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Background: The optimal timing of weaning from venovenous extracorporeal membrane oxygenation (VV ECMO) and its modalities have been rarely studied., Methods: Retrospective, multicenter cohort study over 7 years in two tertiary ICUs, high-volume ECMO centers in France and Italy. Patients with ARDS on ECMO and successfully weaned from VV ECMO were classified based on their mechanical ventilation modality during the sweep gas-off trial (SGOT) with either controlled mechanical ventilation or spontaneous breathing (i.e. pressure support ventilation). The primary endpoint was the time to successful weaning from mechanical ventilation within 90 days post-ECMO weaning., Results: 292 adult patients with severe ARDS were weaned from controlled ventilation, and 101 were on spontaneous breathing during SGOT. The 90-day probability of successful weaning from mechanical ventilation was not significantly different between the two groups (sHR [95% CI], 1.23 [0.84-1.82]). ECMO-related complications were not statistically different between patients receiving these two mechanical ventilation strategies. After adjusting for covariates, older age, higher pre-ECMO sequential organ failure assessment score, pneumothorax, ventilator-associated pneumonia, and renal replacement therapy, but not mechanical ventilation modalities during SGOT, were independently associated with a lower probability of successful weaning from mechanical ventilation after ECMO weaning., Conclusions: Time to successful weaning from mechanical ventilation within 90 days post-ECMO was not associated with the mechanical ventilation strategy used during SGOT. Further research is needed to assess the optimal ventilation strategy during weaning off VV ECMO and its impact on short- and long-term outcomes., (© 2024. The Author(s).)

Objectives: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome., Methods: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied., Results: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients., Conclusion: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: V. C. reports nonfinancial support from Actelion; personal fees and nonfinancial support from Boehringer Ingelheim; personal fees from Bayer/MSD; other from Gilead; personal fees from Novartis; personal fees, nonfinancial support, and other from Roche SAS; personal fees and nonfinancial support from Sanofi; personal fees from Promedior; other from Celgene; personal fees from Galapagos; other from Galecto, personal fees from Astra Zeneca; personal fees from ReImagine; personal fees from Soun; personal fees from BMS; personal fees from PPDi; personal fees from IQVIA; personal fees from Exepi; and personal fees from Shionogi; none of which were related to this work. P.-Y. B. reports grants from Laboratoire Boehringer Ingelheim and Laboratoire Roche and personal fees from Laboratoire Boehringer Ingelheim and Laboratoire Roche, outside the submitted work. H. N. reports grants from Boehringer Ingelheim and Roche/Genentech and personal fees from Actelion Pharmaceuticals, Boehringer Ingelheim, Galapagos, and Roche/Genentech, outside the submitted work. Y. U. reports personal fees from Boehringer Ingelheim and Roche and grants and nonfinancial support from Oxyvie, outside the submitted work. None declared (P. B., M. P. d. C., Y. A., J. L. P., C. P., B. Z., V. B., B. H., A. M., M. M., S. B., C. D., Y. T.-L., E. H.).

Objectives: In the context of postcardiotomy cardiogenic shock (PCCS) following valve replacement surgery, it may be necessary to implant a peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). This procedure, however, carries a risk of prosthetic valve thrombosis. The aim of this retrospective study was to describe the incidence and outcomes of prosthetic valve thrombosis after VA-ECMO support for PCCS and to report the associated risk factors., Methods: All consecutive adult patients who received pVA-ECMO for PCCS following a valve replacement procedure between January 2015 and October 2019 in our institution were included in this retrospective study. Outcome variables were prosthetic valve thrombosis, 30-day and hospital survival, pVA-ECMO-associated adverse events and surgery-related adverse events., Results: During the 4-year study period, 549 patients received pVA-ECMO for PCCS. Among them, 152 had undergone a valve replacement procedure and 9 of these developed prosthetic valve thrombosis. The incidence of valve thrombosis at 30 days was 7.5 ± 2%. The cumulative Incidence of prosthetic valve thrombosis was significantly lower with pVA-ECMO + IABP versus VA-ECMO alone (1.4 ± 1.4% vs 13.7 ± 4.7%, p = 0.021, respectively). Intra-aortic balloon pump use associated with pVA-ECMO (versus pVA-ECMO alone) was an independent protective factor against hospital death (OR = 0.180 [0.068-0.478], p = 0.001)., Conclusions: After PCCS following valve replacement surgery, peripheral femoro-femoral VA-ECMO is associated with a low risk of acute valve thrombosis especially when associated with an IABP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Management of dual antiplatelet therapy (DAPT) in patients on venoarterial-extracorporeal membrane (VA-ECMO) after acute myocardial infarction (AMI) is challenging. Our objective was to describe the frequency, management and outcomes of severe bleeding complications and determine their occurrence risk factors., Material and Methods: We conducted a retrospective observational cohort study including post-AMI cardiogenic shock patients requiring VA-ECMO. Severe bleeding was defined based on the Bleeding Academic Research Consortium classification. We calculated multivariable Fine-Gray models to assess factors associated with risk of severe bleeding., Results: From January 2015 to July 2019, 176 patients received VA-ECMO after AMI and 132 patients were included. Sixty-five (49%) patients died. Severe bleeding occurred in 39% of cases. Severe thrombocytopenia (< 50 G/L) and hypofibrinogenemia (<1,5 g/L) occurred in respectively 31% and 19% of patients. DAPT was stopped in 32% of patients with a 6% rate of stent thrombosis. Anticoagulation was stopped in 39% of patients. Using a multivariate competing risk model, female sex, time on ECMO, troponin at admission and Impella® implantation were independently associated with severe bleeding., Conclusions: Bleeding complications and coagulation disorders were frequent and severe in patients on VA-ECMO after AMI, leading of antiplatelet therapy withdrawal in one third of patients., Competing Interests: Declaration of competing interest Matthieu Schmidt reports lecture fees from Getinge, Drager and Xenios outside the submitted work. Alain Combes reports grants from Getinge, personal fees from Getinge, Baxter and Xenios outside the submitted work. Charles Edouard Luyt reported personal fees from Bayer Healthcare, Carmat, Faron, Merck Sharp & Dohme, ThermoFischer Brahms, and Biomérieux; and grants from Bayer Healthcare outside the submitted work. Guillaume Lebreton reports lecture fees from Livanova and Abiomed, outside of the submitted work. The other authors declare that they have no conflicts of interest related to the purpose of this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Despite systemic thrombolysis, a few patients with high-risk pulmonary embolism (PE) remain hemodynamically unstable. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a considerable lifesaving therapy but systemic thrombolysis before cannulation could carry a high risk of hemorrhage and alter the prognosis., Methods: Between June 2012 and June 2023, we retrospectively analyzed from three intensive care units in Sorbonne University, ECMO-related complications and 90-day mortality for high-risk PE patients who received ECMO without previous systemic thrombolysis compared to those cannulated after systemic thrombolysis failure. Hospital discharge survivors were assessed for long-term health-related quality of life and echocardiographic evaluations., Results: 72 high-risk PE patients [median age 48 (37-61) years, Simplified Acute Physiology Score II (SAPS II) 74 (60-85)] were placed on VA-ECMO for 5 (5-7) days. 31 (43%) patients underwent pre-ECMO thrombolysis (thrombolysis ECMO group, T +) compared to 41 patients (57%, no thrombolysis ECMO group, T-). There was more pre-ECMO cardiac arrest in the thrombolysis ECMO group (94% vs. 67%, p = 0.02). Ninety-day survival was not different between groups (39% vs 46%, log-rank test, p = 0.31). There was no difference in severe hemorrhages (61% vs 59%, p = 1). Twenty-five over 28 patients attended follow-up at a median time of 69 (52-95) months. Long-term quality of life was acceptable and none of them experienced chronic thromboembolic pulmonary hypertension., Conclusions: Ninety-day survival and bleeding events rates did not differ in patients treated with VA-ECMO after systemic thrombolysis compared to those who were not. Recent systemic thrombolysis, as a single parameter, should not be considered as a contraindication for VA-ECMO in high-risk PE., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of the Review: Antiphospholipid syndrome (APS) is a rare systemic autoimmune disorder that can escalate into a 'thrombotic storm' called the catastrophic antiphospholipid syndrome (CAPS), frequently requiring ICU admission for multiple organ failure. This review aims to offer insight and recent evidence on critically-ill APS patients., Recent Findings: The CAPS classification criteria define this condition as the involvement of at least three organs/systems/tissues within less than a week, caused by small vessel thrombosis, in patients with elevated antiphospholipid antibodies levels. These criteria do not encompass the full spectrum of critically-ill thrombotic APS patients and they need to be cautiously used for the bedside diagnosis of CAPS. Thrombocytopenia is the laboratory hallmark of CAPS, sometimes dropping below 20G/L, but a complete thrombotic microangiopathy pattern is infrequent. Anticoagulation is the pivotal treatment for APS and CAPS, associated with improved outcome. Triple therapy - the combination of anticoagulation, high-dose corticosteroids, and either plasma exchange or intravenous immunoglobulins - remains the standard treatment for CAPS patients. Eculizumab, an anti-C5 monoclonal antibody, may be useful in refractory patients. Despite significant progress, CAPS mortality rate remains high. Its diagnosis and management are complex, requiring a close multidisciplinary cross talk between APS specialists and intensivists., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m 2 ( P < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m 2 , P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg -1 ( P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index. NEW & NOTEWORTHY This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.

Objectives: The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing., Methods: Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing., Results: Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition., Conclusions: In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To describe ventilator-associated pneumonia (VAP) recurrence in COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO) support, and to evaluate the impact of antimicrobial treatment duration of the first VAP episode on VAP recurrence., Methods: Adult patients with COVID-19 severe pneumonia on ECMO admitted between March 2020 and January 2022 were retrospectively included. Primary outcome was incidence of VAP recurrence, and secondary outcome was the impact of duration of antimicrobial treatment on VAP recurrence., Results: Among the 252 included patients, 226 (90%) developed a first VAP. Sixteen had lung abscess and were excluded, leaving 210 patients. VAP recurrence occurred in 172 patients (82%), with a median (IQR) time from first VAP to recurrence of 10 (7-13) days. Pseudomonas aeruginosa and Enterobacteriaceae were respectively responsible for 28% and 52% of first VAP, and 51% and 62% of first recurrence episodes. Among the 210 patients with a first VAP, 158 (75%) received a short course of antibiotics [< 8 days, median (IQR) duration 6 (5-7) days] and 52 (25%) received a prolonged course of antibiotics [≥ 8 days, median (IQR) duration 9 (8-10) days]. Estimated cumulative incidence of VAP recurrence, taking into account death and extubation as competing risks, was not different in patients with short- and prolonged-antimicrobial treatment., Conclusions: In patients with severe Covid-19-ARDS requiring ECMO support, VAP recurrence occurs frequently, with Enterobacteriaceae and Pseudomonas aeruginosa as predominant causative microorganisms. An antimicrobial treatment of ≥ 8 days for the treatment of first VAP episode did not reduce the risk of VAP recurrence, as compared to shorter duration., (© 2024. The Author(s).)

