Nicolas Bréchot

Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton.

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of angptl4 by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.

Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock.

Objectives:Profound myocardial depression can occur during severe septic shock. Although good outcomes of venoarterial extracorporeal membrane oxygenation–treated children with refractory septic shock have been reported, little is known about adults’ outcomes. This study was designed to assess the outcomes and long-term health-related quality-of-life of patients supported by venoarterial extracorporeal membrane oxygenation for refractory cardiac and hemodynamic failure during severe septic shock. Design:A retrospective, single-center, observational study and a cross-sectional survey to assess health-related quality of life by the Short Form-36 questionnaire and frequencies of anxiety, depression and posttraumatic stress disorder symptoms by the Hospital Anxiety and Depression Scale and the Impact of Event Scale, respectively. Setting:A 26-bed tertiary intensive care unit in a university hospital. Patients:We evaluated the outcomes of patients who received venoarterial extracorporeal membrane oxygenation rescue therapy for refractory cardiovascular failure during bacterial septic shock. Results are expressed as medians (range). Measurements and Main Results:From January 2008 to September 2011, 14 patients, 45 years old (28–66), seven males, none with a history of left ventricular dysfunction, received venoarterial extracorporeal membrane oxygenation for septic shock refractory to conventional treatment, 24 hours (3–108) after shock onset. All exhibited severe myocardial dysfunction at extracorporeal membrane oxygenation implantation. Left ventricular ejection fraction was 16% (10% to 30%), cardiac index was 1.3 L/min/m2 (0.7–2.2 ) and systemic resistance vascular index was 3162 (2047–7685). All were receiving high-dose catecholamines and had signs of multiple organ failure: pH 7.16 (6.68–7.39), blood lactate 9 (2–17) mmol/L, PaO2/FIO2 87 (28–364), Simplified Acute Physiology Score III 84 (75–106) and Sepsis-Related Organ Failure Assessment score 18 (8–21). Twelve patients (86%) could be weaned off venoarterial extracorporeal membrane oxygenation after 5.5 days (2–12) days of support and 10 patients (71%) were discharged to home and were alive after a median follow-up of 13 months (3–43). All 10 survivors had normal left ventricular ejection fraction and reported good health-related quality of life at long-term follow-up. Conclusions:Venoarterial extracorporeal membrane oxygenation rescued more than 70% of the patients who developed refractory cardiovascular dysfunction during severe bacterial septic shock. Survivors reported good long-term quality of life. Venoarterial extracorporeal membrane oxygenation might represent a valuable therapeutic option for adults in severe septic shock with refractory cardiac and hemodynamic failure.

Modulation of Macrophage Activation State Protects Tissue from Necrosis during Critical Limb Ischemia in Thrombospondin-1-Deficient Mice

Background Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI. Methods and Findings Using a genetic model of tsp-1 −/− mice subjected to femoral artery excision, we report that tsp-1 −/− mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1 −/− and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1 −/− mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1 −/− mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1 −/− mice, thereby demonstrating that macrophages mediated tissue protection in these mice. Conclusion This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia.

What is the niche for extracorporeal membrane oxygenation in severe acute respiratory distress syndrome

Purpose of reviewThis article reviews the results of case series and trials which evaluated venovenous extracorporeal membrane oxygenation (VV-ECMO) for severe respiratory failure. Potential indications of the technique in this setting are discussed. Recent findingsMajor technological improvements in extracorporeal membrane oxygenation (ECMO) machines and the positive results of the conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial have reignited interest in VV-ECMO in patients with severe acute respiratory distress syndrome (ARDS) and persistent hypoxemia or hypercarbia on conventional mechanical ventilation. The technique has also been successfully used as a rescue therapy for the most severe ARDS cases associated with the recent Influenza A(H1N1) pandemic. However, as the CESAR study was criticized for methodological limitations and because results of nonrandomized case-series of ECMO are prone to selection biases, indications for VV-ECMO remain highly controversial. SummaryBefore widespread diffusion of VV-ECMO for severe ARDS, new trials should test the efficacy of early initiation of the technique with tight control of mechanical ventilation in the control group, initiation of ECMO prior to transportation to ECMO centers, and the use of ECMO in every patient randomly assigned to receive it.

