Early sepsis bundle compliance for non-hypotensive patients with intermediate versus severe hyperlactemia

    Early Sepsis Bundle Compliance for Non-Hypotensive Patients with Intermediate Versus Severe Hyperlactemia Daniel E. Leisman, Jason A. Zemmel D’Amore, Jeanie L. Gribben, Mary Frances Ward, Kevin D. Masick, Andrea R. Bianculli, Kathryn H. Bradburn, John K. D’Angelo, Martin E. Doerfler PII: DOI: Reference:

S0735-6757(17)30028-1 doi:10.1016/j.ajem.2017.01.029 YAJEM 56428

To appear in:

American Journal of Emergency Medicine

Received date: Revised date: Accepted date:

6 December 2016 13 January 2017 14 January 2017

Please cite this article as: Leisman Daniel E., Zemmel D’Amore Jason A., Gribben Jeanie L., Ward Mary Frances, Masick Kevin D., Bianculli Andrea R., Bradburn Kathryn H., D’Angelo John K., Doerfler Martin E., Early Sepsis Bundle Compliance for NonHypotensive Patients with Intermediate Versus Severe Hyperlactemia, American Journal of Emergency Medicine (2017), doi:10.1016/j.ajem.2017.01.029

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ACCEPTED MANUSCRIPT Title: Early Sepsis Bundle Compliance for Non-Hypotensive Patients with Intermediate Versus Severe Hyperlactemia Authors List: Daniel E. Leisman, BS;1,2 Jason A. Zemmel D’Amore, MD;1 Jeanie L. Gribben, BS;1 Mary Frances Ward, MS, ANP;3,4 Kevin D. Masick, PhD;5 Andrea R. Bianculli, BS;1 Kathryn H. Bradburn, BA;1 John K. D’Angelo, MD;1 Martin E. Doerfler, MD;6

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Affiliations: 1. Department of Emergency Medicine, Hofstra-Northwell School of Medicine, Hempstead, NY 2. Icahn School of Medicine at Mount Sinai, New York, NY 3. Department of Neurosurgery, Hofstra-Northwell School of Medicine, Hempstead, NY 4. Feinstein Institute for Medical Research, Manhasset, NY 5. Krasnoff Quality Management Institute, Northwell Health System, New Hyde Park, NY 6. Department of Medicine, Hofstra-Northwell School of Medicine, Hempstead, NY Reprints will not be ordered

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Corresponding author: Daniel E. Leisman Department of Emergency Medicine Northwell Health System 300 Community Drive Manhasset, NY, 11030 (p): (516) 941-8468 (f): (516) 562-3710 (e): [email protected]

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Funding: This investigation was funded in part by a grant from the Center for Medicare and Medicaid Innovation to the High Value Healthcare Collaborative, of which the study sites’ umbrella health system was a part. This grant helped fund the underlying quality improvement program and database in this study. Conflict of Interest: The authors have no financial conflicts of interest to disclose.

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ACCEPTED MANUSCRIPT ABSTRACT Objective: To compare the association of 3-hour sepsis bundle compliance with hospital mortality in nonhypotensive sepsis patients with intermediate versus severe hyperlactemia.

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Methods: This was a cohort study of all non-hypotensive, hyperlactemic sepsis patients captured in a prospective quality-improvement database, treated October 2014 to September 2015 at five tertiary-care

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centers. We defined sepsis as 1)infection, 2)≥2 SIRS criteria, and 3)≥1 organ dysfunction criterion. “Time-zero” was the first time a patient met all sepsis criteria. Inclusion criteria: systolic blood pressure >90mmHg, mean

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arterial pressure >65mmHg, and serum lactate ≥2.2mmol/L. Primary exposures: 1)intermediate(2.2-3.9mmol/L)

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versus severe(≥4.0mmol/L) hyperlactemia and 2)full 3-hour bundle compliance. Bundle elements:

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1. Blood cultures before antibiotics 2. Parenteral antibiotics administered ≤180 minutes from ≥2 SIRS and lactate ordered, or ≤60 minutes from “time-zero”, whichever occurred first. 3. Lactate result available ≤90 minutes post-order 4. 30mL/kg crystalloid bolus initiated ≤30 minutes from “time-zero”.

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The primary outcome was 60-day in-hospital mortality.

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Results: 2,417 patients met inclusion criteria. 704(29%) had lactate ≥4.0mmol/L versus 1,775 patients with lactate 2.2-3.9mmol/L. Compliance was 75% for antibiotics and 53% for fluids. Full-compliance was

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comparable between lactate groups (n=200(29%) and 488(28%), respectively). We observed 424(17.5%) mortalities: intermediate/non-compliant – 182(14.9%), intermediate/compliant – 41(8.4%), severe/noncompliant – 147(29.2%), severe/compliant – 54(27.0%) [difference-of-differences=4.3%, CI=2.6-5.9%]. In multivariable regression, mortality predictors included severe hyperlactemia (OR=1.99, CI=1.51-2.63) and bundle compliance (OR=0.62, CI=0.42-0.90), and their interaction was significant: p(interaction)=0.022. Conclusion: We observed a significant interaction between 3-hour bundle compliance and initial hyperlactemia. Bundle compliance may be associated with greater mortality benefit for non-hypotensive sepsis patients with less severe hyperlactemia.

