Risk factors for mortality despite early protocolized resuscitation for severe sepsis and septic shock in the emergency department

    Risk Factors for Mortality despite Early Protocolized Resuscitation for Severe Sepsis and Septic Shock in the Emergency Department Byron C. Drumheller MD, Anish Agarwal MD, Mark E. Mikkelsen MD, MSCE, S. Cham Sante MD, Anita L. Weber PhD, Munish Goyal MD, David F. Gaieski MD PII: DOI: Reference:

S0883-9441(15)00545-6 doi: 10.1016/j.jcrc.2015.10.015 YJCRC 51987

To appear in:

Journal of Critical Care

Please cite this article as: Drumheller Byron C., Agarwal Anish, Mikkelsen Mark E., Sante S. Cham, Weber Anita L., Goyal Munish, Gaieski David F., Risk Factors for Mortality despite Early Protocolized Resuscitation for Severe Sepsis and Septic Shock in the Emergency Department, Journal of Critical Care (2015), doi: 10.1016/j.jcrc.2015.10.015

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ACCEPTED MANUSCRIPT Risk Factors for Mortality despite Early Protocolized Resuscitation for Severe Sepsis and Septic

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Shock in the Emergency Department

Byron C. Drumheller, MDa, Anish Agarwal, MDa, Mark E. Mikkelsen, MD, MSCEb,c, S Cham

Department of Emergency Medicine, Perelman School of Medicine at the University of

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Sante, MDa, Anita L. Weber, PhDc, Munish Goyal, MDd, David F. Gaieski, MDe

Pennsylvania, 3400 Spruce Street, Philadelphia PA, 19104 Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Perelman School

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of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia PA, 19104 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the

Department of Emergency Medicine, Washington Hospital Center, Georgetown University

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University of Pennsylvania, 3400 Spruce Street, Philadelphia PA, 19104

School of Medicine, 110 Irving Street NW, Washington DC, 20010 e

Department of Emergency Medicine, Sidney Kimmel Medical College at Thomas Jefferson

University, 111 S. 11th Street, Philadelphia PA, 19107

Byron C. Drumheller, MDa – [email protected] (corresponding author) Anish Agarwal, MDa – [email protected] Mark E. Mikkelsen, MD, MSCEb,c – [email protected] S Cham Sante, MDa – [email protected]

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ACCEPTED MANUSCRIPT Anita L. Weber, PhDc – [email protected] Munish Goyal, MDd – [email protected]

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David F. Gaieski, MDe – [email protected]

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Manuscript Word Count: 3,584

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Running Title: Risk Factors for Severe Sepsis Mortality

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Funding: None

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Disclosures: None of the authors possess any financial, intellectual or other conflicts of interest.

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ACCEPTED MANUSCRIPT Abstract

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Purpose: Identify risk factors associated with in-hospital mortality among emergency

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department (ED) patients with severe sepsis and septic shock managed with early protocolized resuscitation.

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Methods: Retrospective, observational cohort study in an academic, tertiary-care ED. We

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enrolled 411 adult patients with severe sepsis and lactate ≥ 4.0 mmol/L (n=203) or septic shock (n=208) who received protocolized resuscitation from 2005 – 2009. ED variables, microbial

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cultures, and in-hospital outcomes were obtained from the medical record. Multivariable regression was used to identify factors independently associated with in-hospital mortality.

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Results: Mean age was 59.5 ± 16.3 years, 57% were male. Mean lactate was 4.8 mmol/L (3.5-

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6.7), 54% had positive cultures, and 27% received vasopressors in the ED. One hundred and five (26%) patients died in-hospital. Age, active cancer, do not resuscitate status on ED arrival, lack

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of fever, hypoglycemia, and intubation, were independently associated with increased in-hospital

death.

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mortality. Lactate clearance and diabetes were associated with a decreased risk of in-hospital

Conclusions: We identified a number of factors that were associated with in-hospital mortality among ED patients with severe sepsis or septic shock despite treatment with early protocolized resuscitation. These findings provide insights into aspects of early sepsis care that can be targets for future intervention.

Keywords: sepsis, septic shock, emergency services, mortality, risk factors, early goal-directed therapy

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ACCEPTED MANUSCRIPT 1. Introduction Despite the extensive progress made during the past decade and a half in the early

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resuscitation of patients with severe sepsis and septic shock, in-hospital mortality for such

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patients presenting to the emergency department (ED) remains at or above 20%, compared to

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10% for ST-segment elevation myocardial infarction and 15% for hemorrhagic shock from major trauma [1-4]. Emphasis on improved detection, early antimicrobial administration, and

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aggressive hemodynamic optimization has undoubtedly led to improved outcomes in severe sepsis and septic shock over time [5]. What now remains to be answered is why one in five of

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these patients still dies before leaving the hospital?

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While a number of recent studies have identified individual factors associated with mortality in ED patients with severe sepsis or septic shock [6-11], there is a paucity of research

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evaluating which of these factors are independently predictive of mortality when examined

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together. In particular, no prior studies have assessed a comprehensive set of variables within a population of critically ill ED patients with severe sepsis or septic shock treated with early

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protocolized resuscitation [12, 13]. Furthermore, existing ED-based sepsis prognostic scores that incorporate a large number of variables such as the Mortality in Emergency Department Sepsis (MEDS) [14] and predisposition, infection, response, and organ failure (PIRO) [15] were derived from primarily low acuity populations and are significantly less accurate in patients with severe sepsis or septic shock [16, 17]. Identifying which factors are associated with poor outcome can help guide future early interventions targeted to further reduce mortality in this at-risk population. Our objective was to identify independent risk factors for in-hospital mortality among ED patients with severe sepsis or septic shock that all received early protocolized resuscitation. 4

ACCEPTED MANUSCRIPT 2. Materials and Methods 2.1. Study Design and Population

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This was a retrospective, single-center observational cohort study of patients admitted

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through the ED with severe sepsis and septic shock at the Hospital of the University of

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Pennsylvania (HUP) from January 1, 2005 to December 31, 2009. The study was approved by the Institutional Review Board of the University of Pennsylvania with an exemption from

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informed consent.

HUP is an approximately 800-bed urban, academic tertiary care center with a 40-bed ED

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that treats approximately 65-70,000 patients per year. In 2004, the ED began aggressively screening for severe sepsis or septic shock patients eligible for early protocolized resuscitation

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and instituted a comprehensive treatment algorithm based on the study by Rivers et al. [1].

