Fluid And Catheter Treatment Trial Research Articles

Prognostic value of time-varying dead space estimates in mechanically ventilated patients with acute respiratory distress syndrome

BackgroundThe dead space fraction (VD/VT) has proven to be a powerful predictor of higher mortality in acute respiratory distress syndrome (ARDS). However, its measurement relies on expired carbon dioxide, limiting its widespread application in clinical practice. Several estimates employing routine variables have been found to be reliable substitutes for direct measurement of VD/VT. In this study, we evaluated the prognostic value of these dead space estimates obtained in the first 7 days following the initiation of ventilation. MethodsThis retrospective observational study was conducted using data from the Chinese database in intensive care (CDIC). Eligible participants were adult ARDS patients receiving invasive mechanical ventilation while in the intensive care unit between 1st January 2014 and 31st March 2021. We collected data during the first 7 days of ventilation to calculate various dead space estimates, including ventilatory ratio (VR), corrected minute ventilation (V˙Ecorr), VD/VT (Harris–Benedict), VD/VT (Siddiki estimate), and VD/VT (Penn State estimate) longitudinally. A time-dependent Cox model was used to handle these time-varying estimates. ResultsA total of 392 patients (median age 66 [interquartile range: 55–77] years, median SOFA score 9 [interquartile range: 7–12]) were finally included in our analysis, among whom 132 (33.7%) patients died within 28 days of admission. VR (hazard ratio [HR]=1.04 per 0.1 increase, 95% confidence interval [CI]: 1.01 to 1.06; P=0.013), V˙Ecorr (HR=1.08 per 1 increase, 95% CI: 1.04 to 1.12; P < 0.001), VD/VT (Harris–Benedict) (HR=1.25 per 0.1 increase, 95% CI: 1.06 to 1.47; P=0.006), and VD/VT (Penn State estimate) (HR=1.22 per 0.1 increase, 95% CI: 1.04 to 1.44; P=0.017) remained significant after adjustment, while VD/VT (Siddiki estimate) (HR=1.10 per 0.1 increase, 95% CI: 1.00 to 1.20; P=0.058) did not. Given a large number of negative values, VD/VT (Siddiki estimate) and VD/VT (Penn State estimate) were not recommended as reliable substitutes. Long-term exposure to VR >1.3, V˙Ecorr >7.53, and VD/VT (Harris–Benedict) >0.59 was independently associated with an increased risk of mortality in ARDS patients. These findings were validated in the fluid and catheter treatment trial (FACTT) database. ConclusionsIn cases where VD/VT cannot be measured directly, early time-varying estimates of VD/VT such as VR, V˙Ecorr, and VD/VT (Harris–Benedict) can be considered for predicting mortality in ARDS patients, offering a rapid bedside application.

Validation of Prognostic Club Cell Secretory Protein (CC16) Cut-point in an Independent ALTA Cohort.

Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)). The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial. In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test. Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, P < .001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All P < .05). In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality.

Impact of Time-Varying Intensity of Mechanical Ventilation on 28-Day Mortality Depends on Fluid Balance in Patients With Acute Respiratory Distress Syndrome: A Retrospective Cohort Study.

BackgroundRecent studies have mainly focused on the association between baseline intensity of mechanical ventilation (driving pressure or mechanical power) and mortality in acute respiratory distress syndrome (ARDS). It is unclear whether the association between the time-varying intensity of mechanical ventilation and mortality is significant and varies according to the fluid balance trajectories.MethodsWe conducted a secondary analysis based on the NHLBI ARDS Network’s Fluid and Catheter Treatment Trial (FACTT). The primary outcome was 28-day mortality. The group-based trajectory modeling (GBTM) was employed to identify phenotypes based on fluid balance trajectories. Bayesian joint models were used to account for informative censoring due to death during follow-up.ResultsA total of 1,000 patients with ARDS were included in the analysis. Our study identified two phenotypes of ARDS, and compared patients with Early Negative Fluid Balance (Early NFB) and patients with Persistent-Positive Fluid Balance (Persistent-PFB) accompanied by higher tidal volume, higher static driving pressure, higher mechanical power, and lower PaO2/FiO2, over time during mechanical ventilation. The 28-day mortality was 14.8% in Early NFB and 49.6% in Persistent-PFB (p < 0.001). In the Bayesian joint models, the hazard ratio (HR) of 28-day death for time-varying static driving pressure [HR 1.03 (95% CI 1.01–1.05; p < 0.001)] and mechanical power [HR 1.01 (95% CI 1.002–1.02; p = 0.01)] was significant in patients with Early NFB, but not in patients with Persistent-PFB.ConclusionTime-varying intensity of mechanical ventilation was associated with a 28-day mortality of ARDS in a patient with Early NFB but not in patients with Persistent-PFB.

