Shock, a fulminant syndrome of circulatory collapse and tissue hypoperfusion, remains one of the most formidable challenges in critical care [1] - [3] . Despite advances in hemodynamic monitoring, organ support, and targeted therapies, mortality rates remain unacceptably high [4] - [10] . The quest for reliable biomarkers that can anticipate outcomes, guide interventions, and refine prognostic accuracy is both urgent and ongoing [11] - [17] .

Albumin, the most abundant plasma protein, is traditionally recognized for its role in oncotic pressure maintenance [18] - [23] . However, its clinical significance extends far beyond simple fluid balance. Albumin functions as a transporter, antioxidant, and modulator of inflammation [24] - [29] .

Hypoalbuminemia—whether due to capillary leak, hepatic synthetic failure, or catabolic degradation—is not merely an epiphenomenon but may contribute causally to organ dysfunction and adverse outcomes [30] - [34] .

Although individual studies have linked low serum albumin to increased mortality in shock, the magnitude, consistency, and potential modifiers of this association have not been comprehensively quantified. The present systematic review and meta-analysis aims to fill this knowledge gap, leveraging global data to clarify the prognostic role of hypoalbuminemia in shock.

This systematic review and meta-analysis adhered to PRISMA 2020 guidelines [35] - [40] and was prospectively registered with PROSPERO under the ID number: CD420251132055 ( https://www.crd.york.ac.uk/PROSPERO/view/CRD420251132055 ) [41] [42] . Two independent reviewers oversaw each phase of the review—screening, eligibility assessment, study selection, and inclusion—resolving disagreements through consultation with a third reviewer.

Search Results: The database search yielded 568,758 records, with 566,998 removed as duplicates or ineligible by automated tools. Title/abstract screening excluded 1722 of the remaining 1760 records. Thirty-eight full-text articles were assessed for eligibility, resulting in 11 studies included in the final synthesis ( Figure 1 ).

In Table 3 , risk of bias was evaluated for all 11 included cohort studies using the Newcastle-Ottawa Scale (NOS). The majority of studies (n > 10) achieved high-quality ratings (7 - 9 stars), reflecting low risk of bias. A smaller number scored in the moderate-quality range (5 - 6 stars), typically due to limited adjustment for potential confounders in the comparability domain. All studies received full scores in the selection domain, indicating representative shock patient cohorts, appropriate non-exposed comparators, and objective ascertainment of serum albumin levels. The outcome domain was also consistently strong, with complete and objective mortality ascertainment and adequate follow-up in all cases. The primary limitation observed was that some studies adjusted only for age or a limited set of covariates, rather than a broader range of important prognostic factors, which may allow residual confounding. Overall, the methodological quality of the included studies was high, supporting the validity of the meta-analysis findings.

Notes: NOS scoring followed the cohort-study template. Selection items were awarded based on ICU/septic shock cohorts with laboratory-confirmed albumin exposure and mortality measured after baseline. Comparability starred once for adjustment of key confounders and additionally if age plus ≥ 1 comorbidity/clinical severity variable were adjusted. Outcome items were starred for medical-record ascertainment and sufficient follow-up (in-hospital or 30-day). Where reporting was unclear, conservative assumptions were applied.

Study Characteristics: Summary of Included Studies is presented in Table 4 . The studies represented four continents, with Asia contributing nearly half of all included studies. Most were retrospective cohort designs (n = 11), with two prospective cohorts. Albumin cut-offs ranged from 2.45 g/dL to 40 g/L. Mortality endpoints included 30-day, in-hospital, and 1-year mortality. All studies adjusted for key clinical covariates.

Figure 2 presents the forest plot of the meta-analysis of the association between hypoalbuminemia and mortality in shock patients. In Figure 2(a) , the forest plot of the seven included studies demonstrates a consistent association between hypoalbuminemia and increased mortality in patients with shock. The pooled odds ratio, represented by the diamond, lies to the right of the line of no effect (OR = 1), with confidence intervals that do not cross unity, indicating a statistically significant relationship. Most individual studies reported odds ratios greater than 1, suggesting that low serum albumin levels were associated with higher mortality risk, while a small number of studies showed results closer to the null but with wide confidence intervals that still overlapped with the overall effect. The observed heterogeneity (I² statistic) reflects some variability across studies, likely attributable to differences in patient populations, shock subtypes, albumin cut-off thresholds, and study designs. Despite this, the direction of effect remained

consistent across studies, reinforcing the robustness of the pooled estimate. Overall, these findings support hypoalbuminemia as a significant and independent predictor of mortality among patients with shock. In Figure 2(b) , the four HR studies also showed a significant association, with I² = 0%, indicating remarkable consistency.

