Isoproterenol Improves Hemodynamics And Right Ventricle-Pulmonary Artery Coupling After Heart Transplantation.

BACKGROUND: Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol 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. METHODS: We conducted a one-year retrospective observational study including patients receiving isoproterenol and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively at 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). RESULTS: From June 2022 to June 2023, 25 patients, median [IQR25-75] age 54 [38-61] years, were included. Before isoproterenol introduction, all patients received dobutamine and 15 (60%) were on veno-arterial extracorporeal membrane oxygenation. Isoproterenol significantly increased heart rate from 84 [77-99] (no-iso) to 91 [88-106] (low-iso) and 102 [90-122] bpm (high-iso, p<0.001). Similarly, cardiac index raised from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] l/min/m2 (p<0.001) with concomitant increase of indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m2, p<0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance tended to decrease from 2.9 (1.4-3.6) WU to 2.3 (1.3-3.5) WU, p=0.06. Right ventricular ejection fraction/systolic PAP evaluating RV-PA coupling increased after isoproterenol from 0.8 to 0.9 and 1 %.mmHg-1 (p=0.001). CONCLUSIONS: 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.

Recurrent ventilator-associated pneumonia in severe Covid-19 ARDS patients requiring ECMO support.

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.

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.

Increasing sweep gas flow reduces respiratory drive and dyspnea in non-intubated veno-arterial ECMO patients - a pilot study.

BACKGROUND.: Data on assessment and management of dyspnea in patients on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock are lacking. We hypothesized that increasing sweep gas flow through the VA-ECMO oxygenator may decrease dyspnea in non-intubated VA-ECMO patients exhibiting clinically significant dyspnea, with a parallel reduction in respiratory drive. METHODS.: Non-intubated, spontaneously breathing, supine patients on VA-ECMO for cardiogenic shock who presented with a visual analog dyspnea scale (dyspnea-VAS) ≥ 40/100 mm were included. Sweep gas flow was increased up to +6 L/min by three steps of +2 L/min each. Dyspnea was assessed with dyspnea-VAS and Multidimensional Dyspnea Profile. The respiratory drive was assessed by the electromyographic activity of the alae nasi and parasternal muscles. RESULTS.: We included 21 patients. On inclusion, median dyspnea-VAS was 50 ([interquartile range] 45-60) mm and sweep gas flow was 1.0 L/min (0.5-2.0). An increase in sweep gas flow significantly decreased dyspnea-VAS (50[45-60] at baseline vs 20[10-30] at 6L/min; p<0.001). The decrease in dyspnea was greater for the sensory component of dyspnea (-50%[43-75]) than for the affective and emotional components (-17%[0-25] and -12%[0-17], p<0.001). An increase in sweep gas flow significantly decreased electromyographic activity of the alae nasi and parasternal muscles (-23%[36-10] and -20[41-0], p<0.001). There was a significant correlation between the sweep gas flow and the dyspnea-VAS (r=-0.91 95%CI[-0.94, -0.87]), between the respiratory drive and the sensory component of dyspnea (r=0.29 95%CI[0.13, 0.44]), between the respiratory drive and the affective component of dyspnea (r=0.29 95%CI[0.02, 0.54]) and between the sweep gas flow and the alae nasi and parasternal (r=-0.31 95%CI[-0.44, -0.22] and r=-0.25 95%CI[-0.44, -0.16]). CONCLUSION.: In critically ill patients with VA-ECMO, an increase in sweep gas flow through the oxygenation membrane decreases dyspnea, possibly mediated by a decrease in respiratory drive.

Impact of COVID-19 on posttraumatic stress disorder in ICU survivors: a prospective observational comparative cohort study.

