Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on Metabolism.

The recreational use of nitrous oxide (N2O), also called laughing gas, has increased significantly in recent years. In 2022, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recognized it as one of the most prevalent psychoactive substances used in Europe. Chronic nitrous oxide (N2O) exposure can lead to various clinical manifestations. The most frequent symptoms are neurological (sensitive or motor disorders), but there are also other manifestations like psychiatric manifestations or cardiovascular disorders (thrombosis events). N2O also affects various neurotransmitter systems, leading to its anesthetic, analgesic, anxiolytic and antidepressant properties. N2O is very challenging to measure in biological matrices. Thus, in cases of N2O intoxication, indirect biomarkers such as vitamin B12, plasma homocysteine and plasma MMA should be explored for diagnosis and assessment. Others markers, like oxidative stress markers, could be promising but need to be further investigated.

Targeted Metabolomics Analysis Suggests That Tacrolimus Alters Protection against Oxidative Stress.

Tacrolimus (FK506) is an immunosuppressant that is experiencing a continuous rise in usage worldwide. The related side effects are known to be globally dose-dependent. Despite numerous studies on FK506, the mechanisms underlying FK506 toxicity are still not well understood. It is therefore essential to explore the toxicity mediated by FK506. To accomplish this, we conducted a targeted metabolomic analysis using LC-MS on the plasma samples of patients undergoing FK506 treatment. The aim was to identify any associated altered metabolic pathway. Another anti-calcineurin immunosuppressive therapy, ciclosporin (CSA), was also studied. Increased plasma concentrations of pipecolic acid (PA) and sarcosine, along with a decrease in the glycine/sarcosine ratio and a tendency of increased plasma lysine was observed in patients under FK506 compared to control samples. Patients under CSA do not show an increase in plasma PA compared to the control samples, which does not support a metabolic link between the calcineurin and PA. The metabolomics changes observed in patients under FK506 highlight a possible link between FK506 and the action of an enzyme involved in both PA and sarcosine catabolism and oxidative pathway, the Peroxisomal sarcosine oxidase (PIPOX). Moreover, PA could be investigated as a potential biomarker of early nephrotoxicity in the follow-up of patients under FK506.

The relationship between residential exposure to atmospheric pollution and circulating miRNA in adults living in an urban area in northern France.

INTRODUCTION: MicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2. METHOD: We included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010-2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmospheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multivariate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p < 0.1. RESULTS: The mean annual exposure between 2011 and the year of inclusion was 26.4 ± 2.0 µg/m3 for PM10 and 24.7 ± 5.1 µg/m3 for NO2. Each 2 µg/m3 increment in PM10 exposure was associated with an 8.6% increment (95%CI [3.1; 14.3]; pFDR = 0.019) in miR-451a expression. A 5 µg/m3 increment in NO2 exposure was associated with a 5.3% increment ([0.7; 10]; pFDR = 0.056) in miR451a expression, a 3.6% decrement (95%CI [-6.1; -1.1]; pFDR = 0.052) in miR-223-3p expression, a 3.8% decrement (95%CI[-6.8; -0.7]; pFDR = 0.079) in miR-28-3p expression, a 4.3% decrement (95%CI [-7.7; -0.8]; pFDR = 0.055) in miR-146a-5p expression, and a 4.0% decrement (95% CI[-7.4; -0.4]; pFDR = 0.059) in miR-23a-5p expression. The difference between the two housekeeping microRNAs miR-93-5p and miR-191-5p was also associated with PM10 and NO2 exposure. CONCLUSION: Our results suggest that circulating miRNAs are potentially valuable biomarkers of the effects of air pollution.

Plasma thymic stromal lymphopoietin (TSLP) in adults with non-severe asthma: the EGEA study.

Thymic stromal lymphopoietin (TSLP), a cytokine involved in severe asthma treatment, was never studied in non-severe asthma.Among 969 adults from a large epidemiological study, cross-sectional analyses showed that plasma TSLP levels were associated with increased age and BMI, male sex, smoking and high TSLP levels (one IQR increase) with current asthma and poor lung function. High TSLP levels were also associated with persistence of asthma attacks (aOR=2.14 (95% CI 1.23 to 3.72)) and dyspnoea (aOR=2.71 (95% CI 1.39 to 5.28)) 10 years later.Our results suggest that TSLP could be a cytokine of interest in non-severe asthma, and its determinants of circulating levels could be considered in asthma management.