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ACCEPTED MANUSCRIPT INTRODUCTION Background Sepsis and septic shock are global drivers of mortality, estimated to account for 5 million deaths

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annually1. An extensive body of literature has demonstrated compliance with early-action sepsis bundles, mandating immediate intravenous fluid resuscitation and empiric broad-spectrum

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antimicrobial therapy, to be associated with reduced hospital mortality for these patients2-8.

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Hyperlactemia is considered by many to be an important indicator of sepsis-induced tissue

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hypoperfusion and has also been consistently shown to predict sepsis mortality 9-15.

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The quantitative threshold for lactate elevation as a bundle trigger, or “time-zero” entry point, has been the subject of debate for 25 years. The first sepsis consensus definitions (Sepsis-1) in 1991

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recommended lactate ≥4.0mmol/L as an indicator of septic shock and a time-zero entry point16. While

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the 2001 Sepsis-2 definitions lowered the lactate threshold for sepsis-induced tissue hypoperfusion to

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3.0mmol/L17, subsequent Society for Critical Care Medicine (SCCM) and National Quality Forum (NQF) recommendations continued to support 4.0mmol/L as cut-off for bundle triggers18,19. During that time, a number of studies suggested patients with more intermediate hyperlactemia, with serum levels 2.1-4.0mmol/L, are also at increased risk for decompensation and mortality, and may benefit from early sepsis bundle application11-13,20. The recent SCCM and European Society for Intensive Care Medicine (ESICM) Sepsis-3 definitions include lactate level ≥2.1mmol/L to clinically identify septic shock21.

Importance These new definitions acknowledge intermediate hyperlactemia as a risk-factor for sepsis mortality21, and analyses that accompany the definitions compare severe (≥4.0mmol/L) vs. intermediate (>2.0mmol/L) hyperlactemia as predictors of hospital death 13. However, the differential effect of initial sepsis bundle compliance (i.e., initial treatment) in these groups has not been well investigated. While Page 3 of 26

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ACCEPTED MANUSCRIPT sepsis may be viewed as a question of whether a patient is or is not septic, the dysregulated host response of sepsis may be seen as a continuum where patients experience progressively worsening organ dysfunction21. As a result, it is conceivable that patients with earlier or less severe

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hypoperfusion,( and specifically with intermediate versus severe hyperlactemia), might be at an earlier point along such a continuum, and could therefore demonstrate a comparatively greater

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mortality benefit from bundle compliant initial care. If true, these patients would represent a high-

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impact target population. Such knowledge would further our understanding of best practice in

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managing sepsis patients.

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Study Goal

We conducted an analysis of a hemodynamically stable sepsis cohort, identified from a prospective,

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multisite quality improvement (QI) sepsis database. We aimed to determine the differential 60-day in-

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hospital mortality benefit associated with bundle compliance for non-hypotensive sepsis patients

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presenting with intermediate hyperlactemia compared to those with severe hyperlactemia. As a secondary analysis, we also assessed 28-day in-hospital mortality and need for mechanical ventilation.

METHODS

This was a multisite, observational cohort study, examining data from a sepsis quality improvement (QI) database operating across 11 hospitals in a single U.S. health system. The health system began a sepsis QI program in 2009 and adopted a defined algorithm and three-hour bundle in 2010 to screen and treat sepsis patients22. To measure bundle compliance and outcomes for quality and research purposes, data for all consecutive sepsis and septic shock patients were prospectively captured in an internally managed QI database. We abstracted records for hyperlactemic, nonhypotensive sepsis patients treated in 2015 at any of the health system’s 5 tertiary hospitals into a

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ACCEPTED MANUSCRIPT separate research registry to compare the association of bundle compliance with in-hospital mortality in patients with intermediate versus severe hyperlactemia.

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Database Methods A dedicated team of data abstractors at each site screened all patients with known or suspected

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infection and > 2 SIRS criteria for database capture. Abstractors only recorded information for

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patients meeting database inclusion criteria: 1) a suspected or confirmed infection, 2) ≥2 SIRS

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criteria17, and 3) lactate ≥2.2mmol/L or hypotension (systolic blood pressure <90mmHg or mean arterial pressure <65mmHg) or ≥1 sepsis organ-dysfunction criteria (outlined below). Relevant data

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were abstracted into the QI database using a standardized data collection form, which abstractors submitted to a centralized data collection unit. Abstractors excluded patients: < 18 years; with

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advance directives precluding bundle interventions; who declined interventions; who were admitted

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from the ED directly to palliative care or hospice; or who were enrolled in an IRB-approved clinical

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trial that precluded standard application of the bundle. Demographic and clinical data obtained included patient age, sex, primary payer, initial lactate level, signs of hypoperfusion or organ dysfunction, and comorbidities at baseline, as well as treatment and laboratory data-points. Database managers monitored database quality monthly. Quality control was applied by monthly gap-analyses between QI database records and a database of all hospital discharges administered by New York State.23 Records for patients with a discharge diagnosis of sepsis who were missing from the database were reviewed to determine if database inclusion criteria were met, and entered if appropriate. Patients who were “missed” by the treating clinician would have had their initial sepsis episode entered as the first time all objective inclusion criteria were met based on manual review of the medical record. All abstractors received standardized training at the beginning of data-collection involvement.

