Prone positioning in severe acute respiratory distress syndrome.

BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

Prevalence and risk factors of hypotension associated with preload-dependence during intermittent hemodialysis in critically ill patients.

BACKGROUND: Hypotension is a frequent complication of intermittent hemodialysis (IHD) performed in intensive care units (ICUs). Passive leg raising (PLR) combined with continuous measurement of cardiac output is highly reliable to identify preload dependence, and may provide new insights into the mechanisms involved in IHD-related hypotension. The aim of this study was to assess prevalence and risk factors of preload dependence-related hypotension during IHD in the ICU. METHODS: A single-center prospective observational study performed on ICU patients undergoing IHD for acute kidney injury and monitored with a PiCCO® device. Primary end points were the prevalence of hypotension (defined as a mean arterial pressure below 65 mm Hg) and hypotension associated with preload dependence. Preload dependence was assessed by the passive leg raising test, and considered present if the systolic ejection volume increased by at least 10% during the test, as assessed continuously by the PiCCO® device. RESULTS: Forty-seven patients totaling 107 IHD sessions were included. Hypotension was observed in 61 IHD sessions (57%, CI95%: 47-66%) and was independently associated with inotrope administration, higher SOFA score, lower time lag between ICU admission and IHD session, and lower MAP at IHD session onset. Hypotension associated with preload dependence was observed in 19% (CI95%: 10-31%) of sessions with hypotension, and was associated with mechanical ventilation, lower SAPS II, higher pulmonary vascular permeability index (PVPI) and dialysate sodium concentration at IHD session onset. ROC curve analysis identified PVPI and mechanical ventilation as the only variables with significant diagnostic performance to predict hypotension associated with preload dependence (respective AUC: 0.68 (CI95%: 0.53-0.83) and 0.69 (CI95%: 0.54-0.85). A PVPI ≥ 1.6 at IHD session onset predicted occurrence of hypotension associated with preload dependence during IHD with a sensitivity of 91% (CI95%: 59-100%), and a specificity of 53% (CI95%: 42-63%). CONCLUSIONS: The majority of hypotensive episodes occurring during intermittent hemodialysis are unrelated to preload dependence and should not necessarily lead to reduction of fluid removal by hemodialysis. However, high PVPI at IHD session onset and mechanical ventilation are risk factors of preload dependence-related hypotension, and should prompt reduction of planned fluid removal during the session, and/or an increase in session duration.

Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial.

INTRODUCTION: In septic shock, pulse pressure or cardiac output variation during passive leg raising are preload dependence indices reliable at predicting fluid responsiveness. Therefore, they may help to identify those patients who need intravascular volume expansion, while avoiding unnecessary fluid administration in the other patients. However, whether their use improves septic shock prognosis remains unknown. The aim of this study was to assess the clinical benefits of using preload dependence indices to titrate intravascular fluids during septic shock. METHODS: In a single-center randomized controlled trial, 60 septic shock patients were allocated to preload dependence indices-guided (preload dependence group) or central venous pressure-guided (control group) intravascular volume expansion with 30 patients in each group. The primary end point was time to shock resolution, defined by vasopressor weaning. RESULTS: There was no significant difference in time to shock resolution between groups (median (interquartile range) 2.0 (1.2 to 3.1) versus 2.3 (1.4 to 5.6) days in control and preload dependence groups, respectively). The daily amount of fluids administered for intravascular volume expansion was higher in the control than in the preload dependence group (917 (639 to 1,511) versus 383 (211 to 604) mL, P = 0.01), and the same held true for red cell transfusions (178 (82 to 304) versus 103 (0 to 183) mL, P = 0.04). Physiologic variable values did not change over time between groups, except for plasma lactate (time over group interaction, P <0.01). Mortality was not significantly different between groups (23% in the preload dependence group versus 47% in the control group, P = 0.10). Intravascular volume expansion was lower in the preload dependence group for patients with lower simplified acute physiology score II (SAPS II), and the opposite was found for patients in the upper two SAPS II quartiles. The amount of intravascular volume expansion did not change across the quartiles of severity in the control group, but steadily increased with severity in the preload dependence group. CONCLUSIONS: In patients with septic shock, titrating intravascular volume expansion with preload dependence indices did not change time to shock resolution, but resulted in less daily fluids intake, including red blood cells, without worsening patient outcome. TRIAL REGISTRATION: Clinicaltrials.gov NCT01972828. Registered 11 October 2013.

