Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS–dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ–mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.

No study has been conducted to demonstrate the feasibility of an opioid-free anesthesia (OFA) protocol in cardiac surgery to improve patient care. The aim of the present study was to evaluate the effect of OFA on post-operative morphine consumption and the post-operative course. After retrospectively registering to clinicaltrial.gov (NCT03816592), we performed a retrospective matched cohort study (1:1) on cardiac surgery patients with cardiopulmonary bypass between 2018 and 2019. Patients were divided into two groups: OFA (lidocaine, dexamethasone and ketamine) or opioid anaesthesia (OA) (sufentanil). The main outcome was the total postoperative morphine consumption in the 48 h after surgery. Secondary outcomes were rescue analgesic use, a major adverse event composite endpoint, and ICU and hospital length of stay (LOS). One hundred ten patients were matched (OFA: n = 55; OA: n = 55). On inclusion, demographic and surgical data for the OFA and OA groups were comparable. The total morphine consumption was higher in the OA group than in the OFA group (15 (6–34) vs 5 mg (2–18), p = 0.001). The pain score during the first 48 post-operative hours did not differ between the two groups. Creatinine values did not differ on the first post-operative day (80 (IQR: 66–115) vs 77 mmol/l (IQR: 69–95), p = 0.284). Incidence of the composite endpoint was lower in the OFA group (25 patients (43%) vs 38 patients (68%), p = 0.021). The time to extubation and the ICU stays were shorter in the OFA group (3 (1–5) vs 5 (3–6) hours, p = 0.001 and 2 (1–3) vs 3 (2–5) days, p = 0.037). The use of OFA was associated with lower morphine consumption. OFA might be associated with shorter intubation time and ICU stays. Further randomized studies are needed to confirm these results. This study was retrospectively registered to ct2 (identifier: NCT03816592 ) on January 25, 2019.

Minimal invasive heart surgery (MIHS) presents several benefits, but provides intense and prolonged post-operative pain. Our objective was to compare efficacy of serratus anterior plane block (SAPB) with continuous wound infiltration (CWI) for management of post-operative pain following MIHS. It’s retrospective, monocentric study between November 2016 to April 2017. The study was performed at the University hospital of Dijon, Burgundy, France. All patients scheduled for MIHS was included. Data was collected retrospectively. During this period, 20 patients had SAPB and 26 had CWI. SAPB was performed before extubation with a single injection of 0.5 mg/kg of ropivacaïne (5 mg/ml). In the CWI group, catheter was inserted in the subcutaneous space by the surgeon at the end of the procedure. A 10 ml bolus of ropivacaïne (7.5 mg/mL) was followed by a continuous infusion (2 mg/ml) between 7 and 12 ml/h for 48 h. Morphine consumption and visual analog score (VAS) were recorded for 48 h. Length of stay in intensive care unit and hospital was also collected. Morphine consumption and VAS score were significantly lower in SAPB group (p < 0.01). Length of stay in intensive care and hospital was significantly was decreased in SAPB group. SAPB appears effective in reducing postoperative MIHS pain.

COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.

Despite the abundant literature on vasopressor therapy, few studies have focused on vasopressor-sparing strategies in patients with shock. We performed a scoping-review of the published studies evaluating vasopressor-sparing strategies by analyzing the results from randomized controlled trials conducted in patients with shock, with a focus on vasopressor doses and/or duration reduction. We analyzed 143 studies, mainly performed in septic shock. Our analysis demonstrated that several pharmacological and non-pharmacological strategies are associated with a decrease in the duration of vasopressor therapy. These strategies are as follows: implementing a weaning strategy, vasopressin use, systemic glucocorticoid administration, beta-blockers, and normothermia. On the contrary, early goal directed therapies, including fluid therapy, oral vasopressors, vitamin C, and renal replacement therapy, are not associated with an increase in vasopressor-free days. Based on these results, we proposed an evidence-based vasopressor management strategy.