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Papers by Paul Lanken

BACKGROUND: Physicians often fail to use lung-protective ventilation (LPV) in patients with acute... more BACKGROUND: Physicians often fail to use lung-protective ventilation (LPV) in patients with acute lung injury. OBJECTIVE: To use physician documentation to identify why physicians did not initiate or continue LPV in patients with acute lung injury. METHODS: This was a retrospective cohort study in a university hospital. The study period was September 2000 through November 2002. In our primary analysis,

Academic medicine : journal of the Association of American Medical Colleges, 2015

To examine whether an Internet-based learning module and small-group debriefing can improve medic... more To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs). In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small-group, faculty-led debriefing. Primary study outcomes were changes in self-assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear model...

A25. TRANSLATING ACUTE RESPIRATORY DISTRESS SYNDROME AND VENTILATOR INDUCED LUNG INJURY: MECHANISMS TO OUTCOMES, 2011

Annals of the American Thoracic Society, 2014

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that can develop at variou... more Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that can develop at various times after major trauma. To identify and characterize distinct phenotypes of ARDS after trauma, based on timing of syndrome onset. Latent class analyses were used to identify patterns of ARDS onset in a cohort of critically ill trauma patients. Identified patterns were tested for associations with known ARDS risk factors and associations were externally validated at a separate institution. Eleven plasma biomarkers representing pathophysiologic domains were compared between identified patterns in the validation cohort. Three patterns of ARDS were identified; class I (52%) early onset on Day 1 or 2, class II (40%) onset on Days 3 and 4, and class III (8%) later onset on Days 4 and 5. Early-onset ARDS was associated with higher Abbreviated Injury Scale scores for the thorax (P < 0.001), lower lowest systolic blood pressure before intensive care unit admission (P = 0.003), and a greater red blood cell transfusion requirement during resuscitation (P = 0.030). In the external validation cohort, early-onset ARDS was also associated with a higher Abbreviated Injury Scale score for the thorax (P = 0.001) and a lower lowest systolic blood pressure before intensive care unit enrollment (P = 0.006). In addition, the early-onset phenotype demonstrated higher plasma levels of soluble receptor for advanced glycation end-products and angiopoietin-2. Degree of hemorrhagic shock and severity of thoracic trauma are associated with an early-onset phenotype of ARDS after major trauma. Lung injury biomarkers suggest a dominant alveolar-capillary barrier injury pattern in this phenotype.

The FASEB Journal, 2007

We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related fact... more We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related factor 2) as a susceptibility gene in a murine model of oxidant-induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up-regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (-617 C/A) significantly (P<0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (-617 CC). In a nested case-control study, patients with the -617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8; P=0.021) relative to patients with the wild type (-617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.

PLoS ONE, 2012

Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypo... more Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p,0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated Blymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multicenter GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.

Journal of Critical Care, 2012

Purpose: Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit le... more Purpose: Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma. Materials and Methods: This was a single-center nested case-control study within a prospective cohort study of major trauma patients. Using an enzyme-linked immunosorbent assay test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI. Results: Patients who developed ALI had lower levels of endocan on admission (mean, 3.5 ± 1.4 ng/mL vs 4.9 ± 2.6 ng/mL in controls; P = .02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69; 95% confidence interval, 0.49-0.97; P = .03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity. Conclusions: Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.

Journal of Cellular and Molecular Medicine, 2009

Rationale-Acute lung injury (ALI) is a syndrome with significant morbidity and mortality, but its... more Rationale-Acute lung injury (ALI) is a syndrome with significant morbidity and mortality, but its genetic susceptibility is not clearly understood. In the present study, we characterized functional promoter single nucleotide polymorphisms (SNPs) in the phase II antioxidant gene NQO1 (NAD(P) H:quinone oxidoreductase1) to evaluate its role in susceptibility to ALI.