Induced hypothermia in severe bacterial meningitis: a randomized clinical trial.

IMPORTANCE: Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE: To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS: An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS: Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES: Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS: After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE: Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00774631.

Expiratory flow-volume loop profile and patient outcome in chronic obstructive pulmonary disease in acute respiratory failure: a prospective observational study in a single intensive care unit.

BACKGROUND: Expiratory flow-volume (EFV) loops are continuously displayed on the screen of intensive care unit (ICU) ventilators. OBJECTIVES: It was the aim of this study to investigate the relationships of EFV to chronic obstructive pulmonary disease (COPD) patient outcome. METHODS: This is a prospective study on COPD patients who received invasive mechanical ventilation for acute respiratory failure in the ICU. Within the 24-hour post-intubation period, the angle of the EFV slope during the last 50% of expiration was computed and patients were stratified into 4 quartiles. Resistance, compliance of the respiratory system and change in end-expiratory lung volume above relaxation volume were assessed. Patients were followed up to hospital discharge. The main outcome was hospital mortality. Secondary outcomes were ICU mortality, length of ICU stay, duration of invasive ventilation, number of intubations, oxygen and non-invasive ventilation. RESULTS: Thirty-eight patients were analysed. The first quartile comprised 9 patients (median angle 11°, interquartile range 8-12), the second 10 patients (median angle 26°, range 19-30), the third 10 patients (median angle 42°, range 39-46), and the fourth 9 patients (median angle 53°, range 49-64). Hospital and ICU mortality were not different between groups. Lengths of ICU and hospital stay and length of invasive ventilation were significantly different between groups, with the highest values observed in the first quartile. The rate of oxygen use and non-invasive ventilation in the ICU and at hospital discharge was significantly different between groups, with the highest rate observed in the first quartile. There was a significant negative correlation between angle and resistance, compliance of the respiratory system and change in end-expiratory lung volume above the relaxation volume. CONCLUSION: The slope of the angle during the last 50% of expired volume in the COPD patients was associated with worsened respiratory mechanics and higher morbidity.

Comparison of Alpha 200 and CoughAssist as intermittent positive pressure breathing devices: a bench study.

BACKGROUND: Intermittent positive pressure breathing (IPPB) is used in non-intubated patients to increase lung volume and to enhance coughing. Alpha 200 (Salvia Lifetec, Kronberg, Germany) is a specific IPPB device. CoughAssist (Respironics France, Carquefou, France) is a mechanical insufflator-exsufflator used to remove secretions in patients with inefficient cough. Both can also be used for intubated or tracheotomized patients. We assessed the impact of various artificial airways on the ability of the Alpha 200 and CoughAssist to generate insufflated volume. METHODS: We measured the insufflated volume and pressure at the airway opening in a lung model under 2 conditions of compliance (30 or 60 mL/cm H(2)O) at single resistance of 5 cm H(2)O/L/s. The devices were used at 2 set pressures: 30 and 40 cm H(2)O. The Alpha 200 was set at 2 inflation flows: 0.5 and 1 L/s, whereas CoughAssist was set at its highest value of 10 L/s. Measurements were done without (control) and with different size endotracheal tubes and tracheostomy cannulae. The relationships between insufflated volume and measured pressure were analyzed using linear regressions. RESULTS: The slopes and intercepts of the control relationship between insufflated volume and pressure were significantly greater with Alpha 200 at each set flow than with CoughAssist. As artificial airways were used, the insufflated volume did not differ from the control with CoughAssist, while with Alpha 200 it increased at each flow setting and for all mechanical conditions. The largest differences in insufflated volume between the 2 devices were observed for the largest endotracheal tubes and tracheostomy cannulas and for the lowest inflation flow setting in Alpha 200. These results can be explained in terms of how the devices function, as CoughAssist adapts by increasing flow, while Alpha 200 adapts by increasing inspiratory time. CONCLUSIONS: This bench study has shown that in the presence of artificial airways the value of the insufflated volume generated by the CoughAssist device was significantly lower than that generated by the Alpha 200 device.

