Philippe Jolliet

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.

Effects of the prone position on gas exchange and hemodynamics in severe acute respiratory distress syndrome.

OBJECTIVES To address the following issues regarding the use of prone position ventilation in patients with severe acute respiratory distress syndrome (ARDS): a) response rate; b) magnitude and duration of improved oxygenation in responders during a 12-hr trial and the consequences of returning to the supine position; c) effects of the prone position on gas exchange and hemodynamics; d) consequences of oxygenation in nonresponders; and e) effects of repeated prone position trials. DESIGN Prospective, nonrandomized interventional study. SETTING Medical intensive care unit, university tertiary care center. PATIENTS Nineteen consecutive, mechanically ventilated patients (age 45+/-20 yrs, mean+/-SD) with ARDS and severe hypoxemia, defined as PaO2/FiO2 of < or = 150 with FiO2 of > or = 0.6 persisting for < or =24 hrs, and a pulmonary artery occlusion pressure of <18 mm Hg. INTERVENTIONS Patients were turned prone for 2 hrs. Nonresponders were returned supine, but responders were maintained prone for 12 hrs before being returned to the supine position. The procedure was repeated on a daily basis in all patients, until inclusion criteria were no longer met or the patients died. MEASUREMENTS AND MAIN RESULTS Hemodynamic, blood gas, and gas exchange measurements were performed at the following time points: a) baseline supine; b) after 30 mins prone; and c) after 120 mins prone. Additional measurements for nonresponders were taken after 30 mins supine. For responders, additional measurements were taken after 12 hrs prone and 30 mins supine. Patients were considered responders if an increase in PaO2 of > or = 10 torr (> or =1.3 kPa), or increase in the PaO2/FiO2 ratio of >20 occurred within 120 mins. Eleven (57%) patients responded to the prone position. There was no difference in initial baseline parameters between responders and nonresponders. After 30 mins, the prone position in responders increased PaO2 and decreased calculated venous admixture (Qva/Qt). This improvement was the maximal obtained, and was maintained throughout the 12-hr prone period. After 12 hrs prone, mean FiO2 had been lowered from 0.85+/-0.16 to 0.66+/-0.18 (p < .05). Thirty minutes after the patients were returned supine, PaO2, PaO2/FiO2, and Qva/Qt were not different from 12-hr prone values, and were improved in comparison with baseline supine values. There was no worsening of gas exchange or hemodynamics in nonresponders. After the initial trial, a total of 28 additional episodes of prone position ventilation were performed in nine of the 19 patients. Of the 24 additional episodes in the responders, there was a response in 17 (71%) of 24 episodes. In the four additional episodes in nonresponders, there was a response in only one (25%) of four episodes. Response was accompanied by the same beneficial effects on gas exchange and Qva/Qt and absence of effect on hemodynamics as in the initial trial. There was no worsening in gas exchange or hemodynamics in nonresponder trials. CONCLUSIONS Based on the data from this study, the prone position can improve oxygenation in severely hypoxemic ARDS patients without deleterious effects on hemodynamics. This beneficial effect does not immediately disappear on return to the supine position. In our patients, an absence of response to this technique was not accompanied by worsening hypoxemia or hemodynamic instability. Repeated daily trials in the prone position should be considered in the management of ARDS patients with severe hypoxemia.

Neurally adjusted ventilatory assist improves patient-ventilator interaction.