Figure 3 shows the funnel plot of the seven included studies. This funnel plot demonstrates a relatively symmetrical distribution of effect sizes around the pooled estimate. This symmetry suggests a low likelihood of substantial publication bias. Although a few studies show wider confidence intervals, these are evenly distributed on both sides of the pooled effect, and no strong asymmetry is observed. However, given the small number of included studies, visual inspection alone has limited power to detect bias, and complementary statistical tests such as Begg’s should be interpreted alongside the funnel plot. Overall, the plot indicates that the association between hypoalbuminemia and mortality in shock is unlikely to be driven by selective publication of positive findings.

Publication Bias Assessment (Begg’s Test)

Publication bias was evaluated using Begg’s rank correlation test, which was conducted on the log-transformed odds ratios and their standard errors from the seven included studies. The test did not indicate significant small-study effects, with Kendall’s τ = 0.14, p = 0.458. These findings suggest no strong evidence of publication bias among the included studies when assessed by Begg’s method.

To explore the very high heterogeneity (I² = 95%) observed in the odds ratio pool, prespecified subgroup analyses were performed based on serum albumin threshold and study region. The results are summarized in Table 5 .

The prespecified subgroup analyses provide insight into the sources of heterogeneity (I² = 95%) observed in the overall odds ratio pool. Studies that applied a serum albumin cutoff of <35 g/L showed a markedly stronger and more consistent association between hypoalbuminemia and mortality, with substantially reduced heterogeneity (I² = 62%). By contrast, studies with lower or unspecified thresholds reported weaker associations and overlapping confidence intervals. Regional differences were also notable: Asian cohorts demonstrated a larger effect size (pooled OR = 2.62) compared to European and North American cohorts (pooled OR = 1.41). These findings suggest that both methodological choices (albumin threshold) and population characteristics (geographic region) may explain part of the between-study variability. However, residual heterogeneity remains, underscoring that unmeasured clinical or methodological differences likely contribute further to inconsistency.

Hartung-Knapp Adjustment on the pooled OR are presented in Table 6 . In our 7-study dataset, the conventional random-effects pooled effect was OR = 2.10 (95% CI 1.20 - 3.68), while the Hartung-Knapp adjusted summary was OR = 2.10 (95% CI 1.41 - 3.13). The Hartung-Knapp adjustment did not change the statistical conclusion (association remained significant).

Did the conclusion change under Hartung-Knapp? No.

Table 7 presents the results of leave-one-out sensitivity analyses using both the DerSimonian-Laird estimator and the Hartung-Knapp adjustment. Sequential exclusion of individual studies did not materially alter the overall pooled effect estimates, although Hartung-Knapp yielded wider confidence intervals with p-values closer to the 0.05 threshold in some cases. Confirming the robustness of findings ( Table 7 ).

This systematic review and meta-analysis synthesizing 11 studies—seven reporting odds ratios and four reporting hazard ratios—provides strong evidence that hypoalbuminemia is independently associated with increased mortality in patients with shock. Across diverse populations, care settings, and study designs, low serum albumin consistently predicted worse outcomes, underscoring its role as a clinically relevant biomarker of risk.

In summary, this meta-analysis demonstrates that hypoalbuminemia is a strong and independent predictor of mortality in shock, supported by both odds- and hazard-based evidence. The consistency of results across analytic methods and populations reinforces the role of serum albumin as a clinically meaningful biomarker. Future studies should standardize definitions, evaluate age- and region-specific thresholds, and investigate whether therapeutic correction of hypoalbuminemia can modify outcomes.

*Corresponding author.

^#Doctor of Nursing Practice, Certified Pediatric Nurse Practitioner—Primary Care.

^§Doctor of Clinical Laboratory Science, Medical Laboratory Scientist (American Society for Clinical Pathology) certification maintenance; Clinical Laboratory Scientist.