Performance of the coughassist insufflation-exsufflation device in the presence of an endotracheal tube or tracheostomy tube: a bench study.

BACKGROUND: The CoughAssist is a mechanical insufflator-exsufflator designed to assist airway secretion clearance in patients with ineffective cough. The device may benefit intubated and tracheotomized patients. We assessed the impact of various artificial airways on peak expiratory flow (PEF) with the CoughAssist. METHODS: We measured PEF and pressure at the airway opening in a lung model during insufflation-exsufflation with the CoughAssist, at 3 set pressures: 30/-30, 40/-40, and 50/-50 cm H(2)O, first without (control), and then with different sizes (6.5 to 8.5 mm inner diameter) of endotracheal tube (ETT) and tracheostomy tube (6, 7, and 8 mm inner diameter), compliance settings of 30 and 60 mL/cm H(2)O, and resistance settings of 0 and 5 cm H(2)O/L/s). We analyzed the relationship between PEF and pressure with linear regression. RESULTS: With compliance of 30 mL/cm H(2)O and 0 resistance the slope of the control relationship between PEF and pressure was statistically significantly greater than during any conditions with ETT or tracheostomy tube. Therefore, in comparison to the control, the relationship of PEF to pressure significantly went in the direction from top to bottom as the ETT or tracheostomy tube became narrower. The findings were the same with compliance of 30 mL/cm H(2)O and resistance of 5 cm H(2)O/L/s. With compliance of 60 mL/cm H(2)O the highest set pressure values were not achieved and some relationships departed from linearity. The control slope of the relationship between PEF and pressure with compliance of 60 mL/cm H(2)O and 0 resistance did not significantly differ with any ETT or tracheostomy tube. CONCLUSIONS: The artificial airways significantly reduced PEF during insufflation-exsufflation with CoughAssist; the narrower the inner diameter of the artificial airway, the lower the PEF for a given expiratory pressure.

Management and long-term outcome of patients with chronic neuromuscular disease admitted to the intensive care unit for acute respiratory failure: a single-center retrospective study.

BACKGROUND: Patients with chronic neuromuscular disease represent less than 10% of those receiving mechanical ventilation in the intensive care unit (ICU). Little has been reported regarding either ICU management of acute respiratory failure (ARF) in the era of noninvasive mechanical ventilation (NIV) or long-term outcomes. OBJECTIVE: To describe the respiratory management of patients with chronic neuromuscular diseases admitted to our university hospital ICU for ARF, and the long-term outcomes. METHODS: We retrospectively analyzed patients with chronic neuromuscular diseases admitted to our ICU for a first episode of ARF between January 1, 1996, and February 27, 2007. We assessed severity of illness on ICU admission, respiratory management during ICU stay, and outcomes on June 15, 2008. RESULTS: During the study period, 87 patients (44 with hereditary and 43 with acquired neuromuscular diseases) had their first ARF episode that required ICU admission. In the hereditary-diseases group and the acquired-diseases group, respectively, the rates of NIV use during the ICU stay were 82% and 63% (P = .040), the intubation rates were 30% and 56% (P = .02), and the tracheotomy rates were 9% and 12% (difference not significant). At the final assessment (median 3 years) the mortality rate was 58%, and mortality was not significantly related to the type of neuromuscular disease. At final assessment, 46% of the patients were on NIV and 29% had tracheotomy. CONCLUSIONS: In our ICU, chronic neuromuscular disease is an uncommon cause of ARF, for which we often use NIV. These patients had a low probability of death in the ICU. Long-term outcome was independent of the type of neuromuscular disease.

