Objective Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life (HRQOL). Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and HRQOL, and their associations with critical illness and intensive care unit exposures. Design A multi-site prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. Setting 13 intensive care units from 4 academic teaching hospitals. Patients 222 survivors of acute lung injury. Measurements and Main Results At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness), 6-minute walk distance, and the Medical Outcomes Short-Form 36 (SF-36) HRQOL survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one-third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and HRQOL that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the intensive care unit were not associated with weakness. Conclusions Muscle weakness is common after ALI, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and HRQOL that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after ALI. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.

Objective To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury.Design Prospective cohort study.Setting 13 intensive care units at four hospitals in Baltimore, Maryland, USA.Participants 485 consecutive mechanically ventilated patients with acute lung injury.Main outcome measure Two year survival after onset of acute lung injury.Results 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011).Conclusions Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury.Trial registration Clinicaltrials.gov NCT00300248. IntroductionSurvivors of severe critical illness, such as acute lung injury, and its more severe subset, acute respiratory distress syndrome (ARDS), commonly experience increased mortality and morbidity in the months and years after hospital discharge. [1][2][3] Compared with age matched and sex matched controls, patients discharged from intensive care are two to five times more likely to die during three to 15 years' follow-up. 3 Few interventions have been evaluated for improving this increased long term mortality. 4 Randomised trials and meta-analyses have shown that use of volume limited and pressure limited mechanical ventilation (lung protective ventilation) in patients with acute lung injury substantially decreases short term mortality. [5][6][7][8][9] A randomised trial of lung protective ventilation carried out by the ARDS Network 8 found an 8.8% absolute reduction in short term mortality. This trial evaluated a ventilator tidal volume of 6 mL/kg predicted body weight (calculated on the basis of a patient's sex and height 8 ) and a plateau pressure (airway pressure measured after a 0.5 second end inspiratory pause) of ≤30 cm of water compared with a tidal volume of 12 mL/kg predicted body weight and a plateau pressure of ≤50 cm of water. Understanding the effect of lung protective ventilation on long term survival is important, 4 5 especially since critical care interventions with a mortality benefit at hospital dischar...

Rationale: Polymorphisms affecting Toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case-control study in a cohort of intensive care unit patients with sepsis, and a case-control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1 27202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P , 2 3 10 220 ). TLR1 27202G marked a coding SNP that causes higher TLR1-induced NF-kB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1 27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR1 27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR1 27202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and grampositive infection in sepsis.

The reduced tidal volume strategy used in this study was safe. Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a) the sample size was too small to discern small treatment effects; b) the differences in tidal volumes and plateau pressures were modest; or c) reduced tidal volume ventilation is not beneficial.