Biomedical subjects

Alexandre Demoule

Publications and source records attributed to Alexandre Demoule.

15 recordsLinked to original sources

PubMed2006

Impact of IL-10 on diaphragmatic cytokine expression and contractility during Pseudomonas Infection.

Severe weakness of the respiratory muscles, with attendant respiratory failure and death, has been documented in sepsis. In this study, we show that during murine pulmonary infection with Pseudomonas aeruginosa, multiple proinflammatory genes are up-regulated not only within the lungs, but also within the diaphragm. Significant induction of TNF-alpha, IL-1alpha, IL-1beta, IL-6, and IL-18 gene expression occurred within the diaphragm in a bacterial dose-dependent manner. We determined whether the anti-inflammatory cytokine IL-10 could blunt proinflammatory gene expression within the diaphragm under these conditions. The IL-10 receptor was found to be expressed by the diaphragm in vivo as well as in primary diaphragmatic muscle cell cultures. Transduction of myoblasts with an adenoviral vector (Ad-IL-10) induced strong IL-10 expression, and intramuscular injection of the same vector in vivo produced significant increases in IL-10 serum levels. Ad-IL-10 treatment of mice infected with P. aeruginosa significantly inhibited the induction of proinflammatory cytokines within the diaphragm, but not in the infected lungs. Ad-IL-10 treatment also led to greatly improved diaphragmatic force production in infected mice. These results suggest that pulmonary infection triggers proinflammatory gene expression by the diaphragm along with diaphragmatic weakness. Shifting the balance between pro- and anti-inflammatory mediators in favor of the latter by IL-10 gene delivery was able to restore normal diaphragmatic force-generating capacity under these conditions, suggesting a possible avenue for therapeutic intervention.

Animals↗

PubMed2006

Benefits and risks of success or failure of noninvasive ventilation.

OBJECTIVE: Noninvasive ventilation (NIV) fails more frequently for de novo acute respiratory failure (de novo) than for cardiogenic pulmonary edema (CPE) or acute-on-chronic respiratory failure (AOC). The impact of NIV failure and success was compared between de novo and CPE or AOC after adjustment for disease severity. SETTINGS: Patients requiring ventilatory support were enrolled in a prospective survey in 70 French ICUs. Of 1076 patients requiring ventilatory support, 524 were eligible, including 299 de novo (NIV use, 30%) and 225 CPE-AOC (NIV use, 55%). DESIGN AND ANALYSIS: Independent risk factors associated with mortality and length of stay were identified by logistic regression analysis. The adjusted outcome of NIV success or failure was compared to that with endotracheal intubation without NIV. RESULTS: NIV success was independently associated with survival in both de novo, adjusted OR 0.05 (95% CI 0.01-0.42), and CPE-AOC OR 0.03 (CI 0.01-0.24). NIV failure was associated with ICU mortality in the de novo group (OR 3.24, CI 1.61-6.53) but not in the CPE-AOC group. Nosocomial pneumonia was less common in patients successful with NIV. NIV failure was associated with a longer ICU stay in CPE-AOC only. The overall use of NIV was independently associated with a better outcome only in CPE-AOC patients (OR 0.33, CI 0.15-0.73). CONCLUSION: The effect of NIV differs between de novo and CPE-AOC patients because NIV failure is associated with increased mortality for de novo patients. This finding should raise a note of caution when applying NIV in this indication.

Aged↗

PubMed2006

Dyspnea as a noxious sensation: inspiratory threshold loading may trigger diffuse noxious inhibitory controls in humans.

Dyspnea, a leading respiratory symptom, shares many clinical, physiological, and psychological features with pain. Both activate similar brain areas. The neural mechanisms of dyspnea are less well described than those of pain. The present research tested the hypothesis of common pathways between the two sensations. Six healthy men (age 30-40 yr) were studied. The spinal nociceptive flexion reflex (RIII) was first established in response to electrical sural stimulation. Dyspnea was then induced through inspiratory threshold loading, forcing the subjects to develop 70% of their maximal inspiratory pressure to inhale. This led to progressive inhibition of the RIII reflex that reached 50 +/- 12% during the fifth minute of loading (P < 0.001), was correlated to the intensity of the self-evaluated respiratory discomfort, and had recovered 5 min after removal of the load. The myotatic H-reflex was not inhibited by inspiratory loading, arguing against postsynaptic alpha motoneuron inhibition. Dyspnea, like pain, thus induced counterirritation, possibly indicating a C-fiber stimulation and activation of diffuse noxious inhibitory descending controls known to project onto spinal dorsal horn wide dynamic range neurons. This confirms the noxious nature of certain types of breathlessness, thus opening new physiological and perhaps therapeutic perspectives.

