Didier Tassaux

Activation of human macrophages by mechanical ventilation in vitro

Positive-pressure mechanical ventilation supports gas exchange in patients with respiratory failure but is also responsible for significant lung injury. In this study, we have developed an in vitro model in which isolated lung cells can be submitted to a prolonged cyclic pressure-stretching strain resembling that of conventional mechanical ventilation. In this model, cells cultured on a Silastic membrane were elongated up to 7% of their initial diameter, corresponding to a 12% increase in cell surface. The lung macrophage was identified as the main cellular source for critical inflammatory mediators such as tumor necrosis factor-α, the chemokines interleukin (IL)-8 and -6, and matrix metalloproteinase-9 in this model system of mechanical ventilation. These mediators were measured in supernatants from ventilated alveolar macrophages, monocyte-derived macrophages, and promonocytic THP-1 cells. Nuclear factor-κB was found to be activated in ventilated macrophages. Synergistic proinflammatory effects of mechanical stress and molecules such as bacterial endotoxin were observed, suggesting that mechanical ventilation might be particularly deleterious in preinjured or infected lungs. Dexamethasone prevented IL-8 and tumor necrosis factor-α secretion in ventilated macrophages. Mechanical ventilation induced low levels of IL-8 secretion by alveolar type II-like cells. Other lung cell types such as endothelial cells, bronchial cells, and fibroblasts failed to produce IL-8 in response to a prolonged cyclic pressure-stretching load. This model is of particular value for exploring physical stress-induced signaling pathways, as well as for testing the effects of novel ventilatory strategies or adjunctive substances aimed at modulating cell activation induced by mechanical ventilation.Positive-pressure mechanical ventilation supports gas exchange in patients with respiratory failure but is also responsible for significant lung injury. In this study, we have developed an in vitro model in which isolated lung cells can be submitted to a prolonged cyclic pressure-stretching strain resembling that of conventional mechanical ventilation. In this model, cells cultured on a Silastic membrane were elongated up to 7% of their initial diameter, corresponding to a 12% increase in cell surface. The lung macrophage was identified as the main cellular source for critical inflammatory mediators such as tumor necrosis factor-alpha, the chemokines interleukin (IL)-8 and -6, and matrix metalloproteinase-9 in this model system of mechanical ventilation. These mediators were measured in supernatants from ventilated alveolar macrophages, monocyte-derived macrophages, and promonocytic THP-1 cells. Nuclear factor-kappaB was found to be activated in ventilated macrophages. Synergistic proinflammatory effects of mechanical stress and molecules such as bacterial endotoxin were observed, suggesting that mechanical ventilation might be particularly deleterious in preinjured or infected lungs. Dexamethasone prevented IL-8 and tumor necrosis factor-alpha secretion in ventilated macrophages. Mechanical ventilation induced low levels of IL-8 secretion by alveolar type II-like cells. Other lung cell types such as endothelial cells, bronchial cells, and fibroblasts failed to produce IL-8 in response to a prolonged cyclic pressure-stretching load. This model is of particular value for exploring physical stress-induced signaling pathways, as well as for testing the effects of novel ventilatory strategies or adjunctive substances aimed at modulating cell activation induced by mechanical ventilation.

Beneficial effects of helium:oxygen versus air:oxygen noninvasive pressure support in patients with decompensated chronic obstructive pulmonary disease