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Patients were eligible for protocolized resuscitation if they presented to the ED with

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severe sepsis and serum lactate ≥ 4.0 mmol/L or septic shock. Severe sepsis was defined as a suspected source of infection, presence of 2 or more systemic inflammatory response syndrome

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(SIRS) criteria, and evidence of acute organ dysfunction [18, 19]. Septic shock was defined as arterial hypotension (systolic blood pressure < 90 mmHg) despite adequate fluid resuscitation (>1500 ml) or use of vasopressors [1]. While these criteria were recommended for inclusion in the treatment algorithm, physicians could perform protocolized resuscitation on patients they felt had evidence of severe infection coupled with organ dysfunction or shock but did not precisely conform to these definitions (i.e. less than 2 SIRS criteria, organ dysfunction or hypotension not strictly meeting published criteria). Trained research assistants retrospectively reviewed ED visit logs and medical records to identify all patients that received early protocolized resuscitation for severe sepsis or septic

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ACCEPTED MANUSCRIPT shock. We included all patients for whom data from at least two of the three treatment goals (central venous pressure [CVP], mean arterial pressure [MAP], and central venous oxygen

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saturation [ScvO2]) was recorded in the chart. Patients were excluded if they presented with

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concomitant trauma, pregnancy, acute myocardial infarction requiring immediate revascularization, exsanguination as the primary cause for shock, left against medical advice,

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were transferred to another institution, or had previously been enrolled in the study.

2.2. Data Collection

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The following items were recorded from the ED electronic medical record: sociodemographics, comorbidities, triage and worst vital signs, initial laboratory values,

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source(s) of infection, treatments (intravenous fluids, antimicrobial agents, vasopressors, etc.),

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values of CVP, MAP, and ScvO2 after initiation of protocolized resuscitation (initial, lowest, highest, and goal value achieved), and disposition. Data on microbial cultures, length-of-stay,

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and mortality was abstracted from the hospital electronic medical record. Information was

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recorded on a standardized data collection form that was designed with explicit definitions of study variables whenever possible. Five trained investigators who were not blinded to the study hypothesis (B.C.D., A.A., M.E.M., S.C.S, and D.F.G.) conducted the data abstraction, with any conflicts being resolved by an ad hoc committee of at least 2 of the 5 researchers. No formal inter-rater reliability was performed, however data abstraction was verified for accuracy and completeness by a second investigator for approximately 30% of all chart reviews.

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ACCEPTED MANUSCRIPT 2.3. Definitions The primary outcome was in-hospital mortality. SIRS criteria were defined according to

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Bone et al. [18]. Individual organ dysfunctions were defined according to international criteria,

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with adjustments made based on availability of data in the ED (Supplemental Content, Appendix 1) [19]. Sequential Organ Failure Assessment (SOFA) scores were calculated from the worst

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values of included variables obtained during the ED stay, with substitution of the S/F ratio (ratio

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of pulse oximetry saturation percentage to fraction of inspired oxygen) for PaO2/FiO2 ratio in the pulmonary component as described by Pandharipande et al. with one adjustment (Supplemental

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Content, Appendix 2) [20].

Microbial culture results were defined according to recommendations by the Centers for

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Disease Control [21, 22]. Receipt of appropriate antibiotics was defined only amongst those

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patients with positive culture results as administration in the ED of one or more antimicrobial agents to which all available infective pathogens were sensitive according to in vitro testing.

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Time to antibiotic administration was measured in all patients as the time from triage to the

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initial administration of the first antimicrobial agent, with a maximum of 24 hours. For patients with data on appropriateness of antibiotic use, those that received inappropriate antibiotics in the ED were given the maximum time value. Values of CVP, MAP, and ScvO2 were obtained from the medical record after initiation of protocolized resuscitation, defined by the time of vasopressor administration or the first measurement of either CVP or ScvO2. There was no pre-specified location in the medical record in which nursing or physician staff documented these values during the study period, thus each subject had a varying amount of available data. Low or high values of MAP represent those obtained only after initiation of protocolized resuscitation. The goal value for all three

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ACCEPTED MANUSCRIPT measurements represents the first value obtained within the desired range (CVP > 8 mmHg/> 12 if intubated, MAP > 65 mmHg, ScvO2 between 70 – 89% inclusive). If values obtained later

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during the ED course changed to be outside the desired range, the previous goal value was

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removed. If no later values obtained were within the desired range, the goal was considered not to be achieved. However, if any subsequent values obtained were within range, this value was

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then considered the goal value. This process was continued until the patient left the ED.

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Lactate clearance was defined as the percentage change from the initial venous lactate level to the next available lactate level obtained in the ED, even if more than one subsequent

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value was obtained. Repeated measurement of serum lactate was strongly encouraged in the treatment protocol. The timing of repeated measurement was not standardized, thus lactate

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clearance values represent changes over varying time periods. Protocolized resuscitation

2.4. Statistical Analysis

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continued throughout the ED stay until patients’ eventual disposition.

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For descriptive analysis, continuous data are expressed as mean +/- standard deviation if

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normally distributed otherwise as median (interquartile range). Categorical variables are presented as counts and percentages. Student’s t-test for normally-distributed and Wilcoxon’s rank-sum test otherwise were used to compare continuous variables. Chi-squared test or Fischer’s exact method was used for categorical data. Multivariable logistic regression was performed to identify variables independently associated with in-hospital mortality. A stepwise, backward selection method was employed. Variables significant at p < 0.2 in univariable comparisons were entered into the model. To avoid including the same information in the model multiple times, a single variable was selected when one or more variables were based on identical data. Dichotomous measurements of organ failure

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ACCEPTED MANUSCRIPT based on established cutoffs were prioritized over individual laboratory values if both were eligible for the model. Total SOFA score was included in the model, whereas individual organ-

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specific SOFA scores were not. Formal assessment for multicollinearity was performed using

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variance inflation factor (VIF) analysis prior to model creation. No variables, specifically including total SOFA score and individual measures of organ dysfunction used for its

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calculation, showed a VIF statistic > 10, which is indicative of collinearity.

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A list of the individual variables entered into the logistic regression model is provided (Supplemental Content, Appendix 3). Factors significant at p < 0.05 were retained in the final

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model. No variables were forced into the model. For data elements with > 5% missing values and for all missing values of CVP, MAP or ScvO2 goal achievement or lactate clearance, dummy

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variable imputation was performed [23]. For data elements with small numbers of observations,

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exact logistic regression was used. The Hosmer and Lemeshow goodness-of-fit test was used to assess the appropriateness of the model. STATA v. 12.1 software (Stata Datacorp, College

3. Results

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Station, TX) was used for all statistical analyses.

We enrolled 411 patients in the study, 203 (49%) with severe sepsis and lactate ≥ 4.0 mmol/L and 208 (51%) with septic shock. Three hundred six (74%) patients survived to hospital discharge while 105 (26%) patients suffered in-hospital mortality. Hospital length of stay among survivors was a median of 9 days (IQR 5 – 18). Time to death among non-survivors was a median of 4 days (IQR 2 – 10). Mean SOFA score for the entire population was 6.3 +/- 3.1. Sociodemographic, laboratory, and clinical characteristics of the study population are displayed in Table 1. Patients who died tended to be older, had a greater prevalence of several 9

ACCEPTED MANUSCRIPT comorbid conditions including active cancer, cirrhosis, and prior do-not-resuscitate (DNR) orders but a lower prevalence of diabetes, were less likely to be febrile, and had a greater

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prevalence of hypoglycemia and azotemia. Deceased patients also exhibited a greater frequency

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and extent of organ dysfunction particularly neurologic, pulmonary, and coagulation.

