Annette M. Esper

Early Identification of Patients at Risk of Acute Lung Injury: Evaluation of Lung Injury Prediction Score in a Multicenter Cohort Study

RATIONALE Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. OBJECTIVES To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). METHODS In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. MEASUREMENTS AND MAIN RESULTS Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). CONCLUSIONS ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

The role of infection and comorbidity: Factors that influence disparities in sepsis.

Objective:Large healthcare disparities exist in the incidence of sepsis based on both race and gender. We sought to determine factors that may influence the occurrence of these healthcare disparities, with respect to the source of infection, causal organisms, and chronic comorbid medical conditions. Design:Historical cohort study. Setting:U.S. acute care hospitals from 1979 to 2003. Patients:Hospitalized patients with a diagnosis of sepsis were identified from the National Hospital Discharge Survey per codes of the International Statistical Classification of Diseases, Ninth Revision (ICD-9CM). Chronic comorbid medical conditions and the source and type of infection were characterized by corresponding ICD-9CM diagnoses. Interventions:None. Measurements and Main Results:Sepsis incidence rates are mean cases per 100,000 after age adjustment to the 2000 U.S. Census. Males and nonwhite races were confirmed at increased risk for sepsis. Both proportional source distribution and incidence rates favored respiratory sources of sepsis in males (36% vs. 29%, p < .01) and genitourinary sources in females (35% vs. 27%, p < .01). Incidence rates for all common sources of sepsis were greater in nonwhite races, but proportional source distribution was approximately equal. After stratification by the source of infection, males (proportionate ratio 1.16, 95% confidence interval 1.04–1.29) and black persons (proportionate ratio 1.25, 95% confidence interval 1.18–1.32) remained more likely to have Gram-positive infections. Chronic comorbid conditions that alter immune function (chronic renal failure, diabetes mellitus, HIV, alcohol abuse) were more common in nonwhite sepsis patients, and cumulative comorbidities were associated with greater acute organ dysfunction. Compared with white sepsis patients, nonwhite sepsis patients had longer hospital length of stay (2.0 days, 95% confidence interval 1.9–2.1) and were less likely to be discharged to another medical facility (30% whites, 25% blacks, 18% other races). Case-fatality rates were not significantly different across racial and gender groups. Conclusions:Healthcare disparities exist in the incidence of sepsis within all major sources of infection, and males and blacks have greater frequency of Gram-positive infections independent of the infection source. The differential distribution of specific chronic comorbid medical conditions may contribute to these disparities. Large cohort and administrative studies are required to confirm discrete root causes of sepsis disparities.

The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study

IntroductionDiabetes mellitus (DM) is one of the most common chronic co-morbid medical conditions in the USA and is frequently present in patients with sepsis. Previous studies reported that people with DM and severe sepsis are less likely to develop acute lung injury (ALI). We sought to determine whether organ dysfunction differed between people with and without DM and sepsis.MethodsUsing the National Hospital Discharge Survey US, sepsis cases from 1979 to 2003 were integrated with DM prevalence from the Centers for Disease Control and Prevention (CDC) Diabetes Surveillance System.ResultsDuring the study period 930 million acute-care hospitalisations and 14.3 million people with DM were identified. Sepsis occurred in 12.5 million hospitalisations and DM was present in 17% of patients with sepsis. In the population, acute respiratory failure was the most common organ dysfunction (13%) followed by acute renal failure (6%). People with DM were less likely to develop acute respiratory failure (9% vs. 14%, p < 0.05) and more likely to develop acute renal failure (13% vs. 7%, p < 0.05). Of people with DM and sepsis, 27% had a respiratory source of infection compared with 34% in people with no DM (p < 0.05). Among patients with a pulmonary source of sepsis, 16% of those with DM and 23% of those with no DM developed acute respiratory failure (p < 0.05); in non-pulmonary sepsis acute respiratory failure occurred in 6% of people with DM and 10% in those with no DM (p < 0.05).ConclusionsIn sepsis, people with diabetes are less likely to develop acute respiratory failure, irrespective of source of infection. Future studies should determine the relationship of these findings to reduced risk of ALI in people with DM and causative mechanisms.

Extending international sepsis epidemiology: the impact of organ dysfunction

In the previous issue of Critical Care, Blanco and colleagues contributed to a growing body of literature on the international epidemiology of severe sepsis. Taken together, these studies confirm that the sepsis incidence is high, that the development of organ dysfunction is a major determinant of mortality and that the occurrence of organ dysfunction is influenced by chronic comorbid medical conditions. It is clear that early detection of organ dysfunction and serial sequential organ dysfunction scoring provides us with the best chance to optimize clinical care. Identifying factors that contribute to the development of organ dysfunction in sepsis will lead to the development of new treatment modalities that will reduce mortality. Future studies must therefore focus on the impact of new treatment modalities for preventing progression to multiple organ dysfunction syndrome and consequent mortality in sepsis.

