Effects of perioperative β-blockers on inflammatory response

To the Editor: Surgery-induced tissue damage leads to the release of damage-associated molecular patterns (DAMPs), triggering the inflammatory response. Similarly, perioperative trauma and stress can disrupt the neuroendocrine and immune systems, activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, and promote the release of catecholamines and changes in cytokines. The principal functions of the inflammatory biomarkers are detailed in Supplementary Table 1, https://links.lww.com/CM9/C539. The initial pro-inflammatory cytokine storm is followed by a proportional compensatory anti-inflammatory response, with a reduction in apoptotic T cells and a shift toward the immunosuppressive T helper 2 (Th2) phenotype after surgery. Unbalanced responses due to excessive immune activation and immunosuppression increase the body’s susceptibility, ultimately resulting in tissue and multi-organ functional damage.[1] Inflammatory markers such as interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and IL-1β are associated with postoperative complications, including postoperative atrial fibrillation, postoperative cognitive dysfunction, impaired intestinal barrier, and postoperative infection.[2] The activation of sympathetic nerves and the release of catecholamines appear to play a complex role in regulating immune responses. The activation of β2 receptors is related to the suppression of early traumatic pro-inflammatory responses and the promotion of the shift from cellular immunity to humoral immunity. Moreover, research has shown that β1-blockers reduce IL-6 and TNF-α levels and alleviate related complications in sepsis and surgery-treated mice, which may be further related to the inhibition of nuclear factor kappa B (NF-κB) activity by β1 adrenergic receptors, and thus to the inhibition of cytokine and high mobility group box 1 protein (HMGB-1) secretion.[3,4] The different regulatory effects of adrenergic receptors on immune responses likely differ due to the duration of action, receptor type, and target cells. During the perioperative period, there is an association between the application of β-blockers and a reduced risk of adverse cardiac events. Existing reviews and meta-analyses summarize the benefits of using β-blockers in immune inflammatory regulation and prognosis in sympathetic activation conditions such as sepsis, traumatic brain injury, and perioperative tumor metastasis.[5] However, there is presently no consensus among researchers on the impact of β-blockers on immune markers during the perioperative period. This study aimed to hypothesize the role of β-blockers in inflammation and explore their effects on perioperative inflammatory biomarkers and postoperative atrial fibrillation (POAF), thus providing insights into β-blockers’ potential use in managing perioperative inflammation. This study was complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol for this meta-analysis was entered in the International Prospective Register of Systematic Reviews (PROSPERO) on July 21, 2023 (No. CRD42023443896). PubMed (1966–2025), Embase (1947–2025), and Web of Science (1900–2025) were searched from database inception to May 1, 2025. The search strategy using the example of Embase, the search strategy with the full queries applied is shown in Supplementary Table 2, https://links.lww.com/CM9/C539. Medical Subject Heading (MeSH) terms were used alongside free text. Additionally, closely relevant references to identified articles were searched manually. The meta-analysis included only randomized controlled trials comparing β-blockers (intravenous or oral) with controls (placebo or no intervention) that were initiated in the perioperative period in adult patients (aged 18 years or older). Eligible trials reported at least one of the inflammatory biomarkers including IL-4, IL-6, IL-8, IL-10, IL-1RA, IL-1β, TNF-α, interferon (IFN)-γ, IFN-γ/IL-4, CRP, and white blood cell (WBC). Exclusion criteria included non-randomized controlled trial (RCT) studies, animal studies, interventions with combination drugs, using other drugs as controls, duplicate samples, and lack of raw data. Primary outcomes focused on inflammatory biomarkers (IL-4, IL-6, IL-8, IL-10, IL-1RA, IL-1β, TNF-α, IFN-γ, CRP, and WBC) at different postoperative time points (T1: 0–6 h postoperatively, time point closest to 0 h; T2: 6–24 h postoperatively, time point closest to 24 h; T3: 2–7 days postoperatively, time point closest to 2 days). These were the most commonly used biomarkers and time points in the identified relevant studies. POAF was a secondary outcome. Studies with multiple intervention groups were pooled following Cochrane recommendations. The Meta-analysis was performed if at least two studies were available; otherwise, results were summarized narratively. Data presented as medians or ranges were converted into means and standard deviations (SDs) by the method described by Wan et al.