Objectives: Physicians with training in anesthesiology, emergency medicine, internal medicine, neurology, and surgery may gain board certification in critical care medicine upon completion of fellowship training. These clinicians often only spend a portion of their work effort in the ICU. Other work efforts that benefit an ICU infrastructure, but do not provide billing opportunities, include education, research, and administrative duties. For employed or contracted physicians, there is no singular definition of what constitutes an intensive care full-time equivalent (FTE). Nevertheless, hospitals often consider FTEs in assessing hiring needs, salary, and eligibility for benefits., Data Sources: Review of existing literature, expert opinion., Study Selection: Not applicable., Data Extraction: Not applicable., Data Synthesis: Not applicable., Conclusions: Understanding how an FTE is calculated, and the fraction of an FTE to be assigned to a particular cost center, is therefore important for intensivists of different specialties, as many employment models assign salary and benefits to a base specialty department and not necessarily the ICU., Competing Interests: Dr. Nurok serves as an advisor to Avant-garde Health, and he receives stock options for this role. Dr. Nunnally is a member of the Board of Regents of the American College of Critical Care Medicine. As such, he serves as an honorary member of the Society of Critical Care Medicine Council. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose: The outcomes of immunocompromised patients with cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) are seldom documented, making ECMO candidacy decisions challenging. This study aims (1) to report outcomes of immunocompromised patients treated with VA-ECMO, (2) to identify pre-ECMO predictors of 90-day mortality, (3) to assess the impact of immunodepression on 90-day mortality, and (4) to describe the main ECMO-related complications., Methods: This is a retrospective, propensity-weighted study conducted in two French experienced ECMO centers., Results: From January 2006 to January 2022, 177 critically ill immunocompromised patients (median (interquartile range, IQR) age 49 (32-60) years) received VA-ECMO. The main causes of immunosuppression were long-term corticosteroids/immunosuppressant treatment (29%), hematological malignancy (26%), solid organ transplant (20%), and solid tumor (13%). Overall 90-day and 1-year mortality were 70% (95% confidence interval (CI) 63-77%) and 75% (95% CI 65-79%), respectively. Older age and higher pre-ECMO lactate were independently associated with 90-day mortality. Across immunodepression causes, 1-year mortality ranged from 58% for patients with infection by human immunodeficiency virus (HIV) or asplenia, to 89% for solid organ transplant recipients. Hemorrhagic and infectious complications affected 39% and 54% of patients, while more than half the stay in intensive care unit (ICU) was spent on antibiotics. In a propensity score-weighted model comparing the 177 patients with 942 non-immunocompromised patients experiencing cardiogenic shock on VA-ECMO, immunocompromised status was independently associated with a higher 90-day mortality (odds ratio 2.53, 95% CI 1.72-3.79)., Conclusion: Immunocompromised patients undergoing VA-ECMO treatment face an unfavorable prognosis, with higher 90-day mortality compared to non-immunocompromised patients. This underscores the necessity for thorough evaluation and careful selection of ECMO candidates within this frail population., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020., Results: Median time from ibrutinib initiation was 6.6 [3-18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5-11] vs. 4 [3-7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1-2] vs. 0 [0-2]; p < 0.001) and higher rates of fungal [21% vs. 8%, p = 0.001] and viral [17% vs. 5%, p = 0.027] infections in patients receiving ibrutinib, ICU (27% vs. 38%, p = 0.254) and day-90 mortality (52% vs. 48%, p = 0.785) were similar between the two groups., Conclusion: In ibrutinib-treated patients, severe infections requiring ICU admission were associated with a dismal prognosis, mostly impacted by initial organ failures. Opportunistic agents should be systematically screened by ICU clinicians in this immunocompromised population., (© 2023. The Author(s).)

Purpose: The impact of VA-ECMO on early renal recovery (within 7 days after ECMO onset) in patients with pre-ECMO acute kidney injury and cardiogenic shock is unknown., Material and Methods: This retrospective single-center study included adult patients with cardiogenic shock rescued by VA-ECMO and severe AKI occurring before ECMO implantation (pre-ECMO AKI). Patients with early renal recovery (defined as at least a 50% decrease in peak serum creatinine or weaning from renal replacement therapy) were compared to patients without early renal recovery., Results: During 7 years, 145 patients with severe pre-ECMO AKI were included. Eighty-two patients had no early renal recovery whereas 63 had early renal recovery within 7 days after VA-ECMO onset. The median time to early renal recovery was 4 (3,6) days. Nephrotoxic antibiotics (HR = 0.35 [95% CI, 0.21-0.59], p < 0.001), median fluid balance during the first 7 days of VA-ECMO (HR = 0.77 [95% CI, 0.64-0.93], p = 0.008), pre-ECMO AKI stage 3 (HR = 0.36 [95% CI, 0.20-0.64], p < 0.001) and median vasoactive-inotropic score (HR = 0.99 [95% CI, 0.98,1.00], p = 0.035) were independently associated with no early renal recovery., Conclusions: Only 43% of patients with severe pre-ECMO AKI had early renal recovery after VA-ECMO initiation., Competing Interests: Declaration of Competing Interest Pr Combes reports grants from Getinge, and personal fees from Getinge, Baxter, and Xenios outside the submitted work. Pr Schmidt reports receiving personal fees from Getinge, Baxter, and Xenios, outside the submitted work. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy., Methods: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment., Results: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone., Conclusion: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Fulminant myocarditis is a rare and severe disease whose definite and etiological diagnoses rely on pathological examination. Albeit, myocardial biopsy can be associated with significant morbidity and mortality, its therapeutic consequences are unclear. We conducted a study to determine the diagnostic yield, the safety and the therapeutic consequences of myocardial biopsy in patients with fulminant clinically suspected myocarditis unweanable from mechanical circulatory support (MCS)., Methods: Monocenter, retrospective, observational cohort study in a 26-bed French tertiary ICU between January 2002 and February 2019. Inclusion of all fulminant clinically suspected myocarditis patients undergoing in-ICU myocardial biopsy while being on MCS. The primary endpoint was the proportion of patients classified as definite myocarditis using Bonaca criteria before and after including myocardial biopsy results., Results: Forty-seven patients (median age 41 [30-47], female 53%) were included: 55% died before hospital discharge, 34% could be bridged-to-recovery and 15% bridged-to-transplant. Myocardial biopsy was endomyocardial or surgical in 36% and 64% cases respectively. Tamponade requiring emergency pericardiocentesis occurred in 29% patients after endomyocardial biopsy. After adding the biopsy results in the Bonaca classification algorithm the percentage of definite myocarditis raised from 13 to 55% (p < 0.0001). The rate of biopsy-related treatments modifications was 13%, leading to patients' recovery in only 4% patients., Conclusions: In clinically suspected myocarditis unweanable from MCS, myocardial biopsy increased the rate of definite myocarditis but was associated with a low rate of treatment modification and a significant proportion of adverse events. We believe the benefit/risk ratio of myocardial biopsy should be more carefully weighted in these frail and selected patients than suggested by actual guidelines. Further prospective studies are now needed to determine its value in patients under MCS., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

Introduction: Systemic lupus erythematosus (SLE) is non-organ specific autoimmune disease with mainly skin, joint, and kidney involvement. SLE-related acute lung disease (ALD) is rare, poorly investigated and can lead to acute respiratory failure. We conducted a retrospective study aiming to describe clinical features, treatments and outcome of SLE-related APD., Methods: We retrospectively included all patients with SLE and ALD admitted from November 1996 and September 2018 to La Pitié-Salpêtrière Hospital, after exclusion of viral or bacterial lung infection, cardiac failure or any other alternate diagnosis., Results: During the time of the study, 14 patients with 16 episodes were admitted to our center: female 79%, mean age ± SD at admission 24 ± 11 years. ALD was inaugural of the SLE in 70% cases. SLE main organ involvement were: arthritis 93%, skin 79%, serositis 79%, hematological 79%, kidney 64%, neuropsychiatric 36% and cardiac 21%. 11 episodes required ICU admission for a median time of 8 days. Chest CT-scan revealed mostly basal consolidation and ground-glass opacities. When available, bronchoalveolar lavage mostly revealed a neutrophilic alveolitis with alveolar hemorrhage in 67% cases. Symptomatic respiratory treatments were: oxygen 81%, high-flow nasal canula oxygen 27%, non-invasive ventilation 36%, mechanical ventilation 64% and venovenous extracorporeal membrane oxygenation 18%. SLE-specific treatments were: corticosteroids 100%, cyclophosphamide 56% and plasma exchange 25%. All patients but one survived to ICU and hospital discharge. Two patients had a relapse of SLE-related ALD but none had interstitial lung disease during follow-up., Conclusion: Systemic lupus erythematosus-related acute respiratory failure is a severe event, mostly occurring at SLE onset, typical harboring a basal consolidation pattern on chest CT-scan and alveolar hemorrhage on BAL pathological examination. Mortality in our cohort is lower than previously reported but these results needs to be confirmed in further larger studies.

Antibiotic resistance is a major health problem and will be probably one of the leading causes of deaths in the coming years. One of the most effective ways to fight against resistance is to decrease antibiotic consumption. Intensive care units (ICUs) are places where antibiotics are widely prescribed, and where multidrug-resistant pathogens are frequently encountered. However, ICU physicians may have opportunities to decrease antibiotics consumption and to apply antimicrobial stewardship programs. The main measures that may be implemented include refraining from immediate prescription of antibiotics when infection is suspected (except in patients with shock, where immediate administration of antibiotics is essential); limiting empiric broad-spectrum antibiotics (including anti-MRSA antibiotics) in patients without risk factors for multidrug-resistant pathogens; switching to monotherapy instead of combination therapy and narrowing spectrum when culture and susceptibility tests results are available; limiting the use of carbapenems to extended-spectrum beta-lactamase-producing Enterobacteriaceae, and new beta-lactams to difficult-to-treat pathogen (when these news beta-lactams are the only available option); and shortening the duration of antimicrobial treatment, the use of procalcitonin being one tool to attain this goal. Antimicrobial stewardship programs should combine these measures rather than applying a single one. ICUs and ICU physicians should be at the frontline for developing antimicrobial stewardship programs., (© 2023. The Author(s).)

Background: Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections. Few data are available regarding neutropenic patients with NSTIs. Our objectives were to describe the characteristics and management of neutropenic patients with NSTIs in intensive care units (ICUs). We conducted a retrospective multicentre cohort study in 18 ICUs between 2011 and 2021. Patients admitted with NSTIs and concomitant neutropenia at diagnosis were included and compared to non-neutropenic patients with NSTIs. The relationship between therapeutic interventions and outcomes was assessed using Cox regression and propensity score matching., Results: 76 neutropenic patients were included and compared to 165 non-neutropenic patients. Neutropenic patients were younger (54 ± 14 vs 60 ± 13 years, p = 0.002) and had less lower limb (44.7% vs 70.9%, p < 0.001) and more abdomino-perineal NSTIs (43.4% vs 18.8%, p < 0.001). Enterobacterales and non-fermenting gram-negative bacteria were the most frequently isolated microorganisms in neutropenic patients. In-hospital mortality was significantly higher in neutropenic than in non-neutropenic patients (57.9% vs 28.5%, p < 0.001). Granulocyte colony-stimulating factor (G-CSF) administration was associated with a lower risk of in-hospital mortality in univariable Cox (hazard ratio (HR) = 0.43 95% confidence interval (CI) [0.23-0.82], p = 0.010) and multivariable Cox (adjusted HR = 0.46 95% CI [0.22-0.94], p = 0.033) analyses and after overlap propensity score weighting (odds ratio = 0.25 95% CI [0.09; 0.68], p = 0.006)., Conclusions: Critically ill neutropenic patients with NSTIs present different clinical and microbiological characteristics and are associated with a higher hospital mortality than non-neutropenic patients. G-CSF administration was associated with hospital survival., (© 2023. The Author(s).)