Study Inclusion/Exclusion Criteria Page 5 of 26

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ACCEPTED MANUSCRIPT The inclusion criterion for this study was treatment in a tertiary care facility and capture in the QI database (i.e., confirmed or suspected infection, ≥2 SIRS, and organ dysfunction or lactate ≥2.2mmol/L). We excluded all database patients who initially presented with hypotension (systolic

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blood pressure <90mmHg or mean arterial pressure <65mmHg) and who did not have a lactate level ≥2.2mmol/L. We excluded patients with lactate <2.2 rather than <2.1 because at the time of algorithm

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development, lactate ≤2.1mmol/L was within the error-margin of normal for the sites’ laboratories and

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not collected: the QI database inclusion criteria require ≥1 hypoperfusion or organ-dysfunction

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criterion be met and use ≥2.2 as the inclusion threshold for lactate.

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Study Definitions

Sepsis was defined as 1) infection, 2) ≥2 SIRS criteria, and 3) lactate ≥ 2.2mmol/L or acute organ-

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dysfunction (not otherwise explained by the patient’s past medical history). Organ-dysfunction criteria

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were: acute kidney injury (AKI), coagulopathy, hypoxia, elevated bilirubin (≥2.0mg/dL), and altered

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mentation. AKI was serum creatinine >2.0 mg/dL in the absence of chronic kidney disease or 50% increase from known baseline. Coagulopathy was platelet count < 150,000 cells/μm 3, international normalized ratio (INR) >1.5, activated partial thromboplastin time >30 seconds, or partial thromboplastin time >60 seconds. Hypoxia was a new, increased oxygen requirement to maintain SaO2 > 90% or a PaO2/FiO2 ratio < 300. Altered mentation was an acute change in mental status determined by clinical judgment of the treating physician. To expedite algorithm inclusion, locally developed consensus-criteria, nicknamed ‘Super-SIRS’ (included in Table 1), were employed as an additional time-zero entry-point if ≥2 criteria were met at ED triage. In this investigation, all patients had lactate ≥2.2mmol/L, and we report the distribution of these additional organ dysfunction measures within the study population.

We defined time-zero as the first laboratory result time or vital sign measurement time where a patient met all inclusion criteria: i.e., the first time a patient had 1) confirmed or suspected infection, Page 6 of 26

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ACCEPTED MANUSCRIPT and 2) ≥2 SIRS, and 3) ≥1 organ dysfunction criterion or lactate ≥2.2mmol/L or ≥2 “Super-SIRS” criteria (see Table 1). We select this point as “time-zero” because it is the first time that the treating physician had enough information available to confirm that the patient was eligible for and should

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have received care adherent to the study sites’ algorithm and 3-hour bundle. All sepsis patients, as

provided in Figure 1S). 3-hour bundle elements were:

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1. Blood cultures drawn prior to antibiotic administration

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defined above, met eligibility for the algorithm and 3-hour bundle (detailed algorithm description

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2. Source-directed, broad-spectrum, parenteral antibiotics administered within 180 minutes of sepsis identification (i.e., ≥2 SIRS and a lactate ordered) or 60 minutes of time-zero (i.e., ≥2 SIRS and

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available laboratory results or vital signs indicating hypoperfusion or organ-dysfunction), whichever occurs earlier.

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SIRS)

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3. Lactate result available within 90 minutes of order (ordered upon recognition of infection with

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4. 30mL/kg intravenous crystalloid bolus initiated within 30 minutes of time-zero

We define bundle compliance as accomplishment of all 4 bundle elements, and non-compliance as failure to achieve ≥1 bundle element. The intention was to provide bundle compliant care to all eligible patients. Care beyond 3-hours was not protocolized and at the physician’s discretion. We define intermediate hyperlactemia as an initial lactate ≥2.2mmol/L and <4.0mmol/L, and severe hyperlactemia as a lactate ≥4.0mmol/L.

Study Data For this study, we extracted data for all eligible encounters in the QI database into a separate, IRBapproved research registry. Demographic variables extracted included age, sex, and body mass index (BMI). Clinical data included comorbidity status at presentation (congestive heart failure (CHF), Page 7 of 26

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ACCEPTED MANUSCRIPT chronic renal failure (CRF), chronic obstructive pulmonary disease (COPD), liver failure, immune modifying medications (IMMs), metastatic disease, and leukemia, lymphoma, or multiple myeloma), site of infection (e.g., respiratory, urinary, etc.), suspected nosocomial etiology, whether the patient

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met ‘Super-SIRS’ criteria at triage, whether chest radiography indicated a lower respiratory tract infection at the time of the initial sepsis episode, initial lactate, and hypoperfusion or organ-

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dysfunction criteria at presentation.

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The exposures of interest were intermediate vs. severe hyperlactemia at presentation and 3-hour bundle compliance. Treatment data included times of intravenous fluid resuscitation initiation, lactate

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order and result, blood culture collection, and parenteral broad-spectrum antibiotic administration, as well as ordered fluid volumes. Detailed methods of capture and calculation for these measures have

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Outcomes

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been described.24

The primary outcome was 60-day in-hospital mortality. We also report 28-day in-hospital mortality. We assessed need for mechanical ventilation (defined as either: via endotracheal intubation or bilevel positive airway pressure) as a secondary outcome. In the context of the multifactorial nature of septic disease and the ‘composite’ nature of mortality as a sepsis outcome,25 we reasoned mechanical ventilation to be an appropriate secondary outcome that was captured in the database and more temporally proximal to the exposures assessed than mortality. We also considered hemodynamic collapse requiring vasopressor administration as a secondary outcome, but low event rates, particularly in the compliant groups, precluded this analysis. Other measures of organ support that would have been candidates for secondary outcomes could not be obtained from the database (e.g., renal replacement therapy utilization).

