Prohaska et al. Journal of Intensive Care (2018) 6:11 DOI 10.1186/s40560-018-0278-8 RESEARCH Open Access Intravenous immunoglobulin fails to improve ARDS in patients undergoing ECMO therapy Stefanie Prohaska1, Andrea Schirner1, Albina Bashota1, Andreas Körner1, Gunnar Blumenstock2 and Helene A. Haeberle1* Abstract Background: Acute respiratory distress syndrome (ARDS) is associated with high mortality rates. ARDS patients suffer from severe hypoxemia, and extracorporeal membrane oxygenation (ECMO) therapy may be necessary to ensure oxygenation. ARDS has various etiologies, including trauma, ischemia-reperfusion injury or infections of various origins, and the associated immunological responses may vary. To support the immunological response in this patient collective, we used intravenous IgM immunoglobulin therapy to enhance the likelihood of pulmonary recovery. Methods: ARDS patients admitted to the intensive care unit (ICU) who were placed on ECMO and treated with (IVIG group; n = 29) or without (control group; n = 28) intravenous IgM-enriched immunoglobulins for 3 days in the initial stages of ARDS were analyzed retrospectively. Results: The baseline characteristics did not differ between the groups, although the IVIG group showed a significantly reduced oxygenation index compared to the control group. We found no differences in the length of ICU stay or ventilation parameters. We did not find a significant difference between the groups for the extent of inflammation or for overall survival. Conclusion: We conclude that administration of IgM-enriched immunoglobulins as an additional therapy did not have a beneficial effect in patients with severe ARDS requiring ECMO support. Trial registration: Clinical Trials: NCT02961166; retrospectively registered. Keywords: Intravenous immunoglobulin, ARDS, Inflammation, ECMO Background ARDS patients include individualized ventilation and Acute respiratory distress syndrome (ARDS) is charac- fluid management, adequate infection control, including terized by pulmonary inflammation that can be caused early application of broad-spectrum anti-infectives, by pulmonary and extrapulmonary origins. Sepsis, neuromuscular blockade using cisatracurium, sedation bacterial pneumonia, polytrauma, and aspiration pneu- strategies, prone positioning, and finally extracorporeal monia are the most common causes of ARDS [1]. Pre- membrane oxygenation (ECMO) to ensure oxygenation dictors of survival include age, the type of underlying [3–5]. Although the incidence of ARDS is relatively high, medical condition, the severity of pulmonary injury, the with five to eight cases per 100,000 European inhabitants presence of extrapulmonary organ dysfunction, and on- and even more in the USA, the various pathomechan- going sepsis [2]. Currently, clinical attempts to rescue isms are only partially understood, resulting in different experimental approaches to understand immune responses during early ARDS [6]. * Correspondence: [email protected] 1Department of Anesthesiology and Intensive Care Medicine, Medical One well-described issue is decreased immunoglobulin Faculty, University Hospital Tübingen, Eberhard-Karls University, levels in patients with severe infection [6] as an element Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany of the immunological response in the initial phase of Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Prohaska et al. Journal of Intensive Care (2018) 6:11 Page 2 of 8 inflammation in response to sepsis [7]. Therefore, one bacteria (MRGN) was suspected. IVIG dosing was per- approach to support critically ill patients is intravenous formed according to the instruction of the manufacturer: administration of IgM-enriched immunoglobulins since 0.4 ml/kg/h (up to 100 ml) as the initial dose, followed this could potentially decrease the severity of inflamma- by 0.2 ml/kg/h for 72 h until a total dose of 15 mg/kg tion. Although this treatment was omitted in recent sep- was achieved. Twenty-nine patients did not receive im- sis guidelines due to a lack of supporting evidence in munoglobulins (control group). high-quality trials [8], several studies, including one Vasopressors (Norepinephrine; Arterenol® Sanofi-Aventis; meta-analysis, describe beneficial effects of immunoglob- Germany) were used after volume resuscitation according ulins in acute pneumonia induced by drug-resistant to the sepsis guideline (13). Renal replacement therapy was bacterial infections [9–11]. Furthermore, several case re- performed with citrate anticoagulation (Multifiltrate, ports describe beneficial effects of antiviral therapy in Fresenius Medical Care, Bad Homburg v.d.H. Germany) in combination with intravenous immunoglobulin therapy patients with acute renal failure. in immune-compromised patients [12–14]. Based on Data were retrospectively extracted from an ARDS- these data, we treated patients with ARDS requiring specific database at our institution. Since the electronic ECMO therapy with IgM-enriched immunoglobulins im- patient management system was changed during this mediately after intensive care unit (ICU) admission. The time frame, not all required data were available for all objective of this study was to investigate whether intra- ARDS patients. venous immunoglobulin administration could improve MRSA and VRE screening was performed routinely in the clinical course of ARDS in patients treated with all patients admitted to the ICU. ECMO. Therefore, mortality, the duration of ECMO To identify causal infections, bronchoalveolar lavage therapy, the incidence of renal replacement therapy, the (BAL) samples, blood cultures, urinary samples, and duration of vasopressor and anti-infective therapy, perioperative samples were analyzed. In patients at risk, length of stay in the ICU, and length of stay in the hos- PCR for atypical pathogens was also performed in BAL pital were analyzed retrospectively in 57 ARDS patients samples. Infection was defined as > 106 colony-forming requiring ECMO therapy. units (CFU) in BAL and/or urinary cultures. For blood cultures, any replicate of bacterial growth was defined as Methods infection. During flu season, influenza infection was de- The study was approved by the local research ethics tected by PCR. BAL samples were also analyzed for committee of the University Hospital and the Eberhard- other viral pathogens, such as cytomegalovirus (CMV) Karls University Tübingen, Germany. and herpes simplex virus (HSV). Positive findings for these viruses were confirmed by cell cultures. Patients Study patients with unknown pathogens and immune suppression were Patients with severe ARDS treated with ECMO therapy additionally screened for other pathogens. between January 2012 and January 2016 at our institution Anti-infective therapy was applied according to the were analyzed retrospectively. In all patients, ECMO ther- local guideline considering local resistance patterns. apy was required due to hypoxia and/or increased pul- monary resistance precluding protective lung ventilation. Statistical analysis Categorical data are reported as numbers and percent- Therapy ages, and continuous data are summarized with the ECMO therapy was performed according to the guide- median and range (i.e., the minimum and maximum lines of the Extracorporeal Life Support Organization values) unless otherwise indicated. To compare categor- (ELSO) using ILA-active Systems (Novalung, Stolberg, ical variables or outcomes, such as the occurrence of Germany [15]. Fifty-seven patients were analyzed. infection or in-hospital death, between the IVIG group Twenty-eight patients were treated with IgM-enriched (n = 28 patients) and the control group, which included immunoglobulins (Pentaglobin®; Biotest; Dreieich, 29 patients who did not receive IVIG therapy, the chi- Germany) (IVIC-group). Pentaglobin is an IgM-enriched squared test was used. For inter-group comparisons of polyvalent immunoglobulin preparation derived from a continuous data, the two-tailed two-sample t test was plasma pool. It contains 6 mg of IgM, 6 mg of IgA, and generally performed. If the original data exhibited a log- 38 mg of IgG (63% IgG1, 26% IgG2, 4% IgG3, and 7% normal distribution, e.g., ICU length of stay (LOS), then IgG4) per millilitre. raw data were log-transformed prior to analysis with the The indication for IgM-enriched immunoglobulin t test. A p value < 0.05 was assumed to indicate a statisti- (IVIG) treatment was determined at the discretion of the cally significant difference between the groups. The data treating intensivist. IVIG was applied if a viral infection analysis was performed using JMP® 11.0 statistical soft- or an infection due to multi-resistant gram-negative ware (SAS Institute Inc., Cary, NC, USA). Prohaska et al. Journal of Intensive Care (2018) 6:11 Page 3 of 8 Results Infections Patients In 66% of the control patients and 82% of the IVIG-- A total of 57 patients with ARDS requiring