Adult↗

PubMed2006

Pressure-volume curves with and without muscle paralysis in acute respiratory distress syndrome.

OBJECTIVE: Pressure-volume (PV) curves are recorded after induction of complete muscle paralysis, which may limit their clinical use. The feasibility of recording PV curves without paralysis has not been tested. In 19 patients with acute respiratory distress syndrome (ARDS) and no hemodynamic instability we prospectively evaluated whether PV curves can be safely and reliably recorded under deep sedation without neuromuscular blockade. METHODS: After standardized sedation (continuous infusion of midazolam and fentanyl) PV curves were recorded during apneic sedation, defined as absence of respiratory effort during a 6-s expiratory pause and during paralysis induced by cis-atracurium. MEASUREMENTS AND RESULTS: Agreement between PV curve parameters in the two conditions was evaluated. Curves were obtained from 10 cmH2O and from zero end-expiratory pressure in all patients under apneic sedation. In five patients propofol was given in addition to midazolam and fentanyl, and in two of them fluid resuscitation was needed. A strong agreement was found for respiratory system compliance and the lower inflection point and for chest wall compliance in the five patients whose esophageal pressure was measured. The variability of the measurements, however, should be taken into account in clinical practice. CONCLUSION: Neuromuscular blockade can be dispensed with when recording PV curves in many ARDS patients. Reliable PV curves can be obtained under anesthesia alone, with no serious adverse effects.

Adult↗

PubMed2006

Increased use of noninvasive ventilation in French intensive care units.

OBJECTIVES: A prospective survey of French intensive care units (ICUs) in 1997 showed moderate and variable use of noninvasive ventilation (NIV). This study examined changes in NIV use in French ICUs after the intervening 5years. SETTINGS: Patients were enrolled in a prospective survey in 70 French ICUs. METHODS: Three-week survey, with prospective inclusion of all patients requiring ventilatory support. MEASUREMENTS AND RESULTS: Overall 1,076 patients received ventilatory support (55% of admissions). First-line NIV was significantly more common than 5years earlier, overall (23% vs. 16%) and especially in patients not intubated before ICU admission (52% vs. 35%). Reasons for respiratory failure were coma (33%), cardiogenic pulmonary edema (8%), acute-on-chronic respiratory failure (17%), and de novo respiratory failure (41%). Significant increases in NIV use were noted for acute-on-chronic respiratory failure (64% vs. 50%) and de novo respiratory failure (22% vs. 14%). Among patients given NIV, 38% subsequently required endotracheal intubation (not significantly different). Independent risk factors for NIV failure were high SAPS II and de novo respiratory failure, whereas factors associated with success were good NIV tolerance and high body mass index. CONCLUSIONS: NIV use has significantly increased in French ICUs during the past 5years, and the success rate has remained unchanged. In patients not previously intubated, NIV is the leading first-line ventilation modality. The proportion of patients successfully treated with NIV increased significantly over the 5-year period (13% vs. 9% of all patients receiving ventilatory support).

Acute Disease↗

PubMed2006

Endotoxin triggers nuclear factor-kappaB-dependent up-regulation of multiple proinflammatory genes in the diaphragm.