Statistical Analysis Page 8 of 26

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ACCEPTED MANUSCRIPT We report continuous variables as means (standard deviations) or medians (interquartile ranges), and categorical variables as proportions. We constructed 95% confidence intervals and performed

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analyses with SPSS version 24.0 (IBM, Armonk, NY).

To assess differential mortality, we constructed multivariable logistic regression models that adjusted

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for variables we anticipated a priori to be confounding: age, whether sepsis was identified in the ED

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versus an inpatient unit, pre-existing CHF, pre-existing CRF, malignancy, lower respiratory infection

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confirmed by chest radiography, altered mentation at presentation, hypoxia, AKI, and coagulopathy. We selected these factors in an effort to control for comorbidity burden and severity of organ

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dysfunction at presentation. We also included ED versus inpatient identified sepsis specifically because inpatients with new sepsis would necessarily have developed sepsis complicating another

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medical condition, bundle compliance might be more easily achieved in the ED, and because

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population-level literature has suggested mortality may be higher for sepsis patients who do not

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present with sepsis at hospital arrival26.

We manually entered bundle compliance status into the model, a categorical variable for intermediate vs severe hyperlactemia, and an interaction term between compliance and hyperlactemia, followed by the above-stated covariates. (Non-compliance and intermediate hyperlactemia were set as the reference values, respectively). All terms were manually entered into the model and retained regardless of significance. We assessed goodness-of-fit with Hosmer-Lemeshow test where the null hypothesis, that the model fit the data, was accepted for p>0.05. We were not able to assess additional potential interactions (e.g., with CHF) without exceeding our allotted degrees of freedom which would have risked over-fitting. We repeated this procedure to test differential risk for 28-day hospital mortality and again for mechanical ventilation. There were no missing data for any data-field included in the models.

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ACCEPTED MANUSCRIPT Sensitivity Analysis As a post-hoc sensitivity analysis, we computed a new compliance variable based solely on the interventional elements of the bundle (i.e., intravenous fluids initiated within 30 minutes, and antibiotic

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administered within both 60 minutes of time-zero and 180 minutes of ≥2 SIRS criteria). For this analysis we classified patients as compliant if both antibiotic and fluid initiation goals of the bundle

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were met, irrespective lactate order-to-result time and blood culture elements. We then ran the

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models for 60-day mortality, 28-day mortality, and mechanical ventilation as specified above using

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this alternative compliance definition.

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RESULTS Subject Characteristics

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The QI database contained records for 7,239 patient encounters during the 2015 period. 2,417 cases

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would ultimately be eligible for study analyses (Figure 1). 704(29%) of these patients had a lactate

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>3.9mmol/L. The full compliance rate was 29% within severe and 28% within intermediate hyperlactemia populations. Compliance with fluids and antibiotics bundle elements alone was 47% for severely hyperlactemic patients vs. 36% for the intermediate group. We report distribution of baseline demographic, clinical, and treatment characteristics across the four groups of the cohort in Table 2.

Unadjusted Outcomes Unadjusted outcomes are shown in Table 2. Of the 424(17.5%) in-hospital mortalities occurring within 60 days, we observed 182(14.9%) in the intermediate/non-compliant group versus 41(8.4%) in the intermediate/compliant group [difference between compliant and non-compliant: 6.5%, confidence interval (CI): 3.1%–9.5%], while the severe/non-compliant group experienced 147(29.2%) versus 54(27.0%) mortalities in the severe/compliant group [difference between compliant and noncompliant: 2.2%, CI:(-)5.4%–9.4%] [difference of differences: 4.3%, CI: 2.6%–5.9%]. 586(24.2%) total patients required mechanical ventilation: 273(22.3%) intermediate lactate level patients receiving nonPage 10 of 26

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ACCEPTED MANUSCRIPT compliant bundle care versus 63(12.9%) intermediate lactate level/compliant patients [difference between compliant and non-compliant: 9.4%, CI: 5.4%–13.0%] and 191(37.9%) severe lactate level/non-compliant patients versus 59(29.5%) severe lactate level/compliant patients [difference

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between compliant and non-compliant: 8.4%, CI: 0.6%–15.7%] [difference of differences: 1.0%, CI: (-

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)1.6%–3.4% ].

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Outcomes on Adjustment

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Results from adjusted models are summarized in Table 3. As expected, in multiple logistic regression adjusted for: age, whether sepsis was identified in the ED or after admission, CHF, CRF, positive

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chest radiography, active malignancy, altered mentation, hypoxia, AKI, and coagulopathy, lactate ≥4.0mmol/L was associated with increased 60-day mortality (adjusted odds ratio(AOR): 1.99, CI:

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1.51-2.61, p<0.001) and bundle compliance was associated with decreased 60-day mortality (AOR:

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0.62, CI: 0.42-0.90, p=0.013) (Table 4a). We observed a significant interaction effect between bundle

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compliance and lactate group, with p(interaction)=0.022; i.e., the effect of bundle compliance in the model was different for patients with different initial lactate levels. The model displayed adequate fit (Hosmer-Lemeshow: χ2=4.3, p=0.83). In sensitivity analysis for 60-day hospital mortality where compliance was defined only as adherence to the fluids and antibiotics elements of the 3-hour bundle, results where similar (Table 4b). Fit remained adequate (Hosmer-Lemeshow: χ2=11.6, p=0.20), and we observed significant association between the outcome and lactate group (AOR: 1.72, CI: 1.25-3.72, p=0.001), antibiotic and fluids compliance (AOR: 0.70, CI: 0.51-0.96, p=0.029), and the interaction of lactate group with antibiotic and fluids compliance (p(interaction)=0.004).