Evolution of treatments for patients with acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxemic respiratory failure. ALI/ARDS patients require intensive care with prolonged mechanical ventilation. Despite advances in our understanding of the pathophysiology of ALI/ARDS, mortality rates remain > 30% and survivors suffer significant decrements in their quality of life. The evolving understanding of ALI/ARDS and the complex interactions involved in ALI/ARDS open the door for many potential targets for treatment. The condition is characterised by an acute inflammatory state that leads to increased capillary permeability and accumulation of proteinaceous pulmonary oedema. The changes that occur as a result of this inflammation clinically manifest themselves as hypoxemia, infiltrates on chest radiograph and reduced lung compliance. Many years have been dedicated to analysing the complexities involved in ALI/ARDS in order to improve current and future possibilities for treatment, with the aim of improving patient outcomes. Although some therapies have demonstrated benefits of improved oxygenation, such as surfactant and nitric oxide, these benefits have not translated into reductions in the duration of mechanical ventilation or mortality. Inflammatory mediator-targeted therapies were promising early on; however, larger trials have found therapies such as cytokine modulation, platelet-activating factor inhibition and neutrophil elastase inhibitors to be ineffective in the treatment of ALI/ARDS. Preclinical studies with β2-agonists and granulocyte macrophage colony-stimulating factor have shown promise for restoring alveolar capillary barrier integrity or reducing pulmonary oedema, and further studies are being conducted to test for true clinical benefit. Despite previous therapeutic failures, newer surfactant formulations have shown promise, particularly in patients with direct forms of lung injury, and are currently in Phase III trials. Anticoagulant therapy with activated protein C has been shown to improve survival in sepsis, the most common risk factor for the development of ALI/ARDS, and is now being studied in ALI/ARDS. Until new data emerge, the focus must remain on supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance and prevention of intervening medical complications.

Sex, Race, and the Development of Acute Lung Injury

BACKGROUND Prior studies suggest that mortality differs by sex and race in patients who develop acute lung injury (ALI). Whether differences in presentation account for these disparities remains unclear. We sought to determine whether sexual and racial differences exist in the rate of ALI development and ALI-related mortality after accounting for differences in clinical presentations. METHODS This was a multicenter, observational cohort study of 5,201 patients at risk for ALI. Multivariable logistic regression with adjustment for center-level effects was used to adjust for potential covariates. RESULTS The incidence of ALI development was 5.9%; in-hospital mortality was 5.0% for the entire cohort, and 24.4% for those patients who developed ALI. Men were more likely to develop ALI compared to women (6.9% vs 4.7%, P , .001) and had a nonsignificant increase in mortality when ALI developed (27.6% vs 18.5%, P 5 .08). However, after adjustment for baseline imbalances between sexes these differences were no longer significant. Black patients, compared to white patients, presented more frequently with pneumonia, sepsis, or shock and had higher severity of illness. Black patients were less likely to develop ALI than whites (4.5% vs. 6.5%, P 5 .014), and this association remained statistically significant after adjusting for differences in presentation (OR, 0.66; 95 % CI, 0.45-0.96). CONCLUSIONS Sex and race differences exist in the clinical presentation of patients at risk of developing ALI. After accounting for differences in presentation, there was no sex difference in ALI development and outcome. Black patients were less likely to develop ALI despite increased severity of illness on presentation.

Safety of research bronchoscopy in critically ill patients

OBJECTIVE Bronchoscopy and bronchoalveolar lavage (BAL) are common procedures in intensive care units; however, no contemporaneous safety and outcomes data have been reported, particularly for critically ill patients. DESIGN This is a retrospective analysis of prospectively collected data from teaching hospital adult intensive care units. INTERVENTIONS One hundred mechanically ventilated patients with severe sepsis, septic shock, acute lung injury (ALI), and/or acute respiratory distress syndrome underwent bronchoscopy with unilateral BAL. Data collected included demographics, presence of sepsis or ALI, Pao2 to Fio2 ratio, positive end-expiratory pressure, Acute Physiology and Chronic Health Evaluation score, Sequential Organ Failure Assessment score, and peri- or postprocedural complications. RESULTS Men comprised 51% of the patients; 81% of the patients were black, and 15% were white. The mean age was 52 (SD, ±16) years. The mean Acute Physiology and Chronic Health Evaluation score was 22 (±7.5), whereas the median Sequential Organ Failure Assessment score was 9 (interquartile range, 5-12). Ten patients (10%) had complications during or immediately after the procedure. Hypoxemia during or immediately after the BAL was the most common complication. Ninety percent of the complications were related to transient hypoxemia, whereas bradycardia and hypotension each occurred in 1 patient. Age, female sex, and higher positive end-expiratory pressure were associated with complications. CONCLUSIONS Bronchoscopy with BAL in critically ill patients with sepsis and ALI is well tolerated with low risk of complications, primarily related to manageable hypoxemia.

