Severe sepsis, a systemic disease caused by overwhelming infection, develops in as many as 3 million adults in the United States annually and results in substantial morbidity and mortality (1). Acute respiratory distress syndrome (ARDS) is a devastating complication of severe sepsis. Severe sepsis is the most common etiology of ARDS (2, 3) and is associated with the highest case-fatality rate (3, 4).
Once ARDS develops, lung-protective ventilation is the only intervention known to improve mortality (5). Consequently, it is critical to identify patients at greatest risk of ARDS development early in their clinical course (6). The Lung Injury Prediction score (LIPS), a recently validated clinical prediction score to identify patients at risk for development of acute lung injury (ALI), has not been applied to the severe sepsis population directly (7). Furthermore, while prior studies have examined the epidemiology of ARDS in severe sepsis (2–4, 8–15), predominantly from the intensive care unit (ICU) perspective, to our knowledge, no study has focused their examination on the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED).
It is estimated that two of three patients with severe sepsis enter the health care system through the ED (16); therefore, direct study of this population is justified. The primary aim of our study was to examine the epidemiology of ARDS in patients presenting to the ED with severe sepsis. The secondary aim was to identify risk factors associated with the development of ARDS.
MATERIALS AND METHODS
Study setting and population
We conducted a retrospective, single-center, observational cohort study to examine the epidemiology of severe sepsis-associated ARDS. We began with a well-phenotyped cohort of severe sepsis patients admitted through an academic ED between January 2005 and December 2006 (17). We screened all ED visits to enroll cases of severe sepsis and septic shock in accordance with the International Sepsis Definitions Conference criteria (18). Sepsis was defined as suspected infection (administration of antibiotics in the ED) in the presence of two or more systemic inflammatory response syndrome criteria (18). Severe sepsis was defined as sepsis associated with organ dysfunction, hypoperfusion, or hypotension, and septic shock was defined as sepsis associated with refractory hypotension (18).
Serum lactate levels, drawn with the initial venous blood draw, were measured to assess for hypoperfusion (18, 19). We used a serum-based assay, catalyzed by lactate oxidase, for venous lactate level measurements (mmol/L). The severe sepsis protocol in place during the study period recommended the use of protocol-directed resuscitation in patients with hyperlactatemia (≥4 mmol/L) and/or septic shock, consistent with the trial of Rivers et al. (19). However, resuscitation for each patient enrolled in the study was at the discretion of the clinical team providing care in the ED.
We excluded subsequent visit(s), trauma patients, patients who were discharged or left against medical advice, and patients with a care-limiting, do-not-intubate order. We reviewed the medical record for the hospitalization, including antibiotic administration and the discharge summary, to ensure the validity of severe sepsis during the hospitalization. We recently validated this approach to case selection (20).
The study was approved by the institutional review board of the University of Pennsylvania with an informed consent exemption and Health Insurance Portability and Accountability Act waiver. Trained investigators abstracted clinical data from the medical record using a predrafted case report form. The data recorded from the ED included sociodemographics, comorbidities, vital signs, laboratory results, ED interventions, and admission service and location (ward or ICU) (Table 1). We calculated an ED-based Acute Physiology and Chronic Health Evaluation (APACHE) II score (21) based on baseline vital signs and laboratory values recorded in the ED. We recorded whether mechanical ventilation was initiated in the ED or during the hospitalization and recorded all arterial blood gas (ABG) measurements for intubated patients. Survival status was determined by review of the medical record and the Social Security Death Index, and clinical details at the time of death were abstracted from the medical record, including the discharge summary.
Definition of ARDS
The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days, in accord with prior studies examining disease-specific association with ARDS (22, 23). Acute respiratory distress syndrome was defined based on the Berlin definition as acute hypoxemia (ratio of partial pressure of arterial oxygen to fractional concentration of inspired oxygen (P:F) ≤300) and the presence of bilateral pulmonary infiltrates on chest radiograph not due exclusively to congestive heart failure or fluid overload (24). Acute respiratory distress syndrome was defined as mild (200 < P:F ≤ 300), moderate (100 < P:F ≤ 200), and severe (P:F ≤ 100) (24). We defined the time of onset as the time that the last of the criteria were fulfilled.