Intensive Care Medicine, 1994

To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients w... more To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients with ARDS. Substudy of a multicenter, double-blinded, placebo-controlled trial of HA-1A in septic patients. 63 septic patients with ARDS at the time of study entry. A single intravenous injection of HA-1A (100 mg) or placebo. A quantitative radiographic score, the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3, 5 and 7 days after treatment. The duration of endotracheal intubation did not differ between the two groups. 15 of 30 HA-1A treated patients (50%) and 23 of 33 placebo-treated patients (69.7%) died within 28 days. The daily mortality was always lower in the HA-1A group, but this difference was not statistically significant at 28 days. The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different (p = 0.07). Using logistic regression, a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days (p = 0.03) but not at 14 and 28 days. A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival.

Critical Care Medicine, 2008

The additional impact of development of acute lung injury on mortality in severely-injured trauma... more The additional impact of development of acute lung injury on mortality in severely-injured trauma patients beyond baseline severity of illness has been questioned. We assessed the contribution of acute lung injury to in-hospital mortality in critically ill trauma patients. Prospective cohort study. The contribution of acute lung injury to in-hospital mortality was evaluated in two ways. First, multivariable logistic regression models were used to test the independent association of acute lung injury with in-hospital mortality while adjusting for baseline confounding variables. Second, causal pathway models were used to estimate the amount of the overall association of baseline severity of illness with in-hospital mortality that is attributable to the interval development of acute lung injury. Academic level 1 trauma center. Two hundred eighty-three critically ill trauma patients without isolated head injury and with an Injury Severity Score > or = 16 were evaluated for development of acute lung injury in the first 5 days after trauma. Of the 283 patients, 38 (13.4%) died. The unadjusted mortality rate was nearly three-fold greater in the acute lung injury group (23.9% vs. 8.4%; odds ratio = 3.36; 95% confidence interval 1.67-6.77; p = 0.001). Acute lung injury remained an independent risk factor for death after adjustment for age, baseline Acute Physiologic and Chronic Health Evaluation III score, Injury Severity Score, and blunt mechanism of injury (odds ratio = 2.87; 95% confidence interval 1.29-6.37; p = 0.010). Forty percent of the total association of the baseline Acute Physiologic and Chronic Health Evaluation III score with mortality occurred via an indirect association through acute lung injury, and the remaining 60% via a direct effect. Development of acute lung injury in critically ill trauma patients without isolated head injury contributes independently to in-hospital mortality beyond baseline severity of illness measures. In addition, a significant portion of the association between baseline illness severity and risk of death in these patients might be explained by the interval development of acute lung injury.

Critical Care Medicine, 2009

Objective-We sought to develop a simple point score that would accurately capture the risk of hos... more Objective-We sought to develop a simple point score that would accurately capture the risk of hospital death for patients with acute lung injury (ALI).

Critical Care Medicine, 2005

Many subjects enrolled in research studies have a limited understanding of the research to which ... more Many subjects enrolled in research studies have a limited understanding of the research to which they consented. To develop recommendations to enhance comprehensiveness and understanding of informed consent forms used in critical care clinical trials. Consensus process. We provide recommendations regarding the U.S. federally required basic and additional elements of informed consent as applied to critical care clinical trials. We also identify issues that investigators need to address, if relevant, in the informed consent forms of critical care clinical trials. These include the description, in understandable language, of complex and detailed experimental protocols that are the focus of the clinical trial, disclosure of death as a risk factor if mortality is an outcome variable, and the identification of who can legally serve as the prospective subject's surrogate. We also offer suggestions to enhance subjects' understanding of informed consent forms. The literature on informed consent forms suggest that shorter informed consent forms written at a lower reading level, when read carefully, might provide better subject understanding. Prospective evaluation is needed to determine whether our recommendations enhance the informed consent process.

