Christophe Delclaux

Additive effect on gas exchange of inhaled nitric oxide and intravenous almitrine bismesylate in the adult respiratory distress syndrome

ObjectiveTo assess the additive effect of inhaled nitric oxide (NO) and intravenous almitrine bismesylate (ALM) on gas exchange.DesignProspective self-controlled study.Setting3 medico-surgical intensive care units.Patients17 patients with severe hypoxemia (PaO2/FIO2 ratio: 88±30mmHg, venous admixture: 47±7%) and elevated mean pulmonary artery pressure (MPAP: 30±5mmHg) due to adult respiratory distress syndrome (ARDS).Interventions5 conditions were studied: 1) baseline, 2) 5 to 10ppm of NO during 30min, 3) discontinuation of NO during 30min, 4) ALM infusion (0.5mg/kg) during 30min, 5) ALM infusion (0.5mg/kg) during 30min in combination with 5 to 10ppm of NO.Measurement and resultsThe PaO2/FIO2 ratio rose from 88±30 to 98±37mmHg (NS) with NO alone, and from 92±25 to 130±56mmHg (p<0.01) with NO+ALM (p<0.05 vs NO alone). Seven patients were considered as “NO-responders” (rise in PaO2/FIO2 ratio of 10mmHg or more with NO); in this subgroup the PaO2/FIO2 ratio rose from 87±30 to 128±39mmHg (p<0.05) with NO alone, and from 93±20 to 169±51mmHg (p<0.01) with NO+ALM (p<0.05 versus NO alone). MPAP decreased from 30±5 to 26±5mmHg (p<0.01) with NO alone, increased slightly from 28±5 to 31±5mmHg (NS) with ALM alone and decreased to 27±5mmHg (p<0.05) with NO+ALM.ConclusionsNO+ALM had additive effects on gas exchange while decreasing MPAP in patients with ARDS. The effects of NO alone were small and non significant, except in a subgroup of 7 patients in whom the combination of both therapies had the more pronounced results.

Deterioration of previous acute lung injury during neutropenia recovery

DesignAlthough neutropenia recovery is associated with a high risk of deterioration of respiratory condition, no studies designed to identify risk factors for acute respiratory distress syndrome (ARDS) in this situation have been published. SettingMedical ICU in a French teaching hospital. Subjects We conducted a study to describe critically ill cancer patients with ARDS during neutropenia recovery (defined as the 7-day period centered on the day the neutrophil count rose above 1000/mm3 [day 0]) and to compare them with critically ill cancer patients without ARDS during neutropenia recovery. InterventionsNone. Measurements and Main ResultsDuring a 10-yr period, 62 critically ill cancer patients recovered from neutropenia, of whom 21 experienced ARDS during neutropenia recovery, with a median time of −1 days (−2.5–1) between day 0 and ARDS. In-ICU mortality in these 21 patients was 61.9%. As compared with non-ARDS patients, ARDS patients were less likely to have myeloma and more likely to have leukemia/lymphoma treated with adriamycin, a history of pneumonia before neutropenia, and a neutropenia duration >10 days; they had a shorter time since malignancy diagnosis and a longer time from chemotherapy to neutropenia. Neither the leukocyte counts on day 0 nor those during the 6-day neutropenia recovery period were predictive of ARDS. ConclusionsPatients with acute respiratory failure after prolonged neutropenia complicated by pneumonia are at increased risk for ARDS.

Vascular endothelial growth factor synthesis in the acute phase of experimental and clinical lung injury

Vascular endothelial growth factor (VEGF) is a potent angiogenic and endothelial survival factor, which is abundantly expressed in the normal lung. Conceivably, VEGF may be released by numerous cell types found around the airspaces, including alveolar type 2 cells, alveolar macrophages, and polymorphonuclear neutrophils. Using a bacteria-induced lung injury model in rats, VEGF expression in lung was investigated. Both VEGF protein and VEGF messenger ribonucleic acid (mRNA), 4 and 24 h after bacterial challenge (Pseudomonas aeruginosa), were decreased compared with sham rats. VEGF protein was also investigated in bronchoalveolar lavage (BAL) from patients studied within 7 days of acute respiratory distress syndrome (ARDS) onset and in patients without ARDS. VEGF protein levels in BAL were decreased in patients with ARDS versus those without (14.3 +/- 11.1 pg x mL(-1) versus 76.8 +/- 51.1 pg x mL(-1), p = 0.03). In aggregate, these findings show that the initial phase of acute lung injury is associated with a decrease in vascular endothelial growth factor in the lung. This downregulation may represent a protective mechanism aimed at limiting endothelial permeability, and may participate in the decrease in capillary number that is observed during early acute respiratory distress syndrome.