Identification of novel genes influencing eosinophil-specific protein levels in asthma families.

BACKGROUND: Eosinophils play a key role in the asthma allergic response by releasing cytotoxic molecules such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) that generate epithelium damages. OBJECTIVE: We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families. METHODS: We performed univariate and bivariate genome-wide association analyses of ECP and EDN levels in 1018 subjects from the EGEA study with follow-up in 153 subjects from the Saguenay-Lac-Saint-Jean study and combined the results of these 2 studies through meta-analysis. We then conducted Bayesian statistical fine mapping together with quantitative trait locus and functional annotation analyses to identify the most likely functional genetic variants and candidate genes. RESULTS: We identified 5 genome-wide significant loci (P &lt; 5 × 10^-8) including 7 distinct signals associated with ECP and/or EDN levels. The genes targeted by our fine mapping and functional search include RNASE2 and RNASE3 (14q11), which encode EDN and ECP, respectively, and 4 other genes that regulate ECP and EDN levels. These 4 genes were JAK1 (1p31), a transcription factor that plays a key role in the immune response and acts as a potential therapeutic target for eosinophilic asthma; ARHGAP25 (2p13), which is involved in leukocyte recruitment to inflammatory sites; NDUFA4 (7p21), which encodes a component of the mitochondrial respiratory chain and is involved in cellular response to stress; and CTSL (9q22), which is involved in immune response, extracellular remodeling, and allergic inflammation. CONCLUSION: Analysis of specific phenotypes produced by eosinophils allows the identification of genes that play a major role in allergic response and inflammation, and offers potential therapeutic targets for asthma.

Genome-Wide Association Study of Fluorescent Oxidation Products Accounting for Tobacco Smoking Status in Adults from the French EGEA Study.

Oxidative stress (OS) is the main pathophysiological mechanism involved in several chronic diseases, including asthma. Fluorescent oxidation products (FlOPs), a global biomarker of damage due to OS, is of growing interest in epidemiological studies. We conducted a genome-wide association study (GWAS) of the FlOPs level in 1216 adults from the case-control and family-based EGEA study (mean age 43 years old, 51% women, and 23% current smokers) to identify genetic variants associated with FlOPs. The GWAS was first conducted in the whole sample and then stratified according to smoking status, the main exogenous source of reactive oxygen species. Among the top genetic variants identified by the three GWAS, those located in BMP6 (p = 3 × 10-6), near BMPER (p = 9 × 10-6), in GABRG3 (p = 4 × 10-7), and near ATG5 (p = 2 × 10-9) are the most relevant because of both their link to biological pathways related to OS and their association with several chronic diseases for which the role of OS in their pathophysiology has been pointed out. BMP6 and BMPER are of particular interest due to their involvement in the same biological pathways related to OS and their functional interaction. To conclude, this study, which is the first GWAS of FlOPs, provides new insights into the pathophysiology of chronic OS-related diseases.

Short-term and residential exposure to air pollution: Associations with inflammatory biomarker levels in adults living in northern France.

INTRODUCTION: Air pollution has an impact on health, and low-grade inflammation might be one of the underlying mechanisms. The objective of the present study of adults from northern France was to assess the associations between short-term and residential exposure to air pollution and levels of various inflammatory biomarkers. METHODS: The cross-sectional Enquête Littoral Souffle Air Biologie Environnement (ELISABET) study was conducted from 2011 to 2013 in the Lille and Dunkirk urban areas of northern France. Here, we evaluated the associations between PM10, NO2 and O3 exposure (on the day of the blood sample collection and on the day before, and the mean annual residential level) and levels of the inflammatory biomarkers high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, IL-22, and tumor necrosis factor α. RESULTS: We assessed 3074 participants for the association with hsCRP and a subsample of 982 non-smokers from Lille for the association with plasma cytokine levels. A 10 µg/m3 increment in PM10 and NO2 levels on the day of sample collection and on the day before was associated with a higher hsCRP concentration (3.43% [0.68; 6.25] and 1.75% [-1.96; 5.61], respectively, whereas a 10 µg/m3 increment in O3 was associated with lower hsCRP concentration (-1.2% [-3.95; 1.64]). The associations between mean annual exposure and the hsCRP level were not significant. Likewise, the associations between exposure and plasma cytokine levels were not statistically significant. CONCLUSION: Short-term exposure to air pollution was associated with higher serum hsCRP levels in adult residents of two urban areas in northern France. Our results suggest that along with other factors, low-grade inflammation might explain the harmful effects of air pollution on health.