BACKGROUND: Sepsis-induced diaphragmatic force loss and failure are associated with an increased exposure of the muscle to proinflammatory mediators. OBJECTIVES: Our objectives were to test the hypothesis that force-inhibiting mediators may arise in large part from the diaphragm itself and to evaluate the roles of mechanical stress, free radicals, and the nuclear factor (NF)-kappaB transcription factor pathway in endotoxin (LPS)-induced proinflammatory responses of the diaphragm. METHODS: Murine diaphragm and limb muscle cells were exposed to LPS in vitro and in vivo. Proinflammatory gene expression was measured using RNase protection assays (tumor necrosis factor [TNF]-alpha, TNF-alpha receptor p55, interleukin [IL]-1alpha, IL-1beta, IL-6, macrophage inflammatory peptide-2, intercellular adhesion molecule-1, Fas ligand, and inducible nitric oxide synthase) and ELISAs (TNF-alpha, IL-6, and macrophage inflammatory peptide-2). Cyclical muscle cell stretch and free-radical scavengers (N-acetylcysteine and catalase) were used to alter mechanical and oxidative stress levels, respectively. Pharmacologic (pyrrolidinedithiocarbamate) and dominant-negative transfection strategies were used to inhibit the NF-kappaB pathway. RESULTS: In primary diaphragm muscle cell cultures, modulation of mechanical stress levels or free-radical exposure did not alter responses to LPS stimulation. However, pharmacologic blockade of the NF-kappaB pathway and dominant-negative molecular inhibition of IKB kinase-beta strongly suppressed LPS-induced proinflammatory gene expression. In vivo, acute endotoxemia induced significantly greater mRNA and protein levels for proinflammatory mediators in the diaphragm as compared with limb muscle. Basal expression levels of proinflammatory genes were significantly higher in the diaphragm. CONCLUSIONS: Constitutive and LPS-induced proinflammatory gene expression are exaggerated in the diaphragm compared with limb muscles and are critically dependent on the NF-kappaB pathway. We suggest the diaphragm may be relatively predisposed to proinflammatory responses.

Animals↗

PubMed2006

Relationship between pressure-volume curve and markers for collagen turn-over in early acute respiratory distress syndrome.

OBJECTIVE: In acute respiratory distress syndrome, the relationships between changes in the elastic behavior of the respiratory system and biological markers of extra-cellular matrix or surfactant turn-over could give some insights into its pathophysiological determinants. DESIGN AND MEASUREMENTS: In 17 patients with acute respiratory distress syndrome, we assessed the relationship between chord compliance measured on pressure-volume curves obtained at two levels of positive end-expiratory pressure (0 and 10[Symbol: see text]cm[Symbol: see text]H(2)O) and biological markers of collagen turn-over or surfactant degradation in bronchoalveolar lavage fluid obtained simultaneously in the early phase of the disease (first 4 days). MAIN RESULTS: The compliance of the respiratory system obtained from the pressure-volume curves was significantly correlated with markers for collagen turn-over (type III procollagen peptide and matrix metalloproteinase 2) and with markers of surfactant degradation (type-IIA secretory phospholipase A2). The correlations were stronger when the curve was traced from positive end-expiratory pressure, suggesting that this condition may improve the assessment of tissue mechanics. A logarithmic relationship best described the correlation between compliance and type III procollagen peptide, in agreement with a collagen-dependent model of maximal distension. The marker for surfactant degradation was associated with ongoing alveolar inflammation (cellularity of bronchoalveolar lavage fluid and tumor necrosis factor-alpha concentration). Interleukin-10, an anti-inflammatory mediator, showed no correlation with compliance. CONCLUSION: These preliminary data suggest that a severe reduction in compliance in the early phase of acute respiratory distress syndrome is associated with both collagen deposition and surfactant degradation.

Adult↗

PubMed2005

Physiologic effects of noninvasive ventilation during acute lung injury.

A prospective, crossover, physiologic study was performed in 10 patients with acute lung injury to assess the respective short-term effects of noninvasive pressure-support ventilation and continuous positive airway pressure. We measured breathing pattern, neuromuscular drive, inspiratory muscle effort, arterial blood gases, and dyspnea while breathing with minimal support and the equipment for measurements, with two combinations of pressure-support ventilation above positive end-expiratory pressure (10-10 and 15-5 cm H2O), and with continuous positive airway pressure (10 cm H2O). Tidal volume was increased with pressure support, and not with continuous positive airway pressure. Neuromuscular drive and inspiratory muscle effort were lower with the two pressure-support ventilation levels than with other situations (p < 0.05). Dyspnea relief was significantly better with high-level pressure-support ventilation (15-5 cm H2O; p < 0.001). Oxygenation improved when 10 cm H2O positive end-expiratory pressure was applied, alone or in combination. We conclude that, in patients with acute lung injury (1) noninvasive pressure-support ventilation combined with positive end-expiratory pressure is needed to reduce inspiratory muscle effort; (2) continuous positive airway pressure, in this setting, improves oxygenation but fails to unload the respiratory muscles; and (3) pressure-support levels of 10 and 15 cm H2O provide similar unloading but differ in their effects on dyspnea.