Results were similar when 28-day hospital mortality was the outcome (Table 3, Tables 1aS, 1bS). In a model testing predictors of mechanical ventilation (Hosmer-Lemeshow: χ2=11.4, p=0.20), both compliance and initial lactate were significantly associated with the outcome (AOR: 0.69, CI: 0.500.95, p=0.024; and AOR: 1.69, CI: 1.30-2.20, p<0.001, respectively), but the interaction between the Page 11 of 26

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ACCEPTED MANUSCRIPT two variables was not significant on adjustment (p(interaction)=0.34). In sensitivity analysis, the model assessing mechanical ventilation did not adequately fit the data (Hosmer-Lemeshow: χ2=18.1,

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p=0.02) (Table 3, Tables 2aS, 2bS).

DISCUSSION

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In this multisite analysis of 2,417 non-hypotensive sepsis patients, the effect of initial bundle

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compliance was associated with a larger mortality risk-reduction for patients with intermediate

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hyperlactemia than for patients with lactate >3.9mmol/L. However, the magnitude of reduced mechanical ventilation risk associated with bundle compliance was comparable between lactate

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groups. We cautiously interpret this to suggest that the population with the less severe presentation

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derived greater benefit from early application of initial bundle care.

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Importantly, this analysis excluded patients who were hypotensive at their initial sepsis presentation.

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We made this exclusion due to the observational nature of the study. In the context of the study question, including these patients would present substantial issues of data endogeneity. Clinically, hypotensive patients are more easily identified as septic in their initial presentation, suggesting hypotension would have been associated with bundle compliance27. Hypotension is often concomitant with, and many times a likely cause of, tissue hypoperfusion and contemporary thinking suggests hypotension resulting from systemic inflammatory vasodilation and microvascular thrombosis to be an important mechanism of injury in septic shock28. As a result, we would have expected a second confounding association, between hypotension and more severe hyperlactemia. Further, hypotension is a predictor of mortality12,13,21, suggesting at least three major dimensions of bias had these patients been included.

This exclusion also presents a key lens for interpreting our findings. For one, this is likely a factor explaining the low mortality rate for the intermediate hyperlactemia group. More interestingly, we Page 12 of 26

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ACCEPTED MANUSCRIPT observe high mortality in the severe hyperlactemia group, supporting prior literature that this nonhypotensive cryptic shock population is at high risk for mortality. However, the significant interactioncoefficient between lactate and bundle compliance indicated the association of reduced mortality and

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bundle compliance was significant only for patients with intermediate hyperlactemia in this study. While it is possible this may be explained by the smaller sample size for the severe hyperlactemia

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group, or by unmeasured differences between groups, the severe hyperlactemia patients may have

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simply not responded as well to initial resuscitation. Should this observation prove reproducible, this

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would be new evidence supporting the framework that a less severe presentation of sepsis benefits

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from equal rates of successful adherence to a 3-hour sepsis bundle.

We also note that a full 50% of the cohort assessed were intermediate hyperlactemia patients

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receiving non-compliant care. While likely inflated by the exclusion of initially hypotensive patients,

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this large proportion nevertheless represents a large target population for future quality initiatives,

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regardless of whether treatment response truly differs by initial hyperlactemia severity. Importantly, the low overall compliance rates, particularly given that the study population is drawn from highperforming sites8,22,24, suggest hemodynamically stable sepsis patients may be at heightened risk of under-recognition and under-treatment in general. Notably, our 29% compliance rates are comparable to the pre-implementation rates in a prior large study by Liu and colleagues that assessed an initiative specifically targeting intermediate lactate patients. Our 44% adherence to antibiotics and fluids in the intermediate lactate cohort is comparable to that study’s postimplementation adherence rates.

Our results suggest that early intervention for less severely ill patients could put them in better position with respect to disease progression, supporting the approach to sepsis care that emphasizes prevention of delayed decompensation. Our results are consistent with the paper by Liu and colleagues that suggested hemodynamically stable sepsis patients with intermediate lactate may Page 13 of 26

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derive benefit from initial bundle care,20 although we are unaware of a direct comparison of this population to a “cryptic shock” population with lactate ≥4.0. These findings warrant further exploration. Future studies should attempt to determine the differential effect of bundle compliance in a larger

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population using more generalizable definitions of sepsis and more comprehensive characterizations

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of patients’ physiologic status at the time of presentation.

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Interestingly, the interaction effect was significant only for mortality, while the association between

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bundle compliance and reduced risk for mechanical ventilation was preserved across lactate groups. We could not investigate this seemingly contradictory finding further because we were unable to

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assess other organ-support requirements as outcomes, such as renal replacement therapy. It could be non-respiratory organ dysfunction contributes disproportionately to mortality in sepsis, and

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consider this question as well.