OBJECTIVE To test the hypothesis that, in decompensated chronic obstructive pulmonary disease (COPD), noninvasive pressure support ventilation using 70:30 helium:oxygen instead of 70:30 air:oxygen could reduce dyspnea and improve ventilatory variables, gas exchange, and hemodynamic tolerance. DESIGN Prospective, randomized, crossover study. SETTING Medical intensive care unit, university tertiary care center. PATIENTS Nineteen patients with severe COPD (forced 1-sec expiratory volume of 0.83+/-0.3 l) hospitalized in the intensive care unit for noninvasive pressure support ventilation after initial stabilization with noninvasive pressure support for no more than 24 hrs after intensive care unit admission. INTERVENTIONS Noninvasive pressure support ventilation was administered in the following randomized crossover design: a) 45 min with air:oxygen or helium:oxygen; b) no ventilation for 45 min; and c) 45 min with air:oxygen or helium:oxygen. MEASUREMENTS AND MAIN RESULTS Air:oxygen and helium:oxygen decreased respiratory rate and increased tidal volume and minute ventilation. Helium:oxygen decreased inspiratory time. Both gases increased total respiratory cycle time and decreased the inspiratory/total time ratio, the reduction in the latter being significantly greater with helium:oxygen. Peak inspiratory flow rate increased more with helium:oxygen. PaO2 increased with both gases, whereas PaCO2 decreased more with helium:oxygen (values shown are mean+/-SD) (52+/-6 torr [6.9+/-0.8 kPa] vs. 55+/-8 torr [7.3+/-1.1 kPa] and 48+/-6 torr [6.4+/-0.8 kPa] vs. 54+/-7 torr [7.2+/-0.9 kPa] for air:oxygen and helium:oxygen, respectively; p<.05). When hypercapnia was severe (PaCO2 >56 torr [7.5 kPa]), PaCO2 decreased by > or =7.5 torr (1 kPa) in six of seven patients with helium:oxygen and in four of seven patients with air:oxygen (p<.01). Dyspnea score (Borg scale) decreased more with helium:oxygen than with air:oxygen (3.7+/-1.6 vs. 4.5+/-1.4 and 2.8+/-1.6 vs. 4.6+/-1.5 for air:oxygen and helium:oxygen, respectively; p<.05). Mean arterial blood pressure decreased with air:oxygen (76+/-12 vs. 82+/-14 mm Hg; p<.05) but remained unchanged with helium:oxygen. CONCLUSION In decompensated COPD patients, noninvasive pressure support ventilation with helium:oxygen reduced dyspnea and PaCO2 more than air:oxygen, modified respiratory cycle times, and did not modify systemic blood pressure. These effects could prove beneficial in COPD patients with severe acute respiratory failure and might reduce the need for endotracheal intubation.

Helium-oxygen versus air-oxygen noninvasive pressure support in decompensated chronic obstructive disease: A prospective, multicenter study.

ObjectiveTo study whether noninvasive pressure support ventilation (NIPSV) with helium/oxygen (He/oxygen), which can reduce dyspnea, Paco2, and work of breathing more than NIPSV with air/oxygen in decompensated chronic obstructive pulmonary disease, could have beneficial consequences on outcome and hospitalization costs. DesignProspective, randomized, multicenter study. SettingIntensive care units of three tertiary care university hospitals. PatientsAll patients with chronic obstructive pulmonary disease admitted to the intensive care units for NIPSV during a 24-month period. InterventionsPatients were randomized to NIPSV with air/oxygen or He/oxygen. NIPSV settings, number of daily trials, decision to intubate, and intensive care unit and hospital discharge criteria followed standard practice guidelines. ResultsA total of 123 patients (male/female ratio, 71:52; age, 71 ± 10 yrs, Acute Physiology and Chronic Health Evaluation II, 17 ± 4) were included. Intubation rate (air/oxygen 20% vs. He/oxygen 13%) and length of stay in the intensive care unit (air/oxygen 6.2 ± 5.6 vs. He/oxygen 5.1 ± 4 days) were comparable. The post–intensive care unit hospital stay was lower with He/oxygen (air/oxygen 19 ± 12 vs. He/oxygen 13 ± 6 days, p < .002). Cost of NIPSV gases was higher with He/oxygen, but total hospitalization costs were lower by

Effects of helium-oxygen on intrinsic positive end-expiratory pressure in intubated and mechanically ventilated patients with severe chronic obstructive pulmonary disease

3,348 per patient with He/oxygen. No complications were associated with the use of He/oxygen. ConclusionHe/oxygen did not significantly reduce intubation rate or intensive care unit stay, but hospital stay was shorter and total costs were lower. He/oxygen NIPSV can be safely administered and could prove to be a cost-effective strategy.

Patient-ventilator interactions during partial ventilatory support: a preliminary study comparing the effects of adaptive support ventilation with synchronized intermittent mandatory ventilation plus inspiratory pressure support.