Characteristics and outcomes of HIV-1–infected patients with acute respiratory distress syndrome ☆ ☆☆

PURPOSE We determined the prevalence of risk factors for the development of acute respiratory distress syndrome (ARDS), outcomes of critical illness, and the impact of highly active antiretroviral therapy in HIV-1-infected patients. We hypothesized that in an urban county hospital, HIV-1-infected patients with ARDS would have a higher mortality than their HIV-1-uninfected counterparts. MATERIALS AND METHODS Subjects were enrolled between 2006 and 2012. Baseline patient demographics, comorbidities, illness severity, causes of ARDS, and clinical outcomes were obtained. The primary end point was hospital mortality. RESULTS A total of 178 subjects with ARDS were enrolled in the study; 40 (22%) were infected with HIV-1. The median CD4 count was 75 (15.3-198.3), and 25% were on highly active antiretroviral therapy. HIV-1-infected subjects were significantly younger (44 vs 52 years; P < .01) and had higher rates of asthma, chronic obstructive pulmonary disease, pneumonia, history of hospital-acquired infections, and prior sepsis. HIV-1-infected subjects had greater illness severity by Acute Physiology and Chronic Health Evaluation II scores (29 [24-31] vs 24 [22-25]; P < .01). Hospital mortality was not higher among HIV-1-infected subjects compared with HIV-1-uninfected subjects (50.0% vs 38.4%; P = .19). CONCLUSIONS In patients with ARDS, HIV-1 infection was associated with greater illness severity but was not associated with higher mortality in ARDS. Future studies need to be done to evaluate the factors that contribute to high morbidity and mortality in medically vulnerable populations who develop ARDS.

Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands (www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. Measurements and Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82‐0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0‐10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502)

Diabetes and acute respiratory distress syndrome: can we finally believe the epidemiology?

The acute respiratory distress syndrome (ARDS) is a lifethreatening disorder that occurs in critically ill patients with a variety of heterogeneous diagnoses. Although ARDS-associated mortality has declined over the years, mortality remains high at approximately 25–40%. Previous epidemiological studies identified at-risk diagnoses that are associated with an increased susceptibility for developing ARDS; however, only 20–40% of patients with these at-risk diagnoses (such as sepsis, trauma, or aspiration) progress to ARDS. Therefore, other factors may alter the progression to ARDS, such as the presence of preexisting chronic comorbid conditions. One common comorbid condition encountered in the critically ill population, diabetes mellitus, has previously been reported to influence the development of ARDS. Initially, a prospective study of critically ill patients with septic shock revealed a decreased risk of ARDS in diabetics when compared with nondiabetics (25% vs 47%, respectively, p = 0.03), a finding that persisted even after adjustment for potential confounding factors (1). Subsequently, other studies have explored the relationship between diabetes and the development of ARDS and reported very similar findings (2–7), except for one study in patients undergoing high-risk surgery that found diabetics were more likely to develop postoperative acute lung injury (8). In the most recent prospective observational study of patients with at-risk diagnoses in this issue of Critical Care Medicine, Yu et al (9) investigate further the association between diabetes and ARDS. As a result of their large sample size (n = 3,860 subjects) and rigorous methods, this study definitively confirms the inverse relationship between diabetes and ARDS and expands our knowledge by demonstrating that the protective association occurs in patients with all types of diabetes. Furthermore, this study verifies that the presence of diabetes does not impact 60-day mortality in those patients in whom ARDS develop. The mechanisms responsible for this association between diabetes and ARDS remain unclear; however, the influence of diabetic medications, hyperglycemia, and the impact of the metabolic syndrome on inflammation may intersect to alter the development of ARDS (10). The effect of acute hyperglycemia on the development of ARDS is conflicting. Although hyperglycemia exacerbates inflammation and injury, studies have not demonstrated an association between acute hyperglycemia and the development of ARDS (1). Therefore, the association between diabetes and ARDS may involve nonglycemic factors. For example, a variety of medications commonly used in patients with diabetes may contribute to the protective effects of diabetes on the development of ARDS. Prior clinical studies have reported that medications, such as aspirin and statins, are independently associated with a decreased risk of ARDS (11, 12). However, the study by Yu et al (9) reported that these medications do not account for the protective effect of diabetes on ARDS development. As Yu et al (9) acknowledged, the lack of an association of these medications may be accounted for by the low prevalence of and potential misclassification of their use. The study has multiple strengths. Yu et al (9) performed a large observational study in patients at risk for the development of ARDS that allows for examination of multiple potential confounders including the type of diabetes, acute hyperglycemia, and a variety of diabetes medications. They used established criteria to classify the different types of diabetes, and they also underwent training regarding the radiographic criteria for ARDS in order to minimize misclassification. The study also has some important limitations. Although they used predefined criteria to differentiate type 1 and type 2 diabetics, 23% of the patients with diabetes remained unclassified. In addition, blood glucose levels were only collected within the first 24 hours of ICU admission. Therefore, the impact of glucose control and glucose variability could not be examined. As hemoglobin A1C levels were not available, patients with previously undiagnosed diabetes may have been misclassified as not having diabetes. Therefore, obtaining hemoglobin A1C levels would potentially improve the identification and classification of diabetes in these critically ill patients. *See also p. 2720.