Circulating Dipeptidyl Peptidase 3 Modulates Systemic and Renal Hemodynamics Through Cleavage of Angiotensin Peptides.

BACKGROUND: High circulating DPP3 (dipeptidyl peptidase 3) has been associated with poor prognosis in critically ill patients with circulatory failure. In such situation, DPP3 could play a pathological role, putatively via an excessive angiotensin peptides cleavage. Our objective was to investigate the hemodynamics changes induced by DPP3 in mice and the relation between the observed effects and renin-angiotensin system modulation. METHODS: Ten-week-old male C57Bl/6J mice were subjected to intravenous injection of purified human DPP3 or an anti-DPP3 antibody (procizumab). Invasive blood pressure and renal blood flow were monitored throughout the experiments. Circulating angiotensin peptides and catecholamines were measured and receptor blocking experiment performed to investigate the underlying mechanisms. RESULTS: DPP3 administration significantly increased renal blood flow, while blood pressure was minimally affected. Conversely, procizumab led to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamines release that explains blood pressure maintenance upon DPP3 administration. CONCLUSIONS: High circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release.

Static compliance of the respiratory system in COVID-19 related ARDS: an international multicenter study.

BACKGROUND: Controversies exist on the nature of COVID-19 related acute respiratory distress syndrome (ARDS) in particular on the static compliance of the respiratory system (Crs). We aimed to analyze the association of Crs with outcome in COVID-19-associated ARDS, to ascertain its determinants and to describe its evolution at day-14. METHODS: In this observational multicenter cohort of patients with moderate to severe Covid-19 ARDS, Crs was measured at day-1 and day-14. Association between Crs or Crs/ideal body weight (IBW) and breathing without assistance at day-28 was analyzed with multivariable logistic regression. Determinants were ascertained by multivariable linear regression. Day-14 Crs was compared to day-1 Crs with paired t-test in patients still under controlled mechanical ventilation. RESULTS: The mean Crs in 372 patients was 37.6 ± 13 mL/cmH2O, similar to as in ARDS of other causes. Multivariate linear regression identified chronic hypertension, low PaO2/FiO2 ratio, low PEEP, and low tidal volume as associated with lower Crs/IBW. After adjustment on confounders, nor Crs [OR 1.0 (CI 95% 0.98-1.02)] neither Crs/IBW [OR 0.63 (CI 95% 0.13-3.1)] were associated with the chance of breathing without assistance at day-28 whereas plateau pressure was [OR 0.93 (CI 95% 0.88-0.99)]. In a subset of 108 patients, day-14 Crs decreased compared to day-1 Crs (31.2 ± 14.4 mL/cmH2O vs 37.8 ± 11.4 mL/cmH2O, p < 0.001). The decrease in Crs was not associated with day-28 outcome. CONCLUSION: In a large multicenter cohort of moderate to severe COVID-19 ARDS, mean Crs was decreased below 40 mL/cmH2O and was not associated with day-28 outcome. Crs decreased between day-1 and day-14 but the decrease was not associated with day-28 outcome.

Factors Associated With Pulmonary Embolism Among Coronavirus Disease 2019 Acute Respiratory Distress Syndrome: A Multicenter Study Among 375 Patients.

Risk factors associated with pulmonary embolism in coronavirus disease 2019 acute respiratory distress syndrome patients deserve to be better known. We therefore performed a post hoc analysis from the COronaVirus-Associated DIsease Study (COVADIS) project, a multicenter observational study gathering 21 ICUs from France (n = 12) and Belgium (n = 9). Three-hundred seventy-five consecutive patients with moderate-to-severe acute respiratory distress syndrome and positive coronavirus disease 2019 were included in the study. At day 28, 15% were diagnosed with pulmonary embolism. Known risk factors for pulmonary embolism including cancer, obesity, diabetes, hypertension, and coronary artery disease were not associated with pulmonary embolism. In the multivariate analysis, younger age (< 65 yr) (odds ratio, 2.14; 1.17-4.03), time between onset of symptoms and antiviral administration greater than or equal to 7 days (odds ratio, 2.39; 1.27-4.73), and use of neuromuscular blockers greater than or equal to 7 days (odds ratio, 1.89; 1.05-3.43) were independently associated with pulmonary embolism. These new findings reinforce the need for prospective studies that will determine the predictors of pulmonary embolism among patients with severe coronavirus disease 2019.

Reducing pain by using venous blood gas instead of arterial blood gas (VEINART): a multicentre randomised controlled trial.