A case of pneumomediastinum in a patient with acute respiratory distress syndrome on pressure support ventilation.

During mechanical ventilation for acute respiratory distress syndrome, tidal volume (V(T)) must be reduced. Once switched to pressure-support ventilation, there is a risk that uncontrolled large V(T) may be delivered. A 63-year-old man with community-acquired pneumonia required tracheal intubation and mechanical ventilation, with a V(T) of 6 mL/kg predicted body weight, PEEP of 10 cm H2O, a respiratory rate of 30 breaths/min, and F(IO2) of 0.60. Plateau pressure was 22 cm H2O. He improved and received pressure-support. Twelve days later a chest radiograph showed suspected air leaks, confirmed via computed tomogram (CT), which showed anterior pneumomediastinum. V(T) received over the previous 3 days had averaged 14 mL/kg predicted body weight. The patient was put back onto volume-controlled mode, and 2 days later there were no air leaks. In pressure-support ventilation, V(T) must be closely monitored to ensure lung-protective mechanical ventilation.

Quantitative analysis of acid-base disorders in patients with chronic respiratory failure in stable or unstable respiratory condition.

BACKGROUND: The Stewart approach theorizes that plasma pH depends on P(aCO2), the strong ion difference, and the plasma total concentration of non-volatile weak acids (A(tot)). The conventional approach measures standardized base excess, bicarbonate (HCO3⁻), and the anion gap. OBJECTIVE: To describe acid-base disorders with the Stewart approach and the conventional approach in patients with chronic respiratory failure. METHODS: This was an observational prospective study in a medical intensive care unit and a pneumology ward of a university hospital. There were 128 patients included in the study, of which 14 had more than one admission, resulting in 145 admissions. These were allocated to 4 groups: stable respiratory condition and elevated HCO3⁻ (Group 1, n = 23), stable respiratory condition and non-elevated HCO3⁻ (Group 2, n = 41), unstable respiratory condition and elevated HCO3⁻ (Group 3, n = 44), and unstable respiratory condition and non-elevated HCO3⁻ (Group 4, n = 37). Elevated HCO3⁻ was defined as ≥ 3 standard deviations higher than the mean value we found in 8 healthy volunteers. Measurements were taken on admission. RESULTS: In groups 1, 2, 3, and 4, the respective mean ± SD values were: HCO3⁻ 33 ± 3 mM, 26 ± 3 mM, 37 ± 4 mM, and 27 ± 3 mM (P < .001); strong ion difference 45 ± 3 mM, 38 ± 4 mM, 46 ± 4 mM, and 36 ± 4 mM (P < .001); and A(tot) 12 ± 1 mM, 12 ± 1 mM, 10 ± 1 mM, 10 ± 2 mM (P < .001). Non-respiratory disorders related to high strong ion difference were observed in 12% of patients with elevated HCO3⁻, and in none of those with non-elevated HCO3⁻ (P = .003). Non-respiratory disorders related to low strong ion difference were observed in 9% of patients with non-elevated HCO3⁻, and in none of those with elevated HCO3⁻ (P = .02). Hypoalbuminemia was common, especially in unstable patients (group 3, 66%; group 4, 65%). Normal standardized base excess (16%), HCO3⁻ (28%), and anion gap (30%) values were common. The Stewart approach detected high effective strong ion difference in 13% of normal standardized base excess, and in 20% of normal anion gap corrected for albuminemia, and low effective strong ion difference in 22% of non-elevated HCO3⁻. CONCLUSIONS: In patients with chronic respiratory failure the acid-base pattern is complex, metabolic alkalosis is present in some patients with elevated HCO3⁻, and metabolic acidosis is present in some with non-elevated HCO3⁻. The diagnostic performance of the Stewart approach was better than that of the conventional approach, even when corrected anion gap was taken into account.

