Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure.

BACKGROUND: Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis. METHODS: We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets. RESULTS: Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (Padjusted<0.0005 and 0.0006, respectively), suggesting a role in increased risk of renal dysfunction. In contrast, among EA ARDS patients, the missense variant rs17011368 (I703V) was associated with enhanced mortality at 60-days (P < 0.038). We found higher serum XOR activity in 143 sepsis patients (54.5 ± 57.1 mU/mL) compared to 31 controls (20.9 ± 12.4 mU/mL, P = 1.96 × 10- 13). XOR activity was associated with the lead variant rs185925 among AA sepsis patients with ARDS (P < 0.005 and Padjusted<0.01). Multifaceted functions of prioritized XDH variants, as suggested by various functional annotation tools, support their potential causality in sepsis. CONCLUSIONS: Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Assessment and Impact of Intravenous Medication Fluid Administration in Critically Ill Patients With Acute Respiratory Failure.

BACKGROUND: Positive fluid balance early in critical illness is associated with poor outcomes. Reducing intravenous medication volume may mitigate volume overload. Objective: Assessment of fluid and medication administration and clinical outcomes in acute respiratory failure. METHODS: Single-center, prospective observational study of hemodynamically stable adult patients in a medical intensive care unit (MICU) with acute respiratory failure. RESULTS: Median cumulative total intake volume was 12 890 (interquartile range [IQR] = 8654-22 221) mL (n = 27), and median cumulative intravenous medication volume was 3563 (IQR = 2371-9412) mL over the first 7 days. Medication volume accounted for 27.6% of aggregate fluid volume. Median daily intravenous medication volume administered was 591 (IQR = 339-1082) mL. Cumulative fluid volume was associated with reduced ventilator-free days (r2 = -0.393; P = 0.043), and cumulative fluid volumes during the first 3 and 7 days were associated with increased MICU length of stay (LOS ± standard error 0.73 ± 0.35 d/L, P = 0.047, and 0.38 ± 0.16 d/L, P = 0.021, respectively). Cumulative medication volume administered significantly reduced the likelihood of mechanical ventilator liberation (hazard ratio [HR] = 0.917; 95% CI: 0.854, 0.984; P = 0.016) and MICU discharge (HR = 0.911; 95% CI: 0.843, 0.985; P = 0.019). Small-volume infusion may decrease cumulative intravenous medication volume by 38%. CONCLUSION AND RELEVANCE: Intravenous medication diluent contributes substantially to total fluid intake in patients with acute respiratory failure and is associated with poor outcomes. Reduction of intravenous medication fluid volume to improve clinical outcomes should be further investigated.

Anemia in Critically Ill Patients With Acute Respiratory Distress Syndrome and Posthospitalization Physical Outcomes.

OBJECTIVE: Anemia is common during critical illness and often persists after hospital discharge; however, its potential association with physical outcomes after critical illness is unclear. Our objective was to assess the associations between hemoglobin at intensive care unit (ICU) and hospital discharge with physical status at 3-month follow-up in acute respiratory distress syndrome (ARDS) survivors. METHODS: This is a secondary analysis of a multisite prospective cohort study of 195 mechanically ventilated ARDS survivors from 13 ICUs at 4 teaching hospitals in Baltimore, Maryland. Multivariable regression was utilized to assess the relationships between ICU and hospital discharge hemoglobin concentrations with measures of physical status at 3 months, including muscle strength (Medical Research Council sumscore), exercise capacity (6-minute walk distance [6MWD]), and self-reported physical functioning (36-Item Short-Form Health Survey [SF-36v2] Physical Function score and Activities of Daily Living [ADL] dependencies). RESULTS: Median (interquartile range) hemoglobin concentrations at ICU and hospital discharge were 9.5 (8.5-10.7) and 10.0 (9.0-11.2) g/dL, respectively. In multivariable regression analyses, higher ICU discharge hemoglobin concentrations (per 1 g/dL) were associated with greater 3-month 6MWD mean percent of predicted (3.7% [95% confidence interval 0.8%-6.5%]; P = .01) and fewer ADL dependencies (-0.2 [-0.4 to -0.1]; P = .02), but not with percentage of maximal muscle strength (0.7% [-0.9 to 2.3]; P = .37) or SF-36v2 normalized Physical Function scores (0.8 [-0.3 to 1.9]; P = .15). The associations of physical outcomes and hospital discharge hemoglobin concentrations were qualitatively similar, but none were statistically significant. CONCLUSIONS: In ARDS survivors, higher hemoglobin concentrations at ICU discharge, but not hospital discharge, were significantly associated with improved exercise capacity and fewer ADL dependencies. Future studies are warranted to further assess these relationships.

