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Objective: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis., Design: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial)., Setting: Forty ICUs in Italy., Patients: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95)., Interventions: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1., Measurements and Main Results: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality., Conclusions: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

Purpose: Open lung strategy during ARDS aims to decrease the ventilator-induced lung injury by minimizing the atelectrauma and stress/strain maldistribution. We aim to assess how much of the lung is opened and kept open within the limits of mechanical ventilation considered safe (i.e., plateau pressure 30 cmH 2 O, PEEP 15 cmH 2 O)., Methods: Prospective study from two university hospitals. Thirty-three ARDS patients (5 mild, 10 moderate, 9 severe without extracorporeal support, ECMO, and 9 severe with it) underwent two low-dose end-expiratory CT scans at PEEP 5 and 15 cmH 2 O and four end-inspiratory CT scans (from 19 to 40 cmH 2 O). Recruitment was defined as the fraction of lung tissue which regained inflation. The atelectrauma was estimated as the difference between the intratidal tissue collapse at 5 and 15 cmH 2 O PEEP. Lung ventilation inhomogeneities were estimated as the ratio of inflation between neighboring lung units., Results: The lung tissue which is opened between 30 and 45 cmH 2 O (i.e., always closed at plateau 30 cmH 2 O) was 10 ± 29, 54 ± 86, 162 ± 92, and 185 ± 134 g in mild, moderate, and severe ARDS without and with ECMO, respectively (p < 0.05 mild versus severe without or with ECMO). The intratidal collapses were similar at PEEP 5 and 15 cmH 2 O (63 ± 26 vs 39 ± 32 g in mild ARDS, p = 0.23; 92 ± 53 vs 78 ± 142 g in moderate ARDS, p = 0.76; 110 ± 91 vs 89 ± 93, p = 0.57 in severe ARDS without ECMO; 135 ± 100 vs 104 ± 80, p = 0.32 in severe ARDS with ECMO). Increasing the applied airway pressure up to 45 cmH 2 O decreased the lung inhomogeneity slightly (but significantly) in mild and moderate ARDS, but not in severe ARDS., Conclusions: Data show that the prerequisites of the open lung strategy are not satisfied using PEEP up to 15 cmH 2 O and plateau pressure up to 30 cmH 2 O. For an effective open lung strategy, higher pressures are required. Therefore, risks of atelectrauma must be weighted versus risks of volutrauma., Trial Registration: Clinicaltrials.gov identifier: NCT01670747 ( www.clinicaltrials.gov ).

Purpose of Review: Severe respiratory failure due to the acute respiratory distress syndrome (ARDS) might require rescue therapy measures beyond even extended standard care to ensure adequate oxygenation and survival. This review provides a summary and assessment of treatment options that can be beneficial when the standard approach fails., Recent Findings: 'Life-threatening' conditions or refractory hypoxemia during mechanical ventilation are more a matter of personal rating than an objective diagnosis based on defined and/or unanimously agreed thresholds that would mandate the use of rescue therapies. Although the outcome might vary with different rescue procedures, most of them will improve oxygenation. Prone positioning maintains a predominant role as rescue therapy in severe hypoxemia and does not only improve oxygenation in but also survival of ARDS patients. Recruitment maneuvers can have temporary positive effects. Inhaled nitric oxide, as well as high-frequency oscillatory ventilation might acutely improve oxygenation and can be used as a 'bridge' to alternative rescue therapies, but neither provides any survival advantage by itself and might even be detrimental. Although increasingly employed in other than the rescue indication, extracorporeal membrane oxygenation should still primarily be used in patients who do not respond to differentiated mechanical ventilation, which includes a careful evaluation of nonextracorporeal membrane oxygenation rescue therapies that might be combined in order to overcome the life-threatening situation. Early involvement of an ARDS or extracorporeal membrane oxygenation center should be considered to ensure optimal care., Summary: A well timed, multimodal approach is required for patients with ARDS suffering from life-threatening hypoxemia. Understanding the limits of each type of rescue measure is of vital importance.

Purpose of Review: Extracorporeal respiratory support in patients with acute respiratory distress syndrome is applied either as rescue maneuver for life-threatening hypoxemia or as a tool to reduce the harm of mechanical ventilation. Depending on the blood and gas flow, extracorporeal support may completely substitute the natural lung as a gas exchanger (high-flow venovenous bypass) or reduce the need for mechanical ventilation, enabling the removal of a fraction of the metabolically produced CO2., Recent Findings: Recent studies provide a description on how mechanical ventilation is normally applied in combination with extracorporeal support in acute respiratory distress syndrome. The data show a general trend: a variable decrease of fraction of inspired oxygen (0.9 to 0.7 or 0.4), a consistent decrease in tidal volume (by 2 ml/kg), no change in positive end-expiratory pressure (maintained around 12-13 cmH2O) and a moderate decrease in the respiratory rate (22 to 15 bpm). These ventilatory settings are applied in whatever extracorporeal membrane lung oxygenation modality (venovenous versus venoarterial) and independent from the extent of extracorporeal support (partial or total substitution of gas exchange)., Summary: Mechanical ventilation and extracorporeal support are marginally integrated. The best environment for lung healing - complete lung collapse or protective ventilation strategy or fully open and immobile lung (all three conditions feasible with extracorporeal support) - remains to be defined.