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Table 2 displays infectious and microbiological data. Among the entire cohort, respiratory (30%) and genitourinary (26%) infections were the most common sources, 78% of

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infections were community-acquired, and 54% of patients exhibited positive cultures. Positive

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ascites culture was associated with in-hospital mortality.

Table 3 shows information on ED resuscitation and treatment. Seventy-nine percent of

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patients received appropriate antibiotics according to culture results, 19% were intubated in the ED and 27% received vasopressor agents. The vast majority of patients had available data for

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CVP (94%), MAP (97%), and ScvO2 (83%) goal values and lactate clearance (93%). Patients

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who died received less intravenous fluids within the first 6 hours, were more likely to be intubated, had higher initial CVP and lactate measurements, and achieved a decreased lactate

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clearance as compared to survivors. Table 4 displays the results of the multivariable regression analysis. All of the factors that were significant in univariable comparisons at p < 0.2 and included in the regression analysis are listed. A total of 378 of 411 patients had complete data for all of these variables and were included in the model. Age, active cancer, diabetes, DNR status on ED arrival, temperature never > 100.4°F, glucose < 60 mg/dL, intubation, and lactate clearance were independently associated with in-hospital mortality. The Hosmer and Lemeshow goodness-of-fit test p-value for the model was 0.82.

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ACCEPTED MANUSCRIPT

4. Discussion

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Even with early, aggressive protocolized resuscitation, severe sepsis and septic shock

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remain two of the deadliest conditions encountered in the ED. We identified a number of factors

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with specific themes that were independently associated with in-hospital mortality among a population of such patients all treated with early protocolized resuscitation, which provides

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insight into aspects of early sepsis care that can be targets for future intervention. Intuitively, increasing age and prior DNR status were associated with mortality as shown

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in several prior studies [24-26]. While age is inalterable, clinicians can specifically clarify the intent of any DNR orders to ensure that the patient’s values and preferences are incorporated into

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consistent, patient-centered clinical decision-making [27]. We also found that a history of active

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malignancy was independently associated with mortality. While this is also acutely

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unchangeable, it highlights a population of severe sepsis or septic shock patients where specific interventions may be able to improve currently poor outcomes [28-30]. More systematic

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incorporation of cancer-specific resuscitation strategies into early clinical management and further research on targeted interventions in this susceptible and frequently encountered population are warranted. While sepsis patients frequently exhibit hyperthermia and hyperglycemia as a result of circulating inflammatory mediators and stress hormones, our results showed that hypoglycemia and a lack of fever in the ED were associated with poor outcome among severely ill sepsis patients. Previous studies in the intensive care unit (ICU) have documented similar findings, but this has not been described in an ED population [31, 32]. Both of these findings may be indicative of more profound sepsis-induced metabolic failure or may be more common among

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ACCEPTED MANUSCRIPT elderly or seriously debilitated patients who are also more likely to die [33]. Additionally, clinicians may not recognize these abnormalities in the ED as signs of sepsis severity and may

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not respond appropriately with an increase in resuscitation intensity. Whether early interventions

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to control body temperature and restore euglycemia would improve outcomes, as opposed to these factors simply representing surrogates for under-recognized illness severity, remains

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unclear.

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Our results showed that respiratory failure with the need for ED intubation was associated with mortality while cardiovascular failure or severity of shock was not. Unlike the

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large volume of research focused on optimization of cardiovascular function in early severe sepsis and septic shock, little research has evaluated the significance or treatment of respiratory

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failure in ED sepsis [34]. A variety of mechanisms likely contribute to early respiratory failure

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and need for mechanical ventilation in sepsis; hypoxemia induced by direct pulmonary infection or inflammatory-mediated acute lung injury, profound increases in ventilatory requirement

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associated with tissue hypoperfusion, lactic acidosis, and increased metabolic demands, or

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sepsis-associated encephalopathy and systemic hypotension leading to diminished level of consciousness. While restoration of intravascular volume status and optimization of tissue perfusion via early protocolized resuscitation can counteract some of these effects, the fact that respiratory failure remained associated with mortality in our population that received aggressive cardiovascular optimization suggests that further attempts to optimize pulmonary function could lead to improved outcomes [35-37]. Of all the endpoints of early sepsis resuscitation, achievement of lactate clearance has shown the most consistent association with improved outcomes in the literature, which was replicated in our results [7, 38, 39]. While Nguyen et al. initially reported a cutoff of 10%

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ACCEPTED MANUSCRIPT clearance in the first 6 hours of protocolized treatment of severe sepsis and septic shock patients in the ED, further studies have shown that larger decreases in lactate level or even lactate

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normalization with early aggressive resuscitation are associated with improved outcomes [39,

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40]. Our results support this hypothesis, with survivors exhibiting a median lactate clearance of 51% while non-survivors achieved 24% (Table 3). These findings also highlight a population of

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patients with a sub-optimal response to initial hemodynamic optimization that might benefit from

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additional resuscitative interventions, an approach that has recently been investigated in the ED [41].

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Our finding that a history of diabetes was independently associated with a decreased risk of in-hospital death among patients with severe sepsis or septic shock is the first time this has

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been reported in the literature. While there is consistent preclinical data linking diabetes to

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impaired innate and humoral immune functions as well as increased susceptibility to certain infections, large-scale epidemiological studies including patients with pneumonia, sepsis, or

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infection-related diagnoses have shown contradictory results in regards to mortality [42-45].

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Clinical studies specifically examining critically ill patients with severe sepsis or septic shock have found no association between diabetes and increased mortality when controlling for other factors [46-48]. Interestingly, these and other reports have documented differing patterns of organ dysfunction among patients with diabetes, with an increased risk of renal failure but a decreased frequency of acute respiratory distress syndrome [49]. Further research is needed to replicate our findings and investigate potential causative mechanisms. Several factors previously associated with mortality in ED patients with severe sepsis or septic shock were not significant in our results. Time to antibiotic administration has previously been linked with mortality in ED severe sepsis [10]. Our results showed a trend toward a shorter

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ACCEPTED MANUSCRIPT time to antibiotics among survivors, however the effect did not remain significant in multivariable analysis, possibly because antibiotic administration occurred very rapidly in the

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entire study population. Additionally, we analyzed time to antibiotics as a continuous variable,

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whereas prior studies found a significant association with mortality only at individual very early (<1 hour) cutoffs [10]. Our results also did not find an association between appropriateness of

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ED antibiotics and mortality. Prior research has shown that use of inappropriate antimicrobial

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agents in ED patients with bacteremia was associated with increased in-hospital mortality [11]. These results, as well as others derived from ICU sepsis cohorts, are limited however by a large

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proportion of narrow spectrum antibiotic use and a lack of simultaneous aggressive hemodynamic resuscitation [50]. Finally, we hypothesized that an aggregate measure of organ

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dysfunction such as SOFA score would be independently associated with mortality as indicated