Return to work and lost earnings after acute respiratory distress syndrome: a 5-year prospective, longitudinal study of long-term survivors.

BACKGROUND: Delayed return to work is common after acute respiratory distress syndrome (ARDS), but has undergone little detailed evaluation. We examined factors associated with the timing of return to work after ARDS, along with lost earnings and shifts in healthcare coverage. METHODS: Five-year, multisite prospective, longitudinal cohort study of 138 2-year ARDS survivors hospitalised between 2004 and 2007. Employment and healthcare coverage were collected via structured interview. Predictors of time to return to work were evaluated using Fine and Grey regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data. RESULTS: Sixty-seven (49%) of the 138 2-year survivors were employed prior to ARDS. Among 64 5-year survivors, 20 (31%) never returned to work across 5-year follow-up. Predictors of delayed return to work (HR (95% CI)) included baseline Charlson Comorbidity Index (0.77 (0.59 to 0.99) per point; p=0.04), mechanical ventilation duration (0.67 (0.55 to 0.82) per day up to 5 days; p<0.001) and discharge to a healthcare facility (0.49 (0.26 to 0.93); p=0.03). Forty-nine of 64 (77%) 5-year survivors incurred lost earnings, with average (SD) losses ranging from US$38 354 (21,533) to US$43 510 (25,753) per person per year. Jobless, non-retired survivors experienced a 33% decrease in private health insurance and concomitant 37% rise in government-funded coverage. CONCLUSIONS: Across 5-year follow-up, nearly one-third of previously employed ARDS survivors never returned to work. Delayed return to work was associated with patient-related and intensive care unit/hospital-related factors, substantial lost earnings and a marked rise in government-funded healthcare coverage. These important consequences emphasise the need to design and evaluate vocation-based interventions to assist ARDS survivors return to work.

Oxygen Exposure Resulting in Arterial Oxygen Tensions Above the Protocol Goal Was Associated With Worse Clinical Outcomes in Acute Respiratory Distress Syndrome.

OBJECTIVES: High fractions of inspired oxygen may augment lung damage to exacerbate lung injury in patients with acute respiratory distress syndrome. Participants enrolled in Acute Respiratory Distress Syndrome Network trials had a goal partial pressure of oxygen in arterial blood range of 55-80 mm Hg, yet the effect of oxygen exposure above this arterial oxygen tension range on clinical outcomes is unknown. We sought to determine if oxygen exposure that resulted in a partial pressure of oxygen in arterial blood above goal (> 80 mm Hg) was associated with worse outcomes in patients with acute respiratory distress syndrome. DESIGN: Longitudinal analysis of data collected in these trials. SETTING: Ten clinical trials conducted at Acute Respiratory Distress Syndrome Network hospitals between 1996 and 2013. SUBJECTS: Critically ill patients with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined above goal oxygen exposure as the difference between the fraction of inspired oxygen and 0.5 whenever the fraction of inspired oxygen was above 0.5 and when the partial pressure of oxygen in arterial blood was above 80 mm Hg. We then summed above goal oxygen exposures in the first five days to calculate a cumulative above goal oxygen exposure. We determined the effect of a cumulative 5-day above goal oxygen exposure on mortality prior to discharge home at 90 days. Among 2,994 participants (mean age, 51.3 yr; 54% male) with a study-entry partial pressure of oxygen in arterial blood/fraction of inspired oxygen that met acute respiratory distress syndrome criteria, average cumulative above goal oxygen exposure was 0.24 fraction of inspired oxygen-days (interquartile range, 0-0.38). Participants with above goal oxygen exposure were more likely to die (adjusted interquartile range odds ratio, 1.20; 95% CI, 1.11-1.31) and have lower ventilator-free days (adjusted interquartile range mean difference of -0.83; 95% CI, -1.18 to -0.48) and lower hospital-free days (adjusted interquartile range mean difference of -1.38; 95% CI, -2.09 to -0.68). We observed a dose-response relationship between the cumulative above goal oxygen exposure and worsened clinical outcomes for participants with mild, moderate, or severe acute respiratory distress syndrome, suggesting that the observed relationship is not primarily influenced by severity of illness. CONCLUSIONS: Oxygen exposure resulting in arterial oxygen tensions above the protocol goal occurred frequently and was associated with worse clinical outcomes at all levels of acute respiratory distress syndrome severity.