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although we are not in a position to evaluate this hypothesis with our data, future studies should

This investigation has a number of limitations. As with all non-randomized studies, unintended bias presents an important concern. We control for observed factors with multivariable modeling, but potential for unobserved confounding remains. No physician intends to administer delayed care, so patients receiving compliant versus non-compliant care may be somehow “different”, with the latter perhaps demonstrating a more complex or insidious presentation. We also employ inclusion criteria that align with the direction of Sepsis-3 definitions but that are not entirely concordant with either new or old consensus criteria, limiting direct integration of our findings. We were not able to use these criteria for operational reasons. Also, our window of observation focuses on the initial sepsis episode and care, but downstream outcomes like mortality can be influenced by factors occurring later in the patient’s stay. In the context of this study’s research question, we also acknowledge the inability to capture composite-measures such as SOFA scores a secondary limitation that probably does not intrinsically limit internal-validity, but that poses an obstacle in assessing external-validity. Additional Page 14 of 26

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ACCEPTED MANUSCRIPT limitations include retrospective design, inability to assess other measures of organ support besides mechanical ventilation, and inability to assess inter-rater reliability among QI database abstractors.

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In conclusion, bundle compliance may be low for non-hypotensive sepsis patients with elevated lactate, suggesting this population could benefit from targeted quality initiatives. We observed a

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greater association between bundle compliance and improved mortality for patients with intermediate

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compared to severe elevations in initial lactate level. Our results support rapid sepsis bundle

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application for stable, infected patients with intermediate hyperlactemia.

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3. Jones AE, Brown MD, Trzeciak S, et al. The effect of a quantitative resuscitation strategy on mortality in

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6. Seymour CW, Cooke CR, Heckbert SR, et al. Prehospital intravenous access and fluid resuscitation in

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8. Leisman D, Wie B, Doerfler M, et al. Association of Fluid Resuscitation Initiation Within 30 Minutes of Severe Sepsis and Septic Shock Recognition With Reduced Mortality and Length of Stay. Ann Emerg Med. 2016.

9. Loiacono LA, Shapiro DS. Detection of hypoxia at the cellular level. Crit Care Clin. 2010;26(2):409-421, table of contents. 10. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med. 2007;33(11):1892-1899. 11. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009;37(5):1670-1677. 12. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774. Page 16 of 26

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early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746.

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15. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in

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severe sepsis and septic shock. Crit Care Med. 2004;32(8):1637-1642.

16. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of

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innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-1655.

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17. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250-1256.

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18. Jones AE, Puskarich MA. The Surviving Sepsis Campaign guidelines 2012: update for emergency

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physicians. Ann Emerg Med. 2014;63(1):35-47.

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19. National Quality Forum. Severe Sepsis and Septic Shock: Management Bundles (NQF #0500) 20. Liu VX, Morehouse JW, Marelich GP, et al. Multicenter Implementation of a Treatment Bundle for Sepsis Patients with Intermediate Lactate Values. Am J Respir Crit Care Med. 2015. 21. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 22. Doerfler ME, D'Angelo J, Jacobsen D, et al. Methods for reducing sepsis mortality in emergency departments and inpatient units. Jt Comm J Qual Patient Saf. 2015;41(5):205-211. 23. Statewide Planning and Research Cooperative System (SPARCS). In: Health NYSDo2016. 24. Leisman DE, Doerfler ME, Ward MF, et al. Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts. Crit Care Med. 2016. 25. Mebazaa A, Laterre PF, Russell JA, et al. Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure. J Intensive Care. 2016;4:24.

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ACCEPTED MANUSCRIPT 26. Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA. 2014;312(1):90-92. 27. Amaral AC, Fowler RA, Pinto R, et al. Patient and Organizational Factors Associated With Delays in Antimicrobial Therapy for Septic Shock. Crit Care Med. 2016.

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28. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-851.

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ACCEPTED MANUSCRIPT Table 1. Organ Dysfunction “Time-Zero” Criteria Definitions Organ Dysfunction Criteria

†

Definition Serum creatinine >2.0 mg/dL or 50% increase from known baseline in the absence of chronic kidney disease

2. Thrombocytopenia

Platelet count < 150,000 cells/μm3

3. Coagulopathy§

International normalized ratio (INR) >1.5, activated partial thromboplastin time >30 seconds, or partial thromboplastin time >60 seconds, not otherwise explained by medical history

4. Elevated Bilirubin

Serum bilirubin > 2.0 mg/dL in the absence of pre-existing liver failure

5. Acute Altered Mental Status (AMS)

New altered mentation unrelated to the patient’s prior medical history

6. Hypoxia¶

New increased O2 requirement to maintain SaO2 > 90% or a PaO2/FiO2 ratio < 300

7. ≥2 “Super-SIRS” Criteria at Triage

Locally developed consensus-criteria, where meeting ≥2 criteria at triage was a “time-zero” entry point for 3hour bundle care. “Super-SIRS” criteria were:

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4) 5)

Heart rate greater ≥ 120 Respiratory rate ≥ 24 Systolic blood pressure < 90 mmHg or 40% decrease from known baseline or mean arterial pressure < 65 mmHgᴽ Temperature ≥ 38.0° C (101.0° F) or ≤ 36.0° C (96.8° F) Acutely altered mental status

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1) 2) 3)

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1. Acute Kidney Injury (AKI) ‡

† These 7 “time-zero” triggers were used as 3-hour bundle entry points as well as study inclusion criteria. The intention was for all patients with a suspected infection who met ≥2 SIRS criteria and any one of these criteria to receive carefully adherent to all 3-hour bundle elements. All patients included in this study had a source of infection, met at least 2 SIRS criteria, and met at least one of the above organ dysfunction criteria. Time-zero was the first laboratory result or vital sign measurement time that caused the patient to meet any of the above criteria.