Introduction: Due to its bacteriological spectrum and efficacy in skin and soft tissue infections, ceftobiprole may be of interest for extracorporeal membrane oxygenation (ECMO) cannula-related infection. It is unknown whether ceftobiprole pharmacokinetics (PK) are changed by ECMO., Methods: A retrospective monocentric cohort study was performed of 35 patients with suspected ECMO-related cannula infections (28 on ECMO, seven after ECMO removal), who received ceftobiprole as empiric treatment and had ceftobiprole blood levels measured at trough, peak and CT50 (50% of the dosing interval). Ceftobiprole blood levels of the 28 patients on ECMO were compared with those of the seven patients without ECMO. Factors associated with low ceftobiprole trough levels were also explored., Results: Among the 35 patients included, 29 had a confirmed cannula-related infection and 48 pathogens were isolated. Ceftobiprole MIC was determined in 29 of these 48, and 23 (79%) were susceptible to ceftobiprole. Ceftobiprole blood levels (at trough, peak and CT50) were similar in ECMO and non-ECMO patients. Moreover, in patients whose pathogens responsible for infection were susceptible to ceftobiprole, 94% had a ceftobiprole trough level above the MIC. Ceftobiprole blood levels were decreased in patients with acute renal failure requiring renal replacement therapy (RRT) and in those with increased renal clearance (defined as creatinine clearance > 130 mL/min), independent of ECMO. No other factor was associated with modification of ceftobiprole PK/pharmacodynamics (PK/PD)., Conclusions: The ceftobiprole PK/PD was no different in patients during ECMO or after its withdrawal. Factors associated with decreased ceftobiprole blood levels were patients requiring RRT and those with increased renal clearance., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Purpose: Although eosinophil-induced manifestations can be life-threatening, studies focusing on the epidemiology and clinical manifestations of eosinophilia in the intensive care unit (ICU) are lacking., Methods: A retrospective, national, multicenter (14 centers) cohort study over 6 years of adult patients who presented with eosinophilia ≥ 1 × 10 9 /L on two blood samples performed from the day before admission to the last day of an ICU stay., Results: 620 patients (0.9% of all ICU hospitalizations) were included: 40% with early eosinophilia (within the first 24 h of ICU admission, ICU-Eo1 group) and 56% with delayed (> 24 h after ICU admission, ICU-Eo2 group) eosinophilia. In ICU-Eo1, eosinophilia was mostly due to respiratory (14.9%) and hematological (25.8%) conditions, frequently symptomatic (58.1%, mainly respiratory and cardiovascular manifestations) requiring systemic corticosteroids in 32.2% of cases. In ICU-Eo2, eosinophil-related organ involvement was rare (25%), and eosinophilia was mostly drug-induced (46.8%). Survival rates at day 60 (D60) after ICU admission were 21.4% and 17.2% (p = 0.219) in ICU-Eo1 and ICU-Eo2 patients, respectively. For ICU-Eo1 patients, in multivariate analysis, risk factors for death at D60 were current immunosuppressant therapy at ICU admission, eosinophilia of onco-hematological origin and the use of vasopressors at ICU admission, whereas older age and the use of vasopressors or mechanical ventilation at the onset of eosinophilia were associated with a poorer prognosis for ICU-Eo2 patients., Conclusion: Eosinophilia ≥ 1 × 10 9 /L is not uncommon in the ICU. According to the timing of eosinophilia, two subsets of patients requiring different etiological workups and management can be distinguished., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Long-term outcomes of patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome treated with extracorporeal membrane oxygenation (ECMO) are unknown. Objectives: To assess physical examination, pulmonary function tests, anxiety, depression, post-traumatic stress disorder and quality of life at 6 and 12 months after ECMO onset. Methods: Multicenter, prospective study in patients who received ECMO for COVID-19 acute respiratory distress syndrome from March to June 2020 and survived hospital discharge. Measurements and Main Results: Of 80 eligible patients, 62 were enrolled in seven French ICUs. ECMO and invasive mechanical ventilation duration were 18 (11-25) and 36 (27-62) days, respectively. All were alive, but only 19/50 (38%) returned to work and 13/42 (31%) had recovered a normal sex drive at 1 year. Pulmonary function tests were almost normal at 6 months, except for Dl CO , which was still impaired at 12 months. Mental health, role-emotional, and role-physical were the most impaired domain compared with patients receiving ECMO who did not have COVID-19. One year after ICU admission, 19/43 (44%) patients had significant anxiety, 18/43 (42%) had depression symptoms, and 21/50 (42%) were at risk for post-traumatic stress disorders. Conclusions: Despite the partial recovery of the lung function tests at 1 year, the physical and psychological function of this population remains impaired. Based on the comparison with long-term follow-up of patients receiving ECMO who did not have COVID-19, poor mental and physical health may be more related to COVID-19 than to ECMO in itself, although this needs confirmation.