Critical Care Medicine, 1990

ABSTRACT

Critical Care Medicine, 1997

To determine the effects and net costs of routine chest radiographs in a medical intensive care u... more To determine the effects and net costs of routine chest radiographs in a medical intensive care unit (ICU). A prospective, cohort study. A survey of experts in critical care and pulmonary diseases was undertaken to assess the effect of routine radiographs on patient management. Medical ICU of a university hospital. Eighty randomly selected patients admitted to a medical ICU. Two hundred fourteen experts were surveyed; 118 (55%)/214 responded. Daily interviews with medical ICU clinicians were conducted to assess the radiographic findings in the routine radiographs and actions taken based on these findings. Experts evaluated the findings, their importance, the actions taken, and the probability of complications if the actions had not been taken at that time. Experts also predicted increases in length of stay associated with these complications. Presence of radiographic findings, changes in management because of the findings, net costs of routine chest radiographs, cost per finding that prompted an action, and expected changes in length of stay resulting from the actions were also assessed. Seventy-two (33%) of 221 routine radiographs (95% confidence interval: 25% to 39%) had findings, of which 44 (61%) were judged important, and 18 (8%, 95% confidence interval: 5% to 12%) prompted actions. Experts predicted that each action averted, on average, 2.1 +/- 1.7 days (SD) in the medical ICU. Mean savings per routine radiograph was $98. Net savings from routine chest radiographs remained after sensitivity analysis for expected change in length of stay, percentage of patients with routine radiographs, and percentage of routine radiographs that produce changes in management. The policy of obtaining routine chest radiographs in the medical ICU is effective and results in net savings.

Critical Care Medicine, 2009

To correlate physical examination findings, central venous pressure, fluid output, and central ve... more To correlate physical examination findings, central venous pressure, fluid output, and central venous oxygen saturation with pulmonary artery catheter parameters. Retrospective study. Data from the multicenter Fluid and Catheter Treatment Trial of the National Institutes of Health Acute Respiratory Distress Syndrome Network. Five hundred thirteen patients with acute lung injury randomized to treatment with a pulmonary artery catheter. Correlation of physical examination findings (capillary refill time >2 secs, knee mottling, or cool extremities), central venous pressure, fluid output, and central venous oxygen saturation with parameters from a pulmonary artery catheter. We determined association of baseline physical examination findings and on-study parameters of central venous pressure and central venous oxygen saturation with cardiac index <2.5 L/min/m2 and mixed venous oxygen saturation <60%. We determined correlation of baseline central venous oxygen saturation and mixed venous oxygen saturation and predictive value of a low central venous oxygen saturation for a low mixed venous oxygen saturation. Prevalence of cardiac index <2.5 and mixed venous oxygen saturation <60% was 8.1% and 15.5%, respectively. Baseline presence of all three physical examination findings had low sensitivity (12% and 8%), high specificity (98% and 99%), low positive predictive value (40% and 56%), but high negative predictive value (93% and 86%) for cardiac index <2.5 and mixed venous oxygen saturation <60%, respectively. Central venous oxygen saturation <70% predicted a mixed venous oxygen saturation <60% with a sensitivity 84%,specificity 70%, positive predictive value 31%, and negative predictive value of 96%. Low cardiac index correlated with cool extremities, high central venous pressure, and low 24-hr fluid output; and low mixed venous oxygen saturation correlated with knee mottling and high central venous pressure, but these correlations were not found to be clinically useful. In this subset of patients with acute lung injury, there is a high prior probability that cardiac index and mixed venous oxygen saturation are normal and physical examination findings of ineffective circulation are not useful for predicting low cardiac index or mixed venous oxygen saturation. Central venous oxygen saturation <70% does not accurately predict mixed venous oxygen saturation…

Critical Care Medicine, 2006

To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with ac... more To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume. Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002. Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital. Measurements included the proportion for whom the ventilation tidal volume (TV) was <or=7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was <or=6.5 and <or=8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV <or=7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006). Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians' underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

CHEST Journal, 2010

In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury a... more In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury and diffi cult-to-interpret chest radiographs (CXRs) may hamper efforts to uncover risk factor associations. We assessed the impact of excluding patients with diffi cult-to-classify or equivocal ALI diagnosis on clinical and genetic risk factor associations for ALI after trauma.

BMC Medical Genetics, 2012

Background: We used a genebased replication strategy to test the reproducibility of prior acute l... more Background: We used a genebased replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations.