Rosuvastatin for sepsis-associated acute respiratory distress syndrome.

BACKGROUND: In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. METHODS: We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14. RESULTS: The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. CONCLUSIONS: Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Are physical measures related to patient-centred outcomes in ARDS survivors?

OBJECTIVE: To inform selection of physical measures for studies of acute respiratory distress syndrome (ARDS) survivors within 12 months of ARDS. METHODS: Secondary analysis of data from 6-month survivors participating in a US multicentre prospective study (ARDSNet Long-Term Outcome Study, N=134) or a multisite prospective study in Baltimore, Maryland, USA (Improving Care of Acute Lung Injury Patients, N=99). Physical measures, assessed at 6-month follow-up, were categorised according to the WHO's International Classification of Disability and Health: body functions and structures, activity and participation. Patient-centred outcomes were evaluated at 6 and 12 months: survival, hospitalisation, alive at home status and health-related quality of life. Pearson correlation, linear and logistic regression models were used to quantify associations of physical measures with patient-centred outcomes. MAIN RESULTS: No 6-month body functions and structures measure demonstrated consistent association with 6-month or 12-month outcomes in multivariable regression. The 6 min walk test, an activity measure, was associated with 6-month Short-Form 36 (SF-36) physical component scores (PCS, ß range: 0.99 to 1.52, p<0.05). Participation measures (Functional Performance Inventory, FPI; Instrumental Activities of Daily Living, IADLs) were associated with SF-36 PCS (ß range: FPI, 1.51-1.52; IADL, -1.88 to -1.32; all p<0.05) and Euro-QOL-5D utility score (ß range: FPI, 2.00-3.67; IADL, -2.89 to -2.50; all p<0.01) at 6 and 12 months. CONCLUSIONS: Participation measures better reflect patient's quality of life than measures of body functions and structures within 12 months of ARDS among 6-month survivors, and are recommended for inclusion as a core measure in future studies.

Muscle Weakness and 5-Year Survival in Acute Respiratory Distress Syndrome Survivors.

OBJECTIVES: To longitudinally evaluate the association of post-ICU muscle weakness and associated trajectories of weakness over time with 5-year survival. DESIGN: Longitudinal prospective cohort study over 5 years of follow-up. SETTING: Thirteen ICUs in four hospitals in Baltimore, MD. PATIENTS: One hundred fifty-six acute respiratory distress syndrome survivors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Strength was evaluated with standardized manual muscle testing using the Medical Research Council sum score (range, 0-60; higher is better), with post-ICU weakness defined as sum score less than 48. Muscle strength was assessed at hospital discharge and at 3, 6, 12, 24, 36, and 48 months after acute respiratory distress syndrome. At discharge, 38% of patients had muscle weakness. Every one point increase in sum score at discharge was associated with improved survival (hazard ratio [95% CI], 0.96 [0.94-0.98]), with similar findings longitudinally (0.95 [0.93-0.98]). Having weakness at discharge was associated with worse 5-year survival (1.75 [1.01-3.03]), but the association was attenuated (1.54 [0.82-2.89]) when evaluated longitudinally over follow-up. Persisting and resolving trajectories of muscle weakness, occurring in 50% of patients during follow-up, were associated with worse survival (3.01 [1.12-8.04]; and 3.14 [1.40-7.03], respectively) compared to a trajectory of maintaining no muscle weakness. CONCLUSIONS: At hospital discharge, greater than one third of acute respiratory distress syndrome survivors had muscle weakness. Greater strength at discharge and throughout follow-up was associated with improved 5-year survival. In patients with post-ICU weakness, both persisting and resolving trajectories were commonly experienced and associated with worse survival during follow-up.

Healthcare Resource Use and Costs in Long-Term Survivors of Acute Respiratory Distress Syndrome: A 5-Year Longitudinal Cohort Study.

