Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Prevalence and risk factors of hemodynamic instability associated with preload-dependence during continuous renal replacement therapy in a prospective observational cohort of critically ill patients.

BACKGROUND: Hemodynamic instability is a frequent complication of continuous renal replacement therapy (CRRT). Postural tests (i.e., passive leg raising in the supine position or Trendelenburg maneuver in the prone position) combined with measurement of cardiac output are highly reliable to identify preload-dependence and may provide new insights into the mechanisms involved in hemodynamic instability related to CRRT (HIRRT). We aimed to assess the prevalence and risk factors of HIRRT associated with preload-dependence in ICU patients. We conducted a single-center prospective observational cohort study in ICU patients with acute kidney injury KDIGO 3, started on CRRT in the last 24 h, and monitored with a PiCCO® device. The primary endpoint was the rate of HIRRT episodes associated with preload-dependence during the first 7 days after inclusion. HIRRT was defined as the occurrence of a mean arterial pressure below 65 mmHg requiring therapeutic intervention. Preload-dependence was assessed by postural tests every 4 h, and during each HIRRT episode. Data are expressed in median [1st quartile-3rd quartile], unless stated otherwise. RESULTS: 42 patients (62% male, age 69 [59-77] year, SAPS-2 65 [49-76]) were included 6 [1-16] h after CRRT initiation and studied continuously for 121 [60-147] h. A median of 5 [3-8] HIRRT episodes occurred per patient, for a pooled total of 243 episodes. 131 episodes (54% [CI95% 48-60%]) were associated with preload-dependence, 108 (44%, [CI95% 38-51%]) without preload-dependence, and 4 were unclassified. Multivariate analysis (using variables collected prior to HIRRT) identified the following variables as risk factors for the occurrence of HIRRT associated with preload-dependence: preload-dependence before HIRRT [odds ratio (OR) = 3.82, p < 0.001], delay since last HIRRT episode > 8 h (OR = 0.56, p < 0.05), lactate (OR = 1.21 per 1-mmol L-1 increase, p < 0.05), cardiac index (OR = 0.47 per 1-L min-1 m-2 increase, p < 0.001) and SOFA at ICU admission (OR = 0.91 per 1-point increase, p < 0.001). None of the CRRT settings was identified as risk factor for HIRRT. CONCLUSIONS: In this single-center study, HIRRT associated with preload-dependence was slightly more frequent than HIRRT without preload-dependence in ICU patients undergoing CRRT. Testing for preload-dependence could help avoiding unnecessary decrease of fluid removal in preload-independent HIRRT during CRRT.

Impact of Lung Biopsy on Lung Function in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Video-assisted surgical lung biopsy (SLB) is performed in 10-30% of cases to establish the diagnosis of idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The aim of the study was to analyze the impact of SLB on lung function in patients eventually diagnosed with IPF. METHODS: This is an observational, retrospective, monocentric study of all consecutive patients eventually diagnosed with IPF in multidisciplinary discussion who underwent SLB over 10 years in a specialized center. The primary end point was the variation in forced vital capacity (FVC) before and after the SLB. The secondary end points were the variations in forced expiratory volume in one second (FEV1), total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and morbidity and mortality associated with the SLB. RESULTS: In 118 patients who underwent SLB and were diagnosed with IPF, a relative decrease in FVC of 4.8% (p < 0.001) was found between measurements performed before and after the procedure. The mean FVC decrease was 156 ± 386 mL in an average period of 185 days, representing an annualized decline of 363 ± 764 mL/year. A significant decrease was also observed after SLB in FEV1, TLC, and DLCO. Complications within 30 days of SLB occurred in 14.4% of patients. Two patients (1.7%) died within 30 days, where one of them had poor lung function. Survival at 1 year was significantly poorer in patients with FVC <50% at baseline. CONCLUSION: In this uncontrolled study in patients ultimately diagnosed with IPF, SLB was followed by a significant decline in FVC, which appears to be numerically greater than the average decline in the absence of treatment in the literature. Summary at a Glance: This study evaluated the change in lung function in 118 consecutive patients diagnosed with idiopathic pulmonary fibrosis by surgical lung biopsy. Forced vital capacity decreased by 156 ± 386 mL in a mean of 185 days between the last measurement before and first measurement after biopsy, representing an annualized decline of 363 ± 764 mL/year.

Low-pressure support vs automatic tube compensation during spontaneous breathing trial for weaning.