We used a valid, automated electronic system as an initial screening tool to identify ARDS cases requiring mechanical ventilation (25). In addition, an investigator blinded to the results of the electronic screening tool reviewed the case of the 169 subjects who received mechanical ventilation during their hospitalization to determine whether ARDS criteria were met. Specifically, all chest radiographs and ABG measures during the hospitalization were reviewed for each case. Interrater reliability between the automated system and the investigator was measured using the κ statistic and was found to be 0.75 (95% confidence interval [CI], 0.64–0.86), indicating a moderate degree of reliability. Adjudication, required in 16 cases, was performed by a third investigator blinded to prior ARDS determinations.
We report the rate of ARDS development in the overall cohort, as well as by location (ED, ward, or ICU admission). Furthermore, to contextualize prior studies, we report the rate of ARDS development in patients intubated in the ED and during the hospitalization.
Risk factors for ARDS development
Based on clinical plausibility and/or a relationship with the development of ARDS, we examined the following variables as factors that may be associated with ARDS development: age, sex, race, comorbid conditions (e.g., diabetes mellitus), ED therapy (e.g., time to antibiotics, blood transfusion, fluid resuscitation), cause of ALI (pulmonary vs. nonpulmonary), whether the infection was microbiologically proven, severity of illness (e.g., APACHE II, shock), and the LIPS (3–15). The LIPS incorporates predisposing conditions associated with ARDS development (e.g., shock, aspiration) and risk modifiers (e.g., alcohol abuse as risk factor, diabetes as protective factor) (7). We did not include the initiation of mechanical ventilation as a candidate risk factor, as we considered this intervention to be in the causal pathway toward ARDS development.
We a priori hypothesized that serum lactate levels, given their association with central components in the pathophysiology of ARDS (inflammation, coagulation and endothelial dysfunction, and neutrophil activation), would be associated with ARDS development (17, 26–29). We categorized serum lactate levels as low (<2 mmol/L), intermediate (2–3.9 mmol/L), and high (≥4 mmol/L) (25, 34, 35).
We used the Student t test or Wilcoxon rank sum test to compare continuous variables and the χ2 statistic or Fisher exact test to compare categorical variables between ARDS cases and noncases. We used multivariable logistic regression to identify patient-level factors associated independently with ARDS after adjustment for potential covariates. We used variance inflation factors to assess for multicollinearity. Variables found to be collinear with APACHE II that are constituent variables of the APACHE II score were not included separately (e.g., heart rate, respiratory rate, oxygenation). Emergency department shock state and use of vasoactive agents were found to be collinear; the latter was not included separately. We added potential covariates associated with the development of ARDS at a significance of less than 0.20 one at a time to the base model, which included candidate risk factors associated with the development of ALI at a significance of less than 0.20. We maintained the potential confounder in the model if its inclusion altered the point estimate for the odds ratio of a risk factor by greater than 10% (30). As several important variables (e.g., shock) are incorporated in the LIPS calculation, we first created a model without its inclusion. We then included the LIPS to determine whether the identified factors were associated with ARDS development independent of the LIPS. In sensitivity analyses, given the potential for overfitting the model, we removed those variables that were not significantly associated with ARDS development.
In secondary analyses, we calculated the area under the receiver operating characteristic curve (AUC) to assess for model discrimination in the ability of the LIPS and serum lactate levels to predict ARDS development and the Hosmer-Lemeshow test statistic to assess for model calibration. We compared the predictive ability of LIPS, the baseline APACHE II score, and initial serum lactate levels. We excluded ED ARDS patients in these analyses to examine the ability to predict the development of ARDS. Finally, we used a fractional polynomial regression to depict the fitted relationship between the development of ARDS and initial serum lactate levels as a continuous variable (31). We used Stata 10.0 software for statistical analyses (Stata Datacorp, College Station, Tx).
