Hyperoncotic Albumin (20%) Versus Crystalloids for Mortality in Adults with Sepsis and Septic Shock: An Updated Systematic Review and Meta-Analysis

Background/Objective: Hyperoncotic albumin (20%) has been proposed for sepsis; however, the randomized evidence is inconclusive, and the 2026 Surviving Sepsis Campaign guidelines now suggest crystalloids alone while permitting albumin on a case-by-case basis. We updated the evidence, restricting the intervention to hyperoncotic albumin (≥20%) and the comparator exclusively to crystalloids, and examined whether the benefit was confined to septic shock. Methods: We searched PubMed, EMBASE, and Cochrane CENTRAL (March 2024–March 2026), supplementing a previously published meta-analysis. Randomized trials of hyperoncotic albumin versus crystalloids in adults with sepsis or septic shock reporting all-cause mortality were included. The primary outcome was mortality at the longest follow-up, pooled as risk ratios (RRs) using random-effects models. Given negligible heterogeneity, the estimate was reported under standard, Hartung–Knapp–Sidik–Jonkman (HKSJ), truncated-HKSJ, and fixed-effects methods, with a Bayesian sensitivity analysis. A pre-specified subgroup contrasted septic shock with sepsis without shock. This review was registered in PROSPERO (CRD420261334243). Results: Eight RCTs (n = 3707) provided the data; all administered 20% albumin. Overall, albumin was not robustly associated with reduced mortality (RR 0.94; I2 = 0%), significant only under the pre-registered HKSJ correction (0.91–0.98) but null under the standard, truncated-HKSJ, and fixed-effects models (0.87–1.03, p = 0.17), identifying this as a low-heterogeneity artifact. In septic shock (k = 6), the effect was larger and consistent (RR 0.90, 0.82–0.99, p = 0.03), with no benefit in sepsis without shock (RR 1.10; interaction p = 0.08). The certainty was low (GRADE). Conclusions: In adults with sepsis, hyperoncotic albumin was not associated with a statistically significant reduction in all-cause mortality, and the certainty of evidence was low (GRADE). This is consistent with the 2026 Surviving Sepsis Campaign guidelines, which permit case-by-case use of albumin in this setting but do not recommend its routine use. Adequately powered randomized trials are required.