Impairment of polymorphonuclear neutrophil functions precedes nosocomial infections in critically ill patients

Objective A postinjury immunodepression involving neutrophil functions has been described in critically ill patients. The aim of this prospective study was to search for a relationship between an impairment of neutrophil functions and the subsequent development of nosocomial infection. Design Twenty-one severely ill (simplified acute physiology score II >20 on admission), nonimmunosuppressed patients who were receiving no antibiotics active against methicillin-resistant Staphylococcus aureus and highly resistant Pseudomonas aeruginosa were included. Twelve healthy subjects constituted a control group. Measurements Neutrophil functions (phagocytosis and bactericidal activity toward S. aureus and P. aeruginosa in homologous plasma, reactive oxygen species secretion) were studied at day 4 ± 1 after admission, and occurrence of nosocomial infection was prospectively recorded over the following 5 days. Interleukin-10 concentration was assessed by enzyme-linked immunosorbent assay. Results are expressed as median (25th–75th percentiles). Main Results Six out of the 21 patients acquired a nosocomial infection during the 5 days after blood sampling (infected group). Compared with the patients who did not acquire nosocomial infection (noninfected group, n = 15), the neutrophils of the infected group demonstrated a higher percentage of intracellular bacterial survival (17% [2% to 67%] vs. infected: 62% [22% to 100%], p < .05), leading to an impairment of S. aureus killing in homologous plasma (killed bacteria: 4.93 log10 colony forming units/mL [4.24–5.29] vs. infected: 3.62 log10 colony forming units/mL [0.00–4.58], p < .05). Interleukin-10 plasma concentration was higher in infected patients (78 pg/mL [60–83]) compared with noninfected patients (22 pg/mL [14–58], p < .05). By contrast, P. aeruginosa killing was similar in patients whether or not they acquired a nosocomial infection. Conclusion A decrease in S. aureus killing capabilities of neutrophils can be evidenced within the days before occurrence of a nosocomial infection.

High Bactericidal Efficiency of Type IIA Phospholipase A2 against Bacillus anthracis and Inhibition of Its Secretion by the Lethal Toxin

There is a considerable body of evidence supporting the role of secretory type II-A phospholipase A2 (sPLA2-IIA) as an effector of the innate immune response. This enzyme also exhibits bactericidal activity especially toward Gram-positive bacteria. In this study we examined the ability of sPLA2-IIA to kill Bacillus anthracis, the etiological agent of anthrax. Our results show that both germinated B. anthracis spores and encapsulated bacilli were sensitive to the bactericidal activity of recombinant sPLA2-IIA in vitro. In contrast, nongerminated spores were resistant. This bactericidal effect was correlated to the ability of sPLA2-IIA to hydrolyze bacterial membrane phospholipids. Guinea pig alveolar macrophages, the major source of sPLA2-IIA in an experimental model of acute lung injury, released enough sPLA2-IIA to kill extracellular B. anthracis. The production of sPLA2-IIA was significantly inhibited by B. anthracis lethal toxin. Human bronchoalveolar lavage fluids from acute respiratory distress syndrome patients are known to contain sPLA2-IIA; bactericidal activity against B. anthracis was detected in a high percentage of these samples. This anthracidal activity was correlated to the levels of sPLA2-IIA and was abolished by an sPLA2-IIA inhibitor. These results suggest that sPLA2-IIA may play a role in innate host defense against B. anthracis infection and that lethal toxin may help the bacteria to escape from the bactericidal action of sPLA2-IIA by inhibiting the production of this enzyme.