INTRODUCTION: Venous sampling for blood gas analysis has been suggested as an alternative to arterial sampling in order to reduce pain. The main objective was to compare pain induced by venous and arterial sampling and to assess whether the type of sampling would affect clinical management or not. METHODS: We performed an open-label randomised multicentre prospective study in four French EDs during a 4-week period. Non-hypoxaemic adults, whose medical management required blood gas analysis, were randomly allocated using a computer-generated randomisation list stratified by centres with an allocation ratio of 1:1 using random blocks to one of the two arms: venous or arterial sampling. The primary outcome was the maximal pain during sampling, using the visual analogue scale. Secondary outcomes pertained to ease of sampling as rated by the nurse drawing the blood, and physician satisfaction regarding usefulness of biochemical data. RESULTS: 113 patients were included: 55 in the arterial and 58 in the venous sampling group. The mean maximal pain was 40.5 mm±24.9 mm and 22.6 mm±20.2 mm in the arterial group and the venous group, respectively, accounting for a mean difference of 17.9 mm (95% CI 9.6 to 26.3) (p<0.0001). Ease of blood sampling was greater in the venous group as compared with the arterial group (p=0.02). The usefulness of the results, evaluated by the prescriber, did not significantly differ (p=0.25). CONCLUSIONS: Venous blood gas is less painful for patients than ABG in non-hypoxaemic patients. Venous blood gas should replace ABG in this setting. TRIAL REGISTRATION NUMBER: NCT03784664.

Terrorist threat: Creating a nationwide damage control training program for non-trauma care providers.

INTRODUCTION: The current terrorist threat challenges nations to train numerous non-trauma care providers with different backgrounds in damage control (DC) strategies. The purpose of this work was to propose a specific DC training program. METHODS: A Task Force of 16 civilian and military physicians met for a 24-hour session, to propose the construction of a DC training program for non-specialised caregivers. RESULTS: Existing DC training programs are heterogeneous, mainly theoretical and almost only for physicians. A program entitled Damage Control for Terrorist Attack Victims (DC-TAV) was then proposed. Identified training targets were care providers from prehospital and hospital staffs, with no experience in trauma care. The training objectives were the improvement of individual and collective skills in managing terrorist attacks casualties. The tools selected for training concerned e-learning on a dedicated digital teaching platform (including a core section of four modules with types and mechanisms of injury, basic DC techniques, triage, organisation of emergency medical response and two complementary modules for doctors with DC resuscitation including remote transfusion and DC surgery), hands-on workshops with procedural simulation and full-scale simulation exercises, technical (tourniquets, haemostatic gauzes, needle thoracostomy, chest tube drainage, management of airway, coniotomy) and non-technical (leadership, communication, coordination and triage, decision-making, appropriate use of resources) skills. Finally, an evaluation of the DC-TAV program was planned. CONCLUSIONS: The DC-TAV program is an ambitious, civilian-military, nationwide and long-term program, based on a harmonised standard of care and including multidimensional training. Further studies are required to assess its efficacy.

Clinical impact of upper gastrointestinal endoscopy in critically ill patients with suspected bleeding.

BACKGROUND AND AIMS: Upper gastrointestinal endoscopies' (UGE) profitability is undisputable in patients admitted for an overt upper digestive tract bleeding. In critically ill subjects admitted for other causes, its performances have scarcely been investigated despite its broad use. We sought to question the performance of bedside UGE in intensive care unit (ICU) patients, admitted for another reason than overt bleeding. METHODS: This was a six-year (January 2007-December 2012) retrospective observational study of all UGE performed in a medico-surgical ICU. Exclusion of those performed: in patients admitted for a patent upper digestive bleeding; for a second-look gastroscopy of a known lesion; as a planned interventional procedure. Main demographic and clinical data were recorded; UGE indication and profitability were rated according to its findings and therapeutic impact. Operative values of the indications of UGE were calculated. This study received approval from the Ethics Committee of the French Society of Intensive Care (n° 12-363). RESULTS: Eighty-four patients (74% male, mean age 61 ± 14 years) underwent a diagnostic UGE, all for a suspected upper digestive tract bleeding. The main symptoms justifying the procedure were anemia (52%), digestive bleeding (27%), vomiting (15%), hemodynamic instability (3%) and hyperuremia (3%). The profitability of UGE was rated as major (n = 5; 5.8%); minor (n = 34; 40.5%); or null (n = 45; 53.6%). CONCLUSIONS: When ICU admission is not warranted by a digestive bleeding, UGE has limited diagnostic and therapeutic interest, despite being often performed.

Functional outcome of patients with prolonged hypoglycemic encephalopathy.

