Person:

Kacmarek, Robert

Mechanical ventilation is the most important aspect of supportive care of patients with severe acute respiratory failure. Most research directed to improving the prognosis of these patients has focused on improving support of the injured lung. In this report, current knowledge on innovative ways to manage refractory hypoxemia and ventilation without further damaging the injured lung is briefly discussed.

Many aspects of ventilatory management in patients with ARDS are still controversial and one of the major controversies is should HFO or CMV ideally be used to manage this patients. As shown by David et al. when the two approaches to ventilatory support are applied using similar principles the physiologic outcomes appear to be similar. With both approaches the use of lung recruitment maneuvers early in ARDS (1 to 3 day) after hemodynamic stabilization in patients without baratrauma is promising. The key to managing ARDS regardless of mode is to use an open lung protective ventilatory strategy. It is not the mode that makes the difference, it is the approach used to apply the mode!

Background: There is a need for biomarkers insuring identification of septic patients at high-risk for death. We performed a prospective, multicenter, observational study to investigate the time-course of lipopolysaccharide binding protein (LBP) serum levels in patients with severe sepsis and examined whether serial serum levels of LBP could be used as a marker of outcome. Methodology/Principal Findings: LBP serum levels at study entry, at 48 hours and at day-7 were measured in 180 patients with severe sepsis. Data regarding the nature of infections, disease severity, development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and intensive care unit (ICU) outcome were recorded. LBP serum levels were similar in survivors and non-survivors at study entry (117.4±75.7 µg/mL vs. 129.8±71.3 µg/mL, P = 0.249) but there were significant differences at 48 hours (77.2±57.0 vs. 121.2±73.4 µg/mL, P<0.0001) and at day-7 (64.7±45.8 vs. 89.7±61.1 µg/ml, p = 0.017). At 48 hours, LBP levels were significantly higher in ARDS patients than in ALI patients (112.5±71.8 µg/ml vs. 76.6±55.9 µg/ml, P = 0.0001). An increase of LBP levels at 48 hours was associated with higher mortality (odds ratio 3.97; 95%CI: 1.84–8.56; P<0.001). Conclusions/Significance: Serial LBP serum measurements may offer a clinically useful biomarker for identification of patients with severe sepsis having the worst outcomes and the highest probability of developing sepsis-induced ARDS.

Background: Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. Methods: Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IκBα), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL6) gene expression in the lungs and TNF-α and IL-6 protein serum concentrations were analyzed. Results: High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IκBα, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. Conclusions: The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.

Background: Although much has evolved in our understanding of the pathogenesis and factors affecting outcome of patients with acute respiratory distress syndrome (ARDS), still there is no specific pharmacologic treatment for ARDS. Several clinical trials have evaluated the utility of corticoids but none of them has demonstrated a definitive benefit due to small sample sizes, selection bias, patient heterogeneity, and time of initiation of treatment or duration of therapy. We postulated that adjunctive treatment of persistent ARDS with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and a decrease in mortality. Methods/design This is a prospective, multicenter, randomized, controlled trial in 314 patients with persistent moderate/severe ARDS. Persistent ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 24 hours of routine intensive care. Eligible patients will be randomly allocated to two arms: (i) conventional treatment without dexamethasone, (ii) conventional treatment plus dexamethasone. Patients in the dexamethasone group will be treated with a daily dose of 20 mg iv from day 1 to day 5, and 10 mg iv from day 6 to day 10. Primary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after intubation. Secondary outcome is all-cause mortality at day 60 after enrollment. Discussion This study will be the largest randomized controlled clinical trial to assess the role of dexamethasone in patients with persistent ARDS. Trial registration Registered on 21 November 2012 as DEXA-ARDS at ClinicalTrials.gov website (NCT01731795). Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1456-4) contains supplementary material, which is available to authorized users.

Introduction: Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation. Methods: We studied 36 Sprague–Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (VT) (6 ml/kg) and high-VT (20 ml/kg) on 2 cmH2O of positive end-expiratory pressure (PEEP). In low-VT septic animals, 10 cmH2O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period. Results: High-VT MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-VT had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-VT MV prevented these changes. Levels of sPECAM1 in healthy animals on high-VT MV paralleled the sPECAM1 levels of non-ventilated septic animals. Conclusions: Our findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.