Corticosteroids as Adjunctive Therapy for Severe Pneumocystis carinii Pneumonia in Non-Human Immunodeficiency Virus-Infected Patients: Retrospective Study of 31 Patients

The aim of this retrospective study was to assess whether corticosteroid adjunctive therapy (CAT) could prevent death in immunocompromised patients with severe Pneumocystis carinii pneumonia (PCP) who do not have human immunodeficiency virus (HIV) infection, similarly to what has been demonstrated for HIV-infected patients. The charts of all non-HIV-infected patients who were admitted to two medical intensive care units between 1988 and 1996 because of severe PCP, defined by an arterial oxygen pressure (determined while the patient was breathing room air) of <70 mm Hg, and who were treated with trimethoprim-sulfamethoxazole were analyzed retrospectively. Thirty-one patients met the study criteria, of whom 23 received CAT (within 72 hours of antibiotic therapy) and eight did not receive CAT. The need for mechanical ventilation (10 [43%] of 23 vs. 4 [50%] of 8) and the mortality rate (9 [39%] of 23 vs. 4 [50%] of 8) were similar for the two groups. Although this small study does not have a statistical power high enough to rule out the possibility of a difference, the results suggest that CAT does not improve the survival of non-HIV-infected patients as has been described for HIV-infected patients with severe PCP.

Induction of type-IIA secretory phospholipase A2 in animal models of acute lung injury

The aim of this study was to evaluate the presence of type-II secretory phospholipase A2 (sPLA2-IIA) in alveolar space and its possible role in the destruction of surfactant in three rat models of acute lung injury. Alveolar instillation of either lipopolysaccaride or live Pseudomonas aeruginosa resulted in a significant increase in lung oedema and in a decrease in static compliance of the respiratory system together with alveolar-neutrophil influx as compared with healthy control rats. The upregulation of messenger ribonucleic acid and sPLA2-IIA by the lung was evident. This was associated with surfactant degradation and a decrease in large:small ratio of surfactant aggregates in bacteria-instilled rats. A negative correlation between compliance and sPLA2-IIA activity in bronchoalveolar lavage fluid was shown. By contrast, during alpha naphthylthiourea-induced injury, neither alveolar-neutrophil influx nor increase in sPLA2-IIA activity was observed. Additional experiments in rats treated with a specific inhibitor of type-II secretory phospholipase A2 activity (3 acetamine-1-benzyl-2 ethylindolyl-5 oxy; propane phosphonic acid (LY311727)) demonstrated no improvement in physiological parameters despite a biochemical effect, suggesting that its activity is only one of the multiple factors involved in the pathophysiology of lung injury.

Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis

ObjectivePotentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 &mgr;g·kg−1·day−1, 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats. SettingUniversity laboratory. SubjectsSprague-Dawley rats. InterventionsWe compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline. Measurements and Main ResultsMortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 ± 0.14 mL/kPa; bleomycin, 1.44 ± 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 ± 0.09 mL/kPa; control vs. bleomycin, p < .0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p = .0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes). ConclusionsGranulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.

Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.

To cite this article: Mahut B, Trinquart L, Le Bourgeois M, Becquemin M‐H, Beydon N, Aubourg F, Jala M, Bidaud‐Chevalier B, Dinh‐Xuan A‐T, Randrianarivelo O, Denjean A, de Blic J, Delclaux C. Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity. Allergy 2010; 65: 636–644.

Measurement of Dynamic Hyperinflation After a 6-Minute Walk Test in Patients With COPD

BACKGROUND Dynamic hyperinflation (DH) develops in patients with COPD during incremental exercise with a cycle ergometer. The aims of this study were to determine whether DH can be evidenced after walking with a handheld spirometer and to determine its functional consequences. METHODS Fifty patients with COPD (39 men; median age, 60 years [interquartile range (IQR), 54 to 69 years]; FEV(1), 45% predicted [IQR, 31 to 67% predicted]) underwent pulmonary function tests and a 6-min walk test (6MWT). Inspiratory capacity (IC) was measured with the patient in the standing position at rest and immediately after the 6MWT with a portable spirometer. Dyspnea was evaluated directly (change in Borg score during 6MWT) and indirectly (Medical Research Council scale). The first 20 patients performed an incremental exercise test with cycle ergometer that allowed for the measurement of IC at peak exercise and repeatedly during the first 3 min of recovery. RESULTS The median change in IC during the 6MWT was -210 mL (IQR, 55 to -440; n = 50), whereas the median change in IC during the exercise test was -295 mL (IQR, -145 to -515; n = 20). Both the IC and IC changes after 6MWT correlated to values after the exercise test. DH decreased rapidly after the end of the exercise test but was nonsignificantly different from the baseline value after 75 s of recovery. The percentage of decrease in IC during the 6MWT correlated with dyspnea (change in Borg score during 6MWT: r(2) = 0.21; p = 0.0006). CONCLUSIONS DH can be measured during a 6MWT with a handheld spirometer to allow for its evaluation in daily practice and its contribution to dyspnea while walking.