Etienne Gayat

Introduction: Sepsis, the most severe manifestation of infection, remains both common and life-threatening. Beyond the acute phase, growing evidence highlights that sepsis survivors face an increased risk of chronic organ dysfunction, including kidney and heart failure. While early immune mechanisms of sepsis have been extensively studied, the biological processes underlying delayed post-sepsis organ sequelae remain poorly understood. Methods: Using murine models of sepsis, we investigated the long-term impact of sepsis on organ immune landscapes and tissue repair. Fate-mapping experiments were conducted to trace macrophage origin and persistence. Single-cell RNA sequencing of the heart and kidney was performed to characterize macrophage subpopulations and transcriptional reprogramming following sepsis. Functional consequences of this immune remodeling were assessed by challenging post-septic animals with angiotensin II to evaluate secondary injury susceptibility and fibrotic remodeling. Results: Sepsis induced transient multiorgan failure but led to a sustained expansion of tissue macrophages. Fate-mapping demonstrated that this expansion was largely driven by the recruitment and engraftment of monocyte-derived macrophages. Single-cell transcriptomic analyses revealed that post-septic macrophages acquired a distinct proinflammatory and profibrotic signature, consistent with persistent microenvironmental activation. Functionally, this altered macrophage landscape impaired organ resilience, as evidenced by increased mortality and exacerbated cardiac and renal fibrosis upon secondary challenge. Discussion: Our findings identify macrophage reprogramming as a central mechanism linking sepsis to long-term organ vulnerability. The persistence of monocyte-derived macrophages with maladaptive transcriptional profiles promotes fibrotic remodeling and impaired tissue repair. Targeting macrophage recruitment or reprogramming may represent a promising strategy to prevent chronic organ failure among sepsis survivors. SIGNIFICANCE STATEMENT: Sepsis survivors often develop chronic organ dysfunction, yet the mechanisms linking acute infection to long-term damage remain unclear. We show that sepsis triggers expansion of inflammatory and profibrotic macrophages derived from bone marrow precursors in the kidney and heart. These alterations were associated with impaired organ resilience to subsequent injury, which suggest macrophage-driven maladaptive repair as a potential target to improve long-term outcomes after sepsis.

Importance: Before surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.Objective: To evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, Setting, and Participants: Randomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.Intervention: Patients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.Results: Of the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and Relevance: Among patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial Registration: ClinicalTrials.gov Identifier: NCT03374449

Aims: Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low‐dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP).Methods: From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex.Results: We included 29 patients (age 52 [46–64] years, 69% female). NOR median time to peak effect on MAP was 74 [53–94] s. After bolus administration, MAP increased by 24% (15–31%). A 2‐comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters.Conclusion: We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target‐controlled infusion.

BACKGROUND: This analysis provides details on baseline and changes in quality of life (QoL) and its components as measured by EQ-5D-5L questionnaire, as well as association with objective outcomes, applying high-intensity heart failure (HF) care in patients with acute HF. METHODS: In STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) patients with acute HF were randomized just before discharge to either usual care or a high-intensity care strategy of guideline-directed medical therapy up-titration. Patients ranked their state of health on the EQ-5D visual analog scale score ranging from 0 (the worst imaginable health) to 100 (the best imaginable health) at baseline and at 90 days follow-up. RESULTS: In 1072 patients with acute HF with available assessment of QoL (539/533 patients assigned high-intensity care/usual care) the mean baseline EQ-visual analog scale score was 59.2 (SD, 15.1) with no difference between the treatment groups. Patients with lower baseline EQ-visual analog scale (meaning worse QoL) were more likely to be women, self-reported Black and non-European ( P P P P P P _interaction =0.87). CONCLUSIONS: Early up-titration of guideline-directed medical therapy significantly improves all dimensions of QoL in patients with HF and improves prognosis regardless of baseline self-assessed health status. The likelihood of achieving optimal doses of HF medications does not depend on baseline QoL. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03412201.