PurposeTo determine if, compared with pressure support (PS), neurally adjusted ventilatory assist (NAVA) reduces trigger delay, inspiratory time in excess, and the number of patient–ventilator asynchronies in intubated patients.MethodsProspective interventional study in spontaneously breathing patients intubated for acute respiratory failure. Three consecutive periods of ventilation were applied: (1) PS1, (2) NAVA, (3) PS2. Airway pressure, flow, and transesophageal diaphragmatic electromyography were continuously recorded.ResultsAll results are reported as median (interquartile range, IQR). Twenty-two patients were included, 36.4% (8/22) having obstructive pulmonary disease. NAVA reduced trigger delay (ms): NAVA, 69 (57–85); PS1, 178 (139–245); PS2, 199 (135–256). NAVA improved expiratory synchrony: inspiratory time in excess (ms): NAVA, 126 (111–136); PS1, 204 (117–345); PS2, 220 (127–366). Total asynchrony events were reduced with NAVA (events/min): NAVA, 1.21 (0.54–3.36); PS1, 3.15 (1.18–6.40); PS2, 3.04 (1.22–5.31). The number of patients with asynchrony index (AI) >10% was reduced by 50% with NAVA. In contrast to PS, no ineffective effort or late cycling was observed with NAVA. There was less premature cycling with NAVA (events/min): NAVA, 0.00 (0.00–0.00); PS1, 0.14 (0.00–0.41); PS2, 0.00 (0.00–0.48). More double triggering was seen with NAVA, 0.78 (0.46–2.42); PS1, 0.00 (0.00–0.04); PS2, 0.00 (0.00–0.00).ConclusionsCompared with standard PS, NAVA can improve patient–ventilator synchrony in intubated spontaneously breathing intensive care patients. Further studies should aim to determine the clinical impact of this improved synchrony.

Patient-Ventilator Asynchrony During Noninvasive Ventilation: A Bench and Clinical Study

BACKGROUND Different kinds of ventilators are available to perform noninvasive ventilation (NIV) in ICUs. Which type allows the best patient-ventilator synchrony is unknown. The objective was to compare patient-ventilator synchrony during NIV between ICU, transport—both with and without the NIV algorithm engaged—and dedicated NIV ventilators. METHODS First, a bench model simulating spontaneous breathing efforts was used to assess the respective impact of inspiratory and expiratory leaks on cycling and triggering functions in 19 ventilators. Second, a clinical study evaluated the incidence of patient-ventilator asynchronies in 15 patients during three randomized, consecutive, 20-min periods of NIV using an ICU ventilator with and without its NIV algorithm engaged and a dedicated NIV ventilator. Patient-ventilator asynchrony was assessed using flow, airway pressure, and respiratory muscles surface electromyogram recordings. RESULTS On the bench, frequent auto-triggering and delayed cycling occurred in the presence of leaks using ICU and transport ventilators. NIV algorithms unevenly minimized these asynchronies, whereas no asynchrony was observed with the dedicated NIV ventilators in all except one. These results were reproduced during the clinical study: The asynchrony index was significantly lower with a dedicated NIV ventilator than with ICU ventilators without or with their NIV algorithm engaged (0.5% [0.4%-1.2%] vs 3.7% [1.4%-10.3%] and 2.0% [1.5%-6.6%], P < .01), especially because of less auto-triggering. CONCLUSIONS Dedicated NIV ventilators allow better patient-ventilator synchrony than ICU and transport ventilators, even with their NIV algorithm. However, the NIV algorithm improves, at least slightly and with a wide variation among ventilators, triggering and/or cycling off synchronization.

Effects of rapid permissive hypercapnia on hemodynamics, gas exchange, and oxygen transport and consumption during mechanical ventilation for the acute respiratory distress syndrome.