OBJECTIVE: To evaluate the time-varying relationship of annual physical, psychiatric, and quality of life status with subsequent inpatient healthcare resource use and estimated costs. DESIGN: Five-year longitudinal cohort study. SETTING: Thirteen ICUs at four teaching hospitals. PATIENTS: One hundred thirty-eight patients surviving greater than or equal to 2 years after acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postdischarge inpatient resource use data (e.g., hospitalizations, skilled nursing, and rehabilitation facility stays) were collected via a retrospective structured interview at 2 years, with prospective collection every 4 months thereafter, until 5 years postacute respiratory distress syndrome. Adjusted odds ratios for hospitalization and relative medians for estimated episode of care costs were calculated using marginal longitudinal two-part regression. The median (interquartile range) number of inpatient admission hospitalizations was 4 (2-8), with 114 patients (83%) reporting greater than or equal to one hospital readmission. The median (interquartile range) estimated total inpatient postdischarge costs over 5 years were $58,500 ($19,700-157,800; 90th percentile, $328,083). Better annual physical and quality of life status, but not psychiatric status, were associated with fewer subsequent hospitalizations and lower follow-up costs. For example, greater grip strength (per 6 kg) had an odds ratio (95% CI) of 0.85 (0.73-1.00) for inpatient admission, with 23% lower relative median costs, 0.77 (0.69-0.87). CONCLUSIONS: In a multisite cohort of long-term acute respiratory distress syndrome survivors, better annual physical and quality of life status, but not psychiatric status, were associated with fewer hospitalizations and lower healthcare costs.

Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome.

OBJECTIVES: Prior studies suggest hypothermia may be beneficial in acute respiratory distress syndrome, but cooling causes shivering and increases metabolism. The objective of this study was to assess the feasibility of performing a randomized clinical trial of hypothermia in patients with acute respiratory distress syndrome receiving treatment with neuromuscular blockade because they cannot shiver. DESIGN: Retrospective study and pilot, prospective, open-label, feasibility study. SETTING: Medical ICU. PATIENTS: Retrospective review of 58 patients with acute respiratory distress syndrome based on Berlin criteria and PaO2/FIO2 less than 150 who received neuromuscular blockade. Prospective hypothermia treatment in eight acute respiratory distress syndrome patients with PaO2/FIO2 less than 150 receiving neuromuscular blockade. INTERVENTION: Cooling to 34-36°C for 48 hours. MEASUREMENTS AND MAIN RESULTS: Core temperature, hemodynamics, serum glucose and electrolytes, and P/F were sequentially measured, and medians (interquartile ranges) presented, 28-day ventilator-free days, and hospital mortality were calculated in historical controls and eight cooled patients. Average patient core temperature was 36.7°C (36-37.3°C), and fever occurred during neuromuscular blockade in 30 of 58 retrospective patients. In the prospectively cooled patients, core temperature reached target range less than or equal to 4 hours of initiating cooling, remained less than 36°C for 92% of the 48 hours cooling period without adverse events, and was lower than the controls (34.35°C [34-34.8°C]; p < 0.0001). Compared with historical controls, the cooled patients tended to have lower hospital mortality (75% vs 53.4%; p = 0.26), more ventilator-free days (9 [0-21.5] vs 0 [0-12]; p = 0.16), and higher day 3 P/F (255 [160-270] vs 171 [120-214]; p = 0.024). CONCLUSIONS: Neuromuscular blockade alone does not cause hypothermia but allowed acute respiratory distress syndrome patients to be effectively cooled. Results support conducting a randomized clinical trial of hypothermia in acute respiratory distress syndrome and the feasibility of studying acute respiratory distress syndrome patients receiving neuromuscular blockade.

Timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome. A prospective cohort study.

RATIONALE: Reducing tidal volume decreases mortality in acute respiratory distress syndrome (ARDS). However, the effect of the timing of low tidal volume ventilation is not well understood. OBJECTIVES: To evaluate the association of intensive care unit (ICU) mortality with initial tidal volume and with tidal volume change over time. METHODS: Multivariable, time-varying Cox regression analysis of a multisite, prospective study of 482 patients with ARDS with 11,558 twice-daily tidal volume assessments (evaluated in milliliter per kilogram of predicted body weight [PBW]) and daily assessment of other mortality predictors. MEASUREMENTS AND MAIN RESULTS: An increase of 1 ml/kg PBW in initial tidal volume was associated with a 23% increase in ICU mortality risk (adjusted hazard ratio, 1.23; 95% confidence interval [CI], 1.06-1.44; P = 0.008). Moreover, a 1 ml/kg PBW increase in subsequent tidal volumes compared with the initial tidal volume was associated with a 15% increase in mortality risk (adjusted hazard ratio, 1.15; 95% CI, 1.02-1.29; P = 0.019). Compared with a prototypical patient receiving 8 days with a tidal volume of 6 ml/kg PBW, the absolute increase in ICU mortality (95% CI) of receiving 10 and 8 ml/kg PBW, respectively, across all 8 days was 7.2% (3.0-13.0%) and 2.7% (1.2-4.6%). In scenarios with variation in tidal volume over the 8-day period, mortality was higher when a larger volume was used earlier. CONCLUSIONS: Higher tidal volumes shortly after ARDS onset were associated with a greater risk of ICU mortality compared with subsequent tidal volumes. Timely recognition of ARDS and adherence to low tidal volume ventilation is important for reducing mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00300248).