Ayu Asakage, M.D., Shiro Ishihara, M.D., Louis Boutin, M.D., François Dépret, Ph.D., Takeshi Sugaya, Ph.D., Naoki Sato, Ph.D., Etienne Gayat, Ph.D., Alexandre Mebazaa, Ph.D., and Benjamin Deniau, Ph.D.. Ann Lab Med 2024;44:144-54. https://doi.org/10.3343/alm.2023.0083

BACKGROUND: Long-term outcomes of patients with severe stroke remain poorly documented. We aimed to characterize one-year outcomes of patients with stroke requiring mechanical ventilation in the intensive care unit (ICU). METHODS: We conducted a prospective multicenter cohort study in 33 ICUs in France (2017–2019) on patients with consecutive strokes requiring mechanical ventilation for at least 24 hours. Outcomes were collected via telephone interviews by an independent research assistant. The primary end point was poor functional outcome, defined by a modified Rankin Scale score of 4 to 6 at 1 year. Multivariable mixed models investigated variables associated with the primary end point. Secondary end points included quality of life, activities of daily living, and anxiety and depression in 1-year survivors. RESULTS: Among the 364 patients included, 244 patients (66.5% [95% CI, 61.7%–71.3%]) had a poor functional outcome, including 190 deaths (52.2%). After adjustment for non-neurological organ failure, age ≥70 years (odds ratio [OR], 2.38 [95% CI, 1.26–4.49]), Charlson comorbidity index ≥2 (OR, 2.01 [95% CI, 1.16–3.49]), a score on the Glasgow Coma Scale 1 day was protective (OR, 0.56 [95% CI, 0.33–0.94]). A sensitivity analysis conducted after exclusion of patients with early decisions of withholding/withdrawal of care yielded similar results. We observed persistent physical and psychological problems at 1 year in >50% of survivors. CONCLUSIONS: In patients with severe stroke requiring mechanical ventilation, several ICU admission variables may inform caregivers, patients, and their families on post-ICU trajectories and functional outcomes. The burden of persistent sequelae at 1 year reinforces the need for a personalized, multi-disciplinary, prolonged follow-up of these patients after ICU discharge. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03335995

Background: The role of positive pressure ventilation, central venous pressure (CVP) and inflammation on the occurrence of acute kidney injury (AKI) have been poorly described in mechanically ventilated patient secondary to coronavirus disease 2019 (COVID-19). Methods: This was a monocenter retrospective cohort study of consecutive ventilated COVID-19 patients admitted in a French surgical intensive care unit between March 2020 and July 2020. Worsening renal function (WRF) was defined as development of a new AKI or a persistent AKI during the 5 days after mechanical ventilation initiation. We studied the association between WRF and ventilatory parameters including positive end-expiratory pressure (PEEP), CVP, and leukocytes count. Results: Fifty-seven patients were included, 12 (21%) presented WRF. Daily PEEP, 5 days mean PEEP and daily CVP values were not associated with occurrence of WRF. 5 days mean CVP was higher in the WRF group compared to patients without WRF (median [IQR], 12 mm Hg [11-13] vs. 10 mm Hg [9–12]; P=0.03). Multivariate models with adjustment on leukocytes and Simplified Acute Physiology Score (SAPS) II confirmed the association between CVP value and risk of WRF (odd ratio, 1.97; 95% confidence interval, 1.12–4.33). Leukocytes count was also associated with occurrence of WRF in the WRF group (14 G/L [11–18]) and the no-WRF group (9 G/L [8–11]) (P=0.002). Conclusions: In mechanically ventilated COVID-19 patients, PEEP levels did not appear to influence occurrence of WRF. High CVP levels and leukocytes count are associated with risk of WRF.

Aims: STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared with usual care. The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration. Methods and results: A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes, from randomization to 1 week later, as decreased (≥30%), stable (10%). The primary endpoint was 180-day HF readmission or death. The effect of HIC vs. usual care was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months, they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs. 2.2% and 4.0% in those with decreased NT-proBNP (P = 0.039 and P = 0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; P = 0.93). Conclusion: Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge, utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate, resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change.

Background: This study aimed to assess the value of blood and urine biomarkers in addition to routine clinical variables in risk stratification of patients admitted to ICU. Methods: Multivariable prognostic models were developed in this post hoc analysis of the French and EuRopean Outcome ReGistry in Intensive Care Units study, a prospective observational study of patients admitted to ICUs. The study included 2087 patients consecutively admitted to the ICU who required invasive mechanical ventilation or a vasoactive agent for more than 24 h. The main outcome measures were in-ICU, in-hospital, and 1 year mortality. Results: Models including only SAPS II or APACHE II scores had c-indexes for in-hospital and 1 year mortality of 0.64 and 0.65, and 0.63 and 0.61, respectively. The c-indexes for a model including age and estimated glomerular filtration rate were higher at 0.69 and 0.67, respectively. Models utilizing available clinical variables increased the c-index for in-hospital and 1 year mortality to 0.80 and 0.76, respectively. The addition of biomarkers and urine proteomic markers increased c-indexes to 0.83 and 0.78. Conclusions: The commonly used scores for risk stratification in ICU patients did not perform well in this study. Models including clinical variables and biomarkers had significantly higher predictive values.