The feasibility of early physical activity in intensive care unit patients: a prospective observational one-center study.

BACKGROUND: Prolonged immobilization may harm intensive care unit (ICU) patients, and early mobilization has been proposed to counteract that process. We describe our experience in early rehabilitation of ICU patients, and its effects on physiologic outcomes. METHODS: We included all patients who stayed in our 14-bed medical ICU for > or = 7 days and received invasive mechanical ventilation for > or = 2 days. The rehabilitation program included chair-sitting, tilting-up (with arms supported or unsupported), and walking. We collected vital signs before and after each intervention. RESULTS: Over a 5-month period we studied 20 patients, after a median ICU stay of 5 days. A contraindication to the intervention was present on 230 days (43%). Sedation (15%), shock (11%), and renal support (9%) were the most frequent contraindications. We obtained complete data from 275 of 424 interventions, 33% of which were performed during mechanical ventilation. The chair-sitting intervention was the most frequent (56%), followed by the tilting-up-with-arms-unsupported intervention (25%), the walking intervention (11%), and the tilting-up arms-supported intervention (8%). The chair-sitting intervention was associated with a significant (P = .03) decline in both heart rate (mean -3.5 beats/min, 95% confidence interval [CI] -6.5 to -0.4 beats/min) and respiratory rate (-1.4 breaths/min, 95% CI -2.6 to 0.1 breaths/min), whereas blood oxygen saturation (measured via pulse oximetry [S(pO(2))]) and mean arterial blood pressure did not change significantly. Heart rate and respiratory rate similarly increased with tilting-up: 14.6 beats/min, 95% CI 10.8 to 18.4 beats/min, and 5.5 breaths/min, 95% CI 3.6 to 7.3 breaths/min with arms unsupported, and 12.4 beats/min, 95% CI 7.0 to 17.9 beats/min and 2.6 breaths/min, 95% CI -0.4 to 5.7 breaths/min with arms supported). Heart rate and respiratory rate also increased with the walking intervention: 6.9 beats/min, 95% CI 2.6 to 11.1 beats/min, and 5.9 breaths/min, 95% CI 3.8 to 8.0 breaths/min. The walking intervention significantly decreased S(pO(2)). An adverse event occurred in 13 (3%) of 424 interventions, but none had harmful consequences. CONCLUSIONS: Early rehabilitation is feasible and safe in patients in the ICU for longer than 1 week. The chair-sitting intervention was associated with nonsignificant oxygenation improvement. The tilting-up intervention was an effort as intense as walking.

Comparison of optimal positive end-expiratory pressure and recruitment maneuvers during lung-protective mechanical ventilation in patients with acute lung injury/acute respiratory distress syndrome.

BACKGROUND: In patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), the use of alveolar-recruitment maneuvers to improve oxygenation is controversial. There is lack of standardization and lack of clinical studies to compare various recruitment maneuvers. Recruitment maneuvers are closely linked to the selection of positive end-expiratory pressure (PEEP), which is also a subject of debate. METHODS: With 12 intubated and mechanically ventilated patients with early ALI/ARDS we conducted a recruitment maneuver (sustained inflation at 40 cm H(2)O for 30 s), then set PEEP at 24 cm H(2)O, and then we reduced PEEP stepwise, by 4 cm H(2)O every 10 min. We kept the fraction of inspired oxygen (F(IO(2))) at 0.8. After each PEEP decrement step we measured P(aO(2)). We defined the "optimal" PEEP as the PEEP step above which P(aO(2)) decreased by > or = 20%. All the patients then underwent a period of ventilation on the same settings: tidal volume 6 mL/kg, PEEP at the level set by the physician before the experiment, plateau pressure < 30 cm H(2)O. Then each patient underwent 3 ventilation strategies, each applied for one hour: optimal PEEP alone; optimal PEEP plus one sustained inflation (40 cm H(2)O for 30 s); and optimal PEEP plus sigh breaths (ie, twice the baseline tidal volume, plateau pressure < 40 cm H(2)O) every 25 breaths. After the application of each PEEP strategy we measured arterial blood gas values and the static compliance of the respiratory system. RESULTS: The mean +/- SD optimal PEEP was 12 +/- 4 cm H(2)O. The measurements from the standardization periods were comparable between the 3 PEEP groups. In the optimal-PEEP-plus-sighs group the changes in P(aO(2)) (85 +/- 96%) and static compliance (14 +/- 20%) were significantly greater than in the 2 other groups. CONCLUSIONS: Sighs superimposed on lung-protective mechanical ventilation with optimal PEEP improved oxygenation and static compliance in patients with early ALI/ARDS.

