A Bayesian Approach for the Cox Proportional Hazards Model with Covariates Subject to Detection Limit

The research on biomarkers has been limited in its effectiveness because biomarker levels can only be measured within the thresholds of assays and laboratory instruments, a challenge referred to as a detection limit (DL) problem. In this paper, we propose a Bayesian approach to the Cox proportional hazards model with explanatory variables subject to lower, upper, or interval DLs. We demonstrate that by formulating the time-to-event outcome using the Poisson density with counting process notation, implementing the proposed approach in the OpenBUGS and JAGS is straightforward. We have conducted extensive simulations to compare the proposed Bayesian approach to the other four commonly used methods and to evaluate its robustness with respect to the distribution assumption of the biomarkers. The proposed Bayesian approach and other methods were applied to an acute lung injury study, in which a panel of cytokine biomarkers was studied for the biomarkers' association with ventilation-free survival

Is there still a role for the lung injury score in the era of the Berlin definition ARDS?

BACKGROUND: The Lung Injury Score (LIS) remains a commonly utilized measure of lung injury severity though the additive value of LIS to predict ARDS outcomes over the recent Berlin definition of ARDS, which incorporates severity, is not known. METHODS: We tested the association of LIS (in which scores range from 0 to 4, with higher scores indicating more severe lung injury) and its four components calculated on the day of ARDS diagnosis with ARDS morbidity and mortality in a large, multi-ICU cohort of patients with Berlin-defined ARDS. Receiver Operator Characteristic (ROC) curves were generated to compare the predictive validity of LIS for mortality to Berlin stages of severity (mild, moderate and severe). RESULTS: In 550 ARDS patients, a one-point increase in LIS was associated with 58% increased odds of in-hospital death (95% CI 14 to 219%, P = 0.006), a 7% reduction in ventilator-free days (95% CI 2 to 13%, P = 0.01), and, among patients surviving hospitalization, a 25% increase in days of mechanical ventilation (95% CI 9 to 43%, P = 0.001) and a 16% increase (95% CI 2 to 31%, P = 0.02) in the number of ICU days. However, the mean LIS was only 0.2 points higher (95% CI 0.1 to 0.3) among those who died compared to those who lived. Berlin stages of severity were highly correlated with LIS (Spearman’s rho 0.72, P < 0.0001) and were also significantly associated with ARDS mortality and similar morbidity measures. The predictive validity of LIS for mortality was similar to Berlin stages of severity with an area under the curve of 0.58 compared to 0.60, respectively (P-value 0.49). CONCLUSIONS: In a large, multi-ICU cohort of patients with ARDS, both LIS and the Berlin definition severity stages were associated with increased in-hospital morbidity and mortality. However, predictive validity of both scores was marginal, and there was no additive value of LIS over Berlin. Although neither LIS nor the Berlin definition were designed to prognosticate outcomes, these findings suggest that the role of LIS in characterizing lung injury severity in the era of the Berlin definition ARDS may be limited

Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI

Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

INTRODUCTION: The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis. METHODS: Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions. RESULTS: Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness. CONCLUSIONS: In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function

Soluble P-Selectin and the Risk of Primary Graft Dysfunction After Lung Transplantation

Background - Platelet activation with subsequent neutrophilic adherence to the vasculature initiates ischemia-reperfusion injury. We hypothesized that higher plasma P-selectin levels reflecting platelet activation would therefore be associated with primary graft dysfunction (PGD) after lung transplantation. Methods - In a prospective, multicenter cohort study of 376 patients who had undergone lung transplantation between 2002 and 2007, we measured soluble P-selectin levels before lung transplantation and at 6 and 24 h after lung reperfusion in 20 patients with grade III PGD (Pao2/fraction of inspired oxygen, < 200 mm Hg [with alveolar infiltrates seen on chest radiographs]) at 72 h after transplantation and 61 control subjects without PGD. Results - Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h after transplantation (odds ratio [OR] per 1 natural log increase in soluble P-selectin at 6 h after lung allograft reperfusion, 3.5; 95% confidence interval [CI], 1.01 to 11.8; p = 0.048) and at 24 h after lung allograft reperfusion (OR, 4.8; 95% CI, 1.4 to 16.1; p = 0.01). Higher preoperative mean pulmonary artery pressure and the use of cardiopulmonary bypass were also associated with an increased risk of PGD. Conclusion - Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h following lung transplantation

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

Abstract Introduction Conservative 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. Methods This 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 &lt;8 mmHg and PAOP ≥18 mm Hg. Results A 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 &lt; 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 &lt;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). Conclusions VPW 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