Club Cell Secretory Protein-Derived Acute Respiratory Distress Syndrome Phenotypes Predict 90-Day Mortality: A Reanalysis of the Fluids and Catheter Treatment Trial.

OBJECTIVES:Club cell secretory protein (CC16) is a protein with potential utility as a lung-specific biomarker for acute respiratory distress syndrome. The purpose of this study was to characterize CC16 in plasma from patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) to determine the prognostic value for patient outcomes in our subgroup of FACTT patients.DESIGN:A secondary biomarker analysis of a prospective randomized-controlled trial. The primary outcome was area under the receiver operating characteristic (AUROC) of CC16 for prediction of 90-day mortality. Secondary outcomes included differences in mortality, length of stay, and ventilator-free days (VFDs) between patients with high and low CC16. Statistical analyses were performed with IBM SPSS Statistics.SETTING:Single-center laboratory analysis.SUBJECTS:Plasma samples from 68 FACTT subjects and 20 healthy controls.INTERVENTIONS:CC16 was measured in patient plasma samples by enzyme-linked immunosorbent assay.MEASUREMENTS AND MAIN RESULTS:Subjects were an average of 48 years old (sd, 16.7 yr old) and 51.5% male. AUROC analysis of CC16 on day 1 showed an area under the ROC curve of 0.78 for prediction of mortality (odds ratio, 1.011; 95% CI, 1.003–1.021) with an optimal cutoff value of 45 ng/mL. Patients in the low CC16 group (<45 ng/mL) had lower mortality (7.5 vs 50.0%; p < 0.001) and similar VFD (11.9 vs 13.2; p = 0.638). When stratified by CC16 concentration, there was no difference between mortality in the fluid liberal (36.4 vs 58.8%; p = 0.256) or conservative (4.3 vs 11.8%; p = 0.366) groups.CONCLUSIONS:CC16 demonstrated an acceptable AUROC for prediction of patient mortality with a cut point of 45 ng/mL. Patients with high CC16 on day 1 had worse outcomes compared with those with low CC16, suggesting a prognostic role for this lung-specific biomarker.

The Effect of Loop Diuretics on 28-Day Mortality in Patients With Acute Respiratory Distress Syndrome.

Background: Diuretics have been widely used in critically ill patients while it remains uncertain whether they can reduce mortality in patients with acute respiratory distress syndrome (ARDS). This study aimed to investigate the associations between diuretics and 28-day mortality in patients with ARDS.Methods: This is a secondary analysis of the ARDS Network Fluid and Catheter Treatment Trial (FACTT) of National Heart, Lung, and Blood Institute. Those patients who did not receive renal replacement therapy within the first 48 h after enrollment in the FACTT were included in the analysis. A marginal structural Cox model (MSCM) was used to investigate the associations between diuretics and 28-day mortality after correction of both the baseline and time-varying variables. The latent class analysis (LCA) and subgroup analysis were performed to identify the kind of patients that could be benefited from diuretics.Results: A total of 932 patients were enrolled, i.e., 558 patients in the diuretics group and 374 patients in the no diuretics group within the first 48 h. The 28-day mortality was lower in the diuretics group (15.1 vs. 28.1%, p < 0.001). In MSCM, diuretics use was related to the improved 28-day mortality (HR 0.78; 95% CI 0.62–0.99; p = 0.04). LCA identified three subtypes, and diuretics were associated with reduced mortality in subtype 3, which was characterized by worse renal function and higher central venous pressure (CVP). A subgroup analysis indicated survival advantage among the female patients, sepsis induced ARDS, and those with the ratio of partial pressure of oxygen to the fractional concentration of inspired oxygen (PaO2/FiO2) ≤ 150 mmHg, and mean arterial pressure (MAP) ≥ 65 mmHg.Conclusion: Loop diuretics were associated with the reduced 28-day mortality in the patients with ARDS, after controlling for time-varying confounders. Randomized trials are required to verify the association.