Proof of concept study of mass cytometry in septic shock patients reveals novel immune alterations.

Innovative single cell technologies such as mass cytometry (CyTOF) widen possibilities to deeply improve characterisation of immune alterations mechanisms in human diseases. So far, CyTOF has not been used in sepsis - a condition characterized by complex immune disorders. Here, we evaluated feasibility of CyTOF analysis in patients with septic shock. We designed a mass cytometry panel of 25 extracellular markers to study mononuclear cells from 5 septic shock patients and 5 healthy donors. We explored single-cell data with global and specific unsupervised approaches such as heatmaps, SPADE and viSNE. We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes. We then showed that CyTOF analysis reveals novel aspects of sepsis-induced immune alterations, e.g. B cell shift towards plasma cell differentiation and uniform response of several monocyte markers defining an immune signature in septic patients. This proof of concept study demonstrates CyTOF suitability to analyse immune features of septic patients. Mass cytometry could thus represent a powerful tool to identify novel pathophysiological mechanisms and therapeutic targets for immunotherapy in septic shock patients.

Assessment of airway closure from deflation lung volume-pressure curve: sigmoidal equation revisited.

OBJECTIVE: To assess a sigmoidal equation for describing airway closure. DESIGN: Experimental study. SETTING: University laboratory. PARTICIPANTS: Eight piglets mechanically ventilated on zero end-expiratory pressure (ZEEP). INTERVENTIONS: Control and lung saline lavage. MEASUREMENTS AND RESULTS: Lungs were inflated up to transpulmonary pressure of 30 cmH(2)O at constant flow (0.12l s(-1)) then deflated at the same flow rate up to the point at which oesophageal pressure was constant, which was assumed to represent complete airway closure. The deflation volume-transpulmonary pressure curve was fitted to: (1) a sigmoidal equation focusing on inflexion point and pressure at maximal compliance increase and (2) an exponential equation above an inflexion point determined by eyeballing. Data deviate from the exponential equation at the point of airway closure onset. The zero-volume intercept was determined. Complete airway closure was reached at -8.3+/-3.5cmH(2)O in control conditions and at -1.3+/-3.7 cmH(2)O after lavage (p < 0.05). Between control and lavage, onset of airway closure was 3.0+/-1.9 vs. 6.0+/-2.8 cmH(2)O (p <0.05), inflexion point 3.2+/-1.8 vs. 7.7+/-2.6 cmH(2)O (p <0.001), pressure at maximal compliance increase -1.9+/-0.7 vs. -0.03+/-2.1cmH(2)O (p <0.05) and zero-volume intercept -1.5+/-1.4 vs. 0.3+/-2.3cmH(2)O (p <0.05). CONCLUSIONS: During mechanical ventilation airways stay open and close around ZEEP in control but are closed above ZEEP after lavage. Inflexion point might reflect onset of airways closure in control. Pressure at maximal compliance increase was not a marker of complete airways closure. In control and lavage, pressure at maximal compliance increase and zero-volume intercept were reasonably equivalent.

Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management.