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by previous studies, which was not confirmed by our findings [9]. Non-survivors had significantly higher SOFA scores in univariate comparison, but this again was not maintained

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after multivariable analysis. Further research should investigate the significance of early multi-

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organ dysfunction as this remains the eventual leading cause of death among patients admitted to the ICU with severe sepsis and septic shock [51]. Two previous studies of ED patients with severe sepsis or septic shock have investigated the relative significance of multiple risk factors on in-hospital or 28-day mortality [12, 25]. Giannazzo et al. examined a range of variables identified by searching the literature in a population of 90 patients with a 28-day mortality of 51%, of whom only 6% were admitted to the ICU, and found that age > 80, insulin use, acute renal failure, and lactate > 5 mmol/L were associated with mortality [12]. Sivayoham et al. analyzed a large dataset of variables among 641 ED sepsis patients admitted to the ICU and found that age, serum albumin, and INR were the

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ACCEPTED MANUSCRIPT factors independently associated with in-hospital mortality in multivariable regression [25]. Their findings were limited, however, by a large amount of missing data and lack of detail on

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who received early goal-directed therapy (EGDT) and to what extent it was implemented.

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Compared to these reports, our study includes a comprehensive dataset of a larger population of more severely ill patients that were all treated with early protocolized resuscitation.

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Our findings have several important limitations. This was a single-center study from a

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tertiary care hospital with a high frequency of patients with cancer, cirrhosis, or organ transplantation. Additionally, our ED had a well-established, protocolized, aggressive approach

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to early sepsis resuscitation. Hence, our results may not be generalizable to dissimilar patient populations that receive less intensive treatment. We also found that slightly fewer patients

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receiving protocolized resuscitation were enrolled in the later years of the study and that patients

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in later study years tended to be sicker (higher mean SOFA scores) than patients included from earlier in the study period. This is likely reflective of a selection bias that occurred over time

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within our ED as physicians became more facile with early, aggressive treatment of sepsis

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patients. Our resuscitation protocol was also based on the traditional EGDT approach, which was recently shown not to decrease mortality versus standard care in three prominent trials [1, 2, 52, 53]. We did not find an association between values of CVP or ScvO2 and mortality, the major aspects of the Rivers protocol questioned by these studies, suggesting that the factors we identified should still be applicable to future populations treated without these specific targets. There are several additional limitations related to our study design. Given the retrospective data collection process, we could have missed data on certain variables that may be associated with mortality, such as nursing home status or prior antibiotic exposure [14, 54]. Additionally, our CVP, MAP, and ScvO2 data relied on retrospective collection of values

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ACCEPTED MANUSCRIPT recorded in the medical record, which was likely not as accurate as if the values were collected prospectively given that documentation may be hindered during care of resource intensive

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critically ill patients in the ED. The inclusion of a large number of candidate variables compared

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to the size of our study population and the number of outcome events may have diminished the accuracy and precision of the multivariable regression results. Ideally, our study would have

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been conducted on a larger sample size. Finally and most importantly, association with mortality

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does not directly imply causation. The results identified here should serve as hypotheses for future interventional studies aimed at decreasing mortality from severe sepsis and septic shock in

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the ED.

In conclusion, we identified a number of factors associated with in-hospital mortality

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among patients with severe sepsis or septic shock despite receipt of early protocolized

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resuscitation in the ED. Further research is needed to prospectively validate these findings and

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then identify and test novel treatment strategies targeted at these markers of disease severity.

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ACCEPTED MANUSCRIPT Appendix 1. Organ dysfunction definitions Neurologic – Glasgow coma scale < 15 or documentation of altered level of consciousness

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compared to baseline in the ED chart

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Cardiovascular – lowest systolic blood pressure < 90 mmHg or lowest mean arterial pressure < 70 mmHg

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Pulmonary – ratio of pulse oximetry saturation (expressed as percentage) to fraction of inspired

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oxygen (S/F ratio) < 452 (corresponds to a pulse oximetry saturation of < 95% breathing a

Hepatic – total bilirubin > 4 mg/dl

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fraction of inspired oxygen of 0.21 in room air at atmospheric pressure)

Renal – creatinine > 2.0 mg/dl (if unknown baseline) or an increase from baseline creatinine of >

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0.5 mg/dl or a current creatinine > 2 * baseline

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Hematologic – platelet count < 100 per mm3

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Coagulation – INR > 1.5 or partial thromboplastic time (PTT) > 60 seconds

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ACCEPTED MANUSCRIPT Appendix 2. Pulmonary SOFA score calculation Given that the study population of Pandharipande et al. consisted of patients undergoing general

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anesthesia or with acute respiratory distress syndrome, very few would have had measurements

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performed breathing room air oxygen concentration, as opposed to our study population which presented to the ED. Thus, we adjusted the S/F ratio cutoff for the lowest SOFA pulmonary score

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of 1 to be < 452 (as opposed to <512), corresponding to room air oxygen saturation < 95%. We

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kept the remainder of the S/F ratio cutoffs the same as Pandharipande et al (SOFA pulmonary

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score 2: < 357, 3: < 214, 4: < 89).

See: Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of

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Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential

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Organ Failure Assessment score. Crit Care Med 2009;37(4):1317-1321.

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ACCEPTED MANUSCRIPT Appendix 3. Variables entered into the logistic regression model (N=378)

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1. Age (years) – continuous

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2. Gender – Male/Female 3. Year of presentation – continuous

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4. Cancer – Yes/No

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5. Neutropenia – Yes/No 6. Cirrhosis – Yes/No

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7. Diabetes – Yes/No

8. Coronary artery disease – Yes/No

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9. Congestive heart failure – Yes/No

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10. Do not resuscitate order present on arrival – Yes/No 11. Initial mean arterial pressure (mmHg) – continuous

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12. Temperature never > 100.4°F – Yes/No

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13. Hemoglobin (g/dl) – continuous 14. Platelet count (per mm3) - continuous 15. Bicarbonate (mEq/l) - continuous 16. Blood urea nitrogen (mg/dl) - continuous 17. Glucose < 60 mg/dl – Yes/No 18. Lactate (mmol/l) - continuous 19. Coagulation organ failure: International normalized ratio > 1.5 or partial thromboplastin time > 60 – Yes/No 20. Organ failure Neurologic – Altered Mental Status – Yes/No

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ACCEPTED MANUSCRIPT 21. Organ failure Pulmonary – S/F ratio < 452 – Yes/No 22. Organ failure Hepatic – Total bilirubin > 4 – Yes/No

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23. SOFA score – continuous

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24. Positive blood culture – Yes/No

26. Methicillin-sensitive Staph aureus – Yes/No

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27. Multidrug resistant gram negatives – Yes/No

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25. Positive ascites culture – Yes/No

28. Intravenous fluids within 6 hours (ml) - continuous

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29. Time to antibiotics (hours) – categorical (<1 hr, 1 - < 3 hrs, 3 - < 6 hrs, > 6 hrs)

