Inflammatory Biomarkers and Outcomes in Acute Lower Limb Ischemia: A Systematic Review and Meta-Analysis

Acute lower limb ischemia (ALLI) is a vascular emergency characterized by abrupt interruption of blood flow, with high risk of limb loss, disability, and death. Beyond ischemic insult, the ensuing inflammatory response drives endothelial injury, tissue necrosis, and systemic repercussions, shaping clinical outcomes.

We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize evidence on inflammatory mechanisms, immune pathways, prognostic biomarkers, and anti-inflammatory therapies in ALLI. PubMed, Embase, Cochrane Library, and Web of Science were searched for studies published in the last 15 years in English or Spanish. Eligible studies included adult patients with ALLI evaluating inflammatory pathways, circulating biomarkers, or therapies targeting inflammation.

Experimental and clinical data highlight the role of the NOD-like receptor family pyrin domain-containing 3 inflammasome, complement cascade (C3a, C5a), and pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in orchestrating neutrophil, macrophage, and T-cell recruitment. These cascades contribute to endothelial disruption, cell death, chronic inflammation, and systemic inflammatory response. Circulating biomarkers, such as high-sensitivity C-reactive protein, IL-6, and particularly the neutrophil-to-lymphocyte ratio (NLR) predict outcomes. Our meta-analysis of 7 studies (1,758 patients) showed that high NLR is associated with a 3-fold higher risk of 30-day mortality or major amputation (odds ratio 3.05; 95% confidence interval 1.69-5.52; P < 0.001). IL-1β inhibitors and other targeted agents show promise, whereas evidence for corticosteroids and TNF-α blockers remains inconsistent.

Inflammation is central to the pathophysiology and prognosis of ALLI. NLR represents a robust, accessible biomarker for early risk stratification. Future strategies should emphasize biomarker-guided, personalized modulation of inflammation, supported by well-designed clinical trials.