ObjectiveTo measure the effects of rapid permissive hypercapnia on hemodynamics and gas exchange in patients with acute respiratory distress syndrome (ARDS).DesignProspective study.Setting: 18-bed, medical intensive care unit, university hospital.Patients11 mechanically ventilated ARDS patients.InterventionPatients were sedated and ventilated in the controlled mode. Hypercapnia was induced over a 30–60 min period by decreasing tidal volume until pH decreased to 7.2 and/or P50 increased by 7.5 mmHg. Settings were then maintained for 2 h.ResultsMinute ventilation was reduced from 13.5±6.1 to 8.2±4.1l/min (mean±SD), PaCO2 increased (40.3±6.6 to 59.3±7.2 mmHg), pH decreased (7.40±0.05 to 7.26±0.05), and P50 increased (26.3±2.02 to 31.1±2.2 mmHg) (p<0.05). Systemic vascular resistance decreased (865±454 to 648±265 dyne·s·cm−5, and cardiac index (CI) increased (4±2.4 to 4.7±2.4 l/min/m2) (p<0.05). Mean systemic arterial pressure was unchanged. Pulmonary vascular resistance was unmodified, and mean pulmonary artery pressure (MPAP) increased (29±5 to 32±6 mmHg,p<0.05). PaO2 remained unchanged, while saturation decreased (93±3 to 90±3%,p<0.05), requiring an increase in FIO2 from 0.56 to 0.64 in order to maintain an SaO2>90%. PvO2 increased (36.5±5.7 to 43.2±6.1 mmHg,p<0.05), while saturation was unmodified. The arteriovenous O2 content difference was unaltered. Oxygen transport (DO2) increased (545±240 to 621±274 ml/min/m2,p<0.05), while the O2 consumption and extraction ratio did not change significantly. Venous admixture (Qva/Qt) increased (26.3±12.3 to 32.8±13.2,p<0.05).ConclusionsThese data indicate that acute hypercapnia increases DO2 and O2 off-loading capacity in ARDS patients with normal plasma lactate, without increasing O2 extraction. Whether this would be beneficial in patients with elevated lactate levels, indicating tissue hypoxia, remains to be determined. Furthermore, even though hypercapnia was well tolerated, the increase in Qva/Qt, CI, and MPAP should prompt caution in patients with severe hypoxemia, as well as in those with depressed cardiac function and/or severe pulmonary hypertension.

Additive beneficial effects of the prone position, nitric oxide, and almitrine bismesylate on gas exchange and oxygen transport in acute respiratory distress syndrome

OBJECTIVE To test the hypothesis that prone position ventilation, nitric oxide, and almitrine bismesylate, each acting by a different mechanism to improve arterial oxygenation, could exert additive beneficial effects when used in combination in patients with severe acute respiratory distress syndrome (ARDS). DESIGN Prospective, nonrandomized, interventional study. SETTING Medical and surgical intensive care units at a university tertiary care center. PATIENTS Twelve patients with ARDS and severe hypoxemia, defined as PaO2/FIO2 of < or = 150 and FIO2 of > or = 0.6, with pulmonary artery occlusion pressure of < 18 mm Hg. INTERVENTIONS Inhaled nitric oxide (20 parts per million for 15 mins) in the supine and prone position, and intravenous almitrine bismesylate while prone (1 mg/kg/hr for 60 mins), alone or combined with nitric oxide. MEASUREMENTS AND MAIN RESULTS Hemodynamic, blood gas, and gas exchange measurements were performed at sequential time points as follows: a) baseline supine; b) nitric oxide in the supine position; c) after return to baseline supine; d) after 30 mins prone; e) after 120 mins prone; f) nitric oxide while prone; g) after return to baseline prone; h) almitrine bismesylate prone; and i) nitric oxide and almitrine bismesylate combined, for 15 mins prone. Patients were considered responders to the prone position if a gain in PaO2 of > or = 10 torr (> or = 1.3 kPa) or a gain in the PaO2/FIO2 ratio of > or = 20 was observed. Seven patients (58%) responded to being turned prone. Compared with supine baseline conditions, nitric oxide and supine position increased arterial oxygen saturation from 89 +/- 1 (SD)% to 92 +/- 3% (p < .05) and nitric oxide plus prone position increased arterial oxygen saturation (94 +/- 3% vs. 89 +/- 4%, p < .05) and decreased the alveolar-arterial oxygen difference from 406 +/- 124 torr (54 +/- 15 kPa) to 387 +/- 108 torr (51 +/- 14 kPa) (p < .05). Almitrine bismesylate increased PaO2/FIO2 vs. baseline (122 +/- 58 vs. 84 +/- 21, p < .05). Almitrine bismesylate decreased the alveolar-arterial oxygen difference vs. baseline from 406 +/- 124 torr (53.9 +/- 16.5 kPa) to 386 +/- 112 torr (51.3 +/- 14.8 kPa) and vs. nitric oxide and supine position from 406 +/- 111 torr (53.9 +/- 14.7 kPa) to 386 +/- 112 torr (51.3 +/- 14.8 kPa) (p < .05). Prone position alone did not improve oxygenation. However, the combination of nitric oxide and almitrine bismesylate increased PaO2/FIO2 vs. nitric oxide supine and nitric oxide prone conditions (147 +/- 69 vs. 84 +/- 25 and 91 +/- 18, respectively; p < .05). In patients responding to the prone position (n = 7), combining nitric oxide and almitrine bismesylate led to further improvement in PaO2 compared with the prone position alone, with PaO2 increasing from 78 +/- 12 torr (10.3 +/- 1.6 kPa) to 111 +/- 55 torr (14.7 +/- 7.3 kPa) (p < .05), which was not the case when either nitric oxide or almitrine bismesylate was added separately. Heart rate and cardiac output were increased by almitrine bismesylate compared with all other measurements. Mean pulmonary arterial pressure was decreased by nitric oxide (27 +/- 7 vs. 30 +/- 7 mm Hg nitric oxide supine vs. baseline supine and 29 +/- 7 vs. 33 +/- 8 mm Hg nitric oxide prone vs. baseline prone, p < .05) and increased by almitrine bismesylate (36 +/- 9 vs. 30 +/- 7 mm Hg baseline supine, 27 +/- 7 mm Hg nitric oxide supine, 33 +/- 8 mm Hg baseline prone, and 29 +/- 7 mm Hg nitric oxide prone; p < .05). The increase in mean pulmonary arterial pressure was totally abolished by nitric oxide (31 +/- 5 vs. 36 +/- 9 mm Hg, p < .05). Minute ventilation, respiratory system compliance, physiologic deadspace, and PaCO2 remained unchanged. CONCLUSION In ARDS patients with severe hypoxemia, arterial oxygenation can be improved by combining the prone position, nitric oxide, and almitrine bismesylate, without deleterious effects.

