Venoarterial extracorporeal membrane oxygenation in immunocompromised patients with cardiogenic shock: a cohort study and propensity-weighted analysis.

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.

Upper gastrointestinal bleeding in adults treated with veno-arterial extracorporeal membrane oxygenation: a cohort study.

OBJECTIVES: Upper gastrointestinal bleeding (UGIB) is a common complication in adults treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for refractory cardiogenic shock or cardiac arrest. We aimed to determine risk factors, prevalence and outcomes associated with VA-ECMO-associated UGIB in adult patients. METHODS: We conducted a retrospective cohort study (2014-2022) on consecutive VA-ECMO patients in the medical and infectious disease intensive care unit of Bichat-Claude Bernard University Hospital, Paris, France. UGIB was defined as (i) an overt bleeding (haematemesis, melena, haematochezia) or (ii) acute anaemia associated with a lesion diagnosed on upper gastrointestinal endoscopy. VA-ECMO-associated UGIB was defined as an UGIB occurring during VA-ECMO, or up to 10 days after decannulation in patients weaned off extracorporeal membrane oxygenation (ECMO). Cause-specific models were used to identify factors associated with UGIB and death, respectively. RESULTS: Among the 455 patients included, 48 (10%) were diagnosed with UGIB after a median of 12 [7; 23] days following ECMO cannulation. Mortality occurred in 36 (75%) patients with UGIB and 243 (60%) patients without. UGIB patients had longer intensive care unit stays (32 [19; 60] vs 18 [7; 37] days; P < 0.01), longer ECMO (14 [9; 18] vs 7 [4; 11] days; P < 0.01) and mechanical ventilation durations (21 [16; 36] vs 10 [5; 20] days; P < 0.01), as compared to non-UGIB patients. Ninety upper gastrointestinal endoscopies were performed, and the most frequent lesions detected were gastro-duodenal ulcers (n = 23, 26%), leading to 11/90 therapeutic procedures. By multivariable analysis, a history of peptic ulcer [cause-specific hazard ratio (CSHR) 2.93, 95% confidence interval (CI) [1.01; 8.51]], a dual antiplatelet therapy (CSHR 2.0, 95% CI [1.07; 3.72]) and extracorporeal cardiopulmonary resuscitation (CSHR 2.78, 95% CI [1.42; 5.45]) were independently associated with an increased risk of UGIB. CONCLUSIONS: In adult patients under VA-ECMO, a history of gastric ulcer, dual antiplatelet therapy and extracorporeal cardiopulmonary resuscitation were independently associated with an increased risk of UGIB. This study highlights the potential role of acute ischaemia-reperfusion injury in the pathophysiology of VA-ECMO-associated UGIB.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience.

While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., (i) the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; (ii) the importance of developing translational research from which therapeutic innovations can emerge; (iii) the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research.