Adult↗

PubMed2005

Expression and regulation of CC class chemokines in the dystrophic (mdx) diaphragm.

In the murine (mdx) model of Duchenne muscular dystrophy, dystrophic changes are much more severe in the diaphragm than in limb muscles, and the diaphragm more closely resembles the human disease phenotype. Chemokines could play a central role in governing such phenotypic differences, as inflammation is an important disease modifier. Here we report that CC chemokine receptors (CCRs 1, 2, 3, 5) and ligands (macrophage inflammatory protein-1alpha, RANTES) are expressed at higher levels in dystrophic than in wild-type muscles across age groups (6, 12, and 24 wk). Moreover, chemokine ligand expression and muscle inflammation are significantly higher in dystrophic diaphragms than in limb muscles of the same animals. In vitro, CCR1 is constitutively expressed by cultured primary diaphragmatic myotubes. Stimulation of myotubes by proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1alpha, interferon-gamma) found within the in vivo dystrophic muscle environment, upregulates CCR1 in mdx and wild-type cultures, and also increases expression of its ligand RANTES to a significantly greater degree in the mdx group. Taken together, our results suggest that CC chemokines may play an important role in sustaining inflammation within the mdx diaphragm, which could help account for its more severe phenotype and also offer a target for therapeutic intervention in Duchenne patients.

Animals↗

PubMed2005

Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies.

Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.

Aged↗

PubMed2005

Patients aged 90 years or older in the intensive care unit.

BACKGROUND: Age is an important prognostic factor in patients admitted to intensive care units (ICUs), but it is not as important as illness severity. However, age seems to remain an important independent triage criterion for ICU admission, and 90 years of age seems to represent a psychological barrier for many ICU physicians. The aim of this preliminary study is to compare the management and outcome of patients aged 90 years or older admitted to a respiratory ICU with those of patients aged 70 years or younger. METHODS: In our matched case-control study over a 6-year period, 36 patients aged 90 years or older (case patients) were selected and matched according to sex with 72 controls chosen in the 20- to 69-year age range. The Simplified Acute Physiology Score (SAPS) II was then computed without using age as a variable. RESULTS: Pre-existing comorbidities were significantly less frequent in cases than in controls (5.1% vs 30.5%, p <.01). Compared to controls, cases were more frequently admitted for cardiac failure (22% vs 7%, p <.05) and less frequently for neurological diseases (0% vs 11%, p <.05). The use of advanced life-support measures in the ICU such as mechanical ventilation, central venous or arterial catheterization, and vasoactive and/or inotropic drugs was not significantly different between case patients and controls. This was also the case for ICU mortality and for the mean duration of ICU and hospital stay. Although there was a trend toward a higher hospital mortality among case patients than among controls, it did not reach statistical significance (47% vs 27%, p =.07). CONCLUSION: Our results reinforce the idea that age alone is not a relevant criterion for ICU admission.

Age Factors↗

PubMed2003

Effects of exhaustive incremental treadmill exercise on diaphragm and quadriceps motor potentials evoked by transcranial magnetic stimulation.

It is unknown whether changes in corticomotor excitability follow exercise in healthy humans. We hypothesized that a fall in the diaphragm and quadriceps motor-evoked potential (MEP) amplitude elicited by transcranial magnetic stimulation of the motor cortex would occur after an incremental exercise task. In 11 healthy subjects, we measured transdiaphragmatic pressure and isometric quadriceps tension in response to supramaximal peripheral magnetic nerve stimulation. MEPs were recorded from these muscles in response to transcranial magnetic stimulation. After baseline measurements, subjects performed a period of submaximal exercise (gentle walking). Measurements were repeated 5 and 20 min after this. The subjects then exercised on a treadmill with an incremental protocol to exhaustion. Transcranial magnetic stimulation was performed at baseline and at 5, 20, 40, and 60 min after exhaustive exercise, and force measurements were obtained at baseline, 20 min, and 60 min. Mean exercise duration was 18 +/- 4 min, and mean maximum heart rate was 172 +/- 10 beats/min. Twitch transdiaphragmatic pressure and twitch isometric quadriceps tension were not different from baseline after exercise, but a significant decrease was observed in diaphragm MEP amplitude 5 and 20 min after exercise (60 +/- 38 and 45 +/- 24%, respectively, of baseline, P = 0.0001). At the same times, the mean quadriceps MEPs were 59 +/- 39 and 74 +/- 32% of baseline (P < 0.0001 and P < 0.01, respectively). Studies using paired stimuli confirmed a likely intracortical mechanism for this depression. Our data confirm significant depression of both diaphragm and quadriceps MEPs after incremental treadmill exercise.