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.

Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation : A prospective, randomized, controlled study

OBJECTIVE To evaluate the benefit of recombinant human growth hormone administration on muscle strength and duration of weaning in critically ill patients undergoing prolonged mechanical ventilation. DESIGN Prospective, randomized, controlled, single-blind study. SETTING Intensive care unit. PATIENTS Twenty patients requiring > or = 7 days of mechanical ventilation for acute respiratory failure. INTERVENTION Random assignment to receive either 0.43 IU (approximately 0.14 mg) recombinant growth hormone/kg body weight/day (treated group), or saline (nontreated group) for 12 days. MEASUREMENTS AND MAIN RESULTS Nutritional support was guided by indirect calorimetry. Cumulative nitrogen balance was positive throughout the study period in the treated group 17.3 (44.9 +/- 17.3[SEM] g/12 days) vs. the nontreated group (-65.8 +/- 11.8 g/12 days) (p<.0001). Despite similar initial plasma concentrations, recombinant growth hormone supplementation resulted in marked increases in growth hormone, insulin like growth factor-1, and insulin concentrations (p<.05, .02, and .0001, respectively, vs. nontreated group). Body impedance determined net fat-free mass increased in the treated group (0.8 +/- 0.6 kg) vs. the nontreated group (-1.1 +/- O.5 kg) (p<.03). Initial peripheral muscle function, assessed by computer-controlled electrical stimulation of the adductor pollicis, was similarly lower in treated and nontreated groups than sex and age-matched normal controls, and decreased further during the study period. Arterial blood gases, cumulative total mechanical ventilation time, and number of hrs/day of mechanical ventilation during weaning were similar in both patient groups. Only three of the ten patients in each group were weaned from mechanical ventilation by day 12. CONCLUSIONS Daily administration of recombinant growth hormone in mechanically ventilated patients with acute respiratory failure promotes a marked nitrogen retention. However, this reaction is accompanied neither by an improvement in muscle strength nor by a shorter duration of ventilatory supports.

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

Inhaled nitric oxide therapy in adults: European expert recommendations.

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.