Simplified frontal EEG in adults under veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: EEG-based prognostication studies in intensive care units often rely on a standard 21-electrode montage (stdEEG) requiring substantial human, technical, and financial resources. We here evaluate whether a simplified 4-frontal electrode montage (4-frontEEG) can detect EEG patterns associated with poor outcomes in adult patients under veno-arterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: We conducted a reanalysis of EEG data from a prospective cohort on 118 adult patients under VA-ECMO, in whom EEG was performed on admission to intensive care. EEG patterns of interest included background rhythm, discontinuity, reactivity, and the Synek's score. They were all reassessed by an intensivist on a 4-frontEEG montage, whose analysis was then compared to an expert's interpretation made on stdEEG recordings. The main outcome measure was the degree of correlation between 4-frontEEG and stdEEG montages to identify EEG patterns of interest. The performance of the Synek scores calculated on 4-frontEEG and stdEEG montage to predict outcomes (i.e., 28-day mortality and 90-day Rankin score [Formula: see text]) was investigated in a secondary exploratory analysis. RESULTS: The detection of EEG patterns using 4-frontEEG was statistically similar to that of stdEEG for background rhythm (Spearman rank test, ρ = 0.66, p < 0.001), discontinuity (Cohen's kappa, [Formula: see text] = 0.955), reactivity ([Formula: see text] = 0.739) and the Synek's score (ρ = 0.794, p < 0.001). Using the Synek classification, we found similar performances between 4-frontEEG and stdEEG montages in predicting 28-day mortality (AUC 4-frontEEG 0.71, AUC stdEEG 0.68) and for 90-day poor neurologic outcome (AUC 4-frontEEG 0.71, AUC stdEEG 0.66). An exploratory analysis confirmed that the Synek scores determined by 4 or 21 electrodes were independently associated with 28-day mortality and poor 90-day functional outcome. CONCLUSION: In adult patients under VA-ECMO, a simplified 4-frontal electrode EEG montage interpreted by an intensivist, detected common EEG patterns associated with poor outcomes, with a performance similar to that of a standard EEG montage interpreted by expert neurophysiologists. This simplified montage could be implemented as part of a multimodal evaluation for bedside prognostication.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Neuron-Specific Enolase Levels in Adults Under Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: We aimed to determine if elevations in serum neuron-specific enolase are associated with brain injury and outcomes in adults who require venoarterial extracorporeal membrane oxygenation. DESIGN: Prospective observational study. SETTING: Two ICUs of a university hospital, Paris, France. PATIENTS: Consecutive adult patients treated with venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock or in-hospital refractory cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum sampled 1, 3, and 7 days after venoarterial extracorporeal membrane oxygenation cannulation was stored at -80°C and neuron-specific enolase concentrations were measured in batches at the end of the study. The association between neuron-specific enolase concentrations and outcomes (28-d mortality and poor outcome, defined by a score of 4-6 on the modified Rankin scale at 90 d) were explored by multivariable logistic regression, with neuron-specific enolase concentrations dichotomized according to median values. One-hundred three patients were included, of whom 26 (25%) received preextracorporeal membrane oxygenation cardiopulmonary resuscitation. Median (interquartile range) day-1, day-3, and day-7 neuron-specific enolase serum concentrations were 37 µg/L (26-51 µg/L), 25 µg/L (19-37) µg/L, and 22 µg/L (17-31 µg/L). After adjustment for Simplified Acute Physiology Score II, preextracorporeal membrane oxygenation cardiopulmonary resuscitation, and Sepsis Organ Failure Assessment score at time of cannulation, a day-3 neuron-specific enolase greater than 25 µg/L remained independently associated with 28-day mortality (adjusted odds ratio, 4.98; 95% CI, 1.86-13.32) and poor outcome at 90 days (adjusted odds ratio, 4.63; 95% CI, 1.81-11.84). A day-3 neuron-specific enolase threshold greater than 80 µg/L had a 100% specificity for prediction of both mortality (95% CI, 92-100%) and poor functional outcome (95% CI, 89-100%). In a subset of patients who underwent brain CT, neuron-specific enolase concentrations were significantly higher in patients diagnosed with stroke, as compared with those without stroke. CONCLUSIONS: In adult patients under venoarterial extracorporeal membrane oxygenation, day-3 serum neuron-specific enolase concentrations are independently associated with short-term mortality and poor functional outcomes. These findings deserve validation in a multicenter setting.

Early EEG for Prognostication Under Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND/OBJECTIVES: Tools for prognostication of neurologic outcome of adult patients under venoarterial ECMO (VA-ECMO) have not been thoroughly investigated. We aimed to determine whether early standard electroencephalography (stdEEG) can be used for prognostication in adults under VA-ECMO. METHODS: Prospective single-center observational study conducted in two intensive care units of a university hospital, Paris, France. Early stdEEG was performed on consecutive adult patients treated with VA-ECMO for refractory cardiogenic shock or refractory cardiac arrest. The association between stdEEG findings and unfavorable outcome was investigated. The primary endpoint was 28-day mortality. The secondary endpoint was severe disability or death at 90 days, defined by a score of 4-6 on the modified Rankin scale. RESULTS: A total of 122 patients were included, of whom 35 (29%) received cardiopulmonary resuscitation before VA-ECMO cannulation. Main stdEEG findings included low background frequency ≤ 4 Hz (n = 27, 22%) and background abnormalities, i.e., a discontinuous (n = 20, 17%) and/or an unreactive background (n = 12, 10%). Background abnormalities displayed better performances for prediction of unfavorable outcomes, as compared to clinical parameters at time of recording. An unreactive stdEEG background in combination with a background frequency ≤ 4 Hz had a false positive rate of 0% for prediction of unfavorable outcome at 28 days and 90 days, with sensitivities of 8% and 6%, respectively. After adjustment for confounders, a lower background frequency was independently associated with unfavorable outcome at 28 days (adjusted odds ratio per 1-Hz increment, 95% CI 0.71, 0.52-0.97), whereas no such independent association was observed at 90 days. CONCLUSION: Standard EEG abnormalities recorded at time of VA-ECMO initiation are predictive of unfavorable outcomes. However, the low sensitivity of these parameters highlights the need for a multimodal evaluation for improving management of care and prognostication.

Factors associated with major adverse kidney events in patients who underwent veno-arterial extracorporeal membrane oxygenation.