[6] The quality of included studies was assessed using the Cochrane risk-of-bias tool, while the quality of evidence was evaluated using GRADEpro GDT software (McMaster University, Hamilton, Ontario, Canada). Using random-effects models for heterogeneity. Statistical analysis was performed with Review Manager 5.4 (Cochrane Collaboration, Oxford, UK) and Stata (StataCorp LLC, College Station, USA). Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for continuous and dichotomous outcomes. Subgroup analyses were performed by age, surgery type, treatment in control group, data reversion or not, and risk of bias. Sensitivity analyses were performed by leave-one-out method, and publication bias was assessed using funnel plots and regression tests. A total of 11 studies were finally screened. The process of literature screening is shown in Supplementary Figure 1, https://links.lww.com/CM9/C539, and the characteristics of the included studies are shown in Supplementary Table 3, https://links.lww.com/CM9/C539. This meta-analysis included a total of 802 patients, of whom 464 patients received β-blockers therapy during the perioperative period and 338 patients were in the control group. A range of inflammatory biomarkers were assessed in all the selected studies, and seven studies additionally analyzed the relationship between β-blockers and POAF. Since only one study was available for analyzing the effects of β-blockers on IL-1β, IL-1RA, and IFN-γ, respectively, the relevant results were presented solely as narrative descriptions based on the original research. The Cochrane risk-of-bias tool indicated that three studies which were at a high risk of bias in one respect, might be low-quality studies [Supplementary Figure 2, https://links.lww.com/CM9/C539]. Six studies reported IL-6 levels at T1 and T2. IL-6 was statistically significantly lower in the β-blocker group at T1 (SMD: –0.50; 95% CI: –0.78 to –0.21; P <0.01), but not at T2 (SMD: –0.22; 95% CI: –0.46 to 0.02; P = 0.07). Subgroup analysis indicated statistically significant reduction in IL-6 in patients over 65 years old (SMD: –0.63; 95% CI: –0.89 to –0.37; P <0.01) and those undergoing open surgery (SMD: –0.65; 95% CI: –0.89 to –0.41; P <0.01) at TI. However, regardless of age or surgical type, β-blockers did not exert a significant effect on IL-6 levels at T2 [Table 1, Supplementary Figure 3, and Supplementary Table 4, https://links.lww.com/CM9/C539]. Table 1 - Summary results of primary outcomes focused on inflammatory biomarkers at different postoperative time points. Variables Number of β-blockers Number of comparison Number of Studies SMD (95% CI) P value T1 IL-6 195 161 6 –0.50 (–0.78, –0.21) <0.01 IL-10 100 66 4 0.26 (–0.66, 0.58) 0.11 WBC 104 59 2 0.26 (–0.08, 0.60) 0.14 IL-4 41 27 2 –0.37 (–0.87, 0.13) 0.14 IL-8 89 90 2 –0.40 (–0.87, 0.07) 0.10 TNF-α 34 34 2 0.21 (–0.62, 1.05) 0.62 T2 IL-6 195 161 6 –0.22 (–0.46, 0.02) 0.07 IL-10 81 46 3 0.26 (–0.11, 0.62) 0.17 CRP 178 131 4 –0.56 (–1.22, 0.10) 0.10 IL-4 41 27 2 –0.44 (–0.94, 0.06) 0.09 IL-8 89 90 2 –0.11 (–0.50, 0.28) 0.57 TNF-α 34 34 2 0.36 (–0.15, 0.88) 0.17 T3 CRP 250 202 5 –0.57 (–0.76, –0.38) <0.01 CI: Confidence interval; CRP: C-reactive protein; IL: Interleukin; SMD: Standardized mean difference; TNF: Tumor necrosis factor; T1: 0–2 h postoperatively, time point closest to 0 h; T2: 6–24 h postoperatively, time point closest to 24 h; T3: 2–7 days postoperatively, time point closest to 2 days; WBC: White blood cell. Four studies reported IL-10 levels at T1 and T2. At both time points, IL-10 was higher in the β-blocker group; however, the difference was not significant (T1 [SMD: 0.26; 95% CI: –0.06 to 0.58; P = 0.11], T2 [SMD: 0.26; 95% CI: –0.11 to 0.62; P = 0.17]). Subgroup analyses showed that β-blockers had no significant effect on IL-10 levels, irrespective of age or surgery type at both T1 and T2 [Table 1, Supplementary Figure 4, Supplementary Table 4, https://links.lww.com/CM9/C539]. While four studies reported CRP levels at T2, and five studies reported CRP levels at T3. CRP levels statistically significantly decreased in the β-blocker group at T3 (SMD: –0.57; 95% CI: –0.76 to –0.38; P <0.01), but not at T2 (SMD: –0.56; 95% CI: –1.22 to 0.10; P = 0.10). Subgroup analysis at T2 showed that β-blockers statistically significantly reduced CRP levels in patients under 65 years old who were undergoing laparoscopic surgery, with data conversion (SMD: –1.28, 95% CI: –1.29 to 0.23; P <0.01), despite 50% heterogeneity [Table 1, Supplementary Figure 4, Supplementary Table 4, https://links.lww.com/CM9/C539]. WBC levels at T1 showed no significant difference between β-blocker and control groups (SMD: 0.26; 95% CI: –0.08 to 0.60; P = 0.14). Although stress-related hormones (epinephrine, norepinephrine, and cortisol) showed no significant difference, adrenocorticotropic hormone was significantly lower in the β-blocker group in one study.[7] IL-4 levels were unaffected by β-blockers at both T1 and T2 (T1 [SMD: –0.37; 95% CI: –0.87 to 0.13; P = 0.14], T2 [SMD: –0.44; 95% CI: –0.94 to 0.06; P = 0.09]), though higher doses showed a significant reduction in IL-4. The levels of IL-1β, IL-1RA, IL-8, IFN-γ, and TNF-α also showed no significant difference between patients with and without perioperative β-blocker administration. The IFN-γ/IL-4 ratio was higher in the β-blocker group than in the controls, suggesting a shift toward Th1 [Table 1, Supplementary Figure4, and Supplementary Figure 5, Supplementary Table 4, https://links.lww.com/CM9/C539]. Seven studies investigated the incidence of POAF. The meta-analysis suggested that β-blockers reduced POAF incidence (OR: 0.33; 95% CI: 0.20 to 0.57; P <0.01). Subgroup analysis revealed a reduction in POAF only in patients undergoing cardiac surgery (OR: 0.32; 95% CI: 0.21 to 0.50, P <0.01). Among the seven studies, five studies reported that β-blockers decreased both the incidence of POAF and the levels of inflammatory biomarkers, especially one study illustrated additionally that patients encountering POAF had significantly higher levels of IL-6 [Supplementary Figure 6, Supplementary Table 4, https://links.lww.com/CM9/C539].[8] In the sensitivity analysis of IL-6 at T2, the exclusion of the study by Shyony et al[9] transformed a nonsignificant difference into a significant one, indicating that the effect of β-blockers on inflammatory biomarkers after surgery is unstable at T2. No significant publication bias was observed. The GRADE assessment indicated an insufficient sample size and a lack of high-quality trials to provide strong evidence for the primary outcomes in this meta-analysis [Supplementary Figures 7 and 8, Supplementary Tables 5 and 6, https://links.lww.com/CM9/C539]. The study shows that perioperative β-blocker administration may be responsible for reducing inflammatory biomarkers, such as IL-6 and CRP, and for decreasing the incidence of POAF. The mechanisms underlying these effects may involve β-blockers which modulate the inflammatory response potentially by reversing stress-induced immune suppression and shifting the immune balance from Th2 to Th1 response. This study provided the key findings that β-blockers significantly reduced IL-6 levels within 0–2 h postoperatively and CRP levels between 2 and 7 days postoperatively. The effects of β-blockers on different periods of inflammatory markers may be explained by the different time course of postoperative changes in inflammatory markers. Our subgroup analysis showed that β-blockers significantly reduced IL-6 levels from 0 to 2 h after surgery in elderly patients undergoing open surgery, signifying that β-blockers may better regulate immune responses in individuals at a high risk of inflammation. Research has validated that the anti-inflammatory effects of β1-blockers in sepsis and animal models. The β2-blockers appear to have beneficial effects mainly in the metabolic regulation of sepsis and in the reduction of cancer metastasis. The target effects of the different β-blockers subtypes warrant further investigation. There are several limitations in our study. First, due to the limited number of studies, the results of subgroup analyses may be influenced by multiple factors simultaneously, making them difficult to interpret. Second, as we did not follow a rigorous search process for meta-analysis of POAF, the effect size could be biased. Third, not all inflammatory markers displayed significant changes, which may be due to large variations in the plasma concentration of inflammatory biomarkers of different patients, the small sample size, and the complexity of surgery-induced inflammation. Fourth, owing to the lack of relevant clinical studies of β-blockers, other postoperative complications such as cancer metastasis, impaired intestinal barrier, lung damage, and neurological dysfunction were not evaluated. Finally, clinicians need to carefully weigh the benefits and potential limitations of β-blocker therapy. The type, dosage, duration of use, and applicable population of β-blockers regulating the perioperative inflammatory response should be further explored. Funding The study was supported by a grant the Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Construction Fund (No. 2024GSPKY21). Conflicts of interest None.

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