Influence of socio-economic status on functional recovery after ARDS caused by SARS-CoV-2: the multicentre, observational RECOVIDS study.

PURPOSE: Survivors after acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) are at high risk of developing respiratory sequelae and functional impairment. The healthcare crisis caused by the pandemic hit socially disadvantaged populations. We aimed to evaluate the influence of socio-economic status on respiratory sequelae after COVID-19 ARDS. METHODS: We carried out a prospective multicenter study in 30 French intensive care units (ICUs), where ARDS survivors were pre-enrolled if they fulfilled the Berlin ARDS criteria. For patients receiving high flow oxygen therapy, a flow ≥ 50 l/min and an FiO2 ≥ 50% were required for enrollment. Socio-economic deprivation was defined by an EPICES (Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examens de Santé - Evaluation of Deprivation and Inequalities in Health Examination Centres) score ≥ 30.17 and patients were included if they performed the 6-month evaluation. The primary outcome was respiratory sequelae 6 months after ICU discharge, defined by at least one of the following criteria: forced vital capacity < 80% of theoretical value, diffusing capacity of the lung for carbon monoxide < 80% of theoretical value, oxygen desaturation during a 6-min walk test and fibrotic-like findings on chest computed tomography. RESULTS: Among 401 analyzable patients, 160 (40%) were socio-economically deprived and 241 (60%) non-deprived; 319 (80%) patients had respiratory sequelae 6 months after ICU discharge (81% vs 78%, deprived vs non-deprived, respectively). No significant effect of socio-economic status was identified on lung sequelae (odds ratio (OR), 1.19 [95% confidence interval (CI), 0.72-1.97]), even after adjustment for age, sex, most invasive respiratory support, obesity, most severe P/F ratio (adjusted OR, 1.02 [95% CI 0.57-1.83]). CONCLUSIONS: In COVID-19 ARDS survivors, socio-economic status had no significant influence on respiratory sequelae 6 months after ICU discharge.

Interest of TAPSE/sPAP ratio for noninvasive pulmonary arterial hypertension risk assessment.

BACKGROUND: Although ventriculoarterial coupling is associated with better survival in pulmonary arterial hypertension (PAH), existing PAH risk assessment method has not considered echocardiographic criteria of right ventricular to pulmonary artery coupling. We aimed to test the prognostic value of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for noninvasive PAH risk assessment. METHODS: We retrospectively studied a cohort of 659 incident PAH patients from 4 independent French PH centers (training cohort: n = 306, validation cohort n = 353) who underwent follow-up TAPSE/sPAP measurement in addition to previously validated noninvasive risk stratification variables. The primary composite outcome was 3-year all-cause mortality or lung transplantation from re-evaluation. RESULTS: Mean age was 55 ± 17 years-old with a majority of female (66%). The three main PAH causes were connective tissue disease (26%), idiopathic (24%) and porto-pulmonary (19%). The primary composite outcome occurred in 71 (23%) patients. Multivariable Cox regression analysis retained 3 noninvasive low-risk criteria as associated with the primary composite outcome: NYHA I-II (p = 0.001), NTproBNP <300 ng/L or BNP <50 ng/L (p = 0.004), and TAPSE/sPAP >0.33 mm/mmHg (p = 0.004). The more the low-risk criteria achieved at follow-up, the better the event-free survival both in the training and validation cohort (log-rank p < 0.001). In the training cohort, the c-index for these 3 criteria, for COMPERA 2.0 and for the noninvasive French Pulmonary Hypertension Network method were 0.75, 95%CI(0.70-0.82), 0.72 95%CI(0.66-0.75), 0.71 95%CI(0.62-0.73), respectively. CONCLUSION: The 3 following dichotomized low-risk criteria: TAPSE/sPAP >0.33 mm/mmHg, NYHA I-II and NTproBNP <300 ng/L or BNP <50 ng/L allow to identify low-risk PAH patients at follow-up.

High-flow nasal cannula oxygen therapy: P-SILI or not P-SILI?

The risk of P-SILI with HFNC is controversial and may be less than with NIV. Some physiological mechanisms of the protective effect of HFNC are hypoxaemia correction, reduction of inspiratory efforts and homogeneity of lung volume distribution. https://bit.ly/3skOEKX.

