China is undergoing a remarkable demographic transition, due to a decrease in birth rates and an increase in longevity. By 2050, one out of every four Chinese, approximately 336 million people, will be aged 65 years or older [1] . Elderly patients are at greater risk of morbidity and mortality during surgery [2] . There is data that reveals that deregulated inflammation is responsible for perioperative morbidity and mortality in the elderly [3] . Furthermore, the perioperative administration of glucocorticoids improves the outcome in patients undergoing surgery, which shows that systemic inflammation is associated with adverse outcomes [4] . The anti-inflammatory mechanisms of glucocorticoids activate many anti-inflammatory genes and repress many pro-inflammatory genes that are active in inflammation [5] . Due to the dangerous side effects, including an increased risk of wound infection and anastomotic leak, prolonged administration of glucocorticoids such as dexamethasone is not recommended [6] . However, there is no increased risk with a single dose of glucocorticoids [7] . Nonsteroidal anti-inflammatory drugs are widely used to effectively relieve pain without respiratory depression in patients, and reduce inflammation by inhibiting cyclooxygenase (COX) [8] . There is a study that suggests that non-steroidal anti-inflammatory drugs can inhibit interleukin-6 by suppressing NF-κB activation and NF-κB-dependent gene expression [9] . Further studies are required in order to elucidate mechanisms of NSAID inhibiting interleukin-6. Whether nonsteroidal anti-inflammatory drugs combined with steroidal anti-inflammatory drugs prove to increase the suppression of IL-6 after surgery still remains to be determined.

The aim of this study was to determine the effect of flurbiprofen combined with prednisolone on interleukin-6 in elderly surgery patients.

NSAIDs are some of the most commonly used drugs in the United States and the rest of the world [11] . There are many applications in the medical field, including some little-known effects. In a previous study, a 35-year-old Japanese woman who was diagnosed with pheochromocytoma, which revealed positive staining using an antihuman IL-6 antibody by immunohistochemical study and showed increased IL-6 mRNA levels by northern blot analysis, showed marked inflammatory reactions and pyrexia as a result of excessive production of IL-6

^ap < 0.05, compared with the T0; ^bp < 0.05, compared with the T1; ^cp < 0.05, compared with the T2.

with serum IL-6 level 262 ng/l (normal; <4.0 ng/l). Following the administration of the nonsteroidal anti-inflammatory drug, naproxen, fever and inflammatory markers were largely overcome [12] . There was, however, no explanation why NSAIDs inhibited IL-6 secretion. In another previous study, after 14 days of treatment with celecoxib or nimesulide, a researcher observed a significant reduction in IL-6 levels in the synovial fluid of patients with knee OA [13] , and Schumacher et al. [14] demonstrated that IL-6 levels decrease in the synovial fluid of osteoarthritic patients after two weeks of oral etodolac. Similarly, diclofenac, ibuprofen and celecoxib used for OA treatment decrease IL-6 and the explanation for the NSAID-induced reduction of the IL-6 concentration is the part inhibition of prostaglandin (PG) production [15] . Prostaglandins have previously been proven to stimulate the production of IL-6 by bone cells [16] . The results of a previous study indicated an inverse correlation, and a higher amount of NSAID application bringing a better outcome, between the amounts of NSAIDs applied and systemic IL-6 and CRP levels in patients with SAH [17] . Basically, NSAIDs have an ability to suppress IL-6 secretion, but more detailed mechanisms need to be elucidated. Our results showing that patients with the administration of flurbiprofen had lower levels of IL-6 after surgery also confirm this. Glucocorticoids are metabolic hormones which possess the ability to suppress immune responses and are used as a therapeutic approach to treat inflammatory diseases caused by an overactive immune system [18] . In an earlier article, the administration of methylprednisolone was proven to have a marked association with a lower incidence of organ failure and pulmonary disorder by reducing levels of the IL-6 and IL-8 inflammatory cytokines and higher PaO₂/FiO₂ ratios by POD 3 [19] . Our results demonstrate that patients with administration of prednisolone had lower levels of IL-6 after surgery, the same as in the above-mentioned researches. The suppression of inflammatory cytokine response was dependent on Toll-like receptor signaling in which the activation of the NF-κB pathway was targeted at several levels, including inhibition of IkB phosphorylation and NF-κB DNA-binding activity as well as upregulation of IkBa synthesis [20] . More notable is that our results demonstrate that patients who have received flurbiprofen and prednisolone had lower levels of IL-6 on day 1, meaning the combination proves an increased suppression of IL-6 after surgery. The increased suppression stems largely from two different mechanisms which inhibit inflammation after surgery. There were examples which have proved NSAIDs and glucocorticoids show different effects on cognitive function after surgery and the development of Alzheimer’s disease for different mechanisms, in which NSAIDs could improve cognitive function after surgery and inhibit AD, but not glucocorticoids [21] [22] . According to our results, the levels of IL-6 after surgery were highest on day 1 (T1), which dropped rapidly on days 2 (T2) and 3 (T3), explaining why there were no significant differences between groups with combined and uncombined medication on T2 and T3, the same as in previous researches [23] .