BACKGROUND: Physicians often fail to use lung-protective ventilation (LPV) in patients with acute... more BACKGROUND: Physicians often fail to use lung-protective ventilation (LPV) in patients with acute lung injury. OBJECTIVE: To use physician documentation to identify why physicians did not initiate or continue LPV in patients with acute lung injury. METHODS: This was a retrospective cohort study in a university hospital. The study period was September 2000 through November 2002. In our primary analysis,

Academic medicine : journal of the Association of American Medical Colleges, 2015

To examine whether an Internet-based learning module and small-group debriefing can improve medic... more To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs). In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small-group, faculty-led debriefing. Primary study outcomes were changes in self-assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear model...

A25. TRANSLATING ACUTE RESPIRATORY DISTRESS SYNDROME AND VENTILATOR INDUCED LUNG INJURY: MECHANISMS TO OUTCOMES, 2011

Annals of the American Thoracic Society, 2014

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that can develop at variou... more Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that can develop at various times after major trauma. To identify and characterize distinct phenotypes of ARDS after trauma, based on timing of syndrome onset. Latent class analyses were used to identify patterns of ARDS onset in a cohort of critically ill trauma patients. Identified patterns were tested for associations with known ARDS risk factors and associations were externally validated at a separate institution. Eleven plasma biomarkers representing pathophysiologic domains were compared between identified patterns in the validation cohort. Three patterns of ARDS were identified; class I (52%) early onset on Day 1 or 2, class II (40%) onset on Days 3 and 4, and class III (8%) later onset on Days 4 and 5. Early-onset ARDS was associated with higher Abbreviated Injury Scale scores for the thorax (P < 0.001), lower lowest systolic blood pressure before intensive care unit admission (P = 0.003), and a greater red blood cell transfusion requirement during resuscitation (P = 0.030). In the external validation cohort, early-onset ARDS was also associated with a higher Abbreviated Injury Scale score for the thorax (P = 0.001) and a lower lowest systolic blood pressure before intensive care unit enrollment (P = 0.006). In addition, the early-onset phenotype demonstrated higher plasma levels of soluble receptor for advanced glycation end-products and angiopoietin-2. Degree of hemorrhagic shock and severity of thoracic trauma are associated with an early-onset phenotype of ARDS after major trauma. Lung injury biomarkers suggest a dominant alveolar-capillary barrier injury pattern in this phenotype.

The FASEB Journal, 2007

We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related fact... more We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related factor 2) as a susceptibility gene in a murine model of oxidant-induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up-regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (-617 C/A) significantly (P<0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (-617 CC). In a nested case-control study, patients with the -617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8; P=0.021) relative to patients with the wild type (-617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.

PLoS ONE, 2012

Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypo... more Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p,0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated Blymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multicenter GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.

Journal of Critical Care, 2012

Purpose: Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit le... more Purpose: Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma. Materials and Methods: This was a single-center nested case-control study within a prospective cohort study of major trauma patients. Using an enzyme-linked immunosorbent assay test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI. Results: Patients who developed ALI had lower levels of endocan on admission (mean, 3.5 ± 1.4 ng/mL vs 4.9 ± 2.6 ng/mL in controls; P = .02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69; 95% confidence interval, 0.49-0.97; P = .03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity. Conclusions: Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.

Journal of Cellular and Molecular Medicine, 2009

Rationale-Acute lung injury (ALI) is a syndrome with significant morbidity and mortality, but its... more Rationale-Acute lung injury (ALI) is a syndrome with significant morbidity and mortality, but its genetic susceptibility is not clearly understood. In the present study, we characterized functional promoter single nucleotide polymorphisms (SNPs) in the phase II antioxidant gene NQO1 (NAD(P) H:quinone oxidoreductase1) to evaluate its role in susceptibility to ALI.