OBJECTIVE: To describe acute kidney injury (AKI) natural history and to identify predictors of major adverse kidney events (MAKE) within 1 year in patients supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO). DESIGN: Retrospective observational study. SETTING: Medical French intensive care unit between January 2014 and December 2016. PATIENTS: Consecutive patients implanted with VA-ECMO ≥ 16 years, VA-ECMO for at least ≥ 48 h, and without end-stage chronic kidney disease (CKD). INTERVENTION: None. MEASUREMENTS: Multivariate logistic regression of factors associated with MAKE at 1 year defined as one of the following criteria within day 360: death and receipt of renal replacement therapy (RRT) or persistent renal dysfunction, i.e., CKD ≥ stage 3 corresponding to an estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73 m2 and MAKE at day 30 and day 90 defined as one of the following criteria within day 30 or day 90: death, receipt of renal replacement therapy and serum creatinine ≥ threefold increase. MAIN RESULTS: 158 consecutive patients were included (male sex: 75.9%; median and interquartile range: age: 59 [47-66], Simplified Acute Physiology Score II: 55 [39-66], Sepsis-related Organ Failure Assessment Score: 9 [7-12], time on VA-ECMO: 7.5 [4-12] days). Among them 145 (91.8%) developed an AKI during the intensive care unit (ICU) stay and 85 (53.8%) needed renal replacement therapy (RRT). 59.9% (91/152), 60.5% (89/147) and 85.1% (120/141) evaluable patients had a MAKE-30, MAKE-90 and MAKE-360, respectively. Factors significantly associated with MAKE-360 were eGFR at baseline (odds ratio (OR) 0.98, confidence interval 95% (CI) [0.97;1.00], p 0.02), Kidney Disease Improving Global Outcome (KDIGO) stage at cannulation (p = 0.03), e.g., stage 3 vs. reference stage 0 OR 10.20 [1.77-58.87], and number of red blood cell (RBC) packs received while under ECMO (OR 1.14, CI 95% [1.01;1.28], p = 0.03). At 1 year among the 51 survivors, almost half of the alive patients (n = 20/51) had a decline of estimated glomerular filtration (eGFR) > 30% mL/min/1.73 m2. Their median eGFR decline was - 26.3% [- 46.6;- 10.7]. CONCLUSION: Patients undergoing VA-ECMO had a high risk of AKI during the ICU stay. Factors associated with MAKE 360 were mainly eGFR at baseline, KDIGO stage at cannulation and, number of RBC packs received while under ECMO. Among survivors at 1 year, almost half of the alive patients (n = 20/51) had a decline eGFR > 30%.

Six-Month Outcome of Immunocompromised Patients with Severe Acute Respiratory Distress Syndrome Rescued by Extracorporeal Membrane Oxygenation. An International Multicenter Retrospective Study.

Rationale: Because encouraging rates for hospital and long-term survival of immunocompromised patients in ICUs have been described, these patients are more likely to receive invasive therapies, like extracorporeal membrane oxygenation (ECMO).Objectives: To report outcomes of immunocompromised patients treated with ECMO for severe acute respiratory distress syndrome (ARDS) and to identify their pre-ECMO predictors of 6-month mortality and main ECMO-related complications.Methods: Retrospective multicenter study in 10 international ICUs with high volumes of ECMO cases. Immunocompromised patients, defined as having hematological malignancies, active solid tumor, solid-organ transplant, acquired immunodeficiency syndrome, or long-term or high-dose corticosteroid or immunosuppressant use, and severe ECMO-treated ARDS, from 2008 to 2015 were included.Measurements and Main Results: We collected demographics, clinical data, ECMO-related complications, and ICU- and 6 month-outcome data for 203 patients (median Acute Physiology and Chronic Health Evaluation II score, 28 [25th-75th percentile, 20-33]; age, 51 [38-59] yr; PaO2/FiO2, 60 [50-82] mm Hg before ECMO) who fulfilled our inclusion criteria. Six-month survival was only 30%, with a respective median ECMO duration and ICU stay of 8 (5-14) and 25 (16-50) days. Patients with hematological malignancies had significantly poorer outcomes than others (log-rank P = 0.02). ECMO-related major bleeding, cannula infection, and ventilator-associated pneumonia were frequent (36%, 10%, and 50%, respectively). Multivariate analyses retained fewer than 30 days between immunodeficiency diagnosis and ECMO cannulation as being associated with lower 6-month mortality (odds ratio, 0.32 [95% confidence interval, 0.16-0.66]; P = 0.002), and lower platelet count, higher Pco2, age, and driving pressure as independent pre-ECMO predictors of 6-month mortality.Conclusions: Recently diagnosed immunodeficiency is associated with a much better prognosis in ECMO-treated severe ARDS. However, low 6-month survival of our large cohort of immunocompromised patients supports restricting ECMO to patients with realistic oncological/therapeutic prognoses, acceptable functional status, and few pre-ECMO mortality-risk factors.