Adult↗

PubMed2003

Intracortical inhibition and facilitation of the response of the diaphragm to transcranial magnetic stimulation.

Respiratory muscles respond to a subcortical automatic command and to a neocortical voluntary command. In diseases such as stroke or motor neurone disease, an abnormal diaphragmatic response to single transcranial magnetic stimuli can identify a central source for respiratory disorders, but this is not likely to be the case in disorders affecting intracortical inhibitory and facilitatory mechanisms. This study describes the response of the diaphragm to paired transcranial magnetic stimulation. Thirteen normal subjects were studied (age range, 22 to 43 years; 7 men; phrenic conduction, <6.8 msec; latency of diaphragmatic motor evoked potential, <20.5 msec). Motor evoked potentials in response to paired stimulation were obtained in eight subjects only, with the motor threshold in the remaining five subjects too high to absorb the loss of power inherent in the double-stimulation montage. Interstimulus intervals less than 5 msec resulted in a statistically significant inhibition (p < 0.01 for interstimulus intervals of 1 and 3 ms), whereas intervals longer than 6 msec were facilitatory (maximal, 15 msec). The diaphragmatic pattern matched that of the biceps brachii. The authors conclude that it is possible to study intracortical inhibition and facilitation of diaphragmatic control, although not in all subjects. Technical improvement should alleviate current limitations and make paired transcranial magnetic stimulation a tool to study respiratory muscle abnormalities in settings in which intracortical interactions are important, such as movement disorders.

Action Potentials↗

PubMed2002

Validation of surface recordings of the diaphragm response to transcranial magnetic stimulation in humans.

The integrity of the central efferent motor pathways to the diaphragm can be assessed by using transcranial magnetic stimulation to measure the latency of the corresponding motor evoked potentials with surface electrodes. Because transcranial magnetic stimulation does not activate the diaphragm alone, signal contamination is a potential problem. To evaluate this issue, surface diaphragmatic motor-evoked potential latencies were compared with latencies recorded from diaphragm needle in 9 healthy volunteers. Surface latencies of muscles likely to contaminate the diaphragm signals (serratus anterior, pectoralis major, and tranversus abdominis) were also recorded. The latencies in response to nonfocal transcranial stimulation from surface electrodes were not significantly different from the needle ones (17 +/- 1.3 vs. 17.2 +/- 1.1 ms, respectively) but were significantly different from the latencies of the other muscles. In two cases, signal contamination appeared likely (serratus anterior in 1 case, abdominal muscles in 1 case). It is possible to reliably measure the latency of the diaphragm response to transcranial magnetic stimulation with adequately positioned surface electrodes.

Adult↗

PubMed2002

Validation of improved recording site to measure phrenic conduction from surface electrodes in humans.

Phrenic nerve stimulation, electrical (ES) or from cervical magnetic stimulation (CMS), allows one to assess the diaphragm contractile properties and the conduction time of the phrenic nerve (PNCT) through recording of an electromyographic response, traditionally by using surface electrodes. Because of the coactivation of extradiaphragmatic muscles, signal contamination can jeopardize the determination of surface PNCTs. To address this, we compared PNCTs with ES and CMS from surface and needle diaphragm electrodes in five subjects (10 phrenic nerves). At a modified recording site, lower and more anterior than usual (lowest accessible intercostal space, costochondral junction) with electrodes 2 cm apart, surface and needle PNCTs were similar (CMS: 6.0 +/- 0.25 ms surface vs. 6.2 +/- 0.13 ms needle, not significant). Electrodes recording the activity of the most likely sources of signal contamination, i.e., the serratus anterior and pectoralis major, showed distinct responses from that of the diaphragm, their earlier occurrence strongly arguing against contamination. With ES and CMS, apparently uncontaminated signals could be consistently recorded from surface electrodes.

Adult↗