[Side effects of immune checkpoint inhibitor therapy : What intensive care specialists need to know]. / Nebenwirkungen nach Immuncheckpointinhibitortherapie : Wissenswertes für Intensivmediziner:innen.

Immunotherapies, and in particular checkpoint inhibitors, have revolutionized the treatment of cancer. However, due to their mechanism of action, the activation of the body's own T cells, side effects are frequently associated with these therapies. So-called immune-related adverse events (irAEs) manifest as autoimmunological phenomena, can occur in any organ system, and even lead to severe organ failure. Due to the time latency of up to months after administration of a checkpoint inhibitor until the first manifestation of an irAE, it is essential to consider a therapy-specific adverse event at any time during therapy. In case of incipient organ failure, discontinuation of the checkpoint inhibitor and rapid initiation of high-dose corticosteroid therapy is essential, which, in the absence of response, should be extended by further immunosuppressive or anti-inflammatory therapies. In general, the response to corticosteroids and extended therapy options is good, and in this sense organ failure is often reversible. Nevertheless, intensive medical care with the possible need for organ-supporting therapies should only be provided strictly according to the patient's wishes and in close consultation with the hematologist/oncologist in charge. Because of the great therapeutic benefit of immunotherapies, their frequent use, and potential to be used in curative lines of therapy in the future, intensive care physicians will also be confronted more frequently with irAEs after checkpoint inhibition. Accordingly, understanding, recognizing, and treating side effects after immunotherapies is increasingly essential for intensivists.

Characteristics and outcomes of patients with acute myeloid leukemia admitted to intensive care unit with acute respiratory failure: a post-hoc analysis of a prospective multicenter study.

BACKGROUND: Acute respiratory failure (ARF) is the leading cause of intensive care unit (ICU) admission in patients with Acute Myeloid Leukemia (AML) and data on prognostic factors affecting short-term outcome are needed. METHODS: This is a post-hoc analysis of a multicenter, international prospective cohort study on immunocompromised patients with ARF admitted to ICU. We evaluated hospital mortality and associated risk factors in patients with AML and ARF; secondly, we aimed to define specific subgroups within our study population through a cluster analysis. RESULTS: Overall, 201 of 1611 immunocompromised patients with ARF had AML and were included in the analysis. Hospital mortality was 46.8%. Variables independently associated with mortality were ECOG performance status ≥ 2 (OR = 2.79, p = 0.04), cough (OR = 2.94, p = 0.034), use of vasopressors (OR = 2.79, p = 0.044), leukemia-specific pulmonary involvement [namely leukostasis, pulmonary infiltration by blasts or acute lysis pneumopathy (OR = 4.76, p = 0.011)] and liver SOFA score (OR = 1.85, p = 0.014). Focal alveolar chest X-ray pattern was associated with survival (OR = 0.13, p = 0.001). We identified 3 clusters, that we named on the basis of the most frequently clinical, biological and radiological features found in each cluster: a "leukemic cluster", with high-risk AML patients with isolated, milder ARF; a "pulmonary cluster", consisting of symptomatic, highly oxygen-requiring, severe ARF with diffuse radiological findings in heavily immunocompromised patients; a clinical "inflammatory cluster", including patients with multi-organ failures in addition to ARF. When included in the multivariate analysis, cluster 2 and 3 were independently associated with hospital mortality. CONCLUSIONS: Among AML patients with ARF, factors associated with a worse outcome are related to patient's background (performance status, leukemic pulmonary involvement), symptoms, radiological findings, the need for vasopressors and the liver SOFA score. We identified three specific ARF syndromes in AML patients, which showed a prognostic significance and could guide clinicians to optimize management strategies.

Extracorporeal membrane oxygenation in adults receiving haematopoietic cell transplantation: an international expert statement.