Fluid Management in Patients with Acute Respiratory Distress Syndrome and Diabetes Mellitus: A propensity score matched analysis of the fluid and catheter treatment trial.

Diabetes mellitus results in an attenuated inflammatory response, reduces pulmonary microvascular permeability, and may decrease the risk of developing acute respiratory distress syndrome (ARDS). Studies have shown that patients with ARDS are better managed by a conservative as compared to liberal fluid management strategy. However, it is not known if the same fluid management principles hold true for patients with comorbid diabetes mellitus and ARDS.As diabetes mellitus results in reduced pulmonary microvascular permeability and an attenuated inflammatory response, we hypothesize that in the setting of ARDS, diabetic patients will be able to tolerate a positive fluid balance better than patients without diabetes.The Fluid and Catheter Treatment Trial (FACTT) randomized patients with ARDS to conservative versus liberal fluid management strategies. In a secondary analysis of this trial, we calculated the interaction of diabetic status and differing fluid strategies on outcomes. Propensity score subclassification matching was used to control for the differing baseline characteristics between patients with and without diabetes.Nine hundred fifty-six patients were analyzed. In a propensity score matched analysis, the difference in the effect of a conservative as compared to liberal fluid management strategy on ventilator free days was 2.23 days (95% CI: -0.97 to 5.43 days) in diabetic patients, and 2.37 days (95% CI: -0.21 to 4.95 days) in non-diabetic patients. The difference in the effect of a conservative as compared to liberal fluid management on 60 day mortality was 2% (95% CI: -11.8% to 15.8%) in diabetic patients, and -7.9% (95% CI: -21.7% to 5.9%) in non-diabetic patients.When comparing a conservative fluid management strategy to a liberal fluid management strategy, diabetic patients with ARDS did not have a statistically significant difference in outcomes than non-diabetic patients.

Higher plasma cystatin C is associated with mortality after acute respiratory distress syndrome: findings from a Fluid and Catheter Treatment Trial (FACTT) substudy

BackgroundCystatin C is a well-validated marker of glomerular filtration rate in chronic kidney disease. Higher plasma concentrations of cystatin C are associated with worse clinical outcomes in heterogenous populations of critically ill patients and may be superior to creatinine in identifying kidney injury in critically ill patients. We hypothesized that elevated levels of plasma cystatin C in patients with acute respiratory distress syndrome (ARDS) would be associated with mortality risk.MethodsIn a retrospective study, cystatin C was measured by nephelometry on plasma obtained at enrollment from 919 patients in the Fluid and Catheter Treatment Trial. Multivariable logistic regression was performed testing the association between quartiles of cystatin C and 60-day mortality. Analyses were stratified by acute kidney injury (AKI) status identified in the first 7 days after enrollment by Kidney Disease: Improving Global Outcomes (KDIGO) criteria.ResultsCystatin C was significantly higher among those patients who died compared to those who survived to 60 days [1.2 (0.9–1.9) mg/L vs. 0.8 (0.6–1.2) mg/L, p < 0.001]. Compared to the lower three quartiles, subjects in the highest quartile of cystatin C had a significantly higher odds of death at 60 days [OR 1.8 (1.2–2.6), p = 0.003 in adjusted analyses]; the odds of death incrementally rose in higher cystatin C quartiles compared to the lowest quartile (OR 1.1, 1.8, and 2.5). In adjusted analyses stratified by AKI status, compared to subjects in the lower three quartiles, subjects in the highest quartile of cystatin C with AKI had a significantly higher odds of death at 60 days both in participants with AKI [OR 1.6 (1.0–2.4), p = 0.048] and those without AKI [OR 2.4 (1.2–5.0), p = 0.017]. In adjusted analyses, there was no significant association between sex-stratified baseline creatinine quartiles and mortality.ConclusionsHigher plasma levels of cystatin C on enrollment were strongly associated with mortality at 60 days in patients with ARDS with and without AKI identified by creatinine-based definitions. Compared to creatinine, cystatin C may be a better biomarker of kidney function in patients with ARDS and therefore identify patients with multiple organ failure at higher risk of death.

Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome.

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 d, false discovery rate = 0.06) in the FACTT cohort. In the Harborview Medical Center cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 d, false discovery rate < 0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1β, IL-6, IL-8, monocyte chemoattractant protein 1, and TNF-α production. Transcriptome analysis of whole blood stimulated with Toll-like receptor 4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS and suggest that this variant may predispose individuals to a greater inflammatory response.

External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome.

Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort. The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied. The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined. We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion.

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy.

We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure. To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification. We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-liberal strategy versus 18% with fluid-conservative, whereas mortality in subphenotype 2 was 40% with fluid-liberal strategy versus 50% in fluid-conservative. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes. This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.

B-Type Natriuretic Peptide, Aldosterone, and Fluid Management in ARDS

Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival. This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality. Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49ng/dL (interquartile range, 1.1-4.3ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vsliberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs12.5 ± 10.3, P< .001) and decreased mortality (19%vs30%, P= .03) (P value for interaction= .01). In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.

Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury.

IntroductionTo determine whether single nucleotide polymorphisms (SNPs) in FAS and related genes are associated with acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS).MethodsWe studied 401 (Caucasian N = 310 and African-American N = 91) patients aged ≥ 13 years with ALI who enrolled in the Fluid and Catheter Treatment Trial (FACTT) between 2000 and 2005 from 20 North American centers. We genotyped 367 SNPs in 45 genes of the Fas/Fas ligand pathway to identify associations between SNPs in Fas pathway genes and the development of AKI by day 2 after enrollment in FACTT, adapting Acute Kidney Injury Network (AKIN) criteria. Written informed consent was obtained from participants or legally authorized surrogates in the original FACTT study and available to use for secondary analysis.ResultsIn Caucasian patients, we identified associations between two SNPs and the incidence of AKI (stage 1 and above): rs1050851 and rs2233417; both are found within the gene for nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA). For rs1050851 and rs2233417, the odds ratios (ORs) were 2.34 (95 % confidence interval (CI) = 1.58–3.46, p = 1.06 × 10−5, FDR = 0.003) and 2.46 (CI = 1.61–3.76, p = 1.81 × 10−5, FDR = 0.003) for each minor allele, respectively. The associations were stronger still for AKIN stage 2–3 with respective ORs 4.00 (CI = 2.10–7.62, p = 1.05 × 10−5, FDR = 0.003) and 4.03 (CI = 2.09–7.77, p = 1.88 × 10−5, FDR = 0.003) for each minor allele homozygote. We observed no significant association between these SNPs and AKI in the smaller subset of African Americans.ConclusionIn Caucasian patients with ALI, the presence of minor alleles in two SNPs in NFKBIA was strongly associated with the development of AKI.Trial registrationNCT00281268. Registered 20/01/2006.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1084-5) contains supplementary material, which is available to authorized users.

Response to Fluid Boluses in the Fluid and Catheter Treatment Trial

Recent emphasis has been placed on methods to predict fluid responsiveness, but the usefulness of using fluid boluses to increase cardiac index in critically ill patients with ineffective circulation or oliguria remains unclear. This retrospective analysis investigated hemodynamic responses of critically ill patients in the ARDS Network Fluid and Catheter Treatment Trial (FACTT) who were given protocol-based fluid boluses. Fluid responsiveness was defined as ≥ 15% increase in cardiac index after a 15 mL/kg fluid bolus. A convenience sample of 127 critically ill patients enrolled in FACTT was analyzed for physiologic responses to 569 protocolized crystalloid or albumin boluses given for shock, low urine output (UOP), or low pulmonary artery occlusion pressure (PAOP). There were significant increases in mean central venous pressure (9.9 ± 4.5 to 11.1 ± 4.8 mm Hg, P < .0001) and mean PAOP (11.6 ± 3.6 to 13.3 ± 4.3 mm Hg, P < .0001) following fluid boluses. However, there were no significant changes in UOP, and there were clinically small changes in heart rate, mean arterial pressure, and cardiac index. Only 23% of fluid boluses led to a ≥ 15% change in cardiac index. There was no significant difference in the frequency of fluid responsiveness between boluses given for shock or oliguria vs boluses given only for low PAOP (24.0% vs 21.8%, P = .59). There were no significant differences in 90-day survival, need for hemodialysis, or return to unassisted breathing between patients defined as fluid responders and fluid nonresponders. In this cohort of critically ill patients with ARDS who were previously resuscitated, the rate of fluid responsiveness was low, and fluid boluses only led to small hemodynamic changes.

Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome.

Thombomodulin (TM) is an activator of protein C and a biomarker for endothelial injury. We hypothesized that (1) elevated plasma levels would be associated with clinical outcomes and (2) polymorphisms in the TM gene would be associated with plasma levels. We studied 449 patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) for whom both plasma and DNA were available. We used logistic regression and receiver operator curves (ROC) to test for associations between soluble TM (sTM) and mortality at 60days. Plasma sTM levels were higher in non-survivors than survivors at baseline [median 147 (IQR, 95-218) vs. 89 (56-129) ng/mL, p<0.0001] and on day 3 after study enrollment [205 (146-302) vs. 127 (85-189), p<0.0001]. The odds of death increased by 2.4 (95% CI 1.5-3.8, p<0.001), and by 2.8 (1.7-4.7, P<0.001) for every log increase in baseline and day 3 sTM levels, respectively, after adjustment for age, race, gender, severity of illness, fluid management strategy, baseline creatinine, and non-pulmonary sepsis as the primary cause of ARDS. By ROC analysis, plasma sTM levels discriminated between non-survivors and survivors [AUC=72% (66-78%) vs. AUC=54% for severity based on Berlin criteria). Addition of sTM improved discrimination based on APACHE III from 77 to 80% (P<0.03). sTM levels at baseline were not statistically different among subjects stratified by genotypes of tag SNPs in the TM gene. Higher plasma sTM levels are associated with increased mortality in ARDS. The lack of association between the sTM levels and genetic variants suggests that the increased levels of sTM may reflect severity of endothelial damage rather than genetic heterogeneity. These findings underscore the importance of endothelial injury in ARDS pathogenesis and suggest that, in combination with clinical markers, sTM could contribute to risk stratification.

Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome*.

In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols. Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock. ICUs of Acute Respiratory Distress Syndrome Network participating hospitals. Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite. Fluid management by protocol. Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite). FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

"Do not resuscitate" decisions in acute respiratory distress syndrome. A secondary analysis of clinical trial data.

Factors and outcomes associated with end-of-life decision-making among patients during clinical trials in the intensive care unit are unclear. We sought to determine patterns and outcomes of Do Not Resuscitate (DNR) decisions among critically ill patients with acute respiratory distress syndrome (ARDS) enrolled in a clinical trial. We performed a secondary analysis of data from the ARDS Network Fluid and Catheter Treatment Trial (FACTT), collected between 2000 and 2005. We calculated mortality outcomes stratified by code status, and compared baseline characteristics of patients who became DNR during the trial with participants who remained full code. Among 809 FACTT participants with a code status recorded, 232 (28.7%) elected DNR status. Specifically, 37 (15.9%) chose to withhold cardiopulmonary resuscitation alone, 44 (19.0%) elected to withhold some life support measures in addition to cardiopulmonary resuscitation, and 151 (65.1%) had life support withdrawn. Admission severity of illness as measured by APACHE III score was strongly associated with election of DNR status (odds ratio, 2.2; 95% confidence interval, 1.85-2.62; P < 0.0001). Almost all (97.0%; 225 of 232) patients who selected DNR status died, and 79% (225 of 284) of patients who died during the trial were DNR. Among patients who chose DNR status but did not elect withdrawal of life support, 91% (74 of 81) died. The vast majority of deaths among clinical trial patients with ARDS were preceded by a DNR order. Unlike other studies of end-of-life decision-making in the intensive care unit, nearly all patients who became DNR died. The impact of variation of practice in end-of-life decision-making during clinical trials warrants further study.