Influence of socioeconomic status on functional recovery after ARDS caused by SARS-CoV-2: a multicentre, observational study.

INTRODUCTION: Prognosis of patients with COVID-19 depends on the severity of the pulmonary affection. The most severe cases may progress to acute respiratory distress syndrome (ARDS), which is associated with a risk of long-term repercussions on respiratory function and neuromuscular outcomes. The functional repercussions of severe forms of COVID-19 may have a major impact on quality of life, and impair the ability to return to work or exercise. Social inequalities in healthcare may influence prognosis, with socially vulnerable individuals more likely to develop severe forms of disease. We describe here the protocol for a prospective, multicentre study that aims to investigate the influence of social vulnerability on functional recovery in patients who were hospitalised in intensive care for ARDS caused by COVID-19. This study will also include an embedded qualitative study that aims to describe facilitators and barriers to compliance with rehabilitation, describe patients' health practices and identify social representations of health, disease and care. METHODS AND ANALYSIS: The "Functional Recovery From Acute Respiratory Distress Syndrome (ARDS) Due to COVID-19: Influence of Socio-Economic Status" (RECOVIDS) study is a mixed-methods, observational, multicentre cohort study performed during the routine follow-up of post-intensive care unit (ICU) functional recovery after ARDS. All patients admitted to a participating ICU for PCR-proven SARS-CoV-2 infection and who underwent chest CT scan at the initial phase AND who received respiratory support (mechanical or not) or high-flow nasal oxygen, AND had ARDS diagnosed by the Berlin criteria will be eligible. The primary outcome is the presence of lung sequelae at 6 months after ICU discharge, defined either by alterations on pulmonary function tests, oxygen desaturation during a standardised 6 min walk test or fibrosis-like pulmonary findings on chest CT. Patients will be considered to be socially disadvantaged if they have an "Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examen de Santé" (EPICES) score ≥30.17 at inclusion. ETHICS AND DISSEMINATION: The study protocol and the informed consent form were approved by an independent ethics committee (Comité de Protection des Personnes Sud Méditerranée II) on 10 July 2020 (2020-A02014-35). All patients will provide informed consent before participation. Findings will be published in peer-reviewed journals and presented at national and international congresses. TRIAL REGISTRATION NUMBER: NCT04556513.

High-flow oxygen therapy versus noninvasive ventilation: a randomised physiological crossover study of alveolar recruitment in acute respiratory failure.

High-flow nasal cannula (HFNC) oxygen therapy has recently shown clinical benefits in hypoxaemic acute respiratory failure (ARF) patients, while the value of noninvasive ventilation (NIV) remains debated. The primary end-point was to compare alveolar recruitment using global end-expiratory electrical lung impedance (EELI) between HFNC and NIV. Secondary end-points compared regional EELI, lung volumes (global and regional tidal volume variation (V T)), respiratory parameters, haemodynamic tolerance, dyspnoea and patient comfort between HFNC and NIV, relative to face mask (FM). A prospective randomised crossover physiological study was conducted in patients with hypoxaemic ARF due to pneumonia. They received alternately HFNC, NIV and FM. 16 patients were included. Global EELI was 4083 with NIV and 2921 with HFNC (p=0.4). Compared to FM, NIV and HFNC significantly increased global EELI by 1810.5 (95% CI 857-2646) and 826 (95% CI 399.5-2361), respectively. Global and regional V T increased significantly with NIV compared to HFNC or FM, but not between HFNC and FM. NIV yielded a significantly higher pulse oxygen saturation/inspired oxygen fraction ratio compared to HFNC (p=0.03). No significant difference was observed between HFNC, NIV and FM for dyspnoea. Patient comfort score with FM was not significantly different than with HFNC (p=0.1), but was lower with NIV (p=0.001). This study suggests a potential benefit of HFNC and NIV on alveolar recruitment in patients with hypoxaemic ARF. In contrast with HFNC, NIV increased lung volumes, which may contribute to overdistension and its potentially deleterious effect in these patients.