31. Vasopressors – Yes/No

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32. Transfusion – Yes/No

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30. Intubated – Yes/No

33. Central venous pressure – initial (mmHg) - continuous

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34. Central venous pressure – > 8 mmHg – Yes/No

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35. Mean arterial pressure - > 65 mmHg – Yes/No 36. Lactate clearance (%) – continuous

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ACCEPTED MANUSCRIPT References

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[1] Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. [2] Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93. [3] McManus DD, Gore J, Yarzebski J, Spencer F, Lessard D, Goldberg RJ. Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI. Am J Med 2011;124:40-7. [4] Cuschieri J, Johnson JL, Sperry J, West MA, Moore EE, Minei JP, et al. Benchmarking outcomes in the critically injured trauma patient and the effect of implementing standard operating procedures. Ann Surg 2012;255:993-9. [5] Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. Jama 2014;311:1308-16. [6] Napoli AM, Machan JT, Corl K, Forcada A. The use of impedance cardiography in predicting mortality in emergency department patients with severe sepsis and septic shock. Acad Emerg Med 2010;17:452-5. [7] Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, et al. Multicenter Study of Early Lactate Clearance as a Determinant of Survival in Patients with Presumed Sepsis. Shock 2009;32:35-9. [8] Pope JV, Jones AE, Gaieski DF, Arnold RC, Trzeciak S, Shapiro NI. Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis. Ann Emerg Med 2010;55:40-6 e1. [9] Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med 2009;37:1649-54. [10] Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, Furia FF, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goaldirected therapy was initiated in the emergency department. Crit Care Med 2010;38:1045-53. [11] Lee CC, Lee CH, Chuang MC, Hong MY, Hsu HC, Ko WC. Impact of inappropriate empirical antibiotic therapy on outcome of bacteremic adults visiting the ED. Am J Emerg Med 2012;30:1447-56. [12] Giannazzo G, Tola F, Vanni S, Bondi E, Pepe G, Grifoni S. Prognostic indexes of septic syndrome in the emergency department. Intern Emerg Med 2006;1:229-33. [13] Hisamuddin NA, Azlan K. The use of laboratory and physiological parameters in predicting mortality in sepsis induced hypotension and septic shock patients attending the emergency department. Med J Malaysia 2012;67:259-64. [14] Shapiro NI, Wolfe RE, Moore RB, Smith E, Burdick E, Bates DW. Mortality in Emergency Department Sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule. Crit Care Med 2003;31:670-5. [15] Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE, Shapiro NI. Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med 2011;39:322-7.

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[16] Carpenter CR, Keim SM, Upadhye S, Nguyen HB. Risk stratification of the potentially septic patient in the emergency department: the Mortality in the Emergency Department Sepsis (MEDS) score. J Emerg Med 2009;37:319-27. [17] de Groot B, Lameijer J, de Deckere ER, Vis A. The prognostic performance of the predisposition, infection, response and organ failure (PIRO) classification in high-risk and lowrisk emergency department sepsis populations: comparison with clinical judgement and sepsis category. Emerg Med J 2014;31:292-300. [18] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55. [19] Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6. [20] Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, et al. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med 2009;37:1317-21. [21] CDC/NHSN Surveillance Definition of Healthcare-Associated Infection and Criteria for Specific Types of Infections in the Acute Care Setting, [22] Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268-81. [23] Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009;37:1670-7. [24] Powell ES, Sauser K, Cheema N, Pirotte MJ, Quattromani E, Avula U, et al. Severe sepsis in do-not-resuscitate patients: intervention and mortality rates. J Emerg Med 2013;44:742-9. [25] Sivayoham N, Rhodes A, Cecconi M. The MISSED score, a new scoring system to predict Mortality In Severe Sepsis in the Emergency Department: a derivation and validation study. Eur J Emerg Med 2014;21:30-6. [26] Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis*. Crit Care Med 2006;34:15-21. [27] Beach MC, Morrison RS. The effect of do-not-resuscitate orders on physician decisionmaking. J Am Geriatr Soc 2002;50:2057-61. [28] Pittet D, Thievent B, Wenzel RP, Li N, Gurman G, Suter PM. Importance of pre-existing co-morbidities for prognosis of septicemia in critically ill patients. Intensive Care Med 1993;19:265-72. [29] Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 2001;344:481-7. [30] Garcia-Carbonero R, Mayordomo JI, Tornamira MV, Lopez-Brea M, Rueda A, Guillem V, et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial. J Natl Cancer Inst 2001;93:31-8.

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[31] Waeschle RM, Moerer O, Hilgers R, Herrmann P, Neumann P, Quintel M. The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability. Crit Care 2008;12:R129. [32] Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 1980;68:344-55. [33] Peres Bota D, Lopes Ferreira F, Melot C, Vincent JL. Body temperature alterations in the critically ill. Intensive Care Med 2004;30:811-6. [34] Fuller BM, Mohr NM, Dettmer M, Kennedy S, Cullison K, Bavolek R, et al. Mechanical ventilation and acute lung injury in emergency department patients with severe sepsis and septic shock: an observational study. Acad Emerg Med 2013;20:659-69. [35] Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med 2015. [36] Carrillo A, Gonzalez-Diaz G, Ferrer M, Martinez-Quintana ME, Lopez-Martinez A, Llamas N, et al. Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure. Intensive Care Med 2012;38:458-66. [37] Richard JC, Bayle F, Bourdin G, Leray V, Debord S, Delannoy B, et al. Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit Care 2015;19:5. [38] Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock*. Crit Care Med 2004;32:1637-42. [39] Walker CA, Griffith DM, Gray AJ, Datta D, Hay AW. Early lactate clearance in septic patients with elevated lactate levels admitted from the emergency department to intensive care: time to aim higher? J Crit Care 2013;28:832-7. [40] Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, et al. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest 2013;143:1548-53. [41] Trzeciak S, Glaspey LJ, Dellinger RP, Durflinger P, Anderson K, Dezfulian C, et al. Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis*. Crit Care Med 2014;42:2482-92. [42] Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA, et al. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. Jama 1996;275:134-41. [43] Esper AM, Moss M, Martin GS. The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study. Crit Care 2009;13:R18. [44] Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003;26:510-3. [45] Schuetz P, Castro P, Shapiro NI. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care 2011;34:771-8. [46] Stegenga ME, Vincent JL, Vail GM, Xie J, Haney DJ, Williams MD, et al. Diabetes does not alter mortality or hemostatic and inflammatory responses in patients with severe sepsis. Crit Care Med 2010;38:539-45. [47] Chang CW, Kok VC, Tseng TC, Horng JT, Liu CE. Diabetic patients with severe sepsis admitted to intensive care unit do not fare worse than non-diabetic patients: a nationwide population-based cohort study. PLoS One 2012;7:e50729.