Cooccurrence of and remission from general anxiety, depression, and posttraumatic stress disorder symptoms after acute lung injury: a 2-year longitudinal study.

OBJECTIVE: To evaluate the cooccurrence, and predictors of remission, of general anxiety, depression, and posttraumatic stress disorder symptoms during 2-year follow-up in survivors of acute lung injury treated in an ICU. DESIGN: Prospective cohort study, with follow-up at 3, 6, 12, and 24 months post-acute lung injury. SETTING: Thirteen medical and surgical ICUs in four hospitals. PATIENTS: Survivors among 520 patients with acute lung injury. MEASUREMENTS AND MAIN RESULTS: The outcomes of interest were measured using the Hospital Anxiety and Depression Scale anxiety and depression subscales (scores ≥ 8 indicating substantial symptoms) and the Impact of Event Scale-Revised (scores ≥ 1.6 indicating substantial posttraumatic stress disorder symptoms). Of the 520 enrolled patients, 274 died before 3-month follow-up; 186 of 196 consenting survivors (95%) completed at least one Hospital Anxiety and Depression Scale and Impact of Event Scale-Revised assessment during 2-year follow-up, and most completed multiple assessments. Across follow-up time points, the prevalence of suprathreshold general anxiety, depression, and posttraumatic stress disorder symptoms ranged from 38% to 44%, 26% to 33%, and 22% to 24%, respectively; more than half of the patients had suprathreshold symptoms in at least one domain during 2-year follow-up. The majority of survivors (59%) with any suprathreshold symptoms were above threshold for two or more types of symptoms (i.e., general anxiety, depression, and/or posttraumatic stress disorder). In fact, the most common pattern involved simultaneous general anxiety, depression, and posttraumatic stress disorder symptoms. Most patients with general anxiety, depression, or posttraumatic stress disorder symptoms during 2-year follow-up had suprathreshold symptoms at 24-month (last) follow-up. Higher Short-Form-36 physical functioning domain scores at the prior visit were associated with a greater likelihood of remission from general anxiety and posttraumatic stress disorder symptoms during follow-up. CONCLUSIONS: The majority of acute lung injury survivors had clinically significant general anxiety, depression, or posttraumatic stress disorder symptoms, and these symptoms tended to co-occur across domains. Better physical functioning during recovery predicted subsequent remission of general anxiety and posttraumatic stress disorder symptoms.

Diagnostic value of pleural fluid obtained from a chest tube collection system.

BACKGROUND: Pleural fluid is typically drawn directly from the pleural space for diagnostic studies, but occasionally analyses are desired when a chest tube is already in place and a traditional approach is not feasible. The diagnostic value of analyzing fluid samples obtained from the pleural fluid collection system after chest tube insertion is unknown. METHODS: We performed a prospective observational study of patients in whom chest tube placement was planned for clinical indications. Diagnostic studies were performed on fluid obtained from the pleural space at the time of tube insertion and then repeated 2, 6, and 24 h later on samples obtained from the fluid collection system. RESULTS: Fifty-five percent of the 23 effusions studied met light's criteria for exudate at baseline. Lactate dehydrogenase (LDH) varied considerably over time from baseline measures with only 25 % of measures at 24 h falling within 25 % of baseline levels. The sensitivity for exudate by LDH remained 100 % with poor specificity ranging 50-69 % with repeat measures. Total protein exhibited less variability with 85 % of measures at 24 h falling within 25 % of baseline measure. Sensitivity and specificity at 24 h were 88 and 82 %, respectively. Repeat measures of cholesterol, albumin, and triglycerides generally correlated well (Spearman's rho > 0.90) with baseline values. Measures of glucose and cell counts varied considerably from baseline. CONCLUSIONS: Analysis of pleural fluid from a chest tube collection system is feasible and can provide useful diagnostic information. Practitioners should consider the test characteristics of each measure when interpreting samples obtained.