PURPOSE: The aim of the present study was to assess the rate of diffuse alveolar damage (DAD) on open lung biopsy (OLB) performed in the ICU for nonresolving ARDS. METHODS: A single-center retrospective study of patients meeting the Berlin definition criteria for ARDS who had undergone OLB for nonresolving ARDS. Patients were classified into mild, moderate and severe ARDS categories and according to the presence or absence of DAD on the OLB. The ARDS categories were assessed at baseline and at the time of the OLB. The OLBs were reviewed by two pathologists blinded to the ARDS classification. The primary endpoint was the rate of DAD according to the ARDS stage in the patients with nonresolving ARDS who had OLB. The secondary endpoint was the ability of DAD to predict ARDS among all the patients who had OLB. The same clinico-histopathological confrontation was cross validated in another ICU. RESULTS: From January 1998 to August 2013, 113 patients underwent OLB for acute hypoxemic respiratory failure, 83 of whom met the inclusion criteria for ARDS. At the time the OLB was performed, 11 of these patients had mild, 56 moderate, and 16 severe ARDS, respectively. The median (1st-3rd quartiles) time to OLB was 13 (10-18) and 9 (6-14) days from the onset of respiratory symptoms and from ARDS onset, respectively, with no statistical difference between the three ARDS groups. DAD was found in 48 (58 %) patients with ARDS, 4 (36 %) in the mild, 33 (59 %) in the moderate, and 11 (69 %) in the severe stage (P = 0.23). For the 113 patients who underwent OLB, the sensitivity and specificity of DAD to the Berlin definition was 0.58 (0.46-0.69) and 0.73 (0.54-0.88), respectively. Similar results were found in the other ICU. CONCLUSIONS: DAD is present in the majority of patients with nonresolving ARDs and its frequency is no different across the three ARDS stages. On this basis, the systematic use of steroids in nonresolving ARDS is not recommended.

Effects of positive end-expiratory pressure on the sigmoid equation in experimental acute lung injury.

OBJECTIVES: To describe inflation and deflation volume-pressure (V-P) curves of the respiratory system by the sigmoidal equation at different levels of positive end-expiratory pressure (PEEP) in acute lung injury. DESIGN: Experimental study. SETTING: Physiological laboratory in a university setting. SUBJECTS: Six pigs of 25 kg each. INTERVENTIONS: Acute lung injury was induced by oleic acid. PEEP was applied from 0 to 15 cm H(2)O and from 15 to 0 cm H(2)O for 10 min in steps of 5 cmH(2)O. MEASUREMENTS AND RESULTS: Inflation and deflation V-P curves were constructed from an automated super-syringe that delivers a constant flow of 7 l/min in both inspiratory and expiratory directions. V-P curves were obtained at each level of PEEP without disconnecting the animal from the ventilator. The experimental data were fitted to the sigmoid equation which provided the true inflection point (c), the point of maximal compliance increase (Pmci) reflecting opening/closure and the point of maximal compliance decrease (Pmcd) reflecting end of recruitment/onset of de-recruitment. The sigmoid equation provided an excellent fit. The values of the coefficients of determination were greater than 0.970 (median 0.996, IQR 0.994-0.997 for the 84 determinations). Negative values of Pmci in the deflation limb of the V-P curve were recorded in five pigs, suggesting closure below the volume range studied. CONCLUSIONS: Inflation and deflation V-P curves at different PEEPs can be fitted by the sigmoid equation. However, further work is needed to investigate the meaning of negative values for Pmci.

Evaluation of recruited lung volume at inspiratory plateau pressure with PEEP using bedside digital chest X-ray in patients with acute lung injury/ARDS.