ObjectiveTo test the hypothesis that replacing 70:30 nitrogen:oxygen (Air-O2) with 70:30 helium:oxygen (He-O2) can decrease dynamic hyperinflation (“intrinsic” positive end-expiratory pressure) in mechanically ventilated patients with chronic obstructive pulmonary disease (COPD), and to document the consequences of such an effect on arterial blood gases and hemodynamics. DesignProspective, interventional study. SettingMedical intensive care unit, university tertiary care center. PatientsTwenty-three intubated, sedated, paralyzed, and mechanically ventilated patients with COPD enrolled within 36 hrs after intubation. InterventionsMeasurements were taken at the following time points, all with the same ventilator settings: a) baseline; b) after 45 mins with He-O2; c) 45 mins after return to Air-O2. The results were then compared to those obtained in a test lung model using the same ventilator settings. Main Results (mean ± sd):Trapped lung volume and intrinsic positive end-expiratory pressure decreased during He-O2 ventilation (215 ± 125 mL vs. 99 ± 15 mL and 9 ± 2.5 cm H2O vs. 5 ± 2.7 cm H2O, respectively;p < .05). Likewise, peak and mean airway pressures declined with He-O2 (30 ± 5 cm H2O vs. 25 ± 6 cm H2O and 8 ± 2 cm H2O vs. 7 ± 2 cm H2O, respectively;p < .05). These parameters all rose to their baseline values on return to Air-O2 (p < .05 vs. values during He-O2). These results were in accordance with those obtained in the test lung model. There was no modification of arterial blood gases, heart rate, or mean systemic arterial blood pressure. In 12/23 patients, a pulmonary artery catheter was in place, allowing hemodynamic measurements and venous admixture calculations. Switching to He-O2 and back to Air-O2 had no effect on pulmonary artery pressures, right and left ventricular filling pressures, cardiac output, pulmonary and systemic vascular resistance, or venous admixture. ConclusionIn mechanically ventilated COPD patients with intrinsic positive end-expiratory pressure, the use of He-O2 can markedly reduce trapped lung volume, intrinsic positive end-expiratory pressure, and peak and mean airway pressures. No effect was noted on hemodynamics or arterial blood gases. He-O2 might prove beneficial in this setting to reduce the risk of barotrauma, as well as to improve hemodynamics and gas exchange in patients with very high levels of intrinsic positive end-expiratory pressure.

Performance characteristics of five new anesthesia ventilators and four intensive care ventilators in pressure-support mode: a comparative bench study.

Objective To compare the effects of adaptive support ventilation (ASV) and synchronized intermittent mandatory ventilation plus pressure support (SIMV-PS) on patient-ventilator interactions in patients undergoing partial ventilatory support. Design Prospective, crossover interventional study. Setting Medical intensive care unit, university tertiary care center. Patients Ten patients, intubated and mechanically ventilated for acute respiratory failure of diverse causes, in the early weaning period, ventilated with SIMV-PS and clinically detectable sternocleidomastoid activity suggesting increased inspiratory load and patient-ventilator dyssynchrony. Interventions Measurement of respiratory mechanics, P0.1, sternocleidomastoid electromyographic activity, arterial blood gases, and systemic hemodynamics in three conditions: 1) after 45 mins with SIMV-PS (SIMV-PS 1); 2) after 45 mins with ASV, set to deliver the same minute-ventilation as during SIMV-PS; 3) 45 mins after return to SIMV-PS (SIMV-PS 2), with settings identical to those of the first SIMV-PS period. Main Results The same minute ventilation was observed during ASV (11.4 ± 3.1 l/min [mean ± sd]) as during SIMV-PS 1 (11.6 ± 3.5 L/min) and SIMV-PS 2 (10.8 ± 3.4 L/min). No parameter was significantly different between SIMV-PS 1 and 2, hence subsequent results refer to ASV vs. SIMV-PS 1. During ASV, tidal volume increased (538 ± 91 vs. 671 ± 100 mL, p < .05) and total respiratory rate decreased (22 ± 7 vs. 17 ± 3 breaths/min, p < .05) vs. SIMV-PS. However, spontaneous respiratory rate increased in six patients, decreased in four, and remained unchanged in one. P0.1 decreased during ASV in all patients except three in whom no change was noted (1.8 ± 0.9 vs. 1.1 ± 1 cm H2O, p < .05). During ASV, sternocleidomastoid electromyogram activity was markedly reduced (electromyogram index, where SIMV-PS 1 = 100, ASV 34 ± 41, SIMV-PS 2 89 ± 36, p < .02) as was palpable muscle activity. No changes were noted in arterial blood gases, pH, or mean systemic pressure during the trial. Conclusion In patients undergoing partial ventilatory support, with clinical and electromyographic signs of increased respiratory muscle loading, ASV provided levels of minute ventilation comparable to those of SIMV-PS. However, with ASV, central respiratory drive and sternocleidomastoid activity were markedly reduced, suggesting decreased inspiratory load and improved patient-ventilator interactions. These preliminary results warrant further testing of ASV for partial ventilatory support.

Expiratory trigger setting in pressure support ventilation: from mathematical model to bedside.