According to our results, the levels of CRP within three days never show a peak and combination of flurbiprofen and prednisolone proved an increased suppression of CRP on each of the three days. Therefore, combined is better than uncombined medication. The levels of CRP are regarded as an early monitor of the condition of a patient over time after surgery [24] . However, CRP was only used as a supplementary predictor for increased complications. In a recent meta-analysis, including 1832 patients who were undergoing colorectal surgery, levels of CRP for the prediction of postoperative complications were assessed, suggesting that the ability of CRP to predict postoperative infectious complications was at its worst on day 1 (area under the curve 0.64) and at its highest on day 4 (area under the curve 0.81) [25] . A distinct possibility for the result is that CRP was increased slowly. TNF-α is major mediators of the acute-phase protein response to tissue damage caused by surgical intervention [26] . However, the levels of TNF-α in our study show no differences between the four groups and four periods (T0, T1, T2, T3). We believe that the smaller sample is the major reason and more patients need to be included in order to confirm this. Our results show that either flurbiprofen or prednisolone could lower the SIRS score. However, combined did not increase the potency. The SIRS score can be determined as fulfilling at least two of the following four criteria: fever > 38.0˚C or hypothermia < 36.0˚C, tachycardia > 90 beats/minute, tachypnea > 20 breaths/minute, leukocytosis > 12 × 10⁹/l or leucopoenia < 4 × 10⁹/l [10] . Perhaps one of two, either flurbiprofen or prednisolone, is surely enough to lower the body temperature, then lower the heart rate. Furthermore, in another study, SIRS was proved not to be a contributor to the prediction of postoperative complications [27] .

Our study had several limitations. Firstly, it included relatively small groups of patients. We need larger groups in order to decrease the uncertainty. Secondly, the observation was limited to the measure of inflammation markers without a postoperative follow-up, especially the length of the hospital stay and being confined to bed. This has limited our judgment on the benefits of flurbiprofen combined with prednisolone. We will be careful to avoid this inconvenience in our future research. Thirdly, time between surgery and blood sample collection on days 1, 2, and 3 was somewhat variable between patients as was the time of initiation of surgery, which altered the dynamics of levels of IL-6, CRP and TNF-α. Finally, we only investigated inflammatory biomarkers before surgery and on days 1, 2 and 3. This was a little short for the length of a hospital stay.

In conclusion, flurbiprofen combined with prednisolone in elderly surgery patients proved to inhibit the levels of inflammatory biomarkers, including increased suppression of IL-6 and CRP.

We thank the Department of Orthopedics at the Eighth Affiliated Hospital, Sun Yat-sen University for providing help in collecting data.

Jiaxin Lin conceived and designed the study. Hui Yang, Shaofen Chen, and Jiao Xu gathered the data and participated in data analysis, with all authors revising it critically for intellectual content. All authors have read and approved the final version of this manuscript.

The authors declare no conflicts of interest regarding the publication of this paper.

Lin, J.X., Yang, H., Chen, S.F. and Xu, J. (2024) Effect of Flurbiprofen Combined with Prednisolone on Interleukin-6 in Elderly Surgery Patients. Pharmacology & Pharmacy, 15, 15-26. https://doi.org/10.4236/pp.2024.152002