BACKGROUND: Posttraumatic stress disorder (PTSD) after a stay in the intensive care unit (ICU) can affect one in five ICU survivors. At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, admission to the ICU for COVID-19 was stressful due to the severity of this disease. This study assessed whether admission to the ICU for COVID-19 was associated with a higher prevalence of PTSD compared with other causes of ICU admission after adjustment for pre-ICU psychological factors. METHODS: This prospective observational comparative cohort study included 31 ICUs. Eligible patients were adult ICU survivors hospitalized during the first wave of COVID-19 pandemic in France, regardless of the reason for admission. The prevalence of presumptive diagnosis of PTSD at 6 months was assessed using the PTSD Checklist for DSM-5 (PCL-5). Sociodemographics, clinical data, history of childhood trauma (Childhood Trauma Questionnaire [CTQ]), and exposure to potentially traumatic events (Life Events Checklist for DSM-5 [LEC-5]) were assessed. RESULTS: Of the 778 ICU survivors included during the first wave of COVID-19 pandemic in France, 417 and 361 were assigned to the COVID-19 and non-COVID-19 cohorts, respectively. Fourteen (4.9%) and 11 (4.9%), respectively, presented with presumptive diagnosis of PTSD at 6 months (p = 0.976). After adjusting for age, sex, severity score at admission, use of invasive mechanical ventilation, ICU duration, CTQ and LEC-5, COVID-19 status was not associated with presumptive diagnosis of PTSD using the PCL-5. Only female sex was associated with presumptive diagnosis of PTSD. However, COVID-19 patients reported significantly more intrusion and avoidance symptoms than non-COVID patients (39% vs. 29%, p = 0.015 and 27% vs. 19%, p = 0.030), respectively. The median PCL-5 score was higher in the COVID-19 than non-COVID-19 cohort (9 [3, 20] vs. 4 [2, 16], p = 0.034). CONCLUSION: Admission to the ICU for COVID-19 was not associated with a higher prevalence of PTSD compared with admission for another cause during the first wave of the COVID-19 pandemic in France. However, intrusion and avoidance symptoms were more frequent in COVID-19 patients than in non-COVID-19 patients. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03991611, registered on June 19, 2019.

Bleeding complications, coagulation disorders, and their management in acute myocardial infarction-related cardiogenic shock rescued by veno-arterial ECMO: A retrospective cohort study.

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.

Ceftazidime/avibactam serum concentration in patients on ECMO.

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.

Early renal recovery after acute kidney injury in patients on venoarterial extracorporeal membrane oxygenation: A retrospective study.

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.

Diagnostic yield, safety and therapeutic consequences of myocardial biopsy in clinically suspected fulminant myocarditis unweanable from mechanical circulatory support.

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.

Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis.

BACKGROUND: Acute myocarditis is an inflammation of the myocardium that can cause life-threatening events. However, anti-inflammatory strategies did not reduce the risk of clinical outcomes in randomized trials. Recently, experimental studies have suggested that specific blockade of the interleukin-1ß immune innate pathway could be effective in acute myocarditis. AIM: To test the hypothesis that inhibition of the interleukin-1ß immune innate pathway can reduce the risk of clinical events in acute myocarditis. METHODS: The "Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis. Patients (n=120) are randomized within 72hours of hospital admission to receive a daily subcutaneous dose of anakinra 100mg or placebo during the hospitalization, in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker. The primary endpoint is the number of days alive free from any myocarditis complication, including ventricular arrhythmias, heart failure, recurrent chest pain requiring medication and ventricular dysfunction (defined as left ventricular ejection fraction<50%), from randomization to 28 days after hospital discharge. At 28 days after discharge, patients with normal left ventricular ejection fraction are then randomized to angiotensin-converting enzyme inhibitor continuation or discontinuation and all patients are followed for 1 year, with regular left ventricular function evaluation. CONCLUSIONS: ARAMIS is the first trial evaluating inhibition of the interleukin-1ß immune innate pathway in the setting of acute myocarditis. Although of small size, it will be the largest randomized trial in acute myocarditis, a serious and poorly studied cardiac condition.

Systemic lupus erythematosus-related acute lung disease.

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 stewardship in the ICU: time to shift into overdrive.

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.

Heart transplantation as salvage treatment of intractable infective endocarditis.