We studied 778 adults who were admitted through the ED with severe sepsis (Fig. 1). In the ED, sepsis was associated with acute organ dysfunction in 544 (69.9%) of 778 patients, hypoperfusion (≥2 mmol/L) in 588 (75.6%) of 778, and hypotension (systolic blood pressure <90 mmHg or use of vasoactive agents) in 360 (46.3%) of 778 patients, to qualify as severe sepsis. The majority of patients (n = 413, 53.1%) were admitted to an ICU. The most common sources of infection in the cohort were respiratory (26.7%), urologic (20.7%), gastrointestinal (15.4%), bacteremia (14.1%), and soft tissue–related infections (9.1%). Microbiologically proven infection was identified in 58.1% (n = 452) of the cohort. The 28-day all-cause mortality for the cohort was 20.0% (156/778).
Incidence of ARDS
The incidence of ARDS was 6.2% (95% CI, 4.6%–8.1%) in the entire cohort (48/778 patients). Acute respiratory distress syndrome developed a median of 1 day after admission (interquartile range [IQR], 1–2 days). At the time of ARDS development, the median P:F was 136 (IQR, 114–220). Based on the initial measures available at the time of ARDS development, 14 patients began with mild ARDS (29.2%), 24 with moderate ARDS (50.0%), and 10 with severe ARDS (20.8%).
Across the continuum of care, seven of 778 patients fulfilled criteria for ARDS in the ED (0.9%; 95% CI, 0.3%–1.8%), five of 364 patients admitted to a general medical or surgical ward developed ARDS requiring mechanical ventilation subsequently (1.4%; 95% CI, 0.5%–3.2%), and 36 of 407 patients admitted to an ICU developed ARDS requiring mechanical ventilation subsequently (8.9%; 95% CI, 6.3%–12.0%). The ICU admissions were significantly more likely to develop incident ARDS (P < 0.001).
Of the 82 patients in whom ventilator support was initiated in the ED, seven fulfilled ARDS criteria in the ED (8.5%; 95% CI, 3.5%–16.8%), and ultimately, 25 fulfilled criteria during the hospitalization (30.5%; 95% CI, 20.8%–41.6%). In the 18 subjects who were intubated in the ED but did not fulfill ARDS criteria until later in the hospitalization, 11 did not fulfill the radiographic criteria for ALI, five had a P:F of greater than 300, and two did not have an ABG in the ED and therefore may have fulfilled criteria for ARDS if additional data had been available. The incidence of ARDS was 26.4% (95% CI, 17.6%–37.0%) in 87 patients who required ventilator support post-ED.
In-hospital, 28-day, and 60-day all-cause mortality rates were significantly greater in those who developed ARDS (P < 0.001; Table 1). Acute respiratory distress syndrome–related in-hospital deaths occurred, on average, early (median, 4 days after hospitalization; IQR, 1–8 days). Multisystem organ failure was present before death in each of the 29 in-hospital, ARDS-related deaths, resulting in 13 cases of in-hospital cardiac arrest.
Association between clinical and physiologic variables and ALI
In univariate analyses, higher initial serum lactate levels, higher severity of illness (e.g., APACHE II scores, shock, organ dysfunction), greater intensity of care in the ED (e.g., use of vasoactive agents, initiation of mechanical ventilation and transfusion), pulmonary cause of sepsis, culture-positive severe sepsis, no medical history of diabetes mellitus, and higher LIPS were associated with the development of ARDS (Table 1) (Fig. 2). The ARDS incidence within each lactate stratum was as follows: three of 190 (1.6%; 95% CI, 0.3–4.5) in the low stratum, 17 of 353 (4.8%; 95% CI, 2.8–7.6) in the intermediate stratum, and 28 of 233 (12.0%; 95% CI, 8.1–16.9) in the high stratum (Fig. 3).