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[48] Schuetz P, Jones AE, Howell MD, Trzeciak S, Ngo L, Younger JG, et al. Diabetes is not associated with increased mortality in emergency department patients with sepsis. Ann Emerg Med 2011;58:438-44. [49] Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, et al. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med 2000;28:2187-92. [50] Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136:1237-48. [51] Vincent JL, Nelson DR, Williams MD. Is worsening multiple organ failure the cause of death in patients with severe sepsis? Crit Care Med 2011;39:1050-5. [52] Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506. [53] Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med 2015. [54] Johnson MT, Reichley R, Hoppe-Bauer J, Dunne WM, Micek S, Kollef M. Impact of previous antibiotic therapy on outcome of Gram-negative severe sepsis. Crit Care Med 2011;39:1859-65.

24

ACCEPTED MANUSCRIPT Table 1. Patient characteristics

57.8 +/- 16.2 180 (59) 122 (45) 130 (48) 17 (6)

40 (43) 47(51) 6 (6)

0.93

25 (6) 85 (21) 37 (9) 48 (12) 62 (15) 143 (35) 11 (3) 45 (11) 2 (0.5) 28 (7) 116 (28) 15 (4) 19 (5) 27 (7) 29 (8) 165 (40) 45 (11) 40 (10) 30 (8) 46 (11) 17 (4)

18 (6) 48 (16) 22 (7) 26 (8) 41 (14) 103 (34) 6 (2) 27 (9) 2 (0.6) 23 (8) 95 (31) 13 (4) 15 (5) 21 (7) 24 (8) 123 (40) 29 (10) 26 (8) 23 (8) 37 (12) 5 (2)

7 (7) 37 (35) 15 (14) 22 (21) 21 (21) 40 (38) 5 (5) 18 (17) 0 (0) 5 (5) 21 (20) 2 (2) 4 (4) 6 (6) 5 (6) 42 (40) 16 (15) 14 (13) 7 (7) 9 (9) 12 (11)

0.81 <0.001 0.046 0.001 0.10 0.38 0.16 0.018 1.00 0.50 0.03 0.37 0.79 0.82 0.50 0.97 0.11 0.15 1.00 0.32 <0.001

98.6 (97.5101.0) 115.1 +/ 26.5 20 (16-24) 102 (84125)

98.8 (97.7101.4)

98.4 (97.4100.2) 115.8 +/23.4 20 (16-25) 100 (81121)

0.007

ED

PT

CE

AC

Triage heart rate (beats/min) Triage respiratory rate (breaths/min) Triage systolic blood pressure (mmHg)

RI P

T

59.5 +/16.3 233 (57) 162 (45) 177 (49) 23 (6)

MA

Gender (male), n (%) Race, n (%) Caucasian African American Other Comorbidities, n (%) Human Immunodeficiency Virus Cancer Hematologic Solid organ Chemotherapy within 4 weeks Immunosuppressiona Neutropenia Cirrhosis Chronic ventilator dependence Hemodialysis Diabetes Metformin use Surgery within 4 weeks Alcoholism Current smoker Hypertension Coronary artery disease Congestive heart failure Chronic obstructive pulmonary disease Organ transplant Do not resuscitate status present on arrival Clinical variables Triage temperature (°F)

InHospital Death (N=105) 64.5 +/15.7 53 (50)

SC

Age (yrs)

Discharged Alive (N=306)

NU

Variable

All Patients (N=411)

114.8 +/27.5 20 (17-24) 103 (84127)

p

<0.001 0.14

0.71 0.80 0.16

25

ACCEPTED MANUSCRIPT 58 (46-72)

0.31

73 (60-91)

74 (61-94)

71 (59-87)

0.18

46 (11) 180 (44) 180 (44) 226 (55) 123.4 +/24.1 28 (22-34) 84 (71100) 42 (33-52)

31 (10) 122 (40) 149 (49) 153 (50) 123.3 +/25.0 27 (22-34) 84 (72-99) 42 (33-51)

15 (14) 0.003 58 (56) 31 (30) 73 (70) <0.001 123.7 +/0.88 21.1 28 (23-33) 0.26 84 (710.89 101) 43 (30-54) 0.50

55 (47-66)

55 (45-68)

13 (8-18) 36 (12) 11.7 +/- 2.8

13 (8-19) 0.86 15 (14) 0.50 11.1 +/0.070 2.7 181 (101- 0.003 280) 137 (1320.84 141) 20 (16-24) 0.048 35 (23-55) <0.001 1.8 (1.30.25 2.7) 107 (800.005 172) 19 (19) <0.001 1.6 (0.70.002 3.6) 1.4 (1.2- <0.001 1.9) 32.0 0.004 (28.239.3) 5.4 (4.10.007 8.2)

ED

CE

Sodium (mEq/L)

PT

Platelet count (per mm3)

AC

Bicarbonate (mEq/L) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Glucose (mg/dL)

Glucose < 60 mg/dL, n (%) Total bilirubin (mg/dL) International normalized ratio Partial thromboplastin time (sec)

Lactate (mmol/L) Organ Failure, n (%) Neurologic: Altered mental status Cardiovascular: Mean arterial pressure

SC

RI P

T

59 (48-75)

55 (46-67)

MA

Highest respiratory rate (breaths/min) Lowest systolic blood pressure (mmHg) Lowest diastolic blood pressure (mmHg) Lowest mean arterial pressure (mmHg) Laboratory values White blood cell count (per mm3) Bandemia > 10%, n (%) Hemoglobin (g/dL)

59 (47-74)

NU

Triage diastolic blood pressure (mmHg) Triage mean arterial pressure (mmHg) Worst Temperature (°F)b Less than 96.8 96.8 – 100.4 Greater than 100.4 Temperature never > 100.4°F Highest heart rate (beats/min)

13 (8-19) 51 (12) 11.5 +/2.8 213 (129304) 137 (133140) 21 (17-24) 29 (19-45) 1.7 (1.12.7) 122 (94177) 28 (7) 1.0 (0.62.5) 1.3 (1.11.7) 30.3 (26.436.7) 4.8 (3.56.7) 139 (34) 327 (80)

221 (145309) 137 (133140) 21 (18-24) 28 (17-41) 1.7 (1.1-2.6) 125 (96177) 9 (3) 0.8 (0.5-2.2) 1.3 (1.1-1.6) 29.8 (25.935.9) 4.7 (3.4-6.4)

91 (30) 247 (81)

48 (46) 80 (76)

0.94

0.003 0.32 26

ACCEPTED MANUSCRIPT

207 (68) 33 (15) 139 (45) 38 (12)

85 (81) 18 (23) 51 (49) 14 (13)

0.009 0.10 0.58 0.81

114 (32)

73 (27)

41 (43)

0.005

48 (12) 131 (32) 119 (29) 113 (27) 2.9 +/- 1.3 6.3 +/- 3.1 208 (51)

41 (13) 100 (33) 93 (30) 72 (24) 2.8 +/- 1.2 5.9 +/- 2.8 151 (50)

7 (7) 31 (30) 26 (25) 41 (39) 3.2 +/- 1.4 7.5 +/- 3.6 57 (55)

0.012

136 (33) 96 (23) 71 (17) 58 (14) 50 (12) 105 (26)