Intensive Care Medicine, 1994

To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients w... more To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients with ARDS. Substudy of a multicenter, double-blinded, placebo-controlled trial of HA-1A in septic patients. 63 septic patients with ARDS at the time of study entry. A single intravenous injection of HA-1A (100 mg) or placebo. A quantitative radiographic score, the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3, 5 and 7 days after treatment. The duration of endotracheal intubation did not differ between the two groups. 15 of 30 HA-1A treated patients (50%) and 23 of 33 placebo-treated patients (69.7%) died within 28 days. The daily mortality was always lower in the HA-1A group, but this difference was not statistically significant at 28 days. The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different (p = 0.07). Using logistic regression, a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days (p = 0.03) but not at 14 and 28 days. A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival.

Critical Care Medicine, 2008

The additional impact of development of acute lung injury on mortality in severely-injured trauma... more The additional impact of development of acute lung injury on mortality in severely-injured trauma patients beyond baseline severity of illness has been questioned. We assessed the contribution of acute lung injury to in-hospital mortality in critically ill trauma patients. Prospective cohort study. The contribution of acute lung injury to in-hospital mortality was evaluated in two ways. First, multivariable logistic regression models were used to test the independent association of acute lung injury with in-hospital mortality while adjusting for baseline confounding variables. Second, causal pathway models were used to estimate the amount of the overall association of baseline severity of illness with in-hospital mortality that is attributable to the interval development of acute lung injury. Academic level 1 trauma center. Two hundred eighty-three critically ill trauma patients without isolated head injury and with an Injury Severity Score > or = 16 were evaluated for development of acute lung injury in the first 5 days after trauma. Of the 283 patients, 38 (13.4%) died. The unadjusted mortality rate was nearly three-fold greater in the acute lung injury group (23.9% vs. 8.4%; odds ratio = 3.36; 95% confidence interval 1.67-6.77; p = 0.001). Acute lung injury remained an independent risk factor for death after adjustment for age, baseline Acute Physiologic and Chronic Health Evaluation III score, Injury Severity Score, and blunt mechanism of injury (odds ratio = 2.87; 95% confidence interval 1.29-6.37; p = 0.010). Forty percent of the total association of the baseline Acute Physiologic and Chronic Health Evaluation III score with mortality occurred via an indirect association through acute lung injury, and the remaining 60% via a direct effect. Development of acute lung injury in critically ill trauma patients without isolated head injury contributes independently to in-hospital mortality beyond baseline severity of illness measures. In addition, a significant portion of the association between baseline illness severity and risk of death in these patients might be explained by the interval development of acute lung injury.

Critical Care Medicine, 2009

Objective-We sought to develop a simple point score that would accurately capture the risk of hos... more Objective-We sought to develop a simple point score that would accurately capture the risk of hospital death for patients with acute lung injury (ALI).

Critical Care Medicine, 2005

Many subjects enrolled in research studies have a limited understanding of the research to which ... more Many subjects enrolled in research studies have a limited understanding of the research to which they consented. To develop recommendations to enhance comprehensiveness and understanding of informed consent forms used in critical care clinical trials. Consensus process. We provide recommendations regarding the U.S. federally required basic and additional elements of informed consent as applied to critical care clinical trials. We also identify issues that investigators need to address, if relevant, in the informed consent forms of critical care clinical trials. These include the description, in understandable language, of complex and detailed experimental protocols that are the focus of the clinical trial, disclosure of death as a risk factor if mortality is an outcome variable, and the identification of who can legally serve as the prospective subject's surrogate. We also offer suggestions to enhance subjects' understanding of informed consent forms. The literature on informed consent forms suggest that shorter informed consent forms written at a lower reading level, when read carefully, might provide better subject understanding. Prospective evaluation is needed to determine whether our recommendations enhance the informed consent process.