Imipenem, Meropenem, or Doripenem To Treat Patients with Pseudomonas aeruginosa Ventilator-Associated Pneumonia

ABSTRACT Only limited data exist on Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) treated with imipenem, meropenem, or doripenem. Therefore, we conducted a prospective observational study in 169 patients who developed Pseudomonas aeruginosa VAP. Imipenem, meropenem, and doripenem MICs for Pseudomonas aeruginosa isolates were determined using Etests and compared according to the carbapenem received. Among the 169 isolates responsible for the first VAP episode, doripenem MICs were lower (P < 0.0001) than those of imipenem and meropenem (MIC50s, 0.25, 2, and 0.38, respectively); 61%, 64%, and 70% were susceptible to imipenem, meropenem, and doripenem, respectively (P was not statistically significant). Factors independently associated with carbapenem resistance were previous carbapenem use (within 15 days) and mechanical ventilation duration before VAP onset. Fifty-six (33%) patients had at least one VAP recurrence, and 56 (33%) died. Factors independently associated with an unfavorable outcome (recurrence or death) were a high day 7 sequential organ failure assessment score and mechanical ventilation dependency on day 7. Physicians freely prescribed a carbapenem to 88 patients: imipenem for 32, meropenem for 24, and doripenem for 32. The remaining 81 patients were treated with various antibiotics. Imipenem-, meropenem-, and doripenem-treated patients had similar VAP recurrence rates (41%, 25%, and 22%, respectively; P = 0.15) and mortality rates (47%, 25%, and 22%, respectively; P = 0.07). Carbapenem resistance emerged similarly among patients treated with any carbapenem. No carbapenem was superior to another for preventing carbapenem resistance emergence.

Bedside Contribution of Electrical Impedance Tomography to Set Positive End-Expiratory Pressure for ECMO-Treated Severe ARDS Patients.

Rationale: Optimal positive end‐expiratory pressure (PEEP) is unknown in patients with severe acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation receiving mechanical ventilation with very low tidal volume. Objectives: To evaluate the ability of electrical impedance tomography (EIT) to monitor a PEEP trial and to derive from EIT the best compromise PEEP in this setting. Methods: A decremental PEEP trial (20‐0 cm H2O) in 5 cm H2O steps was monitored by EIT, with lung images divided into four ventral‐to‐dorsal horizontal regions of interest. The EIT‐based PEEP providing the best compromise between overdistention and collapsed zones was arbitrarily defined as the lowest pressure able to limit EIT‐assessed collapse to less than or equal to 15% with the least overdistention. Driving pressure was maintained constant at 14 cm H2O in pressure controlled mode. Measurements and Main Results: Tidal volume, static compliance, tidal impedance variation, end‐expiratory lung impedance, and their respective regional distributions were visualized at each PEEP level in 15 patients on extracorporeal membrane oxygenation. Low tidal volume (2.9‐4 ml/kg ideal body weight) and poor compliance (12.1‐18.7 ml/cm H2O) were noted, with significantly higher tidal volume and compliance at PEEP10 and PEEP5 than PEEP20. EIT‐based best compromise PEEPs were 15, 10, and 5 cm H2O for seven, six, and two patients, respectively, whereas PEEP20 and PEEP0 were never selected. Conclusions: The broad variability in optimal PEEP observed in these patients with severe ARDS under extracorporeal membrane oxygenation reinforces the need for personalized titration of ventilation settings. EIT may be an interesting noninvasive bedside tool to provide real‐time monitoring of the PEEP impact in these patients.

Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation

Background: Increased left ventricular afterload during peripheral venoarterial-extracorporeal membrane oxygenation (VA-ECMO) support frequently causes hydrostatic pulmonary oedema. Because physiological studies demonstrated left ventricular afterload decrease during VA-ECMO assistance combined with the intra-aortic balloon pump (IABP), we progressively changed our standard practice systematically to associate an IABP with VA-ECMO. This study aimed to evaluate IABP efficacy in preventing pulmonary oedema in VA-ECMO-assisted patients. Methods: A retrospective single-centre study. Results: Among 259 VA-ECMO patients included, 104 received IABP. Weinberg radiological score-assessed pulmonary oedema was significantly lower in IABP+ than IABP– patients at all times after ECMO implantation. This protection against pulmonary oedema persisted when death and switching to central ECMO were used as competing risks (subhazard ratio 0.49, 95% confidence interval (CI) 0.33–0.75; P<0.001). Multivariable analysis retained IABP as being independently associated with a lower risk of radiological pulmonary oedema (odds ratio (OR) 0.4, 95% CI 0.2–0.7; P=0.001) and a trend towards lower mortality (OR 0.54, 95% CI 0.29–1.01; P=0.06). Finally, the time on ECMO free from mechanical ventilation increased in IABP+ patients (2.2±4.3 vs. 0.7±2.0 days; P=0.0003). Less frequent pulmonary oedema and more days off mechanical ventilation were also confirmed in 126 highly comparable IABP+ and IABP– patients, propensity score matched for receiving an IABP. Conclusions: Associating an IABP with peripheral VA-ECMO was independently associated with a lower frequency of hydrostatic pulmonary oedema and more days off mechanical ventilation under ECMO.