97 (32) 67 (22) 56 (18) 43 (14) 43 (14)

39 (37) 29 (28) 15 (15) 15 (14) 7 (7)

ED

PT

NU

SC

RI P

T

292 (71) 51 (17) 190 (46) 52 (13)

MA

< 70 mmHg Pulmonary: SaO2/FiO2 ratio < 452 Hepatic: Total bilirubin > 4 mg/dL Renal: Acute kidney injury Hematologic: Platelet count < 100 (per mm3) Coagulation: International normalized ratio > 1.5 or partial thromboplastin time > 60 sec Number of organ failures, n (%) 0 or 1 2 3 4 or more Number of organ failures SOFA score (points) Septic Shock, n (%) Year of presentation, n(%) 2005 2006 2007 2008 2009 Mortality, n (%)

0.003 <0.001 0.33 0.20

AC

CE

Continuous measures are presented as mean +/- standard deviation if normally distributed or median (interquartile range) otherwise. Categorical variables are presented as counts and percentiles. SaO2 = peripheral oxygen saturation (%); FiO2 = Fraction of inspired oxygen concentration; SOFA = Sequential organ failure assessment a

Any active hematologic malignancy, solid organ malignancy with receipt of chemotherapy within 4 weeks, regular administration of non-corticosteroid immunosuppressive agents, corticosteroids at a prednisone equivalent dose > 10 mg/day, human immunodeficiency virus infection with CD4 count < 200 cells/microliter, or neutropenia (absolute neutrophil count < 500 cells/microliter); bTemperature with the largest absolute deviation from 98.6°F

27

ACCEPTED MANUSCRIPT Table 2. Microbiological Data In-Hospital Death (N=105)

p

27 (7) 16 (4) 125 (30) 107 (26) 72 (18) 10 (2) 33 (8) 5 (1) 6 (1) 14 (3) 57 (14)

21 (7) 14 (5) 88 (29) 78 (25) 57 (19) 8 (3) 25 (8) 3 (1) 4 (1) 10 (3) 43 (14)

6 (6) 2 (2) 37 (35) 29 (28) 15 (14) 2 (2) 8 (8) 2 (2) 2 (2) 4 (4) 14 (13)

0.82 0.38 0.21 0.67 0.31 1.00 1.00 0.61 0.65 0.76 0.85

314 (78) 90 (22)

235 (78) 65 (22)

79 (76) 25 (24)

0.62

222 (54) 189 (46)

161 (53) 145 (47)

61 (58) 44 (42)

0.33

NU

SC

RI P

T

Discharged Alive (N=306)

MA ED

AC

CE

PT

Variable Infectious source, n (%)a Bacteremia Vascular catheter Respiratory Genitourinary Abdominal Central nervous system Skin or soft tissue Surgical site Heart Other Unknown Infection acquisition, n (%) Community Nosocomialb Culture results, n (%) Culture-positive patients Culture-negative patients Positive culture results, n (%)a Blood Urine Sputum Cerebrospinal fluid Wound Stool Ascites Other

All Patients (N=411)

Gram positives, n (%) Methicillin-sensitive staph aureus Methicillin-resistant staph aureus Strep pneumoniae Vancomycin-sensitive enterococcus sp. Vancomycin-resistant

127 (31) 88 (29) 39 (37) 106 (26) 76 (25) 30 (29) 25 (6) 16 (5) 9 (9) 4 (1) 4 (1) 0 (0) 11 (3) 10 (3) 1 (1) 11 (3) 9 (3) 2 (2) 5 (1) 1 (0.3) 4 (4) 64 (16) 46 (15) 18 (17) Among those with Any Positive Cultures All Discharged In-Hospital Patients Alive Death (N=222) (N=161) (N=61)

0.11 0.45 0.24 0.58 0.30 0.74 0.016 0.61

p

16 (7)

9 (6)

7 (11)

0.15

17 (8)

12 (7)

5 (8)

0.78

16 (7) 27 (12)

12 (7) 22 (14)

4 (7) 5 (8)

1.00 0.36

11 (5)

9 (6)

2(3)

0.73 28

ACCEPTED MANUSCRIPT

a

CE

PT

1 (0.6) 12 (7)

0 (0) 2 (3)

1.00 0.36

62 (28) 34 (15) 3 (1) 30 (14) 20 (9) 9 (4) 1 (0.4) 6 (3) 58 (26)

43 (27) 25 (16) 2 (1) 23 (14) 14 (9) 7 (4) 1 (0.6) 5 (3) 46 (29)

19 (31) 9 (15) 1 (2) 7 (11) 6 (10) 2 (3) 0 (0) 1 (2) 12 (20)

0.51 1.00 1.00 0.66 0.80 1.00 1.00 1.00 0.18

10 (4) 4 (2)

8 (5) 3 (2)

2 (3) 1 (2)

0.73 1.00

6 (3) 4 (2) 2 (1) 57 (26)

5 (3) 3 (2) 2 (1) 45 (28)

1 (2) 1 (2) 0 (0) 12 (20)

1.00 1.00 1.00 0.21

165 (74) 44 (20) 11 (5) 2 (1)

116 (72) 35 (22) 8 (5) 2 (1)

49 (80) 9 (15) 3 (5) 0 (0)

0.58

NU

SC

RI P

T

1 (0.4) 14 (6)

MA

ED

enterococcus sp. Coagulase-negative staph sp. Other gram positives Gram negatives, n (%) Escherichia coli Klebsiella sp. Haemophilus influenzae Enterobacteriae sp. Pseudomonas sp. Acinetobacter Stenotrophomonas Other gram negatives Multidrug-resistant gram negatives Anaerobes, n (%) Clostridium difficile Other anaerobes Fungi, n (%) Candida albicans Other fungi Viral, n (%) Polymicrobial, n (%) Number of organisms, n (%) 1 2 3 4

AC

Individual patients may have greater than 1 site of infection or positive culture results; Infection associated with hospitalization > 24 hours within 90 days or residence at a nursing home or long-term care facility. b

29

ACCEPTED MANUSCRIPT

90 (22) 180 (45) 69 (17) 65 (16) 2.0 (1.2-3.8) 76 (19) 111 (27) 11 (3) 36 (9)

74 (24) 134 (44) 44 (16) 50 (17) 1.9 (1.0-3.6) 44 (14) 77 (25) 9 (3) 23 (8)

16 (16) 0.065 46 (45) 25 (25) 15 (15) 2.3 (1.6-4.4) 0.069 32 (30) <0.001 34 (32) 0.15 2 (2) 0.74 13 (12) 0.16

9 (5-12)

8 (5-12)

10 (6-13)

0.046

7 (4-10)

6 (4-10)

7 (4-11)

0.39

269 (70)

194 (68)

75 (75)

0.18

70 (58-84)

70 (58-83)

72 (58-85)

0.98

62 (52-74)

62 (53-72)

61 (52-77)

0.77

353 (88)

267 (90)

86 (84)

0.15

74 (64-80)

74 (65-80)

73 (62-80)

0.69

70 (58-76)