BACKGROUND: During spontaneous breathing trial, low-pressure support is thought to compensate for endotracheal tube resistance, but it actually should provide overassistance. Automatic tube compensation is an option available in the ventilator to compensate for flow-resistance of endotracheal tube. Its effects on patient effort have been poorly investigated. We aimed to compare the effects of low-pressure support and automatic tube compensation during spontaneous breathing trial on breathing power and lung ventilation distribution. RESULTS: We performed a randomized crossover study in 20 patients ready to wean. Each patient received both methods for 30 min separated by baseline ventilation: pressure support 0 cmH2O and automatic tube compensation 100% in one period and pressure support 7 cmH2O without automatic tube compensation in the other period, a 4 cmH2O positive end-expiratory pressure being applied in each. Same ventilator brand (Evita XL, Draeger, Germany) was used. Breathing power was assessed from Campbell diagram with esophageal pressure, airway pressure, flow and volume recorded by a data logger. Lung ventilation distribution was assessed by using electrical impedance tomography (Pulmovista, Draeger, Germany). During the last 2 min of low-pressure support and automatic compensation period breathing power and lung ventilation distribution were measured on each breath. Breathing power generated by the patient's respiratory muscles was 7.2 (4.4-9.6) and 9.7 (5.7-21.9) J/min in low-pressure support and automatic tube compensation periods, respectively (P = 0.011). Lung ventilation distribution was not different between the two methods. CONCLUSIONS: We found that ATC was associated with higher breathing power than low PS during SBT without altering the distribution of lung ventilation.

Acute Respiratory Failure in Obesity-Hypoventilation Syndrome Managed in the ICU.

BACKGROUND: Obesity-hypoventilation syndrome (OHS) is defined as the combination of obesity (body mass index ≥ 30 kg/m2) and daytime arterial hypercapnia (PaCO2 > 45 mm Hg) in the absence of other causes of hypoventilation, and can lead to acute hypercapnic respiratory failure in the ICU. Our objective was to describe the ventilatory management and outcomes of subjects with OHS who were admitted to the ICU for acute hypercapnic respiratory failure. METHODS: We retrospectively built a cohort of subjects with OHS who were admitted for acute hypercapnic respiratory failure in 4 ICUs of the university teaching hospital in Lyon, France, between 2013 and 2017. The main end point was the rate of success of noninvasive ventilation (NIV). Secondary end points were survival from OHS diagnosis to the last follow-up and risk factors for ICU admission and long-term survival. RESULTS: One hundred fifteen subjects with OHS were included. Thirty-seven subjects (32.1%) were admitted to the ICU for acute hypercapnic respiratory failure. Congestive heart failure was the leading cause of acute hypercapnic respiratory failure (54%). At ICU admission, pH before NIV use was median (range) 7.26 (7.22-7.31) and PaCO2 was 70 (61-76) mm Hg. NIV was used as first-line ventilatory support in 36 subjects (97.2%) and was successful in 33 subjects (91.7%). ICU mortality was low (2.7%). The subjects admitted to the ICU were significantly older and had a lower FEV1 and vital capacity at the time of an OHS diagnosis. The difference in the restricted mean survival time was 663 d in favor of subjects not admitted to the ICU. Multivariate analysis showed that lower vital capacity at an OHS diagnosis was significantly associated with a higher risk of ICU admission. No factor was independently associated with long-term overall mortality in multivariate analysis. CONCLUSIONS: Acute hypercapnic respiratory failure in subjects with OHS was generally responsive to NIV and was frequently associated with congestive heart failure.

Impact of comorbidities and delay in diagnosis in elderly patients with pulmonary hypertension.

Patient age at diagnosis of pulmonary hypertension is steadily increasing. The present study sought to analyse clinical characteristics, time to diagnosis and prognosis of pulmonary hypertension in elderly and very elderly patients. A study was conducted in a French regional referral centre for pulmonary hypertension. All consecutive patients diagnosed with pre-capillary pulmonary hypertension were included and categorised according to age: <65 years ("young"), 65-74 years ("elderly") and ≥75 years ("very elderly"). Over a 4-year period, 248 patients were included: 101 (40.7%) were young, 82 (33.1%) were elderly and 65 (26.2%) were very elderly. The median age at diagnosis among the total population was 68 years. Compared with young patients, elderly and very elderly patients had a longer time to diagnosis (7±48, 9±21 and 16±32 months, respectively; p<0.001). Patients ≥75 years also more often had group 4 pulmonary hypertension. The median overall survival was 46±1.4 months, but was only 37±4.9 months in elderly patients and 28±4.7 months in very elderly patients. Survival from the first symptoms and survival adjusted to comorbidity was similar across age groups. Patient age should be taken into account when diagnosing pulmonary hypertension as it is associated with a specific clinical profile and a worse prognosis. The difference in prognosis is likely to be related to a delay in diagnosis and a greater number of comorbidities.

Dysregulation of the endothelin pathway in lymphangioleiomyomatosis with no direct effect on cell proliferation and migration.