Extracorporeal membrane oxygenation: beyond rescue therapy for acute respiratory distress syndrome?

Purpose of review This article summarizes the results of past and more recent series on venovenous extracorporeal membrane oxygenation (VV-ECMO) and discusses its potential indications beyond the rescue of patients with lung failure refractory to conventional mechanical ventilation. Recent findings Successful VV-ECMO treatment in patients with extremely severe influenza A(H1N1)-associated acute respiratory distress syndrome (ARDS) and positive results of the CESAR trial have led to an exponential use of the technology in recent years. Beyond its currently accepted indication as a salvage therapy in ARDS patients with refractory hypoxemia or unable to tolerate volume-limited strategies, VV-ECMO may improve the outcomes of less severe ARDS patients by facilitating lung-protective ventilation. Summary As initiation of VV-ECMO allows significant decrease in tidal volume, plateau and driving pressures, which has been associated with improved survival in ARDS patients, new trials should evaluate the impact of its early initiation in patients with severe but not refractory ARDS.

What role do viruses play in nosocomial pneumonia

Purpose of the review Viruses are an increasingly recognized cause of community-acquired pneumonia (CAP), but their exact role in nosocomial pneumonia is still debated. This review focuses on the role of viruses as a cause of nosocomial pneumonia. Recent findings Respiratory viruses may be responsible for healthcare-associated pneumonia, because affected patients and those with CAP have the same risk factors for viral disease. In mechanically ventilated patients, viruses belonging to the Herpesviridae family, namely herpes simplex virus (HSV) and cytomegalovirus, can be reactivated and cause bronchopneumonitis or ventilator-associated pneumonia, respectively. Recent results confirmed the high rate of HSV reactivation in the distal airways of mechanically ventilated patients, and that patients with high virus loads (>105 copies/ml of bronchoalveolar lavage fluid) have poorer outcomes than those with low or no virus load. However, the responsibility of mimivirus, initially described as a possible cause of pneumonia, was not confirmed for nosocomial pneumonia. Summary Respiratory viruses are mainly responsible for CAP, but they may also cause healthcare-associated pneumonia. HSV bronchopneumonitis and cytomegalovirus pneumonia are not rare diseases, and patients with Herpesviridae lung infections have worse prognoses than those without. Whether or not those Herpesviridae infections are responsible for true morbidity or morbidity remains to be determined.

Performance of existing risk scores around heart transplantation: validation study in a 4-year cohort

Several risk scores exist to help identify best candidate recipients for heart transplantation (HTx). This study describes the performance of five heart failure risk scores and two post‐HTx mortality risk scores in a French single‐centre cohort. All patients listed for HTx through a 4‐year period were included. Waiting‐list risk scores [Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC), Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE‐HF) and Get With The Guidelines‐Heart Failure (GWTG‐HF)] and post‐HTx scores Index for Mortality Prediction After Cardiac Transplantation (IMPACT and CARRS) were computed. Main outcomes were 1‐year mortality on waiting list and after HTx. Performance was assessed using receiver operator characteristic (ROC), calibration and goodness‐of‐fit analyses. The cohort included 414 patients. Waiting‐list mortality was 14.0%, and post‐HTx mortality was 16.3% at 1‐year follow‐up. Heart failure risk scores had adequate discrimination regarding waiting‐list mortality (ROC AUC for HFSS = 0.68, SHFM = 0.74, OPTIMIZE‐HF = 0.72, MAGGIC = 0.70 and GWTG = 0.77; all P‐values <0.05). On the contrary, post‐HTx risk scores did not discriminate post‐HTx mortality (AUC for IMPACT = 0.58, and CARRS = 0.48, both P‐values >0.50). Subgroup analysis on patients undergoing HTx after ventricular assistance device (VAD) implantation (i.e. bridge‐to‐transplantation) (n = 36) showed an IMPACT AUC = 0.72 (P < 0.001). In this single‐centre cohort, existing heart failure risk scores were adequate to predict waiting‐list mortality. Post‐HTx mortality risk scores were not, except in the VAD subgroup.