Role of Non-Invasive Respiratory Supports in COVID-19 Acute Respiratory Failure Patients with Do Not Intubate Orders.

The current gold-standard treatment for COVID-19-related hypoxemic respiratory failure is invasive mechanical ventilation. However, do not intubate orders (DNI), prevent the use of this treatment in some cases. The aim of this study was to evaluate if non-invasive ventilatory supports can provide a good therapeutic alternative to invasive ventilation in patients with severe COVID-19 infection and a DNI. Data were collected from four centres in three European countries. Patients with severe COVID-19 infection were included. We emulated a hypothetical target trial in which outcomes were compared in patients with a DNI order treated exclusively by non-invasive respiratory support with patients who could be intubated if necessary. We set up a propensity score and an inverse probability of treatment weighting to remove confounding by indication. Four-hundred patients were included: 270 were eligible for intubation and 130 had a DNI order. The adjusted risk ratio for death among patients eligible for intubation was 0.81 (95% CI 0.46 to 1.42). The median length of stay in acute care for survivors was similar between groups (18 (10-31) vs. (19 (13-23.5); p = 0.76). The use of non-invasive respiratory support is a good compromise for patients with severe COVID-19 and a do not intubate order.

Cardiopulmonary Exercise Testing to Assess Persistent Symptoms at 6 Months in People With COVID-19 Who Survived Hospitalization: A Pilot Study.

OBJECTIVE: The aim of this pilot study was to assess physical fitness and its relationship with functional dyspnea in survivors of COVID-19 6 months after their discharge from the hospital. METHODS: Data collected routinely from people referred for cardiopulmonary exercise testing (CPET) following hospitalization for COVID-19 were retrospectively analyzed. Persistent dyspnea was assessed using the modified Medical Research Council dyspnea scale. RESULTS: Twenty-three people with persistent symptoms were referred for CPET. Mean modified Medical Research Council dyspnea score was 1 (SD = 1) and was significantly associated with peak oxygen uptake (VO2peak; %) (rho = -0.49). At 6 months, those hospitalized in the general ward had a relatively preserved VO2peak (87% [SD = 20]), whereas those who had been in the intensive care unit had a moderately reduced VO2peak (77% [SD = 15]). Of note, the results of the CPET revealed that, in all individuals, respiratory equivalents were high, power-to-weight ratios were low, and those who had been in the intensive care unit had a relatively low ventilatory efficiency (mean VE/VCO2 slope = 34 [SD = 5]). Analysis of each individual showed that none had a breathing reserve <15% or 11 L/min, all had a normal exercise electrocardiogram, and 4 had a heart rate >90%. CONCLUSION: At 6 months, persistent dyspnea was associated with reduced physical fitness. This study offers initial insights into the mid-term physical fitness of people who required hospitalization for COVID-19. It also provides novel pathophysiological clues about the underlaying mechanism of the physical limitations associated with persistent dyspnea. Those with persistent dyspnea should be offered a tailored rehabilitation intervention, which should probably include muscle reconditioning, breathing retraining, and perhaps respiratory muscle training. IMPACT: This study is the first, to our knowledge, to show that a persistent breathing disorder (in addition to muscle deconditioning) can explain persistent symptoms 6 months after hospitalization for COVID-19 infection and suggests that a specific rehabilitation intervention is warranted.