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‡ Adapted from Kidney Disease | Improving Global Outcomes (KDIGO) criteria for defining acute kidney injury

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§ Adapted from the 2001 International Sepsis Definitions Conference (Sepsis-2) report. ¶ Adapted from the 2001 International Sepsis Definitions Conference (Sepsis-2) report.

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ᴽ Any patient having met Super-SIRS criteria because of hypotension would have been excluded

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ACCEPTED MANUSCRIPT Table 2 – Cohort Characteristics and Unadjusted Outcomes (All Subjects)

≥4.0mmol/L

≥4.0mmol/L

2.2-3.9mmol/L

2.2-3.9mmol/L

Bundle Compliance Group

(All Subjects)

Non-Compliant

Compliant

Non-Compliant

Compliant

N

1225

488

115 (57.5)

632 (51.6)

283 (58)

71 (60,82)

74 (61,84)

72.0 (57, 84.5)

25.1 (21.9, 29.3)

26.6 (22.4, 32.0)

26.1 (22.2, 31.4)

106 (53.0)

735 (60.0)

282 (57.8)

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Hyperlactemia Group

2,417

504

200

Male sex

1,297 (53.7)

267 (53.0)

Age – years (IQR)

73 (60, 84)

72 (60,83)

26.5 (22.4, 31.6)

26.9 (23.1, 31.5)

Medicare

1,430 (59.2)

307 (60.9)

Medicaid

180 (7.5)

40 (7.9)

15 (7.5)

77 (6.3)

48 (9.8)

Commercial Insurance

782 (32.4)

151 (30.0)

74 (37.0)

405 (33.1)

152 (31.1)

76 (15.1)

14 (7.0)

160 (13.1)

37 (7.6)

Comorbidities at Presentation – no (%)†

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BMI – median (IQR)

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Demographics

287 (11.9)

Chronic Obstructive Pulmonary Disease

183 (7.6)

40 (7.9)

18 (9.0)

95 (7.8)

30 (6.1)

Diabetes

826 (34.2)

176 (34.9)

51 (25.5)

432 (35.3)

167 (34.2)

Immune Modifying Medications

170 (7.0)

24 (4.8)

14 (7.0)

92 (7.3)

42 (8.6)

50 (2.1)

11 (2.2)

8 (4.0)

22 (1.8)

9 (1.8)

92 (3.8)

18 (3.6)

7 (3.5)

50 (4.1)

17 (3.5)

525 (21.7)

160 (31.7)

54 (27.0)

250 (20.4)

61 (12.5)

17 (0.7)

6 (1.2)

0 (0.0)

8 (0.7)

3 (0.6)

226 (9.4)

48 (9.5)

18 (9.0)

123 (10.0)

37 (7.6)

19 (0.8)

1 (0.2)

0 (0.0)

13 (1.1)

5 (1.0)

113 (4.7)

20 (4.0)

15 (7.5)

58 (4.7)

20 (4.1)

2,046 (84.7)

379 (75.2)

180 (90.0)

1,035 (84.5)

452 (92.6)

Urinary

559 (23.1)

96 (19.0)

33 (16.5)

310 (25.3)

120 (24.6)

Respiratory

867 (35.9)

183 (36.3)

69 (34.5)

442 (36.1)

172 (35.5)

Gastrointestinal

258 (10.7)

62 (12.3)

29 (14.5)

131 (10.7)

36 (7.4)

Skin

206 (8.5)

25 (5.0)

11 (5.5)

120 (9.8)

50 (10.2)

6 (0.2)

2 (0.4)

1 (0.5)

1 (0.1)

2 (0.4)

Other

241 (10.0)

63 (12.5)

28 (14.0)

104 (8.5)

46 (9.4)

Unknown

280 (11.6)

73 (14.5)

29 (14.5)

117 (9.6)

61 (12.5)

788 (33.3)

151 (30.0)

68 (34.0)

400 (32.7)

169 (34.6)

Metastatic Disease Organ Transplant Chronic Renal Failure HIV/AIDS Nosocomial Infection – no (%)

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Leukemia, Lymphoma, or Multiple Myeloma

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Liver Failure

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Congestive Heart Failure

Presentation and Acuity – no (%)

Sepsis Identified in the Emergency Department Suspected Site of Infection

Central Nervous System

Positive Chest Radiography at Presentation

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ACCEPTED MANUSCRIPT Initial Lactate (mmol/L) – median (IQR)

5.3 (4.6, 6.85)

5.2 (4.4, 6.8)

2.8 (2.4, 3.2)

2.8 (2.4, 3.2)

Acute Kidney Injury§

327 (13.5)

90 (17.9)

38 (19.0)

145 (11.8)

54 (11.1)

Coagulopathy¶

311 (12.9)

76 (15.1)

32 (16.0)

149 (12.2)

54 (11.1)

Bilirubin > 2.0 mg/dL

169 (7.0)