Critical Care Medicine, 1990

ABSTRACT

Critical Care Medicine, 1997

To determine the effects and net costs of routine chest radiographs in a medical intensive care u... more To determine the effects and net costs of routine chest radiographs in a medical intensive care unit (ICU). A prospective, cohort study. A survey of experts in critical care and pulmonary diseases was undertaken to assess the effect of routine radiographs on patient management. Medical ICU of a university hospital. Eighty randomly selected patients admitted to a medical ICU. Two hundred fourteen experts were surveyed; 118 (55%)/214 responded. Daily interviews with medical ICU clinicians were conducted to assess the radiographic findings in the routine radiographs and actions taken based on these findings. Experts evaluated the findings, their importance, the actions taken, and the probability of complications if the actions had not been taken at that time. Experts also predicted increases in length of stay associated with these complications. Presence of radiographic findings, changes in management because of the findings, net costs of routine chest radiographs, cost per finding that prompted an action, and expected changes in length of stay resulting from the actions were also assessed. Seventy-two (33%) of 221 routine radiographs (95% confidence interval: 25% to 39%) had findings, of which 44 (61%) were judged important, and 18 (8%, 95% confidence interval: 5% to 12%) prompted actions. Experts predicted that each action averted, on average, 2.1 +/- 1.7 days (SD) in the medical ICU. Mean savings per routine radiograph was $98. Net savings from routine chest radiographs remained after sensitivity analysis for expected change in length of stay, percentage of patients with routine radiographs, and percentage of routine radiographs that produce changes in management. The policy of obtaining routine chest radiographs in the medical ICU is effective and results in net savings.

Critical Care Medicine, 2009

To correlate physical examination findings, central venous pressure, fluid output, and central ve... more To correlate physical examination findings, central venous pressure, fluid output, and central venous oxygen saturation with pulmonary artery catheter parameters. Retrospective study. Data from the multicenter Fluid and Catheter Treatment Trial of the National Institutes of Health Acute Respiratory Distress Syndrome Network. Five hundred thirteen patients with acute lung injury randomized to treatment with a pulmonary artery catheter. Correlation of physical examination findings (capillary refill time >2 secs, knee mottling, or cool extremities), central venous pressure, fluid output, and central venous oxygen saturation with parameters from a pulmonary artery catheter. We determined association of baseline physical examination findings and on-study parameters of central venous pressure and central venous oxygen saturation with cardiac index <2.5 L/min/m2 and mixed venous oxygen saturation <60%. We determined correlation of baseline central venous oxygen saturation and mixed venous oxygen saturation and predictive value of a low central venous oxygen saturation for a low mixed venous oxygen saturation. Prevalence of cardiac index <2.5 and mixed venous oxygen saturation <60% was 8.1% and 15.5%, respectively. Baseline presence of all three physical examination findings had low sensitivity (12% and 8%), high specificity (98% and 99%), low positive predictive value (40% and 56%), but high negative predictive value (93% and 86%) for cardiac index <2.5 and mixed venous oxygen saturation <60%, respectively. Central venous oxygen saturation <70% predicted a mixed venous oxygen saturation <60% with a sensitivity 84%,specificity 70%, positive predictive value 31%, and negative predictive value of 96%. Low cardiac index correlated with cool extremities, high central venous pressure, and low 24-hr fluid output; and low mixed venous oxygen saturation correlated with knee mottling and high central venous pressure, but these correlations were not found to be clinically useful. In this subset of patients with acute lung injury, there is a high prior probability that cardiac index and mixed venous oxygen saturation are normal and physical examination findings of ineffective circulation are not useful for predicting low cardiac index or mixed venous oxygen saturation. Central venous oxygen saturation <70% does not accurately predict mixed venous oxygen saturation…

Critical Care Medicine, 2006

To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with ac... more To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume. Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002. Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital. Measurements included the proportion for whom the ventilation tidal volume (TV) was <or=7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was <or=6.5 and <or=8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV <or=7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006). Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians' underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

CHEST Journal, 2010

In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury a... more In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury and diffi cult-to-interpret chest radiographs (CXRs) may hamper efforts to uncover risk factor associations. We assessed the impact of excluding patients with diffi cult-to-classify or equivocal ALI diagnosis on clinical and genetic risk factor associations for ALI after trauma.

BMC Medical Genetics, 2012

Background: We used a genebased replication strategy to test the reproducibility of prior acute l... more Background: We used a genebased replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations.