Victoria Bünger

Mechanical ventilation is frequently used in critically ill patients and can itself cause pulmonary damage. Furthermore, hemolysis is common in sepsis and ARDS. Mice receiving mechanical ventilation and an infusion of cell-free hemoglobin (CFH) demonstrated increased impairment of lung mechanics associated with lung edema not fully explainable by the proinflammatory and proedematous effects of CFH. Furthermore, increased plasma concentrations of CFH correlated with reduced pulmonary compliance in patients with severe ARDS and therapy with ECMO.

Background: Despite advanced and early treatment in the intensive care unit (ICU), mortality in patients with sepsis remains high. Sepsis is often associated with hemolysis. In the clinical routine, hemolysis is often overlooked, as markers of hemolysis are often not routinely measured. Aim of this scoping literature review is to quantify the incidence and extent of hemolysis in patients with sepsis and the association with mortality. Methods: Systematic literature search in bibliographic databases MEDLINE, EMBASE and Web of Science for sepsis and hemolysis. Results: A total of 3382 studies underwent title-abstract screening and 169 studies were reviewed in full. There were 34 studies with a total of 27,702 patients with sepsis and reported hemolysis or hemolytic markers and clinical outcomes included in the final analyses. Mortality ranged from 5.4 to 78.6% with a mean mortality of 20.1% across all studies. A significant association between hemolysis or hemolytic markers with increased mortality was observed in nine studies. Conclusions: Although significant associations between hemolysis and outcome in patients with sepsis were observed, hemolytic markers are not yet routinely and regularly monitored in clinical routine on the ICU. Hemolytic markers can provide information about disease severity and outcome on ICU admission and during the course of the disease. Future work should focus on identification of reliable markers of hemolysis with a potential for easy and timely measurements ideally at the patients’ bedside. With an additional definition of monitoring standards, the potential of hemolysis monitoring for prognostication and therapeutic approaches will emerge. Graphical

BACKGROUND: Critically ill patients who receive circulatory or respiratory assist using extracorporeal membrane oxygenation (ECMO) may develop hemolysis, which can complicate the delivery of supportive care and be a potential risk factor for increased morbidity and mortality. Clinically, hemolysis is often identified using laboratory markers such as cell-free hemoglobin (CFH) and haptoglobin (Hp). However, such measurements require photometry or enzyme-linked immunosorbent assay (ELISA) and are labor intensive. In contrast, metabolic downstream products of CFH, such as carboxyhemoglobin (CO-Hb) and methemoglobin (Met-Hb), can be regularly monitored via arterial blood gas analyses in the intensive care unit (ICU). We hypothesized that CO-Hb and Met-Hb values measured during ECMO would correlate with the presence of hemolytic events as measured by CFH values exceeding 50mg/dl. We further hypothesized that CO-Hb and Met-Hb levels would correlate with peri-ECMO mortality. METHODS: Retrospective analysis of 435 patients with acute respiratory distress syndrome (ARDS) and veno-venous ECMO admitted to a tertiary ARDS referral center. Plasma concentrations of CO-Hb and Met-Hb were correlated with hemolytic events. Cutoff values of mean CO-Hb (mCO-Hb) and mean Met-Hb (mMet-Hb) associated with increased ICU mortality were calculated with recursive binary partitioning. Single and multivariable regression models for HE and ICU mortality were trained and compared. RESULTS: Simple and multivariable models including potential confounders identified associations between Met-Hb and hemolytic events (adj. odds ratio [OR] 2.99 [95% confidence interval {CI}, 2.19–4.10], P < .001). A cutoff value with 90% specificity of a hemolytic event was estimated for Met-Hb (1.55%). Both, mean CO-Hb (OR 2.03 [95% CI, 1.60–2.61], P < .001) and Met-Hb (2.78 [1.59–5.09], P < .001) were associated with ICU mortality. Cutoff values for mortality were 2% for mean CO-Hb and 1.25% for mean Met-Hb. The multivariable regression model for mortality including the continuous markers mCO-Hb and mMet-Hb produced an area under the curve (AUC) of 0.803. CONCLUSIONS: In patients with ARDS and ECMO, Met-Hb plasma concentrations were independently associated with hemolytic events. Both, mean CO-Hb and Met-Hb levels were associated with ICU mortality. These markers and their associated cutoff values might serve as a risk indicator in clinical practice.

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.