Blood eosinophil cationic protein and eosinophil-derived neurotoxin are associated with different asthma expression and evolution in adults.

BACKGROUND: Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are proteins released by activated eosinophils whose role in adult asthma remains unclear. OBJECTIVE: To study associations between ECP, EDN and various asthma characteristics in adults from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). METHODS: Plasma ECP and EDN levels were measured by ELISA. Cross-sectional analyses were performed in 941 adults (43±16 years old, 39% with asthma) at EGEA2 (2003-2007). Longitudinal analyses investigated the associations between EDN level at EGEA2 and changes in asthma characteristics between EGEA2 and EGEA3 (2011-2013, n=817). We used generalised estimated equations adjusted for age, sex, smoking status and body mass index to take into account familial dependence. RESULTS: At EGEA2, both high ECP and EDN levels were associated with current asthma (adjusted OR (aOR) (95% CI): 1.69 (1.35-2.12) and 2.12 (1.76-2.57)). Among asthmatics, high EDN level was associated with asthma attacks (aOR: 1.50 (1.13-1.99)), wheezing and breathlessness (aOR: 1.38 (1.05-1.80)), use of asthma treatments (aOR: 1.91 (1.37-2.68)) and bronchial hyper-responsiveness (aOR: 2.03 (1.38-2.97)), even after further adjustment on ECP. High ECP level was associated with high neutrophil count and tended to be associated with chronic bronchitis. High EDN level at EGEA2 was associated with persistent asthma (aOR: 1.62 (1.04-2.52)), nocturnal symptoms (aOR from 2.19 to 3.57), worsening wheezing and breathlessness (aOR: 1.97 (1.36-2.85)) and nocturnal shortness of breath (aOR: 1.44 (1.04-1.98)) between EGEA2 and EGEA3. CONCLUSIONS: EDN and ECP were associated with different asthma expression in adults. EDN could be a potential biomarker to monitor asthma evolution in adults.

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults.

AIM: The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation. METHODS: We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status. RESULTS: Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5). CONCLUSION: Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

PID1 is associated to a respiratory endotype related to occupational exposures to irritants.

BACKGROUND: Studying associations between genes and asthma endotypes and interactions with environment could help to identify new susceptibility genes. We used a previously identified asthma endotype characterized by adult-onset asthma, poor lung function, and high level of Fluorescent oxidation products, a marker of damages due to oxidative stress. This endotype was associated with high occupational exposure to irritants. We aimed to investigate the associations between genes related to oxidative stress and this endotype, and if the associations differed according to irritants exposure. METHODS: We conducted association analyses between the asthma endotype and genetic variants (4715 SNPs) located in 422 genes involved in the "response to oxidative stress" in adults from the Epidemiological study on the Genetic and Environment of Asthma. Analyses using logistic regression were conducted first in all participants, and then separately among high vs. non-exposed participants to assess whether association differs according to irritants exposure. RESULTS: An association was found between the SNP rs1419958 located in PID1 gene and the endotype (P = 2.2E-05), reaching significance level after correction for multiple testing. This association was even more significant in non-exposed participants (P = 1.06E-06) while there was no association in participants with high exposure to occupational irritants. CONCLUSION: This study showed a significant association between an asthma endotype and PID1, a promising candidate gene, the association being different according to the exposure to irritants. These results highlight the interest of studying asthma endotypes in association with genes from candidate pathways and their link with occupational irritants to decipher asthma etiology.

Is COPD associated with increased risk for microaspiration in intubated critically ill patients?

BACKGROUND: Although COPD patients are at higher risk for aspiration when breathing spontaneously, no information is available on the risk for microaspiration in invasively ventilated COPD patients. The aim of our study was to determine the relationship between COPD and abundant microaspiration in intubated critically ill patients. METHODS: This was a retrospective analysis of prospectively collected data, provided by 3 randomized controlled trials on microaspiration in critically ill patients receiving invasive mechanical ventilation for more than 48 h. Abundant microaspiration was defined as the presence of pepsin and or alpha-amylase at significant levels in tracheal aspirates. In all study patients, pepsin and alpha-amylase were quantitatively measured in all tracheal aspirates collected during a 48-h period. COPD was defined using spirometry criteria. RESULTS: Among the 515 included patients, 70 (14%) had proven COPD. Pepsin and alpha-amylase were quantitatively measured in 3873 and 3764 tracheal aspirates, respectively. No significant difference was found in abundant microaspiration rate between COPD and non-COPD patients (62 of 70 patients (89%) vs 366 of 445 (82%) patients, p = 0.25). Similarly, no significant difference was found in abundant microaspiration of gastric contents (53% vs 45%, p = 0.28), oropharyngeal secretions (71% vs 71%, p = 0.99), or VAP (19% vs 22%, p = 0.65) rates between the two groups. No significant difference was found between COPD and non-COPD patients in duration of mechanical ventilation, ICU length of stay, or ICU mortality. CONCLUSIONS: Our results suggest that COPD is not associated with increased risk for abundant microaspiration in intubated critically ill patients.

Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. METHODS: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18-40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. RESULTS: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min-1 kg-1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 µmol/l; interaction 'exercise' × 'group', p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma L-arginine (p < 0.05)-in particular when HbA1c was high (mean estimation: -4.0, p < 0.05)-and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. Graphical abstract CONCLUSIONS/INTERPRETATION: Participants with uncomplicated type 1 diabetes displayed reduced availability of L-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. TRIAL REGISTRATION: clinicaltrials.gov NCT02051504.

Transesophageal echocardiography-associated tracheal microaspiration and ventilator-associated pneumonia in intubated critically ill patients: a multicenter prospective observational study.

BACKGROUND: Microaspiration of gastric and oropharyngeal secretions is the main causative mechanism of ventilator-associated pneumonia (VAP). Transesophageal echocardiography (TEE) is a routine investigation tool in intensive care unit and could enhance microaspiration. This study aimed at evaluating the impact of TEE on microaspiration and VAP in intubated critically ill adult patients. METHODS: It is a four-center prospective observational study. Microaspiration biomarkers (pepsin and salivary amylase) concentrations were quantitatively measured on tracheal aspirates drawn before and after TEE. The primary endpoint was the percentage of patients with TEE-associated microaspiration, defined as: (1) ≥ 50% increase in biomarker concentration between pre-TEE and post-TEE samples, and (2) a significant post-TEE biomarker concentration (> 200 µg/L for pepsin and/or > 1685 IU/L for salivary amylase). Secondary endpoints included the development of VAP within three days after TEE and the evolution of tracheal cuff pressure throughout TEE. RESULTS: We enrolled 100 patients (35 females), with a median age of 64 (53-72) years. Of the 74 patients analyzed for biomarkers, 17 (23%) got TEE-associated microaspiration. However, overall, pepsin and salivary amylase levels were not significantly different between before and after TEE, with wide interindividual variability. VAP occurred in 19 patients (19%) within 3 days following TEE. VAP patients had a larger tracheal tube size and endured more attempts of TEE probe introduction than their counterparts but showed similar aspiration biomarker concentrations. TEE induced an increase in tracheal cuff pressure, especially during insertion and removal of the probe. CONCLUSIONS: We could not find any association between TEE-associated microaspiration and the development of VAP during the three days following TEE in intubated critically ill patients. However, our study cannot formally rule out a role for TEE because of the high rate of VAP observed after TEE and the limitations of our methods.

Exposure to metal fumes and circulating miRNAs in Algerian welders.

PURPOSE: A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury. METHODS: Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses. RESULTS: miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders. CONCLUSION: In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.

Does the oxidative stress play a role in the associations between outdoor air pollution and persistent asthma in adults? Findings from the EGEA study.