Prognostic importance of Kidney, Heart and Interstitial lung diseases (KHI triad) in PH: A machine learning study.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous, severe and progressive disease with an impact on quality of life and life-expectancy despite specific therapies. AIMS: (i) to compare prognosis significance of each PH subgroup in a cohort from a referral center, (ii) to identify phenotypically distinct high-risk PH patient using machine learning. METHODS: Patients with PH were included from 2002 to 2019 and routinely followed-up. We collected clinical, laboratory, imaging and hemodynamic variables. Four-year survival rate of each subgroups was then compared. Next, phenotypic domains were imputed with 5 eigenvectors for missing values and filtered if the Pearson correlation coefficient was>0.6. Thereafter, agglomerative hierarchical clustering was used for grouping phenotypic variables and patients: a heat map was generated and participants were separated using Penalized Model-Based Clustering. P<0.05 was considered significant. RESULTS: 328 patients were prospectively included (mean age 63±18 yo, 46% male). PH secondary to left heart disease (PH-LHD) and lung disease (PH-LD) had a significantly increased mortality compared to pulmonary arterial hypertension (PAH) patients: HR=2.43, 95%CI=(1.24-4.73) and 2.95, 95%CI=(1.43-6.07) respectively. 25 phenotypic domains were pinpointed and 3 phenogroups identified. Phenogroup 3 had a significantly increased mortality (log-rank P=0.046) compared to the others and was remarkable for predominant pulmonary disease in older male, accumulating cardiovascular risk factors, and simultaneous three major comorbidities: coronary artery disease, chronic kidney disease and interstitial lung disease. CONCLUSION: PH-LHD and PH-LD has 2-fold and 3-fold increase in mortality, respectively compared with PAH. PH patients with simultaneous kidney-cardiac-pulmonary comorbidities were identified as having high-risk of mortality. Specific targeted therapy in this phenogroup should be prospectively evaluated.

Long-term survival following initiation of home non-invasive ventilation: a European study.

INTRODUCTION: Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. METHODS: Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. RESULTS: Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA >7 years and slowly progressive NMD >7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age >60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence >4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). CONCLUSION: The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.

Portopulmonary hypertension in the current era of pulmonary hypertension management.

BACKGROUND & AIMS: Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. METHODS: Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS: Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). CONCLUSION: Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. LAY SUMMARY: Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation.

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.

RATIONALE: Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. OBJECTIVES: To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. METHODS: A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. RESULTS: 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-ß0 thalassaemia (S-ß0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-ß0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-ß0 thal patients, respectively, and 50% of SS/S-ß0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. CONCLUSIONS: Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

Sequelae of Acute Respiratory Distress Syndrome: Interest of Rehabilitation.

CASE PRESENTATION: This clinical case presents the history of a woman hospitalized for acute respiratory distress syndrome (ARDS). A 62-year-old woman, with regular physical activity and no history of respiratory disease or smoking, was hospitalized for moderate ARDS with bilateral pneumonitis. Fourteen days later, she was discharged from the intensive care unit and received respiratory physical therapy. One month later, she experienced exertional dyspnea. A regression of alveolar condensation with persistent sequelae at the pulmonary bases was noted. Three months later, the patient continued daily physical activity with satisfactory tolerance. A reduction in alveolar-capillary transfer, inappropriate hyperventilation upon exercise, and impairment of gas exchanges at maximal effort, suggestive of pulmonary shunt, were demonstrated. At the 6-month evaluation, the patient displayed exertional dyspnea with residual bilateral basal consolidations. Six months later, the dyspnea had ceased. The persistence of bilateral basal interstitial syndrome associated with bronchial dilatation and pleural-based consolidations was noted, as well as a stable impaired alveolar-capillary diffusing capacity. DISCUSSION: Upon discharge from intensive care, pulmonary follow-up should be proposed to ARDS survivors. Moreover, pulmonary function testing at rest and exercise is advised as soon as possible to evaluate the respiratory sequelae. This will help to limit the severity of complications through adapted exercise rehabilitation and then regular physical activity.