Risk factors for physical impairment after acute lung injury in a national, multicenter study.

RATIONALE: Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size. OBJECTIVES: To evaluate risk factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization. METHODS: A prospective, longitudinal study of 6- and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form [SF]-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness-related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status. MEASUREMENTS AND MAIN RESULTS: At 6 and 12 months, respectively, mean (± SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (± 8%) and 93% (± 9%), 6-minute-walk distance (as percent-predicted) was 64% (± 22%) and 67% (± 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (± 36%) and 67% (± 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes. CONCLUSIONS: Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors' physical outcomes.

Corticosteroids and transition to delirium in patients with acute lung injury.

OBJECTIVE: Delirium is common in mechanically ventilated patients in the ICU and associated with short- and long-term morbidity and mortality. The use of systemic corticosteroids is also common in the ICU. Outside the ICU setting, corticosteroids are a recognized risk factor for delirium, but their relationship with delirium in critically ill patients has not been fully evaluated. We hypothesized that systemic corticosteroid administration would be associated with a transition to delirium in mechanically ventilated patients with acute lung injury. DESIGN: Prospective cohort study. SETTING: Thirteen ICUs in four hospitals in Baltimore, MD. PATIENTS: Five hundred twenty mechanically ventilated adult patients with acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Delirium evaluation was performed by trained research staff using the validated Confusion Assessment Method for the ICU screening tool. A total of 330 of the 520 patients (64%) had at least two consecutive ICU days of observation in which delirium was assessable (e.g., patient was noncomatose), with a total of 2,286 days of observation and a median (interquartile range) of 15 (9, 28) observation days per patient. These 330 patients had 99 transitions into delirium from a prior nondelirious, noncomatose state. The probability of transitioning into delirium on any given day was 14%. Using multivariable Markov models with robust variance estimates, the following factors (adjusted odds ratio; 95% CI) were independently associated with transition to delirium: older age (compared to < 40 years old, 40-60 yr [1.81; 1.26-2.62], and ≥ 60 yr [2.52; 1.65-3.87]) and administration of any systemic corticosteroid in the prior 24 hours (1.52; 1.05-2.21). CONCLUSIONS: After adjusting for other risk factors, systemic corticosteroid administration is significantly associated with transitioning to delirium from a nondelirious state. The risk of delirium should be considered when deciding about the use of systemic corticosteroids in critically ill patients with acute lung injury.

Timing of limitations in life support in acute lung injury patients: a multisite study*.

OBJECTIVE: Substantial variability exists in the timing of limitations in life support for critically ill patients. Our objective was to investigate how the timing of limitations in life support varies with changes in organ failure status and time since acute lung injury onset. DESIGN, SETTING, AND PATIENTS: This evaluation was performed as part of a prospective cohort study evaluating 490 consecutive acute lung injury patients recruited from 11 ICUs at three teaching hospitals in Baltimore, MD. INTERVENTIONS: None. MEASUREMENTS: The primary exposure was proportion of days without improvement in Sequential Organ Failure Assessment score, evaluated as a daily time-varying exposure. The outcome of interest was a documented limitation in life support defined as any of the following: 1) no cardiopulmonary resuscitation, 2) do not reintubate, 3) no vasopressors, 4) no hemodialysis, 5) do not escalate care, or 6) other limitations (e.g., "comfort care only"). MAIN RESULTS: For medical ICU patients without improvement in daily Sequential Organ Failure Assessment score, the rate of limitation in life support tripled in the first 3 days after acute lung injury onset, increased again after day 5, and peaked at day 19. Compared with medical ICU patients, surgical ICU patients had a rate of limitations that was significantly lower during the first 5 days after acute lung injury onset. In all patients, more days without improvement in Sequential Organ Failure Assessment scores was associated with limitations in life support, independent of the absolute magnitude of the Sequential Organ Failure Assessment score. CONCLUSIONS: Persistent organ failure is associated with an increase in the rate of limitations in life support independent of the absolute magnitude of Sequential Organ Failure Assessment score, and this association strengthens during the first weeks of treatment. During the first 5 days after acute lung injury onset, limitations were significantly more common in medical ICUs than surgical ICUs.