BACKGROUND: Evidences that oxidative stress plays a role in the associations between outdoor air pollution and asthma are growing. We aimed to study the role of plasma fluorescent oxidation products levels (FlOPs; an oxidative stress-related biomarker), as potential mediators, in the associations between outdoor air pollution and persistent asthma. METHODS: Analyses were conducted in 204 adult asthmatics followed up in the French case-control and family study on asthma (EGEA; the Epidemiological study of the Genetic and Environmental factors of Asthma). Persistent asthma was defined as having current asthma at EGEA2 (baseline, 2003-2007) and EGEA3 (follow-up, 2011-2013). Exposures to nitrogen dioxide, nitrogen oxides, road traffic, particulate matter with a diameter ≤ 10 µm (PM10) and ≤ 2.5 µm were estimated by ESCAPE models (2009-2010), and ozone (O3) by IFEN models (2004). We used a mediation analysis to assess the mediated effect by FlOPs levels and the interaction between FlOPs levels and air pollution. RESULTS: FlOPs levels increased with PM10 and O3 (adjusted ß = 0.04 (95%CI 0.001-0.08), aß = 0.04 (95%CI 0.009-0.07) per 10 µg/m3, respectively), and the risk of persistent asthma increased with FlOPs levels (aOR = 1.81 (95%CI 1.08-3.02)). The risk of persistent asthma decreased with exposures to NO2, NOx and PM2.5 (aOR ranging from 0.62 to 0.94), and increased with exposures to PM10, O3, O3-summer and road traffic, the greater effect being observed for O3 (aOR = 1.78, 95% CI 0.73-4.37, per 10 µg/m3). Using mediation analysis, we observed a positive total effect (aOR = 2.16, 95%CI 0.70-11.9), a positive direct effect of O3 on persistent asthma (OR = 1.68, 95%CI 0.57-7.25), and a positive indirect effect mediated by FIOPs levels (aOR = 1.28 (95%CI 1.01-2.29)) accounting for 41% of the total effect. CONCLUSIONS: Our results add insights on the role of oxidative stress in the association between air pollution and persistent asthma.

High level of fluorescent oxidation products and worsening of asthma control over time.

High Fluorescent oxidation products level (FlOPs), a global oxidative stress biomarker, was associated cross-sectionally with poor asthma outcomes but its longitudinal association with asthma evolution has never been examined. We aimed to study the associations between FlOPs level at baseline and changes in current asthma, asthma attacks and asthma control status over 8 years. We used data from the second survey of the French EGEA cohort study as baseline and the third survey as follow-up. At baseline, the mean age of the 489 participants with ever asthma was 39 (± 16) years, 49% were women. Among participants with controlled asthma at baseline, high FlOPs level was significantly associated with worsening of asthma control at follow-up (odds-ratio adjusted for age, sex and smoking status (95% CI): 2.27 (1.32-3.90). No other significant associations were observed. In conclusion, results suggest FlOPs as a predictor of asthma evolution in adults and a good candidate marker in asthma management.

Impact of nutrition route on microaspiration in critically ill patients with shock: a planned ancillary study of the NUTRIREA-2 trial.

BACKGROUND: Microaspiration of gastric and oropharyngeal secretions is the main mechanism of entry of bacteria into the lower respiratory tract in intubated critically ill patients. The aim of this study is to determine the impact of enteral nutrition, as compared with parenteral nutrition, on abundant microaspiration of gastric contents and oropharyngeal secretions. METHODS: Planned ancillary study of the randomized controlled multicenter NUTRIREA2 trial. Patients with shock receiving invasive mechanical ventilation were randomized to receive early enteral or parenteral nutrition. All tracheal aspirates were collected during the 48 h following randomization. Abundant microaspiration of gastric contents and oropharyngeal secretions was defined as the presence of significant levels of pepsin (> 200 ng/ml) and salivary amylase (> 1685 UI/ml) in > 30% of tracheal aspirates. RESULTS: A total of 151 patients were included (78 and 73 patients in enteral and parenteral nutrition groups, respectively), and 1074 tracheal aspirates were quantitatively analyzed for pepsin and amylase. Although vomiting rate was significantly higher (31% vs 15%, p = 0.016), constipation rate was significantly lower (6% vs 21%, p = 0.010) in patients with enteral than in patients with parenteral nutrition. No significant difference was found regarding other patient characteristics. The percentage of patients with abundant microaspiration of gastric contents was significantly lower in enteral than in parenteral nutrition groups (14% vs 36%, p = 0.004; unadjusted OR 0.80 (95% CI 0.69, 0.93), adjusted OR 0.79 (0.76, 0.94)). The percentage of patients with abundant microaspiration of oropharyngeal secretions was significantly higher in enteral than in parenteral nutrition groups (74% vs 54%, p = 0.026; unadjusted OR 1.21 (95% CI 1.03, 1.44), adjusted OR 1.23 (1.01, 1.48)). No significant difference was found in percentage of patients with ventilator-associated pneumonia between enteral (8%) and parenteral (10%) nutrition groups (HR 0.78 (0.26, 2.28)). CONCLUSIONS: Our results suggest that enteral and parenteral nutrition are associated with high rates of microaspiration, although oropharyngeal microaspiration was more common with enteral nutrition and gastric microaspiration was more common with parenteral nutrition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03411447 . Registered 18 July 2017. Retrospectively registered.