Assisted ventilation is a highly complex process that requires an intimate interaction between the ventilator and the patient. The complexity of this form of ventilation is frequently underappreciated by the bedside clinician. In assisted mechanical ventilation, regardless of the specific mode, the ventilator’s gas delivery pattern and the patient’s breathing pattern must match near perfectly or asynchrony between the patient and the ventilator occurs. Asynchrony can be categorized into four general types: flow asynchrony; trigger asynchrony; cycle asynchrony; and mode asynchrony. In an article recently published in BMC Anesthesiology, Hodane et al. have demonstrated reduced asynchrony during assisted ventilation with Neurally Adjusted Ventilatory Assist (NAVA) as compared to pressure support ventilation (PSV). These findings add to the growing volume of data indicating that modes of ventilation that provide proportional assistance to ventilation – e.g., NAVA and Proportional Assist Ventilation (PAV) – markedly reduce asynchrony. As it becomes more accepted that the respiratory center of the patient in most circumstances is the most appropriate determinant of ventilatory pattern and as the negative outcome effects of patient-ventilator asynchrony become ever more recognized, we can expect NAVA and PAV to become the preferred modes of assisted ventilation!

Background: Few studies have investigated the factors affecting aerosol delivery during non-invasive ventilation (NIV). Our aim was to investigate, using a bench-top model, the effect of different ventilator settings and positions of the exhalation port and nebulizer on the amount of albuterol delivered to a lung simulator. Methods: A lung model simulating spontaneous breathing was connected to a single-limb NIV ventilator, set in bi-level positive airway pressure (BIPAP) with inspiratory/expiratory pressures of 10/5, 15/10, 15/5, and 20/10 cmH2O, or continuous positive airway pressure (CPAP) of 5 and 10 cmH2O. Three delivery circuits were tested: a vented mask with the nebulizer directly connected to the mask, and an unvented mask with a leak port placed before and after the nebulizer. Albuterol was collected on a filter placed after the mask and then the delivered amount was measured with infrared spectrophotometry. Results: Albuterol delivery during NIV varied between 6.7 ± 0.4% to 37.0 ± 4.3% of the nominal dose. The amount delivered in CPAP and BIPAP modes was similar (22.1 ± 10.1 vs. 24.0 ± 10.0%, p = 0.070). CPAP level did not affect delivery (p = 0.056); in BIPAP with 15/5 cmH2O pressure the delivery was higher compared to 10/5 cmH2O (p = 0.033) and 20/10 cmH2O (p = 0.014). Leak port position had a major effect on delivery in both CPAP and BIPAP, the best performances were obtained with the unvented mask, and the nebulizer placed between the leak port and the mask (p < 0.001). Conclusions: In this model, albuterol delivery was marginally affected by ventilatory settings in NIV, while position of the leak port had a major effect. Nebulizers should be placed between an unvented mask and the leak port in order to maximize aerosol delivery.

Objectives: A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at ARDS onset. Since the proposal did not mandate PaO2/FiO2 calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO2/FiO2 would not provide accurate assessment of lung injury severity. Design: A prospective, multicentre, observational study. Setting: A network of teaching hospitals. Participants: 478 patients with eligible criteria for moderate (100<PaO2/FiO2≤200) and severe (PaO2/FiO2≤100) ARDS and followed until hospital discharge. Interventions We examined physiological and ventilator parameters in association with the PaO2/FiO2 at ARDS onset, after 24 h of usual care and at 24 h under a SVS. At 24 h, patients were reclassified as severe, moderate, mild (200<PaO2/FiO2≤300) ARDS and non-ARDS (PaO2/FiO2>300). Primary and secondary outcomes Group severity and hospital mortality. Results: At ARDS onset, 173 patients had a PaO2/FiO2≤100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO2/FiO2 category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO2/FiO2 and non-standardised PaO2/FiO2 at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). Conclusions: Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. Trial registration numbers NCT00435110 and NCT00736892.