Total bilirubin as a marker for hemolysis and outcome in patients with severe ARDS treated with veno-venous ECMO

Abstract

Background: Hemolysis is a common complication in critically ill patients with sepsis, acute respiratory distress syndrome (ARDS) or therapy with extracorporeal membrane oxygenation (ECMO). Heme degradation product bilirubin might accumulate in conditions of significant hemolysis. In patients with ARDS and therapy with veno-venous ECMO (vvECMO), the prognostic potential of elevated initial total bilirubin (tBili) was investigated.

Methods: Retrospective analysis of patients with ARDS and vvECMO-therapy (n = 327) admitted to a tertiary ARDS center. A tBili cut-off value was determined by binary recursive partitioning. Baseline characteristics were compared and relevant variables were included in a multivariate logistic regression model with backward variable selection. Primary endpoint was survival within 28 days analyzed with Kaplan-Meier-curves and cox regression. Secondary endpoints included failure free composites for organ dysfunction, renal replacement therapy (RRT), vasopressor therapy and ECMO within 28 days and were compared using competing risk regression analysis.

Results: A cut-off value of 3.6mg/dl divided the cohort for ICU mortality (tBili ≤ 3.6mg/dl: 46% (n = 273) vs. tBili > 3.6mg/dl: 78% (n = 54), p < 0.001). The group with tBili > 3.6mg/dl showed a higher 28-day mortality (HR 3.03 [95%CI 2.07-4.43], p < 0.001) and significantly lower chances of successful recovery from organ dysfunction (subdistribution hazard ratio (SHR) 0.29 [0.13-0.66], p < 0.001), RRT (SHR 0.34 [0.14-0.85], p = 0.02), and ECMO (SHR 0.46 [0.25-0.86], p = 0.015) compared to the group with tBili ≤ 3.6mg/dl. Recovery from vasopressor therapy did not differ between groups (SHR 0.63 [0.32-1.24], p = 0.18).

Conclusion: Patients with ARDS, vvECMO-therapy and tBili > 3.6mg/dl had a higher mortality and lower chances for recovery from organ dysfunction, RRT, and ECMO within 28 days. The tBili-cut-off value may be useful to identify patients at risk for unfavorable outcomes.

Keywords: Acute lung injury; Extracorporeal membrane oxygenation; Hemolysis; Hyperbilirubinemia; Total bilirubin.

Fig. 1

Consort diagram. ECLS – extracorporeal life support; ECMO – extracorporeal membrane oxygenation with veno-veno-arterial (V-VA), venoarterial (V-A), or venovenous (V-V) cannulation

Fig. 2

A Kaplan Meyer Survival Curves for mortality within 28 days (Hazard Ratio 3.03 (95% CI 2.07–4.43), P < 0.001). B Total Bilirubin (tBili) concentration over 28 days after ECMO initiation. Points represent individual tBili values. Lines represent mean values. Green – low initial tBili, orange – high initial tBili. * indicates significantly different values between both groups (Mann–Whitney-U test with Bonferroni correction, p < 0.05). # indicates significantly different tBili values from initial tBili in the low initial tBili group (ANOVA and post-hoc test, p < 0.05). In the high initial tBili group the differences in tBili over time from initial value were not significant

Fig. 3

Cumulative incidence curves within 28 days for recovery from A organ dysfunction (subdistribution hazard ratio (SHR) 0.29 (95% CI 0.13–0.66), P < 0.001), B renal replacement therapy (RRT) (SHR 0.34 (95% CI 0.14–0.85), P = 0.02), C vasopressor use (SHR 0.63 (95% CI 0.32–1.24), P = 0.18) and D ECMO (SHR 0.46 (95% CI 0.25–0.86), P = 0.01)