LAM is a rare low-grade metastasizing lung neoplasm. Inhibitors of mTOR improve clinical outcome of LAM patients by preventing loss of lung function. Nevertheless, other cell targets may be of interest for drug development. Therefore, we explored the potential role of EDN1 (endothelin) in LAM. We report an increased endothelin blood level in LAM patients as well as EDN1 overexpression and EDN1 receptor downregulation in LAM-derived primary cells and in TSC2NEG cells mutated in TSC2. We evidenced EDN pathway dysregulation based on EDN1, EDNRA, EDNRB and ARRB1 mRNA expression in LAM-derived primary cells. We showed overexpression of EDN1 and ARRB1 mRNAs in TSC2NEG cells; these cells lost their ability to respond to stimulation by endothelin. We analyzed the effects of endothelin receptor antagonists alone or in combination with rapamycin, an mTOR inhibitor, on proliferation and migration of LAM cells. Rapamycin treatment of TSC2NEG cells significantly reduced cell proliferation or migration, while none of the tested inhibitors of EDN receptors impaired these functions. We showed that TSC2NEG cells have acquired a transformed phenotype as showed by their ability to grow as spheroids in semi-solid medium and that unlike endothelin receptors antagonists, rapamycin reduced anchorage-independent cell growth and prevented expansion of TSC2NEG spheroids.

Pulmonary hypertension in chronic lung diseases: comparison to other pulmonary hypertension groups.

Group 3 pulmonary hypertension (PH) is a common complication of advanced chronic lung disease. Our hypothesis was that group 3 PH is associated with a more severe baseline presentation and a more severe prognosis compared to group 1 pulmonary arterial hypertension (PAH), chronic thromboembolic PH (group 4), and group 5 PH. We retrospectively analyzed consecutive incident PH patients in a single center between January 2006 and November 2014. Data were acquired from a prospective database. Clinical, functional, and hemodynamic characteristics, as well as survival, were compared between the four groups of precapillary PH. A total of 363 patients were analyzed; 164 patients (45.2%) belonged to group 1 PAH, 109 (30%) to group 3 PH, 65 (17.9%) to group 4 PH, and 25 (6.9%) to group 5 PH. Group 3 patients were predominantly male and were more frequently in New York Heart Association (NYHA) class III/IV. Patients with group 3 and 4 PH were older, had significantly lower 6-min walking distance (6MWD), higher mean pulmonary arterial pressure, higher pulmonary vascular resistance (PVR), and lower cardiac index (CI) than PAH patients. Group 3 and 5 patients had significantly lower total lung capacity (TLC), forced vital capacity (FVC), and FEV1; group 3 patients had the lowest carbon monoxide transfer coefficient values. PH therapy was used in 90.9% of group 3 patients. Univariate analysis of prognostic factors in the overall population showed that age, male gender, NYHA class, groups 3 and 4 PH (vs. PAH), 6MWD, FVC, TLC, carbon monoxide transfer coefficient (KCO), PVR, CI, and venous oxygen saturation were significantly associated with greater mortality. Multivariate analysis showed that age, PH group 4, 6MWD, and KCO but no longer PH group 3 were significantly associated with mortality. Patients with group 3 PH are older, have more severe baseline presentation and lower survival rates than PAH patients in univariate analysis, that seemed to be related to older age.

Pulmonary alveolar proteinosis following cryptococcal meningitis: a possible cause?

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the presence of granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies. A man with no history of infection developed cryptococcal meningitis and a right parahilar cryptococcal mass. Antifungal treatment led to infection control, although there was presence of neurological sequelae. After 3 years, thoracic CT revealed bilateral ground glass opacities and a crazy paving pattern. Transparietal needle biopsy showed proteinaceous alveolar deposits, confirming the diagnosis of PAP. A high titre of serum anti-GM-CSF autoantibodies was found. No specific treatment was started, and radiological lesions decreased progressively. Cryptococcal infection may occur in PAP and in patients with anti-GM-CSF antibodies without PAP. These antibodies dysregulate phagocytosis in monocytes and macrophages, possibly leading to opportunistic infections in previously healthy subjects.

Improvement with infliximab of a disseminated sarcoidosis in a patient with Crohn's disease.

Sarcoidosis and Crohn's disease are systemic granulomatous disorders affecting the lung and the intestine, respectively, with variable involvement of other organs and are seldom associated. While anti-TNF α is a recognized treatment of Crohn's disease, its usage is discussed in sarcoidosis. A 42-year-old man presented with an 11-year-long history of Crohn's disease; upon discovery of an abnormal chest CT scan the diagnosis of multivisceral sarcoidosis was made and, later, a treatment with an anti-TNF α agent, infliximab, was started, because of worsening Crohn's disease recurrences. CT scan demonstrated net regression of pulmonary opacities and hepatosplenic lesions. Pathologies obtained from the intestinal tract and the bronchi of the patient were, respectively, characteristic of Crohn's disease and sarcoidosis leading to the diagnosis of both diseases. We report a rare case of steroid resistant Crohn's disease associated with multivisceral sarcoidosis, treated successfully by an anti-TNF α agent, infliximab.