BACKGROUND: For infective endocarditis (IE) with extensive perivalvular lesions or end-stage cardiac failure, heart transplantation (HT) may be the last resort. METHODS: We retrospectively collected all cases of HT for IE within the International Collaboration on Endocarditis (ICE) network. RESULTS: Between 1991 and 2021, 20 patients (5 women, 15 men), median age 50 years [interquartile range, 29-61], underwent HT for IE in Spain (n = 9), France (n = 6), Switzerland (n = 2), Colombia, Croatia, and USA (n = 1). IE affected prosthetic (n = 10), and native valves (n = 10), primarily aortic (n = 11) and mitral (n = 6). The main pathogens were oral streptococci (n = 8), Staphylococcus aureus (n = 5), and Enterococcus faecalis (n = 2). The major complications included heart failure (n = 18), peri-annular abscess (n = 10), and prosthetic valve dehiscence (n = 4). Eighteen patients had previous cardiac surgery for this episode of IE, and four were on circulatory support before HT (left ventricular assist-device and extra-corporeal membrane oxygenation, 2 patients each). The median time interval between first symptoms of IE and HT was 44.5 days [22-91.5]. The main post-HT complication was acute rejection (n = 6). Seven patients died (35%), four during the first month post-HT. Thirteen (81%) of the 16 patients discharged from the hospital survived with a median follow-up of 35.5 months [4-96.5] after HT, and no relapse of IE. CONCLUSIONS: IE is not an absolute contraindication for HT: Our case series and the literature review support that HT may be considered as a salvage treatment in highly-selected patients with intractable IE.

Pharmacokinetics/pharmacodynamics of ceftobiprole in patients on extracorporeal membrane oxygenation.

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.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Impact of the 2018 French two-score allocation scheme on the profile of heart transplantation candidates and recipients: Insights from a high-volume centre.

BACKGROUND: In 2018, a new cardiac allograft allocation scheme, based on an individual scoring system, considering the risk of death both on the waiting list and after heart transplantation, was implemented in France. AIM: To assess the impact of this new scheme on the profile of transplantation candidates and recipients. METHODS: In this single-centre retrospective study, we included consecutive patients listed and/or transplanted between 01 January 2012 and 30 September 2021 at La Pitié-Salpêtrière Hospital. Baseline characteristics of patients were retrieved from the national CRISTAL registry and were compared according to the type of allocation scheme (before or after 2018). RESULTS: A total of 1098 newly listed transplantation candidates and 855 transplant recipients were included. One-year mortality rates after listing and after transplantation were 12.4% and 20%, respectively. At listing, the proportion of candidates on inotropes significantly declined following the scheme update (26.3 versus 20.9%; P=0.038), reflecting a change in medical practice. At transplantation, recipients had worse kidney function (estimated glomerular filtration rate<60mL/min/1.73 m2: old scheme, 29.7%; new scheme, 46.4%; P<0.001) and were more likely to be on extracorporeal membrane oxygenation support (33.5% versus 28.1%; P=0.080) under the new scheme, reflecting the prioritization of more severe patients. Outcomes after transplantation were not significantly influenced by the allocation system. CONCLUSIONS: The implementation of the 2018 French allocation scheme had a limited impact on the profile of transplantation candidates, but selected more severe patients for transplantation without significant impact on outcomes after transplantation.

Time course, factors related to, and prognostic impact of venoarterial extracorporeal membrane flow in cardiogenic shock.

AIMS: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory cardiogenic shock. However, there is a lack of evidence on how to set the 'optimal' flow. We aimed to describe the evolution of VA-ECMO flows in a cardiogenic shock population and determine the risk factors of 'high-ECMO flow'. METHODS AND RESULTS: A 7 year database of patients supported with VA-ECMO was used. Based on the median flow during the first 48 h of the VA-ECMO run, patients were classified as 'high-flow' or 'low-flow', respectively, when median ECMO flow was ≥3.6 or <3.6 L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60 day mortality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population included 209 patients on VA-ECMO, median age was 51 (40-59) years, and 78% were males. The most frequent aetiology leading to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as 'high-flow'. This group had a higher rate of ischaemic aetiology (16% vs. 30%, P = 0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology Score II score [40 (26-58) vs. 56 (42-74), P < 0.001], higher lactate [3.6 (2.2-5.8) mmol/L vs. 5.2 (3-9.7) mmol/L, P < 0.001], and higher aspartate aminotransferase [97 (41-375) U/L vs. 309 (85-939) U/L, P < 0.001], among others. The 'low-flow' group had less ventilator-associated pneumonia (40% vs. 59%, P = 0.007) and less days on mechanical ventilation [4 (1.5-7.5) vs. 6 (3-12) days, P = 0.009]. No differences were found in lengths of stay or survival according to the ECMO flow. The multivariate analysis showed that risk factors independently associated with 'high-flow' were mechanical ventilation at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1-7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0-1.2). CONCLUSIONS: In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with patients with lower flows.