at 24 and 48 h, and length of post-operative hospital stay were also recorded.

Statistical analysis
All data were expressed as mean ±standard deviation (SD), and analyzed by SPSS software (SPSS for Windows 19.0, SPSS Inc., USA).Oneway analysis of variance (ANOVA, Dunnett's multiple comparisons test) was used for analyzing differences between groups, and p < 0.05 was considered significant.

Demographic profile of patients
A total of 40 patients were enrolled in the study.There were no significant differences in age, sex, height, body weight, fentanyl dosage, surgery time, blood loss and infusion volume between the parecoxib and control groups (Table 1).

Post-operative VAS score and hospital stay
As shown in Figure 1, the VAS scores of patients in the parecoxib group were significantly lower than the control group at 24 and 48 h after surgery (p < 0.05).In addition, the hospitalization period of the parecoxib treatment group was significantly shorter than the control group (p < 0.05) (Table 1).

Plasma levels of ET, TXA2, IL-6 and TNF-α
There were no significant differences in plasma levels of ET (Figure 2), TXA2 (Figure 3), IL-6 (Figure 4) and TNF-α (Figure 5) between the parecoxib group and the control group before surgery (p > 0.05).Interestingly, plasma levels of ET, TXA2, IL-6, and TNF-α in the parecoxib group reduced compared to the control group 24 h after surgery (p < 0.05).However, no significant difference was observed between the two groups 48 h after surgery (p > 0.05).Post-operative rehabilitation quality is influenced by many factors, including surgical procedure and time, stress and inflammatory response, intra-operative anesthesia quality, post-operative analgesic quality, and postoperative complications [11].Thus, the levels of inflammatory cytokines in the plasma, opioid drug dosage, infusion volume, blood loss, surgery time, VAS score, and post-operative hospital stay were recorded in this study to evaluate the efficacy of the therapeutic method.
It is well known that NSAIDs possess favorable anti-inflammatory and analgesic activities.However, traditional non-selective NSAIDs often have side-effects, such as nausea, vomiting and stomach bleeding.[14].Parecoxib is a novel selective NSAID that targeted COX-2 and, has fewer side-effects than traditional non-selective NSAIDs.Parecoxib analgesia can prevent intraoperative nociceptive stimulation, caused by central sensitization and pain up-regulation, to block or reduce the occurrence of postoperative pain.TNF-α and IL-6 are well-known important pro-inflammatory cytokines.TNF-α is a key cytokine in the initiation of systemic inflammatory response, and IL-6 is a downstream cytokines in the inflammatory process.
Additionally, these two pro-inflammatory cytokines are involved in activation of the inflammatory reaction cascade in sepsis and play important roles in the pathogenesis of SIRS [15].ET induces the activation of endothelial cells in the stress response and is harmful to some organs and tissues.TXA 2 is also produced in stress response.Thus, ET and TXA 2 reflect the level of stress response [16,17].In the present study, the treatment of parecoxib, combined with UGPB, significantly decreased the plasma levels of ET, TXA2, IL-6, and TNF-α, indicating that this method alleviated the stress and inflammatory response induced by thoracoscopic surgery.

CONCLUSION
Parecoxib, combined with UGPB, effectively relieves the pain, stress responses, and inflammatory response in patients after thoracoscopic surgery.This treatment would be beneficial for improving the postoperative quality of life of lung cancer and other thoracoscopic surgery patients.
2018 Li X, Cui X, Zhang S, Fu Z.This work is licensed under the Creative Commons Attribution 4.0 International License Trop J Pharm Res, June 2018; 17(6): 1172 seriously affect the sputum excretion and deep breathing of patients [3].

Figure 5 :
Figure 5: TNFα plasma levels of the patients.P, parecoxib group; C, control group; T0, before surgery; T1, 24 h after surgery; T2, 48 h after surgery.*p < 0.05, compared with control group DISCUSSION Lung cancer is the most common cancer in the world, and its incidence is increasing.Lobectomy is commonly used for the treatment of lung cancer.However, the surgery often affects patients' postoperative quality of life and easily leads to chronic pain [10].Thoracic surgery patients usually have deep breathing difficulty and cough expectoration due to the severe pain, which can also lead to respiratory secretions retention, small airway blocking, atelectasis, hypothyroidism and inflammatory responses.In 2001, researchers developed the concept of ERAS for reducing the average length of postoperative hospital stays and improving the quality of patients after surgery [12,13].

Table 1 :
Demographic characteristics of thoracoscopic surgery patients *P < 0.05, compared with control group; ASA, American Society of Anesthesiologists Figure 1: VAS scores of the patients.P, parecoxib group; C, control group; T1, 24 h after surgery; T2, 48 h after surgery.*p < 0.05, compared with control group