Background:During the past few years, many manufacturers have introduced new modes of ventilation in anesthesia ventilators, especially partial-pressure modalities. The current bench test study was designed to compare triggering and pressurization of five new anesthesia ventilators with four intensive care unit ventilators. Methods:Ventilators were connected to a two-compartment lung model. One compartment was driven by an intensive care unit ventilator to mimic “patient” inspiratory effort, whereas the other was connected to the tested ventilator. The settings of ventilators were positive end-expiratory pressures of 0 and 5 cm H2O, and pressure-support ventilation levels of 10, 15, and 20 cm H2O with normal and high “patient” inspiratory effort. For the anesthesia ventilators, all the measurements were obtained for a low (1 l/min) and a high (10 l/min) fresh gas flow. Triggering delay, triggering workload, and pressurization at 300 and 500 ms were analyzed. Results:For the five tested anesthesia ventilators, the pressure-support ventilation modality functioned correctly. For inspiratory triggering, the three most recent anesthesia machines (Fabius, Drägerwerk AG, Lübeck, Germany; Primus, Drägerwerk AG; and Avance, GE-Datex-Ohemda, Munchen, Germany) had a triggering delay of less than 100 ms, which is considered clinically satisfactory and is comparable to intensive care unit machines. The use of positive end-expiratory pressure modified the quality of delivered pressure support for two anesthesia ventilators (Kion, Siemens AG, Munich, Germany; and Felix, Taema, Antony, France). Three of the five anesthesia ventilators exhibited pressure-support ventilation performance characteristics comparable to those of the intensive care unit machines. Increasing fresh gas flow (1 to 10 l/min) in the internal circuit did not influence the pressure-support ventilation performance of the anesthesia ventilators. Conclusion:Regarding trigger sensitivity and the system’s ability to meet inspiratory flow during pressure-supported breaths, the most recent anesthesia ventilators have comparable performances of recent-generation intensive care unit ventilators.

The impact of a cardioprotective protocol on the incidence of cardiac complications after aortic abdominal surgery.

Objective:To evaluate the feasibility of relying on a mathematical model to adjust the optimal level of expiratory trigger, materialized by the ratio of inspiratory flow at the end of inspiratory effort (V′ti) and peak inspiratory flow (V′peak), or V′ti/V′peak, during pressure support, by comparing its predicted values with those measured in intubated patients. Design:Prospective observational study. Setting:Medical intensive care unit, university hospital. Patients:There were 28 intubated patients undergoing pressure support. Interventions:Pressure support as set by the clinician in charge. Measurements and Main Results:A significant correlation was found between predicted and measured V′ti/V′peak ratios (r = .70; p < .001; mean ± sd difference, −0.025 ± 0.07; 95% confidence interval, −0.161 to 0.111). Overall, delayed cycling occurred in obstructive conditions, the delay increasing as obstructive disease was more severe. Conclusions:A significant correlation was observed between predicted values of V′ti/V′peak and those values measured in patients undergoing pressure support. These findings should stimulate further research into the possible applications of this mathematical model to optimize expiratory trigger setting. Furthermore, our findings suggest that expiratory trigger should be adjustable and provide a wider range of cutoff levels than that which is currently available.

Ex utero intrapartum treatment (EXIT) of severe fetal hydrothorax

We analyzed a local database including 468 consecutive patients who underwent elective aortic abdominal surgery over an 8-yr period in a single institution. A new cardioprotective perioperative protocol was introduced in January 1997, and we questioned whether perioperative cardiac outcome could be favorably influenced by the application of a stepwise cardiovascular evaluation based on the American College of Cardiology/American Heart Association guidelines and by the use of antiadrenergic drugs. Clonidine was administered during surgery, and &bgr;-blockers were titrated after surgery to achieve heart rates less than 80 bpm. We compared data of two consecutive 4-yr periods (1993–1996 [control period] versus 1997–2000 [intervention period]). Implementation of American College of Cardiology/American Heart Association guidelines was associated with increased preoperative myocardial scanning (44.3% vs 20.6%;P < 0.05) and coronary revascularization (7.7% vs 0.8%;P < 0.05). During the intervention period, there was a significant decrease in the incidence of cardiac complications (from 11.3% to 4.5%) and an increase in event-free survival at 1 yr after surgery (from 91.3% to 98.2%). Multivariate regression analysis showed that the combined administration of clonidine and &bgr;-blockers was associated with a decreased risk of cardiovascular events (odds ratio, 0.3; 95% confidence interval, 0.1–0.8), whereas major bleeding, renal insufficiency, and chronic obstructive pulmonary disease were predictive of cardiac complications. In conclusion, cardiac testing was helpful to identify a small subset of high-risk patients who might benefit from coronary revascularization. Sequential and selective antiadrenergic treatments were associated with improved postoperative cardiac outcome.

Cardiovascular response to acute normovolaemic haemodilution in patients with severe aortic stenosis: assessment with transoesophageal echocardiography

Ex utero intrapartum treatment (EXIT) of a fetus with severe bilateral hydrothorax is described. EXIT allows therapeutic interventions on the neonate while maintaining fetoplacental circulation. Thus it may be useful for fetuses presenting with severe pleural effusion towards the end of gestation and in whom in utero drainage is technically not possible or available and drainage post partum would result in profound and prolonged hypoxia until sufficient drainage of pleural fluid allowed lung expansion.