BACKGROUND: Little is known about the causes, clinical course and long-term outcome of comatose patients with prolonged hypoglycemic encephalopathy. METHODS: In a multicenter retrospective study conducted in patients hospitalized from July 1, 2004, to July 1, 2014, we investigated functional long-term prognosis and identified prognosis factors of patients admitted in an intensive care unit (ICU) with prolonged neurological manifestations related to hypoglycemia. Eligible patients were adults admitted to the ICU with a Glasgow Coma Score <8 due to hypoglycemia and persistent consciousness disorders after normalizing blood glucose levels. Patients with possible other causes of consciousness disorders, previous cognitive disorders, hypothermia <35 °C or circulatory arrest within 24 h after ICU admission, were excluded. Follow-up phone call was used to determine patients' functional outcome using modified Rankin Scale (mRS) at a minimum of 1-year follow-up with mRS 0-3 defining good and mRS 4-6 poor outcomes. RESULTS: Forty-nine patients were included. Causes of hypoglycemia were various, mainly including insulin or oral antidiabetic drugs abuse (65%) and neuroendocrine carcinoma (16%). Twenty (41%) patients died in the ICU, two (4%) patients further died and nine (18%) patients had a poor outcome at long-term follow-up. Five patients discharged from the ICU with mRS > 3 improved enough to be in the good outcome group 1 year later. Twenty-two (45%) patients underwent therapeutic limitation, mainly related to no expected hope for improvement. On multivariate analysis, only low mRS prior to ICU admission (OR 2.6; 95% CI 1.1-6.3; P = 0.03) and normal brain imaging (OR 7.1; 95% CI 1.1-44; P = 0.03) were significantly predictive of a good outcome. All patients (n = 15) who remained hypoglycemic >480 min had a poor outcome. CONCLUSION: Poor outcome was observed in about 60% of this population of hypoglycemic encephalopathy. However, some patients can recover satisfactorily over time.

Prone positioning in acute respiratory distress syndrome after abdominal surgery: a multicenter retrospective study : SAPRONADONF (Study of Ards and PRONe position After abDOmiNal surgery in France).

BACKGROUND: The recent demonstration of prone position's strong benefit on patient survival has rendered proning a major therapeutic intervention in severe ARDS. Uncertainties remain as to whether or not ARDS patients in the postoperative period of abdominal surgery should be turned prone because of the risk of abdominal complications. Our aim was to investigate the prevalence of surgical complications between patients with and without prone position after abdominal surgery. METHODS: This study was a multicenter retrospective cohort of patients with ARDS in a context of recent abdominal surgery. Primary outcome was the number of patients who had at least one surgical complication that could be induced or worsened by prone position. Secondary outcomes included effects of prone position on oxygenation. Data from the prone group were compared with those from the supine group (not having undergone at least a prone position session). RESULTS: Among 98 patients included, 36 (37%) had at least one prone position session. The rate of surgical complications induced or worsened by prone position did not differ between prone and supine groups [respectively, 14 (39%) vs 27 (44%); p = 0.65]. After propensity score application, there was no significant difference between the two groups (OR 0.72 [0.26-2.02], p = 0.54). Revision surgery did not differ between the groups. The first prone session significantly increased PaO2/FiO2 ratio from 95 ± 47 to 189 ± 92 mmHg, p < 0.0001. CONCLUSION: Prone position of ARDS patients after abdominal surgery was not associated with an increased rate of surgical complication. Intensivists should not refrain from proning these patients.

Effects of Proanthocyanidins on Adhesion, Growth, and Virulence of Highly Virulent Extraintestinal Pathogenic Escherichia coli Argue for Its Use to Treat Oropharyngeal Colonization and Prevent Ventilator-Associated Pneumonia.

OBJECTIVE: In the context of increasing microbial resistance and limited new antimicrobials, we aimed to study the antimicrobial effects of cranberry proanthocyanidin extracts on Escherichia coli growth, adhesion to epithelial cells, and lung infection. DESIGN: Experimental in vitro and in vivo investigation. SETTING: University research laboratory. SUBJECTS: Seventy-eight 6- to 8-week-old male Balb/C mice. INTERVENTIONS: In vitro, the effect of increasing concentrations of cranberry proanthocyanidin on bacterial growth of different clinical E. coli isolates was evaluated. Ex vivo, adhesion of E. coli to fresh human buccal epithelial cells was measured in the presence or absence of cranberry proanthocyanidin using microscopy. In vivo, lung bacterial count, pulmonary immune response (neutrophil murine chemokine keratinocyte-derived cytokine measurement and polymorphonuclear recruitment in bronchoalveolar lavage fluid), and lethality were evaluated in a pneumonia mouse model with E. coli precultured with or without cranberry proanthocyanidin. E. coli isolates originated from ventilated ICU patients with respiratory tract colonization or ventilator- associated pneumonia. They differed in number of virulence genes. MEASUREMENTS AND MAIN RESULTS: A significant inhibition of bacterial growth was observed with increasing concentration of cranberry proanthocyanidin, affecting both time to maximal growth and maximal growth rate (p<0.0001 for both). The minimal concentration at which this effect occurred was 250 µg/mL. Cranberry proanthocyanidin significantly reduced E. coli adhesion to fresh buccal epithelial cells by up to 80% (p<0.001). Bacterial counts in homogenized lungs and bronchoalveolar lavage fluid were decreased after cranberry proanthocyanidin exposition (p<0.05 and p<0.01, respectively). Cranberry proanthocyanidin also decreased KC concentrations and polymorphonuclear cell recruitment in bronchoalveolar lavage fluid (p<0.05 for both). At identical inoculum, mortality was reduced by more than half in mice inoculated with E. coli exposed to cranberry proanthocyanidin (p<0.01). CONCLUSION: Cranberry proanthocyanidins exhibit potent effects on growth, adhesion, and virulence of oropharyngeal and lung isolates of E. coli, suggesting that cranberry proanthocyanidin could be of clinical interest to reduce oropharyngeal colonization and prevent lung infection.