Background: Treatment with veno-venous extracorporeal membrane oxygenation (VV ECMO) has become a frequently considered rescue therapy in patients with severe acute respiratory distress syndrome (ARDS). Hemolysis is a common complication in patients treated with ECMO. Currently, it is unclear whether increased ECMO blood flow (Q̇_EC) contributes to mortality and might be associated with increased hemolysis. Methods: A total of 441 patients with ARDS and VV ECMO, treated in a tertiary ARDS center, were included. The Q̇_EC value for a significant increase in ICU mortality was determined by binary recursive partitioning. Linear regression analysis was performed to analyze a correlation between mean Q̇_EC and mean plasma concentrations of cell-free hemoglobin (CFH). Results: A Q̇_EC of 4 L/min divided the cohort into two groups with significantly different ICU mortality (Q̇_EC ≤ 4 L/min: 39.3% (n = 300) versus Q̇_EC > 4 L/min: 71.6% (n = 141), p < 0.001). Patients with Q̇_EC > 4 L/min had a higher 28-day mortality. Furthermore, a higher mean Q̇_EC was associated with increased CFH and decreased haptoglobin plasma concentrations. Conclusion: In patients with ARDS and VV ECMO, a mean Q̇_EC > 4 L/min is associated with increased mortality, increased CFH and decreased haptoglobin plasma concentrations. Whether increased hemolysis determines the poorer outcome associated with higher Q̇_EC should be the subject of future research.

Background: Hemolysis is a frequent complication in patients with sepsis, ARDS, or extracorporeal membrane oxygenation (ECMO). Haptoglobin (Hp) can scavenge released cell-free hemoglobin (CFH). Hemolysis and low plasma concentrations of Hp may be independently associated with mortality in critically ill patients. Methods: This study used a retrospective analysis of 435 patients with ARDS and veno-venous ECMO therapy, admitted to a tertiary ARDS referral center (01/2007–12/2018). Hp depletion was defined as decrease in plasma Hp concentration Results: Patients with Hp depletion (n = 269) had a significantly higher mortality 28 days after ECMO initiation compared to patients without Hp depletion (43.5% [95% CI 37.52–49.66] vs. 25.3% [19.03–32.74], P < 0.001). Furthermore, patients with Hp depletion had fewer organ dysfunction-free days (subdistribution hazard ratio [SHR] 0.35 [95% CI 0.25–0.50], P < 0.001), lower chances for successful weaning from renal replacement therapy (SHR 0.50 [0.32–0.79], P < 0.001), vasopressor therapy (SHR 0.39 [0.28–0.54], P < 0.001), and ECMO therapy (SHR 0.41 [0.30–0.57], P < 0.001) within 28 days after ECMO initiation. Patients with initial Hp Conclusion: Patients with Hp depletion within the first week of ECMO therapy might benefit from close monitoring of hemolysis with early detection and elimination of the underlying cause. They might be potential candidates for future Hp supplementation therapy to prevent overload of the CFH-scavenger system.

Background: Hemolysis is associated with increased mortality in patients with sepsis, ARDS, or therapy with extracorporeal membrane oxygenation (ECMO). To quantify a critical threshold of hemolysis in patients with ARDS and treatment with veno-venous ECMO, we aimed to identify cutoff values for cell-free hemoglobin (CFH) and haptoglobin (Hp) plasma concentrations associated with a significant increase in ICU mortality. Methods: Patients with ARDS admitted to a tertiary ARDS referral center between 01/2007 and 12/2018 and treatment with veno-venous ECMO were included. Cutoff values for mean CFH (mCFH) and mean Hp (mHp) plasma concentrations dividing the cohort into groups with significantly different ICU mortalities were calculated and patient characteristics were compared. A multiple logistic regression model with stepwise backward variable selection was included. In addition, cutoff values for vulnerable relative timespans for the respective CFH and Hp concentrations were calculated. Results: A quantitative cutoff value of 11 mg/dl for mCFH separated the cohort (n = 442) regarding ICU mortality (mCFH ≤ 11 mg/dl: 38%, [95%-CI: 32.22–43.93] (n = 277) vs. mCFH > 11 mg/dl: 70%, [61.99–76.47] (n = 165), p < 0.001). Analogously, a mHp cutoff value ≤ 0.39 g/l was associated with a significant increase in ICU mortality (mHp ≤ 0.39 g/l: 68.7%, [60.91–75.61] (n = 163) vs. mHp > 0.39 g/l: 38.7%, [33.01–44.72] (n = 279), p < 0.001). The independent association of ICU mortality with CFH and Hp cutoff values was confirmed by logistic regression adjusting for confounders (CFH Grouping: OR 3.77, [2.51–5.72], p < 0.001; Hp Grouping: OR 0.29, [0.19–0.43], p < 0.001). A significant increase in ICU mortality was observed when CFH plasma concentration exceeded the limit of 11 mg/dl on 13.3% of therapy days (≤ 13.3% of days with CFH > 11 mg/dl: 33%; [26.81–40.54] (n = 192) vs. > 13.3% of days with CFH > 11 mg/dl: 62%; [56.05–68.36] (n = 250), p < 0.001). Analogously, a mortality increase was detected when Hp plasma concentration remained ≤ 0.39 g/l for > 18.2% of therapy days (≤ 18.2% days with Hp ≤ 0.39 g/l: 27%; [19.80–35.14] (n = 138) vs. > 18.2% days with Hp ≤ 0.39 g/l: 60%; [54.43–65.70] (n = 304), p < 0.001). Conclusions: Moderate hemolysis with mCFH-levels as low as 11 mg/dl impacts mortality in patients with ARDS and therapy with veno-venous ECMO. Furthermore, a cumulative dose effect should be considered indicated by the relative therapy days with CFH-concentrations > 11 mg/dl. In addition, also Hp plasma concentrations need consideration when the injurious effect of elevated CFH is evaluated.