Independent risk factors associated with increased risk of ARDS development included pulmonary source of sepsis (P < 0.001), microbiologically proven infection (P = 0.01), and higher severity of illness, as measured by the baseline APACHE II score (P = 0.02) and serum lactate levels (Table 2). Specifically, we found that intermediate (P = 0.04) and high serum lactate levels (P = 0.003), when compared with low serum lactate levels, were significantly associated with ARDS development. The presence of diabetes was confirmed to be a protective factor for ARDS development (P = 0.01). In the model that included the LIPS, the LIPS, intermediate and high serum lactate levels, and microbiologically proven infection were found to be associated independently with ARDS development (Table 3). Finally, when the nonsignificant variables were removed, given the potential for overfitting the model, these three identified factors remained significantly associated with ALI development.
We found that the LIPS model discriminated those who did and did not develop ARDS with an AUC of 0.76 (95% CI, 0.69–0.84) and was well calibrated (P = 0.72). The LIPS model predicted ARDS development with greater accuracy than ED APACHE II (AUC, 0.63; 95% CI, 0.54–0.72; P = 0.01). In addition, serum lactate, which demonstrated good discrimination (AUC, 0.73; 95% CI, 0.65–0.81) and was well calibrated (P = 0.27), also predicted ALI development with greater accuracy than APACHE II (P = 0.04). In Figure 3, we present the fitted relationship between initial serum lactate levels and ALI development.
To enhance our understanding of the epidemiology of sepsis-associated ARDS and our ability to risk-stratify at-risk patients, we examined a cohort of severe sepsis patients from the earliest presentation to the health care system, the ED. We found that the rate of sepsis-associated ARDS development varied across the continuum of care. We found that, when ARDS developed, it developed rapidly, was associated with significant mortality, and progressed rapidly to multisystem organ failure in those in whom it was fatal. We identified factors that can be used to risk-stratify patients with severe sepsis at high risk for development of ARDS, including factors present at hospital presentation (i.e., serum lactate levels and a validated clinical prediction score).
The morbidity and mortality associated with ARDS are significant, resulting in high case-fatality rates and demonstrable impairment in neuropsychological and physical function in many survivors (32, 33). Because interventions to improve outcomes are extremely limited once ARDS develops (5), intense focus is being shifted toward prevention and treatment before its development (6).
By focusing our examination on a cohort of severe sepsis patients, beginning at hospital presentation, our study reinforces and enhances our understanding of the epidemiology of sepsis-associated ARDS. We found that progression to ARDS was rapid and conferred a significantly increased risk of in-hospital death. Our findings regarding incidence (7, 14), time to ARDS (7, 13–15), and sepsis-associated ARDS mortality (11–13) are consistent with prior studies. Two recent studies, which investigated heterogeneous groups of patients at risk for development of ALI, each found that 7% of the sepsis patient subgroup developed ARDS (7, 14). Our study, therefore, validates the fact that the vast majority of patients admittedwith severe sepsis will not develop ARDS. Because in-hospital death was 4-fold higher in patients who developed ARDS, these findings also emphasize the need to identify those at greatest risk of ARDS development and to elucidate strategies to prevent ARDS beyond preventive ventilatory approaches (34, 35). Although death occurred relatively early in the hospitalization, culminating in multisystem organ failure complicated by refractory shock, further investigation is required to determine if care delivery in the ED or initial hospital course could be optimized to improve outcomes.
We found that the rate of development differs across time and location. In the ED, approximately 1% of patients presenting with severe sepsis fulfill criteria for ARDS. Consistent with a prior study that examined the prevalence of ARDS in a heterogeneous group of critically ill adults receiving mechanical ventilation in the ED (36), ARDS existed in 8.5% of severe sepsis patients receiving mechanical ventilation in the ED. While our study confirmed that approximately 50% of severe sepsis patients are cared for on the general ward (37, 38), we found that the burden of ARDS development was confined to patients admitted directly to the ICU. These observations contextualize the findings from prior studies (2–15), which detailed the incidence and outcomes of sepsis-associated ARDS from the perspective of the ICU.
