Inflammatory markers in postoperative delirium (POD) and cognitive dysfunction (POCD): A meta-analysis of observational studies

Abstract

Background: The aim of this study was to summarize and discuss the similarities and differences in inflammatory biomarkers in postoperative delirium (POD) and cognitive dysfunction (POCD).

Methods: A systematic retrieval of literature up to June 2017 in PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, and the Wanfang database was conducted. Extracted data were analyzed with STATA (version 14). The standardized mean difference (SMD) and the 95% confidence interval (95% CI) of each indicator were calculated using a random effect model. We also performed tests of heterogeneity, sensitivity analysis, assessments of bias, and meta-regression in this meta-analysis.

Results: A total of 54 observational studies were included. By meta-analysis we found significantly increased C-reactive protein (CRP) (9 studies, SMD 0.883, 95% CI 0.130 to 1.637, P = 0.022 in POD; 10 studies, SMD -0.133, 95% CI -0.512 to 0.246, P = 0.429 in POCD) and interleukin (IL)-6 (7 studies, SMD 0.386, 95% CI 0.054 to 0.717, P = 0.022 in POD; 16 studies, SMD 0.089, 95% CI -0.133 to 0.311, P = 0.433 in POCD) concentrations in both POD and POCD patients. We also found that the SMDs of CRP and IL-6 from POCD patients were positively correlated with surgery type in the meta-regression (CRP: Coefficient = 1.555365, P = 0.001, 10 studies; IL-6: Coefficient = -0.6455521, P = 0.086, 16 studies).

Conclusion: Available evidence from medium-to-high quality observational studies suggests that POD and POCD are indeed correlated with the concentration of peripheral inflammatory markers. Some of these markers, such as CRP and IL-6, play roles in both POD and POCD, while others are specific to either one of them.

Fig 1. Flow diagram of article selection.

Fig 2. Results of the random-effects meta-analysis for the association between inflammatory markers and POD.

Positive values indicate higher levels in POD patients; negative values indicate higher levels in control patients. CRP, C-reactive protein; IL-6, interleukin-6; S-100β, S-100 calcium binding protein beta subunit; NSE, neuron-specific enolase; IL-8, interleukin-8; IL-1β, interleukin-1 beta; TNF-α, tumor necrosis factor alpha; IGF-1, insulin-like growth factor-1; IL-10, interleukin-10; IL-1ra, interleukin-1 receptor antagonist; pre-op, pre-operation; post-op, post-operation; N, number of studies; SMD, standardized mean difference; CI, confidence interval.

Fig 3. Results of the random-effects meta-analysis for the association between inflammatory markers and POCD.

Positive values indicate higher levels in POCD patients; negative values indicate higher levels in control patients. CRP, C-reactive protein; IL-6, interleukin-6; S-100β, S-100 calcium binding protein beta subunit; NSE, neuron-specific enolase; IL-8, interleukin-8; IL-1β, interleukin-1 beta; TNF-α, tumor necrosis factor alpha; IL-10, interleukin-10; IL-1ra, interleukin-1 receptor antagonist; pre-op, pre-operation; post-op, post-operation; N, number of studies; SMD, standardized mean difference; CI, confidence interval.

Fig 4. CRP (Peripheral) levels before surgery in patients with POD (A) and POCD (B).

Fig 5. IL-6 (Peripheral) levels before surgery in patients with POD (A) and POCD (B).

Fig 6. S-100β (Peripheral) Levels Post-Surgery in Patients with POD (A) and POCD (B).

Fig 7. Subgroup analyses for the assessment of impact of surgery type, anesthesia, and ethnicity on peripheral CRP and IL-6 levels perioperatively.

Positive values indicate higher levels in POD/POCD patients; negative values indicate higher levels in control patients. All results are from random-effects models. pre-op, pre-operation; post-op, post-operation; N, number of studies; SMD, standardized mean difference; CI, confidence interval; *Data missing for N = 1 study.