(1) Background: Acute respiratory distress syndrome (ARDS) is a rare complication in multiply injured patients. Due to the rarity of ARDS development after trauma, little is known about outcomes of patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. (2) Methods: This retrospective analysis included n = 1038 ARDS patients admitted to the ARDS center of Charité—Universitätsmedizin Berlin between 2007 and 2018. Patients with trauma-associated ARDS (n = 62) were compared to patients with non-trauma-associated ARDS (n = 976). In a secondary analysis, patients from the group with non-trauma-associated ARDS were 1:1 nearest neighbor matched to patients with trauma-associated ARDS. The primary outcomes were 28-day in-hospital mortality, 60-day in-hospital mortality, and overall in-hospital mortality. (3) Results: Overall in-hospital mortality in trauma-associated ARDS was 29.0% compared to 40.5% in all patients with non-trauma-associated ARDS (p = 0.074). The in-hospital mortality rate in matched patients with non-trauma-associated ARDS (33.9%) was comparable to the trauma-associated ARDS cohort (p = 0.701). Kaplan–Meier curves indicated time-sensitive variations in 28-day and 60-day in-hospital survival. (4) Conclusion: Mortality was not different in patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. Survival rate in the Kaplan–Meier curves stabilized after the critical initial phase and throughout the further 60-day period in patients with trauma-associated ARDS compared to patients with non-trauma-associated ARDS. Since this divergence was less pronounced in the matched cohort, it may be related to the younger age, fewer comorbidities, and lower ARDS severity in patients with trauma-associated ARDS. Patients with trauma-associated ARDS remain a very different cohort compared to patients with non-trauma-associated ARDS. Therefore, the outcome comparison is limited, even after matching.

Packed red blood cells (PRBCs), stored for prolonged intervals, might contribute to adverse clinical outcomes in critically ill patients. In this study, short-term outcome after transfusion of PRBCs of two storage duration periods was analyzed in patients with Acute Respiratory Distress Syndrome (ARDS). Patients who received transfusions of PRBCs were identified from a cohort of 1044 ARDS patients. Patients were grouped according to the mean storage age of all transfused units. Patients transfused with PRBCs of a mean storage age ≤ 28 days were compared to patients transfused with PRBCs of a mean storage age > 28 days. The primary endpoint was 28-day mortality. Secondary endpoints included failure-free days composites. Two hundred and eighty-three patients were eligible for analysis. Patients in the short-term storage group had similar baseline characteristics and received a similar amount of PRBC units compared with patients in the long-term storage group (five units (IQR, 3–10) vs. four units (2–8), p = 0.14). The mean storage age in the short-term storage group was 20 (±5.4) days compared with 32 (±3.1) days in the long-term storage group (mean difference 12 days (95%-CI, 11–13)). There was no difference in 28-day mortality between the short-term storage group compared with the long-term storage group (hazard ratio, 1.36 (95%-CI, 0.84–2.21), p = 0.21). While there were no differences in ventilator-free, sedation-free, and vasopressor-free days composites, patients in the long-term storage group compared with patients in the short-term storage group had a 75% lower chance for successful weaning from renal replacement therapy (RRT) within 28 days after ARDS onset (subdistribution hazard ratio, 0.24 (95%-CI, 0.1–0.55), p < 0.001). Further analysis indicated that even a single PRBC unit stored for more than 28 days decreased the chance for successful weaning from RRT. Prolonged storage of PRBCs was not associated with a higher mortality in adults with ARDS. However, transfusion of long-term stored PRBCs was associated with prolonged dependence of RRT in critically ill patients with an ARDS.