69 (58-76)

70 (61-78)

0.66

131 (83) 26 (17) 259 (76)

93 (85) 17 (15) 194 (77)

38 (81) 9 (19) 65 (71)

0.64

4.8 (3.5-6.7) 2.6 (1.5-4.3)

4.7 (3.4-6.4) 2.2 (1.3-3.6)

AC

CE

PT

ED

3000 (20004000) 127 (79)

SC

MA

Appropriate antibiotics, n (%)a Time to antibiotics (hrs) <1 1-<3 3-<6 6+ Time to antibiotics (hrs) Intubation, n (%) Vasopressors, n (%)b Dobutamine, n (%) Blood transfusion, n (%) Early Protocolized Resuscitation Data Central venous pressure – initial (mmHg) Central venous pressure – minimum (mmHg)c Central venous pressure > 8 mmHg achieved, n (%)d Mean arterial pressure – initial (mmHg) Mean arterial pressure – minimum (mmHg) Mean arterial pressure > 65 mmHg achieved, n (%) Central venous oxygen saturation – initial (%) Central venous oxygen saturation – minimum (%)e Central venous oxygen saturation - worst, n (%)f < 70% > 90% Central venous oxygen saturation 70 - 89% achieved, n (%) Lactate – initial (mmol/L) Lactate – repeat (mmol/L)

NU

Intravenous fluids within 6 hrs (ml)

In-Hospital Death (N=105) 1000 (01000) 2602 (15003500) 50 (79)

1000 (01000) 3000 (20004000) 177 (79)

Discharged Alive (N=306) 950 (0-1000)

T

All Patients (N=411) Variable Intravenous fluids within 1 hr (ml)

RI P

Table 3. Treatments and Protocolized Resuscitation Measures p

0.46 0.012 1.00

0.21

5.4 (4.1-8.2) 0.007 4.0 (2.2-6.2) <0.001 30

ACCEPTED MANUSCRIPT Lactate clearance (%)

44.6 (12.865.1)

51.4 (20.067.1)

23.6 (-2.553.6)

<0.001

Any vasopressor agent including dobutamine. dCVP > 12 if intubated

RI P

b

T

Continuous measures are presented as mean +/- SD if normally distributed or median (interquartile range) otherwise. Categorical variables are presented as counts and percentiles.

AC

CE

PT

ED

MA

NU

SC

Sample sizes for the following variables were: aAppropriate antibiotics, n=223 (54%); cCentral venous pressure – minimum, n=312 (76%); eCentral venous oxygen saturation – minimum, n=184 (45%); fCentral venous oxygen saturation – worst, n=157 (38%)

31

ACCEPTED MANUSCRIPT Table 4. Risk Factors for In-Hospital Mortality (N = 378a)

NU

0.99 (0.98-1.00) 2.04 (1.25-3.33)

P 0.002

T

RI P <0.001 0.116 0.063 0.020 0.098 0.247 0.001

0.148 0.004

SC

3.06 (1.81-5.16) 2.64 (0.79-8.87) 1.92 (0.97-3.80) 0.50 (0.28-0.90) 1.77 (0.90-3.49) 1.54 (0.74-3.20) 6.75 (2.24-20.29)

P 0.002 0.174 0.101

Multivariable Model OR (95% CI) 1.03 (1.01-1.05)

4.31 (2.29-8.12)

<0.001

0.42 (0.21-0.84)

0.014

7.38 (2.07-26.28)

0.002

2.03 (1.14-3.64)

0.017

10.90 (4.12-28.78)

<0.001

AC

CE

PT

ED

Age (yrs) Gender Year of presentation Comorbidities Cancer Neutropenia Cirrhosis Diabetes Coronary artery disease Congestive heart failure Do not resuscitate status present on arrival Vital Signs Triage mean arterial pressure Temperature never > 100.4°F Laboratory Values Hemoglobin Platelet count Bicarbonate Blood urea nitrogen Glucose < 60 mg/dL Lactate Organ Dysfunction Neurologic: Altered mental status Pulmonary: SaO2/FiO2 ratio < 452 Hepatic: Total bilirubin > 4 mg/dL Coagulation: International normalized ratio > 1.5 or partial thromboplastin time> 60 sec Total SOFA score Microbiology Positive blood culture Positive ascites cultureb Methicillin-sensitive staph aureus Multidrug resistant gram

Univariable Model OR (95% CI) 1.02 (1.01-1.04) 0.72 (0.45-1.15) 0.87 (0.73-1.03)

MA

Variable

0.93 (0.85-1.01) 0.080 0.997 (0.995-0.999) 0.003 0.99 (0.95-1.03) 0.547 1.01 (1.00-1.02) 0.026 7.53 (3.25-17.46) <0.001 1.10 (1.03-1.17) 0.007 2.00 (1.24-3.24)

0.005

2.12 (1.20-3.74)

0.010

1.45 (0.74-2.87)

0.282

1.91 (1.14-3.20)

0.014

1.19 (1.10-1.29)

<0.001

1.65 (1.02-2.69) 9.40 (0.74-498.7) 2.11 (0.73-6.11)

0.042 0.095 0.166

0.59 (0.28-1.24)

0.161 32

ACCEPTED MANUSCRIPT

0.007

T

0.612 <0.001 0.290 0.075

<0.001

0.992 (0.986-0.998)

0.006

1.04 (1.00-1.09)

RI P

5.40 (2.74-10.61)

1.34 (0.78-2.31)

0.285

NU

0.9998 (0.9996-0.9999) 1.01 (0.98-1.04) 2.95 (1.69-5.14) 1.32 (0.79-2.22) 1.94 (0.94-4.03)

0.61 (0.30-1.21)

0.155

0.992 (0.986-0.997)

0.001

SC

0.078

MA

negatives Treatments Intravenous fluids within 6 hours Time to antibiotics Intubation Vasopressors Transfusion Early Protocolized Resuscitation Initial central venous pressure Central venous pressure > 8 mmHg achievedc Mean arterial pressure > 65 mmHg achieved Lactate clearance (%)

OR = odds ratio; CI = confidence interval; SOFA = Sequential organ failure assessment; SaO2 = peripheral oxygen saturation (%); FiO2 = Fraction of inspired oxygen concentration N = 33 patients with incomplete data were excluded from the model; bTested using exact logistic regression; c> 12 if intubated

AC

CE

PT

ED

a

33

ACCEPTED MANUSCRIPT Highlights

Our objective was to identify independent risk factors for in-hospital mortality among

T



RI P

ED patients with severe sepsis and lactate > 4 mmol/L or septic shock that all



SC

received early protocolized resuscitation.

We enrolled 411 patients and used multivariable regression to identify the following

NU

factors associated with in-hospital mortality: age, active cancer, diabetes, DNR status on ED arrival, temperature never > 100.4°F, glucose < 60 mg/dl, intubation, and

CE

PT

future intervention.

ED

These findings provide insights into aspects of early sepsis care that can be targets for

AC



MA

lactate clearance.

34