The Use of Ferritin to Identify Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Thrombocytopenia is a common, multifactorial, finding in ICU. Hemophagocytosis is one of the main explanatory mechanisms, possibly integrated into hemophagocytic lymphohistiocytosis syndrome, of infectious origin in the majority of cases in ICU. The hemophagocytic lymphohistiocytosis is probably underdiagnosed in the ICU, although it is associated with dramatic outcomes. The main objectives of this work were to identify the frequency of secondary hemophagocytic lymphohistiocytosis, and the main prognostic factors for mortality. DESIGN/SETTING: We conducted a retrospective observational study in all adult patients admitted with suspected or diagnosed hemophagocytic lymphohistiocytosis, between January 1, 2000, and August 22, 2012. PATIENTS: A total of 106 patients (42%) had significant hemophagocytosis on bone marrow examination, performed for exploration of thrombocytopenia, bicytopenia, or pancytopenia. MEASUREMENTS AND MAIN RESULTS: The median age was 56 (45-68) and the median Simplified Acute Physiology Score 2 was 55 (38-68). The main reason for ICU admission was hemodynamic instability (58%), predominantly related to sepsis (45% cases). The main precipitating factor found was a bacterial infection in 81 of 106 patients (76%), including 32 (30%) with Escherichia coli infection. Forty six of 106 patients (43%) died in the ICU. They were significantly older, had higher Simplified Acute Physiology Score 2, plasma lactate deshydrogenase bilirubin, and serum ferritin. The fibrinogen and the percentage of megakaryocytes were significantly lower in nonsurvivors when compared with survivors. In multivariate analysis, only serum ferritin significantly predicted death related to hemophagocytosis. A serum ferritin greater than 2,000 µg/L predicted death with a sensitivity of 71% and a specificity of 76%. A decreased percentage of megakaryocytes also predicted patient death in the ICU. CONCLUSIONS: Hemophagocytosis is common in thrombocytopenic patients with sepsis, frequently included in a postinfectious hemophagocytic lymphohistiocytosis setting. Our study reveals that ferritin could be a reliable prognostic marker in these patients, and hold particular interest in discussing a specific treatment for hemophagocytic lymphohistiocytosis.

Pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP > 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2-3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). This review discusses the current state of art regarding to epidemiologic aspects of PH, diagnostic approaches and the current classification of PH. In addition, currently available specific PAH therapy is discussed as well as future treatments.

Left ventricular ejection time in acute heart failure complicating precapillary pulmonary hypertension.

BACKGROUND: Novel noninvasive tools may improve the management of patients with pulmonary hypertension (PH) experiencing heart failure. Major right ventricle overload leads to decreased stroke volume, which shortens left ventricular ejection time (LVET). Our arterial tonometry study tested the hypothesis that LVET carries prognostic value in patients with precapillary PH with heart failure. METHODS: Clinical, biologic, and radial artery tonometry variables were prospectively obtained at admission and at day 3 to 5 in 53 consecutive patients with PH admitted to our ICU for clinical deterioration. LVET was measured from the reconstructed aortic pressure curve. RESULTS: Overall ICU mortality (median stay, 5 days) was 17%. At admission, the LVET was shorter in patients with unfavorable outcome (median, 228 milliseconds [25th-75th percentiles, 212-278 milliseconds] vs 257 milliseconds [237-277 milliseconds], P = .032), whereas other tonometric indices were similar. The LVET at entry (237 milliseconds) had 73% sensitivity and 89% specificity for identifying death in the ICU. Other prognostic factors at admission were higher serum levels of brain natriuretic peptide (BNP) and creatinine and lower natremia. Dobutamine requirement, higher furosemide dose, and higher oxygen flow were associated with unfavorable outcome. At the second evaluation, higher serum levels of creatinine and BNP, higher furosemide dose and oxygen flow, and dobutamine or norepinephrine requirement were associated with poor outcome. The change in LVET between admission and follow-up measurement was not associated with outcome. The 90-day mortality was 28%. CONCLUSIONS: Shortened LVET at ICU admission was a prognostic factor in patients with precapillary PH with heart failure. Previously documented prognostic factors were also confirmed in this cohort.

Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis.

AIMS: Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF), especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype (α-smooth muscle actin and collagen I expression, proliferation, migration, and contraction) were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane (SFN), an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions (transforming growth factor ß [TGF-ß]). RESULTS: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and myofibroblastic dedifferentiation in IPF fibroblasts. SFN inhibited TGF-ß profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.

[Protective role of Nrf2 in the lungs against oxidative airway diseases]. / La voie Nrf2 en pathologie respiratoire.

Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular and extracellular antioxidants throughout the epithelial lining fluid and tissues. Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, is involved in cellular and tissue damage related to the pathogenesis of many acute and chronic respiratory diseases. Evidence suggested that nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor that controls antioxidant response element (ARE)-regulated antioxidant and cytoprotective genes has an essential protective role in the lungs against oxidative airway diseases. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies in respiratory diseases. We have reviewed major findings on the mechanisms of lung protection against oxidative stress by Nrf2 and the current literature suggesting that Nrf2 is a valuable therapeutic target.