Invasive mechanical ventilation in patients with fibrosing interstitial pneumonia.

OBJECTIVE: The prognosis of patients with idiopathic pulmonary fibrosis or fibrosing idiopathic nonspecific interstitial pneumonia undergoing invasive mechanical ventilation (MV) for acute respiratory failure is known to be poor. The issue of life support in these patients needs to be reconsidered in light of changes during the past decade in ventilator settings and in the management of acute exacerbation. We therefore aimed to reassess the prognosis of such patients. METHODS: We retrospectively assessed the outcomes of all medical patients with idiopathic pulmonary fibrosis or fibrosing idiopathic nonspecific interstitial pneumonia who required invasive MV in 3 university hospitals in the Paris area from January 2002 to April 2009. RESULTS: In total, 27 patients (mean age, 66 ± 12.8 years) required invasive MV in the intensive care unit: 8 (30%) were successfully weaned from MV, and 6 and 4 were discharged from the intensive care unit and the hospital, respectively. Survivals for patients who did not undergo lung transplant were 22%, 3.7%, and 3.7%, at 30 days, 6 months, and 12 months, respectively. CONCLUSIONS: We confirm that use of invasive MV for acute respiratory failure in patients with idiopathic pulmonary fibrosis or fibrosing idiopathic nonspecific interstitial pneumonia is associated with a high mortality; however, a subset of patients may be discharged alive from the intensive care unit and hospital, providing an opportunity to consider lung transplant in case of eligibility. Our results suggest that invasive MV should not be systematically denied to these patients but discussed on a case-by-case basis.

Clinical features and outcomes in patients with disseminated toxoplasmosis admitted to intensive care: a multicenter study.

BACKGROUND: Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. METHODS: We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. RESULTS: Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P < .01) within 48 hours of ICU admission were associated with mortality. CONCLUSIONS: Severe disseminated toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

Candida albicans impairs macrophage function and facilitates Pseudomonas aeruginosa pneumonia in rat.

OBJECTIVE: To determine whether Candida albicans airway colonization influences Pseudomonas aeruginosa pneumonia prevalence in rats and by which mechanism. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory of a university. SUBJECTS: Male adult Wistar rats weighing 275-300 g. INTERVENTIONS: In vivo: P. aeruginosa pneumonia was induced by bronchial instillation of P. aeruginosa in rats previously instilled or not with live or ethanol-killed C. albicans. In vitro: Alveolar macrophages were incubated with or without live or ethanol-killed C. albicans. MEASUREMENTS AND MAIN RESULTS: Quantitative cultures of lung were done. Lung tumor necrosis factor alpha, interferon gamma, and interleukin-6 levels were measured along with reactive oxygen species (ROS) production by alveolar macrophages. P. aeruginosa pneumonia prevalence was higher in rats given live but not ethanol-killed C. albicans. Instilling live C. albicans alone increased lung tumor necrosis factor-alpha and interferon-gamma but not interleukin-6, and was not associated with clinical or histologic signs of infection. These three cytokines were more abundant in lungs instilled with live C. albicans and P. aeruginosa than in those instilled with P. aeruginosa alone or with ethanol-killed C. albicans and P. aeruginosa. Alveolar macrophages incubated with live C. albicans had decreased ROS production. CONCLUSIONS: C. albicans impedes alveolar macrophage ROS production and is correlated with an increase of P. aeruginosa pneumonia prevalence in rats. These results highlight the previously overlooked impact of airway fungal colonization on lung bacterial infection, and indicate the need for studies on the potential for antifungal therapy to prevent the onset of ventilator-associated pneumonia caused by P. aeruginosa.