Combined advances in haematopoietic cell transplantation (HCT) and intensive care management have improved the survival of patients with haematological malignancies admitted to the intensive care unit. In cases of refractory respiratory failure or refractory cardiac failure, these advances have led to a renewed interest in advanced life support therapies, such as extracorporeal membrane oxygenation (ECMO), previously considered inappropriate for these patients due to their poor prognosis. Given the scarcity of evidence-based guidelines on the use of ECMO in patients receiving HCT and the need to provide equitable and sustainable access to ECMO, the European Society of Intensive Care Medicine, the Extracorporeal Life Support Organization, and the International ECMO Network aimed to develop an expert consensus statement on the use of ECMO in adult patients receiving HCT. A steering committee with expertise in ECMO and HCT searched the literature for relevant articles on ECMO, HCT, and immune effector cell therapy, and developed opinion statements through discussions following a Quaker-based consensus approach. An international panel of experts was convened to vote on these expert opinion statements following the Research and Development/University of California, Los Angeles Appropriateness Method. The Appraisal of Guidelines for Research and Evaluation statement was followed to prepare this Position Paper. 36 statements were drafted by the steering committee, 33 of which reached strong agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and expert panel, and rephrased before an additional round of voting. At the conclusion of the process, 33 statements received strong agreement and three weak agreement. This Position Paper could help to guide intensivists and haematologists during the difficult decision-making process regarding ECMO candidacy in adult patients receiving HCT. The statements could also serve as a basis for future research focused on ECMO selection criteria and bedside management.

Impact of chronic graft-versus-host-disease on intensive care outcome in allogeneic hematopoietic stem cell recipients.

Chronic graft-vs-host-disease (cGvHD) is the most relevant long-term complication after allogeneic stem cell transplantation (HSCT) with major impact on non-relapse mortality, but data on intensive care unit (ICU) outcome are missing. In this retrospective, multicenter study we analyzed 174 adult HSCT recipients with cGvHD requiring intensive care treatment. Skin, pulmonary, liver, and intestinal involvement were present in 76.7%, 47.1%, 38.1% and 24.1%, respectively, and a total of 63.2% had severe cGvHD. Main reasons for ICU admission were respiratory failure (69.7%) and sepsis (34.3%). Hospital- and 3-year OS rates were 51.7% and 28.6%, respectively. Global severity of cGvHD did not impact short- and long-term survival. However, patients with severe liver cGvHD or the overlap subtype had a reduced hospital survival, while severe pulmonary cGvHD was associated with worse long-term survival. In multivariate analysis need for invasive ventilation (HR 1.08 (95% CI 1.02-1.14)) or hemodialysis (HR 1.73 (95% CI 1.14-2.62)) and <1 year since HSCT (HR 1.56 (95% CI 1.03-2.39)) were independently associated with a poorer survival. While the global severity of cGvHD does not per se affect patients' survival after intensive care treatment, pre-existing severe hepatic, intestinal or pulmonary cGvHD is associated with worse outcomes.

End of life decisions in immunocompromised patients with acute respiratory failure.

PURPOSE: To identify patient, disease and organizational factors associated with decisions to forgo life-sustaining therapies (DFLSTs) in critically ill immunocompromised patients admitted to the intensive care unit (ICU) for acute respiratory failure. MATERIAL AND METHODS: We performed a secondary analysis of the international EFRAIM prospective study, which enrolled 1611 immunocompromised patients with acute respiratory failure admitted to 68 ICUs in 16 countries between October 2015 and June 2016. Multivariate logistic analysis was performed to identify independent predictors of DFLSTs. RESULTS: The main causes of immunosuppression were hematological malignancies (50%) and solid tumor (38%). Patients had a median age of 63 yo (54-71). A pulmonologist was involved in the patient management in 38% of cases. DFLSTs had been implemented in 28% of the patients. The following variables were independently associated with DFLSTs: 1) patient-related: older age (OR 1.02 per one year increase, 95% confidence interval(CI) 1.01-1.03,P < 0.001), poor performance status (OR 2.79, 95% CI 1.98-3.93, P < 0.001); 2) disease-related: shock (OR 2.00, 95% CI 1.45-2.75, P < 0.001), liver failure (OR 1.59, 95% CI 1.14-2.21, P = 0.006), invasive mechanical ventilation (OR 1.79, 95% CI 1.31-2.46, P < 0.001); 3) organizational: having a pulmonologist involved in patient management (OR 1.85, 95% CI 1.36-2.52, P < 0.001), and the presence of a critical care outreach services (OR 1.63, 95% CI 1.11-2.38, P = 0.012). CONCLUSIONS: A DFLST is made in one in four immunocompromised patient admitted to the ICU for acute respiratory failure. Involving a pulmonologist in patient's management is associated with less non beneficial care.

Veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe respiratory failure in adult cancer patients: a retrospective multicenter analysis.

PURPOSE: The question of whether cancer patients with severe respiratory failure benefit from veno-venous extracorporeal membrane oxygenation (vv-ECMO) remains unanswered. We, therefore, analyzed clinical characteristics and outcomes of a large cohort of cancer patients treated with vv-ECMO with the aim to identify prognostic factors. METHODS: 297 cancer patients from 19 German and Austrian hospitals who underwent vv-ECMO between 2009 and 2019 were retrospectively analyzed. A multivariable cox proportional hazards analysis for overall survival was performed. In addition, a propensity score-matched analysis and a latent class analysis were conducted. RESULTS: Patients had a median age of 56 (IQR 44-65) years and 214 (72%) were males. 159 (54%) had a solid tumor and 138 (47%) a hematologic malignancy. The 60-day overall survival rate was 26.8% (95% CI 22.1-32.4%). Low platelet count (HR 0.997, 95% CI 0.996-0.999; p = 0.0001 per 1000 platelets/µl), elevated lactate levels (HR 1.048, 95% CI 1.012-1.084; p = 0.0077), and disease status (progressive disease [HR 1.871, 95% CI 1.081-3.238; p = 0.0253], newly diagnosed [HR 1.571, 95% CI 1.044-2.364; p = 0.0304]) were independent adverse prognostic factors for overall survival. A propensity score-matched analysis with patients who did not receive ECMO treatment showed no significant survival advantage for treatment with ECMO. CONCLUSION: The overall survival of cancer patients who require vv-ECMO is poor. This study shows that the value of vv-ECMO in cancer patients with respiratory failure is still unclear and further research is needed. The risk factors identified in the present analysis may help to better select patients who may benefit from vv-ECMO.

Critical care management of chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

Association of Acute Kidney Injury Receiving Kidney Replacement Therapy With Prognosis of Critically Ill Patients With and Without Cancer: A Retrospective Study.

OBJECTIVES: To assess outcomes of cancer patients receiving kidney replacement therapy due to acute kidney injury in ICUs and compare these with other patient groups receiving kidney replacement therapy in ICUs. DESIGN: Retrospective registry analysis. SETTING: Prospectively collected database of 296,424 ICU patients. PATIENTS: Patients with and without solid cancer with acute kidney injury necessitating kidney replacement therapy were identified and compared with those without acute kidney injury necessitating kidney replacement therapy. INTERVENTIONS: Descriptive statistics were used to ascertain prevalence of acute kidney injury necessitating kidney replacement therapy and solid cancer in ICU patients. Association of acute kidney injury necessitating kidney replacement therapy and cancer with prognosis was assessed using logistic regression analysis. To compare the attributable mortality of acute kidney injury necessitating kidney replacement therapy, 20,154 noncancer patients and 2,411 cancer patients without acute kidney injury necessitating kidney replacement therapy were matched with 12,827 noncancer patients and 1,079 cancer patients with acute kidney injury necessitating kidney replacement therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-five thousand three hundred fifty-six ICU patients (11.9%) had solid cancer. Acute kidney injury necessitating kidney replacement therapy was present in 1,408 (4.0%) cancer patients and 13,637 (5.2%) noncancer patients. Crude ICU and hospital mortality was higher in the cancer group (646 [45.9%] vs 4,674 [34.3%], p < 0.001, and 787 [55.9%] vs 5,935 [43.5%], p < 0.001). In multivariable logistic regression analyses, odds ratio (95% CI) for hospital mortality was 1.73 (1.62-1.85) for cancer compared with no cancer 3.57 (3.32-3.83) for acute kidney injury necessitating kidney replacement therapy and 1.07 (0.86-1.33) for their interaction. In the matched subcohort, attributable hospital mortality of acute kidney injury necessitating kidney replacement therapy was 56.7% in noncancer patients and 48.0% in cancer patients. CONCLUSIONS: Occurrence rate of acute kidney injury necessitating kidney replacement therapy and prognosis in ICU patients with solid cancer are comparable with other ICU patient groups. In cancer, acute kidney injury necessitating kidney replacement therapy is associated with higher crude hospital mortality. However, the specific attributable mortality conveyed by acute kidney injury necessitating kidney replacement therapy is actually lower in cancer patients than in noncancer patients. Diagnosis of cancer per se does not justify withholding kidney replacement therapy.

Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. METHODS: This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. FINDINGS: 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0-7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1-27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3-4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3-4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37-4·57]), bacterial infection (2·12 [1·11-4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05-3·10]). INTERPRETATION: Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. FUNDING: Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique.

Bacteremia in critically ill immunocompromised patients with acute hypoxic respiratory failure: A post-hoc analysis of a prospective multicenter multinational cohort.

PURPOSE: The characteristics and impact of bacteremia have not been widely investigated in immunocompromised patients with acute respiratory failure (ARF). METHODS: We performed a secondary analysis of a prospective cohort of immunocompromised patients with ARF (EFRAIM study). After exclusion of blood cultures positive for coagulase negative Staphylococci, we compared patients with (n = 236) and without (n = 1127) bacteremia. RESULTS: The incidence of bacteremia was 17%. Bacterial pneumonia and extra-pulmonary ARDS were the main causes of ARF in bacteremic patients. Bacteremia involved gram negative rods (48%), gram positive cocci (40%) or were polymicrobial (10%). Bacteremic patients had more hematological malignancy, higher SOFA scores and increased organ support within 7 days. Bacteremia was associated with higher crude ICU mortality (40% versus 32%, p = 0.02), but neither hospital (49% versus 44%, p = 0.17) nor 90-day mortality (60% versus 56%, p = 0.25) were different from non-bacteremic patients. After propensity score matching based on baseline characteristics, the difference in ICU mortality lost statistical significance (p = 0.06), including in a sensitivity analysis restricted to patients with pneumonia. CONCLUSIONS: We analyzed a large population of immunocompromised patients with ARF and an incidence of bacteremia of 17%. We could not demonstrate an impact of bacteremia on mortality after adjusting for baseline characteristics.

Long-term Respiratory Extracorporeal Membrane Oxygenation and Prognosis: A Retrospective Analysis.

The duration of extracorporeal membrane oxygenation (ECMO) treatments increases, however, data presented from prolonged support is limited. We retrospectively analyzed all patients during a 4-year period undergoing respiratory ECMO for duration of therapy, demographics, therapy-associated parameters, and outcome according to ECMO duration (<28 days and ≥28 days = long-term ECMO). Out of 55 patients undergoing ECMO for ARDS or during bridging to lung transplantation, 18 were on ECMO for ≥28 days (33%). In the long-term group, median ECMO run time was 40 days (interquartile range 34-54 days). Hospital survival was not significantly different between the groups (54% in short-term and 50% in long-term ECMO patients). There was a significantly higher proportion of patients suffering from malignancy in the group of long-term nonsurvivors. Recovery occurred after more than 40 days on ECMO in 3 patients. The longest ECMO run time in a hospital survivor was 65 days. Duration of ECMO support alone was no prognostic factor and should not represent a basis for decision-making. In patients suffering from malignancy, long-term ECMO support seems to be a factor of adverse prognosis, if not futile.

A bi-centric experience of extracorporeal carbon dioxide removal (ECCO2 R) for acute hypercapnic respiratory failure following allogeneic hematopoietic stem cell transplantation.

Acute respiratory failure (ARF) is the main reason for ICU admission following allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal CO2 removal (ECCO2 R) can be used as an adjunct to mechanical ventilation in patients with severe hypercapnia but has not been assessed in HSCT recipients. Retrospective analysis of all allogeneic HSCT recipients ≥18 years treated with ECCO2 R at two HSCT centers. 11 patients (m:f = 4:7, median age: 45 [IQR: 32-58] years) were analyzed. Acute leukemia was the underlying hematologic malignancy in all patients. The time from HSCT to ICU admission was 37 [8-79] months, and 9/11 (82%) suffered from chronic graft-versus-host disease (GVHD) with lung involvement. Pneumonia was the most frequent reason for ventilatory decompensation (n = 9). ECCO2 R was initiated for severe hypercapnia (Pa CO2 : 96 [84-115] mm Hg; pH: 7.13 [7.09-7.27]) despite aggressive mechanical ventilation (invasive, n = 9; non-invasive, n = 2). ECCO2 R effectively resolved blood gas disturbances in all patients, but only 2/11 (18%) could be weaned off ventilatory support, and one (9%) patient survived hospital discharge. Progressive respiratory and multiorgan dysfunction were the main reasons for treatment failure. ECCO2 R was technically feasible but resulted in a low survival rate in our cohort. A better understanding of the prognosis of ARF in patients with chronic GVHD and lung involvement is necessary before its use can be reconsidered in this setting.

Intraoperative Off-Label Reversal of Apixaban by Andexanet Alfa while on VA-ECMO Immediately After Emergent Surgery for Acute Type A Aortic Dissection.

The authors report a case of intraoperative reversal of apixaban with andexanet alfa in a patient supported with venoarterial extracorporeal membrane oxygenation due to low- cardiac-output immediately after surgery for acute type A aortic dissection and massive intraoperative transfusion with administration of procoagulants. In this patient, andexanet alfa's off-label use was not associated with acute thrombotic complications despite being given during extracorporeal life support and after previous administration of prothrombin complex concentrates.

Prevalence and Impact of Vitamin D Deficiency in Critically Ill Cancer Patients Admitted to the Intensive Care Unit.

Vitamin D deficiency is frequent in cancer patients and a risk factor for morbidity and mortality during critical illness. This single-center retrospective study analyzed 25-hydroxyvitamin D levels in critically ill cancer patients (n = 178; hematologic, n = 108; solid, n = 70) enrolled in a prospective ICU registry. The primary analysis was the prevalence of vitamin D deficiency (<20 ng/mL) and the severe deficiency (≤12 ng/mL). Secondary analyses included risk factors for vitamin D deficiency and its impact on ICU, hospital, and 1-year mortality. The prevalence of vitamin D deficiency and severe deficiency was 74% (95% CI: 67-80%) and 54% (95% CI: 47-61%). Younger age, relapsed/refractory disease, and a higher sepsis-related organ failure assessment (SOFA) score were independent risk factors for vitamin D deficiency (p < 0.05). After adjusting for relapsed/refractory disease, infection, the SOFA score, and the early need for life-supporting interventions, severe vitamin D deficiency was an independent predictor of hospital mortality (OR: 2.21, 95% CI: 1.03-4.72, p = 0.04) and 1-year mortality (OR: 3.40, 95% CI: 1.50-7.71, p < 0.01), but not of ICU mortality. Conclusion: Vitamin D deficiency is common in critically ill cancer patients requiring ICU admission, but its impact on short-term mortality in this group is uncertain. The observed association of severe vitamin D deficiency with the post-ICU outcome warrants clinical consideration and further study.

[Immuno-Oncology Meets Intensive Care Medicine: CAR-T cells]. / Immunonkologie trifft Intensivmedizin: CAR-T-Zellen.

CAR-T cells, genetically modified tumor-targeted t-cells, revolutionized the treatment of refractory B-cell malignancies. CAR-T cell treatment however, is invariably associated with severe immune-mediated toxicities, namely Cytokine Release Syndrome (CRS) and neurological toxicity (CRES/ICANS). Although knowledge on the pathomechanism of these toxicities is still very limited, recent findings including mouse models might allow prediction, earlier recognition and targeted treatment of patients suffering from these potentially life-threatening side effects. This article summarizes current knowledge and recent findings on the management of severe CAR-T associated toxicities and gaps of knowledge stressing the importance of an interdisciplinary approach including hematology-oncology and Intensive Care Medicine.

Changes in critically ill cancer patients' short-term outcome over the last decades: results of systematic review with meta-analysis on individual data.

PURPOSE: The number of averted deaths due to therapeutic advances in oncology and hematology is substantial and increasing. Survival of critically ill cancer patients has also improved during the last 2 decades. However, these data stem predominantly from unadjusted analyses. The aim of this study was to assess the impact of ICU admission year on short-term survival of critically ill cancer patients, with special attention on those with neutropenia. METHODS: Systematic review and meta-analysis of individual data according to the guidelines of meta-analysis of observational studies in epidemiology. DATASOURCE: Pubmed and Cochrane databases. ELIGIBILITY CRITERIA: Adult studies published in English between May 2005 and May 2015. RESULTS: Overall, 7354 patients were included among whom 1666 presented with neutropenia at ICU admission. Median ICU admission year was 2007 (IQR 2004-2010; range 1994-2012) and median number of admissions per year was 693 (IQR 450-1007). Overall mortality was 47.7%. ICU admission year was associated with a progressive decrease in hospital mortality (OR per year 0.94; 95% CI 0.93-0.95). After adjustment for confounders, year of ICU admission was independently associated with hospital mortality (OR for hospital mortality per year: 0.96; 95% CI 0.95-0.97). The association was also seen in patients with neutropenia but not in allogeneic stem cell transplant recipients. CONCLUSION: After adjustment for patient characteristics, severity of illness and clustering, hospital mortality decreased steadily over time in critically ill oncology and hematology patients except for allogeneic stem cell transplant recipients.

Twenty-year experience with extracorporeal life support as bridge to lung transplantation.

OBJECTIVES: Extracorporeal life support is increasingly used to bridge deteriorating candidates to lung transplantation. Nevertheless, only few systematic reports with a limited number of patients exist describing this practice and its changes over time. METHODS: We retrospectively reviewed our institutional database and performed an era analysis to identify trends over time and risk factors for mortality. After applying propensity score matching, outcomes of bridged patients were compared with those of standard lung transplantation recipients. RESULTS: Extracorporeal life support was used in 120 patients as an intention to bridge to lung transplantation. Eleven patients (9.2%) were bridged between 1998 and 2004, 39 patients (32.5%) were bridged between 2005 and 2010, and 70 patients were bridged (58.3%) between 2010 and 2017. In the first era, the main bridging modality was venoarterial-extracorporeal membrane oxygenation (n = 10, 90.9%), whereas venovenous devices were primarily used in later eras (second era: n = 18, 46.2%; third era: n = 39, 55.8%). In the second and third eras, 9 patients (23.1%) and 24 patients (34.3%) could be bridged awake. Short-term outcome was poor in the first era, with only 36.4% of patients discharged alive but improved in later eras (53.8% and 77.1%; P = .002). Extracorporeal life support-bridged patients showed an impaired short-term outcome compared with standard recipients. However, survival conditional on 90 days did not differ among the groups (P = .178). In univariate and multivariate analyses, awake extracorporeal life support was protective for survival, whereas acute retransplantation was a risk factor for mortality. CONCLUSIONS: Over the past 2 decades, the role of extracorporeal life support bridging evolved from an acute rescue therapy to a semi-elective procedure. Stratified outcome analysis revealed that extracorporeal life support bridging yielded similar long-term survival compared with nonbridged patients.

Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) causes multiple organ dysfunction frequently leading to intensive care unit (ICU) referral and/or death. We report on a series of critically ill adult patients treated with a non-etoposide-based regimen including interleukin 1 antagonist anakinra, intravenous immunoglobulin (IVIG), and/or corticosteroids (CS) for HLH. METHODS: Eight adult (≥18 years) ICU patients having received treatment with anakinra ± IVIG ± CS for HLH between March 2014 and March 2016 at a large tertiary care university hospital (Medical University of Vienna, Vienna, Austria) were retrospectively analyzed. RESULTS: Eight patients (median age: 38 years; range: 20-58 years; 4 males and 4 females) received anakinra together with IVIG (n = 7) and/or high-dose CS (n = 5) for suspected reactive HLH (median H-score: 214; range: 171-288). Seven (88%) patients required vasopressors and invasive mechanical ventilation and 6 (75%) patients required renal replacement therapy (median Sequential Organ Failure Assessment [SOFA] score at HLH diagnosis: 9.5; range: 6-14). Six patients showed a significant decline in the SOFA score at 1 and 2 weeks following treatment initiation (P = .03), and the remainder 2 patients experienced early death. Five patients survived to ICU discharge, 4 of them could further be discharged from hospital (hospital survival rate: 50%). No overt treatment-related toxicity was noted. CONCLUSION: Anakinra in combination with IVIG and/or CS resulted in a hospital survival rate of 50% in 8 critically ill adult patients with HLH despite a vast degree of organ dysfunction and the need for aggressive ICU treatment. Further research on non-etoposide-based treatment strategies for HLH in critically ill adults is warranted.

Influence of neutropenia on mortality of critically ill cancer patients: results of a meta-analysis on individual data.

BACKGROUND: The study objective was to assess the influence of neutropenia on outcome of critically ill cancer patients by meta-analysis of individual data. Secondary objectives were to assess the influence of neutropenia on outcome of critically ill patients in prespecified subgroups (according to underlying tumor, period of admission, need for mechanical ventilation and use of granulocyte colony stimulating factor (G-CSF)). METHODS: Data sources were PubMed and the Cochrane database. Study selection included articles focusing on critically ill cancer patients published in English and studies in humans from May 2005 to May 2015. For study selection, the study eligibility was assessed by two investigators. Individual data from selected studies were obtained from corresponding authors. RESULTS: Overall, 114 studies were identified and authors of 30 studies (26.3% of selected studies) agreed to participate in this study. Of the 7515 included patients, three were excluded due to a missing major variable (neutropenia or mortality) leading to analysis of 7512 patients, including 1702 neutropenic patients (22.6%). After adjustment for confounders, and taking study effect into account, neutropenia was independently associated with mortality (OR 1.41; 95% CI 1.23-1.62; P = 0.03). When analyzed separately, neither admission period, underlying malignancy nor need for mechanical ventilation modified the prognostic influence of neutropenia on outcome. However, among patients for whom data on G-CSF administration were available (n = 1949; 25.9%), neutropenia was no longer associated with outcome in patients receiving G-CSF (OR 1.03; 95% CI 0.70-1.51; P = 0.90). CONCLUSION: Among 7512 critically ill cancer patients included in this systematic review, neutropenia was independently associated with poor outcome despite a meaningful survival. Neutropenia was no longer significantly associated with outcome in patients treated by G-CSF, which may suggest a beneficial effect of G-CSF in neutropenic critically ill cancer patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026347 . Date of registration: Sept 18 2015.