BACKGROUND: We wanted to assess whether there was a significant relationship between recruited lung volume (V(rec)) and change in density on digital processed chest x-ray measured at 2 different levels of inspiratory plateau pressure corresponding to 2 PEEP levels in patients with acute lung injury or ARDS. METHODS: In 14 subjects, PEEP 5 cm H2O and 15 cm H2O were prospectively applied in a random order for 10 min. At the end of each period, chest x-ray was taken using a digital portable device, and a pressure-volume curve of the respiratory system was performed. We also assessed P(aO2), and the static and the dynamic (C(dyn,rs)) compliance of the respiratory system. Change in end-expiratory lung volume between tidal breath and relaxation volume of the respiratory system was determined. Radiological attenuation was measured on chest x-rays in 4 regions of interest in the right lung, and in 3 regions of interest in the left lung, drawn in posterior intercostal spaces from top to bottom, by using dedicated software. The ratio of lung density in each region between PEEP 15 and PEEP 5 (rP15/P5) and their arithmetic mean (µP15/P5) were computed. V(rec) was determined from the pressure-volume curves. RESULTS: The median value of rP15/P5 in the 98 lung levels was 0.91 (0.80-1.01), which was significantly different from 1 (P < .001). The values of rP15/P5 were not significantly different between the lung levels. The median values of V(rec) and µP15/P5 were 288 (173-402) mL and 0.90 (0.80-0.97), respectively. There was a significant negative correlation between V(rec) and µP15/P5 (R = -0.77, P = .01). The reduction in µP15/P5 tended to correlate with the increase in C(dyn,rs) (R = -0.49, P = .077) or in P(aO2) (R = -0.53, P = .05) between PEEP 15 cm H2O and PEEP 5 cm H2O. CONCLUSIONS: Digital chest x-ray done at the bedside in acute lung injury/ARDS subjects was able to detect a reduction in density between PEEP 5 cm H2O and PEEP 15 cm H2O, which correlated with V(rec).

Efficacy and safety of recruitment maneuvers in acute respiratory distress syndrome.

Recruitment maneuvers (RM) consist of a ventilatory strategy that increases the transpulmonary pressure transiently to reopen the recruitable lung units in acute respiratory distress syndrome (ARDS). The rationales to use RM in ARDS are that there is a massive loss of aerated lung and that once the end-inspiratory pressure surpasses the regional critical opening pressure of the lung units, those units are likely to reopen. There are different methods to perform RM when using the conventional ICU ventilator. The three RM methods that are mostly used and investigated are sighs, sustained inflation, and extended sigh. There is no standardization of any of the above RM. Meta-analysis recommended not to use RM in routine in stable ARDS patients but to run them in case of life-threatening hypoxemia. There are some concerns regarding the safety of RM in terms of hemodynamics preservation and lung injury as well. The rapid rising in pressure can be a factor that explains the potential harmful effects of the RM. In this review, we describe the balance between the beneficial effects and the harmful consequences of RM. Recent animal studies are discussed.

Inhaled bronchodilator administration during mechanical ventilation: how to optimize it, and for which clinical benefit?

Bronchodilators are frequently used in ICU patients, and are the most common medications administered by inhalation during mechanical ventilation. The amount of bronchodilator that deposits at its site of action depends on the amount of drug, inhaled mass, deposited mass, and particle size distribution. Mechanical ventilation challenges both inhaled mass and lung deposition by specific features, such as a ventilatory circuit, an endotracheal tube, and ventilator settings. Comprehensive in vitro studies have shown that an endotracheal tube is not as significant a barrier for the drug to travel as anticipated. Key variables of drug deposition are attachments of the inhalation device in the inspiratory line 10 to 30 cm to the endotracheal tube, use of chamber with metered-dose inhaler, dry air, high tidal volume, low respiratory frequency, and low inspiratory flow, which can increase the drug deposition. In vivo studies showed that a reduction by roughly 15% of the respiratory resistance was achieved with inhaled bronchodilators during invasive mechanical ventilation. The role of ventilatory settings is not as clear in vivo, and primary factors for optimal delivery and physiologic effects were medication dose and device location. Nebulizers and pressurized metered-dose inhalers can equally achieve physiologic end points. The effects of bronchodilators should be carefully evaluated, which can easily be done with the interrupter technique. With the non-invasive ventilation, the data regarding drug delivery and physiologic effects are still limited. With the bilevel ventilators the inhalation device should be located between the leak port and face mask. Further studies should investigate the effects of inhaled bronchodilators on patient outcome and methods to optimize delivery of inhaled bronchodilators during non-invasive ventilation.