The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury

Expanded abstractCitationMikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC: The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012, 185:1307-1315.BackgroundCognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.MethodsObjectiveThe objectives were to determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial and to determine the frequency and risk factors for long-term neuropsychological impairment.DesignA prospective, multicenter cohort study of a subset of survivors from the Fluid and Catheter Treatment Trial (FACTT) was conducted.SettingThe FACTT enrolled patients from 38 North American hospitals between June 2000 and October 2005.SubjectsTo be eligible for the ALI Cognitive Outcomes Study (ACOS), subjects had to be enrolled in the FACTT and the EA-PAC (Economic Assessment of the Pulmonary Artery Catheter) trial. The FACTT enrolled mechanically ventilated adults who met the American-European Consensus Conference criteria for ALI.InterventionIn an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, neuropsychological function at 2 and 12 months after hospital discharge was assessed.OutcomesThe primary outcome was the result of a validated telephone battery of standardized neuropsychological tests administered to consenting, English-speaking subjects at 2 and 12 months after hospital discharge.ResultsOf 406 eligible survivors, 261 patients were approached to participate and 213 consented. One hundred twenty-two subjects, including 102 subjects at 12 months, were tested at least once. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors, respectively. Long-term cognitive impairment was present in 41 (55%) of the 75 survivors who completed cognitive testing. Depression, post-traumatic stress disorder, and anxiety were present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors, respectively. Enrollment in a conservative fluid management strategy (P <0.005) was associated with cognitive impairment, and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P <0.02) and psychiatric (P <0.02) impairment.ConclusionsNeuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. A fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

Von Willebrand factor and angiopoietin-2

von Willebrand factor and angiopoietin-2

Fluid Balance, Diuretic Use, and Mortality in Acute Kidney Injury

Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients. Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria. 306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P=0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased. A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance.

Vascular pedicle width in acute lung injury: correlation with intravascular pressures and ability to discriminate fluid status

IntroductionConservative fluid management in patients with acute lung injury (ALI) increases time alive and free from mechanical ventilation. Vascular pedicle width (VPW) is a non-invasive measurement of intravascular volume status. The VPW was studied in ALI patients to determine the correlation between VPW and intravascular pressure measurements and whether VPW could predict fluid status.MethodsThis retrospective cohort study involved 152 patients with ALI enrolled in the Fluid and Catheter Treatment Trial (FACTT) from five NHLBI ARDS (Acute Respiratory Distress Syndrome) Network sites. VPW and central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) from the first four study days were correlated. The relationships between VPW, positive end-expiratory pressure (PEEP), cumulative fluid balance, and PAOP were also evaluated. Receiver operator characteristic (ROC) curves were used to determine the ability of VPW to detect PAOP <8 mmHg and PAOP ≥18 mm Hg.ResultsA total of 71 and 152 patients provided 118 and 276 paired VPW/PAOP and VPW/CVP measurements, respectively. VPW correlated with PAOP (r = 0.41; P < 0.001) and less well with CVP (r = 0.21; P = 0.001). In linear regression, VPW correlated with PAOP 1.5-fold better than cumulative fluid balance and 2.5-fold better than PEEP. VPW discriminated achievement of PAOP <8 mm Hg (AUC = 0.73; P = 0.04) with VPW ≤67 mm demonstrating 71% sensitivity (95% CI 30 to 95%) and 68% specificity (95% CI 59 to 75%). For discriminating a hydrostatic component of the edema (that is, PAOP ≥18 mm Hg), VPW ≥72 mm demonstrated 61.4% sensitivity (95% CI 47 to 74%) and 61% specificity (49 to 71%) (area under the curve (AUC) 0.69; P = 0.001).ConclusionsVPW correlates with PAOP better than CVP in patients with ALI. Due to its only moderate sensitivity and specificity, the ability of VPW to discriminate fluid status in patients with acute lung injury is limited and should only be considered when intravascular pressures are unavailable.