We found that the LIPS, initial serum lactate levels, and the presence of a microbiologically proven infection were independently associated with ARDS development. As such, our study confirms the ability of the LIPS to predict ARDS development in severe sepsis patients and identifies serum lactate at initial presentation as a novel, simple risk-stratification tool to predict ARDS development. In contrast to microbiologic data, which requires time for processing and growth, often yielding a culture diagnosis after ARDS has developed, LIPS and lactate are available at hospital admission.
Recently, Agrawal and colleagues (39) found that inflammatory (interleukin 8) and endothelial (angiopoietin 2) biomarkers predict the development of ARDS independent of sepsis and illness severity in critically ill patients. In contrast to interleukin 8 and angiopoietin 2, serum lactate levels are routinely measured as part of protocolized sepsis care. As such, serum lactate levels appear to be a useful, clinically available tool to predict ARDS development in addition to their better characterized ability to identify patients at risk of death (17, 26), irrespective of hemodynamic status (17, 40).
Our study, which focused on risk factors present in the mostproximal phase of the hospitalization, confirms the notion that severity of illness and a pulmonary source of infection are risk factors for the development of ARDS (3, 10, 14, 41, 42), whereas diabetes is protective (19). As constituent variables of the LIPS, these risk factors are incorporated in the clinical risk prediction score to identify patients at high risk ofARDS development. Importantly, the presence of shock inthe ED was not independently associated with ARDS development. Prior ICU-based studies report an incidence of ARDS development in septic shock patients of approximately 40% (11, 12, 15). In contrast, we found that 12% of patients fulfilling hemodynamic criteria for septic shock in the ED developed ARDS. Collectively, these findings suggest that theprognostic utility of shock is muted when present in the ED, as compared with shock, which persists or develops in theICU.
Our study has several potential limitations. First, ARDS misclassification is a potential limitation based on our retrospective study design and our reliance on available radiographs and blood gas measurements. To minimize this potential bias, we based our determination of ARDS on established criteria (24), used a valid, electronic screening tool (25), and verified the accuracy of our determination through a separate case review by an independent physician investigator. Second, our decision to limit our cases to ARDS requiring mechanical ventilation to identify those most at risk of subsequent death may have resulted in misclassification as some nonventilated patients may have met criteria for ARDS; however, this nondifferential misclassification would bias our results toward the null. Third, we acknowledge the potential for ascertainment bias. Despite the use of an established protocol to measure serum lactate in patients with suspected infection, we acknowledge that a potential delay exists between sepsis recognition and the serum lactate measurement. Fourth, although limited to two cases, it is possible that these patients would have fulfilled criteria in the ED for ARDS if a blood gas had been obtained. Fifth, we focused our observational study design on clinical details present on ED arrival. As a result, we are unable to comment on the trajectory of other longitudinal organ failure measures (e.g., Sequential Organ Failure Assessment scores) during the hospitalization, the potential impact of ED length of stay on care delivery and outcomes, or the impact of initial ventilator settings, as these data were not available. Furthermore, whether different initial resuscitation strategies or late fluid-management strategies would have altered the rate of ARDS development and ARDS-related outcomes remains unclear and requires further investigation (43). Finally, as a single-center study, our findings warrant external validation.
We found that the rate of ARDS development in a cohort of patients admitted with severe sepsis was low overall, yet differed significantly across time and location. When ARDS developed, it developed rapidly and was associated with a high case-fatality rate. Finally, we found that initial serum lactate measurements and a validated clinical prediction score (LIPS) at hospital presentation can be used to risk-stratify patients with severe sepsis at high risk of ARDS development.
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