Chirag V. Shah

Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock

Principle:Serum lactate is a potentially useful biomarker to risk-stratify patients with severe sepsis; however, it is plausible that elevated serum lactate is simply a manifestation of clinically apparent organ dysfunction and/or shock (i.e., refractory hypotension). Objective:To test whether the association between initial serum lactate level and mortality in patients presenting to the emergency department (ED) with severe sepsis is independent of organ dysfunction and shock. Design:Single-center cohort study. The primary outcome was 28-day mortality and the risk factor variable was initial venous lactate (mmol/L), categorized as low (<2), intermediate (2–3.9), or high (≥4). Potential covariates included age, sex, race, acute and chronic organ dysfunction, severity of illness, and initiation of early goal-directed therapy. Multivariable logistic regression analyses were stratified on the presence or absence of shock. Setting:The ED of an academic tertiary care center from 2005 to 2007. Patients:Eight hundred thirty adults admitted with severe sepsis in the ED. Interventions:None. Measurements and Main Results:Mortality at 28 days was 22.9% and median serum lactate was 2.9 mmol/L. Intermediate (odds ratio {lsqb;OR{rsqb; = 2.05, p = 0.024) and high serum lactate levels (OR = 4.87, p < 0.001) were associated with mortality in the nonshock subgroup. In the shock subgroup, intermediate (OR = 3.27, p = 0.022) and high serum lactate levels (OR = 4.87, p = 0.001) were also associated with mortality. After adjusting for potential confounders, intermediate and high serum lactate levels remained significantly associated with mortality within shock and nonshock strata. Conclusions:Initial serum lactate was associated with mortality independent of clinically apparent organ dysfunction and shock in patients admitted to the ED with severe sepsis. Both intermediate and high serum lactate levels were independently associated with mortality.

Endotracheal tube intraluminal volume loss among mechanically ventilated patients.

ObjectiveTo measure endotracheal tube intraluminal volume loss among mechanically ventilated patients. DesignProspective observational study. SettingMedical intensive care unit (19 beds) of an urban university-affiliated teaching hospital. PatientsA total of 101 patients with acute respiratory failure requiring >24 hrs of mechanical ventilation. InterventionsNone. Measurements and Main ResultsAcoustic reflectometry was employed to measure the intraluminal volume of 13-cm endotracheal tube segments. The endotracheal tube segment volumes were statistically smaller among endotracheal tubes used in patients compared with unused endotracheal tubes (5.4 ± 0.7 vs. 6.0 ± 0.6 mL, p < .001). The average percentage difference in endotracheal tube segment volumes, between the unused endotracheal tubes and the endotracheal tubes used in patients, was 9.8% (range, 0–45.5%). The percentage difference in the endotracheal tube segment volumes increased significantly with increasing duration of tracheal intubation (r2 = .766, p < .001). The minimum diameter of the endotracheal tube segments was also statistically smaller among endotracheal tubes used in patients compared with the unused endotracheal tubes (7.5 ± 0.4 vs. 6.7 ± 1.2 mm, p < .001). ConclusionsEndotracheal tube intraluminal volume loss is common among patients with acute respiratory failure requiring mechanical ventilation and increases with prolonged tracheal intubation.

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

RATIONALE The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. OBJECTIVES To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. METHODS We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation. MEASUREMENTS AND MAIN RESULTS Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearmans rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02). CONCLUSIONS Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

Factors Associated With Nonadherence to Early Goal-Directed Therapy in the ED

BACKGROUND Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the ED. EGDT appears to be underused, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED. METHODS This was a cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005 to 2007. EGDT eligibility was defined as a serum lactate >or= 4 mmol/L or systolic BP< 90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was used to adjust for potential confounding. RESULTS EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0% to 100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female sex of the patient (P = .001), female sex of the clinician (P = .041), serum lactate (rather than hemodynamic) criterion for EGDT (P = .018), and nonconsultation to the Severe Sepsis Service (P < .001). CONCLUSIONS Despite a formalized protocol, we found that EGDT was underused. We identified potential barriers to the effective implementation of EGDT at the patient, clinician, and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence.

Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma.

Background:Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients. Methods:We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score ≥16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2–5 single nucleotide polymorphisms were conducted. Results:Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio = 1.87, 95% confidence interval 1.06–3.33; p = 0.022) and Pro147Ser (TT, odds ratio = 2.13, 95% confidence interval 1.14–4.10; p = 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio = 0.42, 95% confidence interval 0.20–0.85; p = 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2–4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008). Conclusions:Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis.

Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case–control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein‐1 (MCP‐1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)‐inducible protein (IP‐10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL‐13) (p = 0.05) and higher levels of IL‐2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)‐α, and IFN‐γ decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

The Epidemiology of Acute Respiratory Distress Syndrome in Patients Presenting to the Emergency Department With Severe Sepsis.

ABSTRACT Background: Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED). Methods: This was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development. Results: The incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care: 0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2–3.9 mmol/L) (P = 0.04) and high (≥4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01). Conclusions: In patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis.

The impact of development of acute lung injury on hospital mortality in critically ill trauma patients

Objective: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. Design: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. Setting:Academic level 1 trauma center. Patients:Two hundred eighty-three critically ill trauma patients without isolated head injury and with an Injury Severity Score ≥16 were evaluated for development of acute lung injury in the first 5 days after trauma. Measurements and Main Results: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. Conclusions: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.

Plasma Intercellular Adhesion Molecule-1 and von Willebrand Factor in Primary Graft Dysfunction After Lung Transplantation

Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule‐1 (ICAM‐1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM‐1 and vWF. At each postoperative timepoint, mean plasma ICAM‐1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM‐1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM‐1 are associated with PGD following lung transplantation.

A Simple Clinical Predictive Index for Objective Estimates of Mortality in Acute Lung Injury

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). Design:This is a secondary analysis of data from two randomized trials. Baseline clinical variables collected within 24 hours of enrollment were modeled as predictors of hospital mortality using logistic regression and bootstrap resampling to arrive at a parsimonious model. We constructed a point score based on regression coefficients. Setting:Medical centers participating in the Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSnet). Patients:Model development: 414 patients with nontraumatic ALI participating in the low tidal volume arm of the ARDSnet Acute Respiratory Management in ARDS study. Model validation: 459 patients participating in the ARDSnet Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury study. Model Validation: 459 patients participating in the ARDSnet Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury trial. Interventions:None. Measurements and Main Results:Variables comprising the prognostic model were hematocrit <26% (1 point), bilirubin ≥2 mg/dL (1 point), fluid balance >2.5 L positive (1 point), and age (1 point for age 40-64 years, 2 points for age ≥65 years). Predicted mortality (95% confidence interval) for 0, 1, 2, 3, and 4+ point totals was 8% (5% to 14%), 17% (12% to 23%), 31% (26% to 37%), 51% (43% to 58%), and 70% (58% to 80%), respectively. There was an excellent agreement between predicted and observed mortality in the validation cohort. Observed mortality for 0, 1, 2, 3, and 4+ point totals in the validation cohort was 12%, 16%, 28%, 47%, and 67%, respectively. Compared with the Acute Physiology Assessment and Chronic Health Evaluation III score, areas under the receiver operating characteristic curve for the point score were greater in the development cohort (0.72 vs. 0.67, p = 0.09) and lower in the validation cohort (0.68 vs. 0.75, p = 0.03). Conclusions:Mortality in patients with ALI can be predicted using an index of four readily available clinical variables with good calibration. This index may help inform prognostic discussions, but validation in nonclinical trial populations is necessary before widespread use.