Aims: Antiphospholipid syndrome (APS) is a rare autoimmune disease defined by thrombotic events occurring in patients with persistent antiphospholipid antibodies. Cardiac manifestations in critically-ill APS patients are poorly investigated. We conducted a study to assess the prevalence, the characteristics and the prognosis of cardiac manifestations in thrombotic APS patients admitted to intensive care unit (ICU)., Methods and Results: A French, national, multicentre, retrospective study, conducted, from January 2000 to September 2018, including all APS patients admitted to 24 participating centres' ICUs with any new thrombotic (arterial, venous or microvascular) manifestation. Cardiac manifestations were defined as any new cardiac abnormalities relying on clinical examination, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and coronarography. One hundred and thirty-six patients (female 72%) were included. Mean age at ICU admission was 46 ± 15years. Cardiac manifestations were present in 71 patients (53%). In patients with cardiac involvement, median left ventricular ejection fraction (LVEF) was 40% [28-55], troponin was elevated in 93% patients, coronary angiogram (n = 19, 27%) disclosing a coronary obstruction in 21%. CMR (n = 21) was abnormal in all cases, with late gadolinium enhancement in 62% of cases. Cardiac manifestations were associated with a non-significant increase of mortality (32% vs. 19%, p = 0.08). After 1-year follow-up, median LVEF was 57% [44-60] in patients with cardiac involvement., Conclusion: Cardiac involvement is frequent in critically-ill thrombotic APS patients and may be associated to more severe outcome. Increased awareness on this rare cause of myocardial infarction with or without obstructive coronary artery is urgently needed., Competing Interests: Declaration of competing interest MK has received research grant from Federation Francaise de Cardiologie and French Heath Ministry, consulting fees from Sanofi, Bayer, Kiniksa and Eligo. MPdC has received a research grant from Octapharma, Federation Française de Cardiologie and Société Française de Médecine Interne, lecture fee from Sanofi and LFB., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown., Objective: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS., Methods: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy-associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal., Results: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W- group). Cumulative probabilities of 10-year survival in W+ versus W- groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W- groups were 72% versus 58% (P = 0.3) and 2.5 (0.3-4) versus 1 (0-2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model., Conclusions: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The United States spends more for intensive care units (ICUs) than do other high-income countries. We used time-driven activity-based costing (TDABC) to analyze ICU costs for initiation of veno-venous extracorporeal membrane oxygenation (VV ECMO) for respiratory failure to estimate how much of the higher ICU costs at 1 US site can be attributed to the higher prices paid to ICU personnel, and how much is caused by the US site's use of a higher cost staffing model. We accompanied our TDABC approach with narrative review of the ECMO programs, at Cedars-Sinai (Los Angeles), Hôpital Pitié-Salpêtrière (Paris), and The Alfred Hospital (Melbourne) from 2017 to 2019. Our primary outcome was daily ECMO cost, and we hypothesized that cost differences among the hospitals could be explained by the efficiencies and skill mix of involved clinicians and prices paid for personnel, equipment, and consumables. Our results are presented relative to Los Angeles' total personnel cost per VV ECMO patient day, indexed at 100. Los Angeles' total indexed daily cost of care was 147 (personnel: 100, durables: 5, and disposables: 42). Paris' total cost was 39 (26% of Los Angeles) (personnel: 12, durables: 1, and disposables: 26). Melbourne's total cost was 53 (36% of Los Angeles) (personnel: 32, durables: 2, and disposables: 19) (rounded). The higher personnel prices at Los Angeles explained only 26% of its much higher personnel costs than Paris, and 21% relative to Melbourne. Los Angeles' higher staffing levels accounted for 49% (36%), and its costlier mix of personnel accounted for 12% (10%) of its higher personnel costs relative to Paris (Melbourne). Unadjusted discharge rates for ECMO patients were 46% in Los Angeles (46%), 56% in Paris, and 52% in Melbourne. We found that personnel salaries explained only 30% of the higher personnel costs at 1 Los Angeles hospital. Most of the cost differential was caused by personnel staffing intensity and mix. This study demonstrates how TDABC may be used in ICU administration to quantify the savings that 1 US hospital could achieve by delivering the same quality of care with fewer and less-costly mix of clinicians compared to a French and Australian site. Narrative reviews contextualized how the care models evolved at each site and helped identify potential barriers to change., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Background: Lung reactivations of Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) have been reported in COVID-19 patients. Whether or not those viral reactivations are more frequent than in other patients is not known., Methods: Retrospective monocentric cohort study of 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation and who were tested for HSV and CMV in bronchoalveolar lavage performed during fiberoptic bronchoscopy for ventilator-associated pneumonia suspicion. Rates of HSV and CMV lung reactivations, and HSV bronchopneumonitis were assessed and compared with an historical cohort of 89 patients with severe influenza pneumonia requiring invasive mechanical ventilation., Results: Among the 145 COVID-19 patients included, 50% and 42% had HSV and CMV lung reactivations, respectively, whereas among the 89 influenza patients, 63% and 28% had HSV and CMV lung reactivations, respectively. Cumulative incidence of HSV lung reactivation (taking into account extubation and death as competing events) was higher in influenza than in COVID-19 patients (p = 0.03), whereas the rate of HSV bronchopneumonitis was similar in both groups (31% and 25%, respectively). Cumulative incidence of CMV lung reactivation (taking into account extubation and death as competing events) was similar in COVID-19 and influenza patients (p = 0.07). Outcomes of patients with HSV or CMV lung reactivations were similar to that of patients without, whatever the underlying conditions, i.e., in COVID-19 patients, in influenza patients, or when all patients were grouped., Conclusions: HSV and CMV lung reactivations are frequent in COVID-19 patients, but not more frequent than in patients with influenza-associated severe pneumonia, despite a higher severity of illness at intensive care unit admission of the latter and a longer duration of mechanical ventilation of the former. Although no impact on outcome of HSV and CMV lung reactivations was detected, the effect of antiviral treatment against these Herpesviridae remains to be determined in these patients., (© 2022. The Author(s).)

Objectives: Systemic rheumatic diseases (SRDs) are a group of inflammatory disorders that can need intensive care unit (ICU) admission during a flare-up, requiring administration of immunosuppressants. We undertook this study to determine the frequency, outcome, and occurrence associated factors of infections in flare-up SRD patients receiving immunosuppressant., Methods: Monocenter, a retrospective study including SRD patients admitted to ICU for a flare-up requiring immunosuppressant from 2004 to 2019. The primary endpoint was in-ICU-acquired infections., Results: Ninety-eight patients (female/male ratio: 1.6; mean age at admission: 39.5 ± 17.4 years) were admitted to the ICU for a SRD flare-up, inaugural in 61.2% cases. A specific treatment was given to every patient: corticosteroids 100%, cyclophosphamide 45.9%, plasma exchange 46.9%. Ninety-five infections occurred in 35 (36%) patients mainly pneumonias. The overall in-hospital mortality was 17.3%, and 46% of patients with a nosocomial infection died during their ICU stay. The logistic regression multivariable model retained renal replacement therapy and mechanical ventilation as independent predictors of infection., Conclusion: In-ICU-acquired infection in SRD flare-up is a frequent event associated with organ failures but not with in-ICU use of immunosuppressants. These data suggest that the fear of infection should not withhold a careful in-ICU use of immunosuppressive drugs. Key Points • In-ICU infections are frequent in flare-up systemic rheumatic disease patients. • Infections are associated with increased mortality. • Cyclophosphamide given in ICU was not independently associated with infection. • Severe neutropenia occurred in 27% of patients receiving cyclophosphamide in ICU., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19-related myocarditis., Objectives: This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19-related myocarditis fulfilling MIS-A criteria (MIS-A + ) or not (MIS-A - )., Methods: A monocentric retrospective analysis of consecutive fulminant COVID-19-related myocarditis in a 26-bed intensive care unit (ICU)., Results: Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19-related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%. In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A - patients compared with MIS-A + patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A - patients (31% vs 4%). MIS-A + had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A - had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A - patients (54%) but in none of the MIS-A + patients., Conclusion: MIS-A + and MIS-A - fulminant COVID-19-related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients' management and further understanding of their pathophysiology., Competing Interests: Funding Support and Author Disclosures This study was supported by the Fondation de France, ‘‘Tous unis contre le virus’’ framework Alliance (Fondation de France, AP-HP, Institut Pasteur) in collaboration with Agence Nationale de la Recherche (ANR Flash COVID19 program), by the SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University ICOViD programs, by the Programme Hospitalier de Recherche Clinique PHRC-20-0375 COVID-19 (principal investigator D Gorochov). The authors declare that a patent application has been filed on these results. Dr Pineton de Chambrun was supported for this study by a grant from la Société Française Nationale de Médecine Interne (SNFMI-2021). Dr Pineton de Chambrun has received a research grant from Octapharma; and has received lecture fees from Sanofi. Dr Kerneis has received research grants from the Fédération Française de Cardiologie, French Ministry of Health; and has received consulting fees from Bayer, Sanofi, and Kiniksa. Dr Montalescot has received research grants from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, Merck Sharp and Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi. Dr Combes has received grants and personal fees from Maquet, Xenios, and Baxter outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia., Methods: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28., Results: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups., Conclusion: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context., Design: Monocenter, retrospective, observational cohort study., Setting: A French tertiary center., Patients: All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients., Interventions: None., Measurements and Main Results: Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04)., Conclusions: Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted., Competing Interests: Dr. Weiss received funding from MedDay Pharmaceuticals. Dr. Boch disclosed government work. Dr. Idbaih’s institution received funding from Sanofi, Nutritheragène, Air Liquide, Carthera, and Transgene Research; he received funding from Novocure and Leo Pharma. Dr. Demoule’s institution received funding from Fisher & Paykel and the French Ministry of Health; he received funding from Fisher & Paykel, Philips, Baxter, the French Ministry of Health, Getinge, Respinor, Lungpacer, Lowenstein, and Gilead. Dr. Demeret received funding from Laboratoire Français du fractionnement et des biotechnologies and Union Chimique Belge. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Amniotic fluid embolism (AFE) is a rare but often catastrophic complication of pregnancy that leads to cardiopulmonary dysfunction and severe disseminated intravascular coagulopathy (DIC). Although few case reports have reported successful use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) with AFE, concerns can be raised about the increased bleeding risks with that device., Methods: This study included patients with AFE rescued by VA-ECMO hospitalized in two high ECMO volume centers between August 2008 and February 2021. Clinical characteristics, critical care management, in-intensive care unit (ICU) complications, and hospital outcomes were collected. ICU survivors were assessed for health-related quality of life (HRQL) in May 2021., Results: During that 13-year study period, VA-ECMO was initiated in 54 parturient women in two high ECMO volume centers. Among that population, 10 patients with AFE [median (range) age 33 (24-40), SAPS II at 69 (56-81)] who fulfilled our diagnosis criteria were treated with VA-ECMO. Pregnancy evolved for 36 (30-41) weeks. Seven patients had a cardiac arrest before ECMO and two were cannulated under cardiopulmonary resuscitation. Pre-ECMO hemodynamic was severely impaired with an inotrope score at 370 (55-1530) μg/kg/min, a severe left ventricular ejection fraction measured at 14 (0-40)%, and lactate at 12 (2-30) mmol/L. 70% of these patients were alive at hospital discharge despite an extreme pre-ECMO severity and massive blood product transfusion. However, HRQL was lower than age-matched controls and still profoundly impaired in the role-physical, bodily pain, and general health components after a median of 44 months follow-up., Conclusion: In this rare per-delivery complication, our results support the use of VA-ECMO despite intense DIC and ongoing bleeding. Future studies should focus on customized, patient-centered, rehabilitation programs that could lead to improved HRQL in this population., (© 2022. The Author(s).)

Objectives: The impact of bronchoalveolar lavage on regional ventilation in mechanically ventilated patients with acute respiratory distress syndrome has rarely been described. Our objectives were use electrical impedance tomography to describe lung impedance variation post bronchoalveolar lavage and identify morphologic patterns according to respiratory failure severity., Design: Monocenter physiologic study on mechanically ventilated patients., Setting: University medical ICU., Interventions: After a recruitment maneuver, tidal impedance variation distributions (a surrogate for impact of bronchoalveolar lavage on tidal volume distribution), end-expiratory lung impedance (correlated with end-expiratory lung volume and used to quantify postbronchoalveolar lavage derecruitment), respiratory mechanics, and blood gases were recorded before and over 6 hours post bronchoalveolar lavage with Pao2 to the Fio2 ratio. Patients were grouped according to their prebronchoalveolar lavage, that is, Pao2 to the Fio2 ratio less than 200 or greater than or equal to 200., Results: Twenty-one patients (median [interquartile range] age 55 yr [50-58 yr]; 13 males), 13 with Pao2 to the Fio2 ratio less than 200, were included. Unlike that latter group, bronchoalveolar lavage significantly impacted tidal impedance variation distribution in patients with Pao2 to the Fio2 ratio greater than or equal to 200, with a ventilation shift to the contralateral lung (from 54% to 42% in the bronchoalveolar lavage side), which persisted up to 6 hours post bronchoalveolar lavage. Similarly, end-expiratory lung impedance was less distributed in the bronchoalveolar lavage side post procedure of patients with Pao2 to the Fio2 ratio greater than or equal to 200, but the difference did not reach statistical significance (p = 0.09). As reported for tidal impedance variation, end-expiratory lung impedance distribution in patients with severe or moderate acute respiratory distress syndrome did not change significantly during the 6 hours post bronchoalveolar lavage. Although bronchoalveolar lavage effects on gas exchanges were minor in all patients, static compliance in patients with Pao2 to the Fio2 ratio greater than or equal to 200 was significantly lower post bronchoalveolar lavage (p = 0.04)., Conclusions: The negative impact of bronchoalveolar lavage on regional ventilation, which persisted at least 6 hours, appeared to be more profound in patients with normal lung function or mild acute respiratory distress syndrome. In contrast, regional ventilation, lung recruitment, respiratory mechanics, and gas exchanges were modestly impacted by the bronchoalveolar lavage in patients with severe or moderate acute respiratory distress syndrome. That finding is reassuring and supports not summarily proscribing bronchoalveolar lavage for the most severely ill with acute respiratory distress syndrome., Competing Interests: Dr. Luyt received funding from Bayer Healthcare, Merck, and ThermoFisher Brahms, Biomerieux, Carmat, and Correvio. Dr. Combes received lecture fees from Getinge and Baxter. Dr. Schmidt received lecture fees from Getinge, Dräger, and Xenios. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Postoperative mediastinitis, a feared complication after cardiac surgery, is associated with high mortality, especially of critically ill patients. Candida species infections are rare and severe, with poorly known outcomes. We conducted a case-control study to describe the characteristics, management and outcomes of patients with postoperative Candida mediastinitis., Methods: This French, monocentre, retrospective study included all patients with postoperative Candida mediastinitis (January 2003-February 2020) requiring intensive care unit admission. Candida mediastinitis patients (henceforth cases) were matched 1:1 with postoperative bacterial mediastinitis (henceforth control), based on 3 factors during mediastinitis management: age >40 years, cardiac transplantation and invasive circulatory device used. The primary end point was the probability of survival within 1 year after intensive care unit (ICU) admission., Results: Forty cases were matched to 40 controls. The global male/female ratio was 2.1, with mean age at admission 47.9 ± 13.8 years. Candida species were: 67.5% albicans, 17.5% glabrata, 15% parapsilosis, 5.0% tropicalis, 2.5% krusei and 2.5% lusitaniae. The median duration of mechanical ventilation was 23, 68.8% of patients received renal replacement therapy and 62.5% extracorporeal membrane oxygenation support. The probability of survival within the first year after ICU admission was 40 ± 5.5% and was significantly lower for cases than for controls (43 ± 8% vs 80 ± 6.3%, respectively; Log-rank test: P < 0.0001). The multivariable Cox proportional hazards model retained only renal replacement therapy [hazard ratio (HR) 3.7, 95% confidence interval (CI) 1.1-13.1; P = 0.04] and Candida mediastinitis (HR 2.4, 95% CI 1.1-5.6; P = 0.04) as independently associated with 1-year mortality., Conclusions: Candida mediastinitis is a serious event after cardiac surgery and independently associated with 1-year mortality. Further studies are needed to determine whether deaths are directly attributable to Candida mediastinitis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To determine the characteristics and outcomes of patients prone-positioned during extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and lung CT pattern associated with improved respiratory system static compliance after that intervention., Design: Retrospective, single-center study over 8 years., Settings: Twenty-six bed ICU in a tertiary center., Measurements and Main Results: A propensity score-matched analysis compared patients with prone-positioning during extracorporeal membrane oxygenation and those without. An increase of the static compliance greater than or equal to 3 mL/cm H2O after 16 hours of prone-positioning defined prone-positioning responders. The primary outcome was the time to successful extracorporeal membrane oxygenation weaning within 90 days of postextracorporeal membrane oxygenation start, with death as a competing risk. Among 298 venovenous extracorporeal membrane oxygenation-treated adults with severe acute respiratory distress syndrome, 64 were prone-positioning extracorporeal membrane oxygenation. Although both propensity score-matched groups had similar extracorporeal membrane oxygenation durations, prone-positioning extracorporeal membrane oxygenation patients' 90-day probability of being weaned-off extracorporeal membrane oxygenation and alive was higher (0.75 vs 0.54, p = 0.03; subdistribution hazard ratio [95% CI], 1.54 [1.05-2.58]) and 90-day mortality was lower (20% vs 42%, p < 0.01) than that for no prone-positioning extracorporeal membrane oxygenation patients. Extracorporeal membrane oxygenation-related complications were comparable for the two groups. Patients without improved static compliance had higher percentages of nonaerated or poorly aerated ventral and medial-ventral lung regions (p = 0.047)., Conclusions: Prone-positioning during venovenous extracorporeal membrane oxygenation was safe and effective and was associated with a higher probability of surviving and being weaned-off extracorporeal membrane oxygenation at 90 days. Patients with greater normally aerated lung tissue in the ventral and medial-ventral regions on quantitative lung CT-scan performed before prone-positioning are more likely to improve their static compliance after that procedure during extracorporeal membrane oxygenation., Competing Interests: Dr. Combes received grants from Getinge and personal fees from Getinge, Baxter, and Xenios outside the submitted work. Dr. Schmidt received personal fees from Getinge, Drager, 3M, and Xenios, outside the submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35-56) years, with a median body mass index of 30 (27-35) kg/m 2 , and a Sepsis-related Organ Failure Assessment score of 12 (8-16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin-antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p  < 0.01) and fibrin formation markers (fibrin monomers, p  < 0.001) significantly increased, further resulting in significant decreases in platelet count ( p  < 0.0001) and fibrinogen level ( p  < 0.001). PAI-1 levels significantly decreased from baseline to day 7 ( p  < 0.0001) in all ARDS patients. These changes were more marked in COVID-19 patients, resulting in 14 nonfatal and 3 fatal bleeding. Additional studies are warranted to determine whether monitoring of thrombin generation and fibrinolysis markers might help to early predict bleeding complications in COVID-19 patients supported by ECMO., Competing Interests: None declared., (Thieme. All rights reserved.)