48 (9.5)

12 (6.0)

77 (6.2)

33 (6.8)

Altered Mental Status

393 (16.3)

106 (20.1)

40 (20.0)

192 (15.7)

55 (11.3)

Hypoxiaᴽ

315 (13.0)

103 (20.4)

28 (14.0)

156 (12.7)

28 (5.7)

Super SIRS Criteria at Triage – no (%)‡

538 (22.4)

126 (25.4)

46 (23.0)

278 (22.8)

88 (18.0)

7 (-44, 65)

35.5 ( -52, 118)

-22 ( -48.5, 5)

44 ( -23, 150)

-23.5 ( -53.5, 5)

Fluid initiation ≤ 30 minutes

1,275 (52.8)

190 (37.7)

200 (100)

397 (32.4)

488 (100)

Fluid volume given (Liters) – median (IQR)

1.5 (1.0; 2.0)

1.5 (0.5, 2.5)

2.0 (1.5, 3.0)

1.0 (0.5, 2.0)

2.0 (1.0, 2.125)

Lactate order to result time – median (IQR)

44 (21,86)

53 (21, 122.5)

34.5 ( 21, 51)

49 ( 21, 108)

37 ( 21, 55)

329 (65.3)

200 (100)

845 (69.0)

488 (100)

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Time to fluids initiation – median◊ (IQR)

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InterventionsΩ

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3.1 (2.6, 4.3)

1,862 (77.0)

Blood cultures drawn before antibiotics

1,662 (68.8)

282 (56.0)

200 (100)

692 (56.5)

488 (100)

Time to antibiotic administration – median (IQR)

52 (-2, 137)

70 ( 11, 229)

25 (-6.5, 59.5)

70 (1, 204.5)

22 (-11, 65.5)

Antibiotics ≤60 min (time-zero) and ≤180 min(2 SIRS)

1,805 (74.7)

325 (64.5)

200 (100)

792 (64.7)

488 (100)

134 (26.6)

200 (100)

272 (22.2)

488 (100)

73 (3.0)

19 (3.8)

0 (0)

54 (4.4)

0 (0)

323 (13.4)

86 (17.1)

0 (0)

237 (19.3)

0 (0)

470 (19.4)

157 (31.2)

0 (0)

313 (25.6)

0 (0)

863 (35.7)

242 (48.0)

0 (0)

621 (50.7)

0 (0)

688 (28.5)

0 (0)

200 (100)

0 (0)

488 (100)

60-Day Hospital Mortality – no (%)

424 (17.5)

147 (29.2)

54 (27.0)

182 (14.9)

41 (8.4)

28-Day Hospital Mortality – no (%)

388 (16.1)

138 (27.4)

52 (26.0)

162 (13.2)

36 (7.4)

Mechanical Ventilation Required – no (%)

586 (24.2)

191 (37.9)

59 (29.5)

273 (22.3)

63 (12.9)

Vasopressors Administered – no (%)

262 (11.1)

111 (22.0)

20 (10.0)

112 (9.1)

19 (3.9)

7 (4, 13)

7.5 (4,14)

7 (3,14)

7 (4,12)

6 (4,11)

One Two Three All Four

Unadjusted Outcomes

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Zero

1,094 (45.3)

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Both fluids & antibiotic bundle goal compliance No. of bundle elements accomplished – no(%)

Median length of stay – days (IQR)

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Lactate order to result ≤ 90 minutes

† Comorbidities reflect status at time-zero, and would not reflect conditions that developed subsequently during hospital stay. § Acute Kidney Injury defined as creatinine >2.0 or 50% increase from a known baseline. ¶ Coagulopathy defined as platelet count < 150,000 cells/µm3, international normalized ratio > 1.5, or partial thromboplastin time > 60 seconds. ᴽ Hypoxia defined as PaO2 /FiO2 < 300 or an increased O2 requirement to maintain SaO2 >90%. Ω All times are in minutes, and reflect the time elapsed from time-zero unless otherwise indicated. A negative time indicates an intervention performed before time-zero. E.g., a patient whose fluid resuscitation began 20 minutes before laboratory results indicating organ dysfunction became available have a fluid initiation time of -20.

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◊ All crystalloid was 0.9% normal saline solution.

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Outcome Primary Outcome

Model Fit

60-day in-hospital mortality

Factor Tested

Odds Ratio

95% CI

p value

2

Bundle Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

0.62 1.99 1.91

0.42 – 0.90 1.51 – 2.63 1.10 – 3.31

0.013 < 0.001 0.022

2

Bundle Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

0.59 2.14 1.99

0.39 – 0.88 1.61 – 2.84 1.13 – 3.50

0.010 < 0.001 0.017

0.69 1.69 1.29

0.50 – 0.95 1.30 – 2.22 0.77 – 2.17

0.024 < 0.001 0.34

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Table 3. Adjusted Outcomes from Multivariable Logistic Regression Analyses

0.70 1.72 2.02

0.51 – 0.96 1.25 – 2.37 1.24 – 3.28

0.029 0.001 0.004

Antibiotic and Fluids Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

0.65 1.86 2.07

0.47 – 0.91 1.34 – 2.58 1.26 – 3.40

0.013 < 0.001 0.004

0.83 1.66 1.20

0.63 – 1.10 1.22 – 2.25 0.76 – 1.90

0.189 < 0.001 0.43

Χ =4.3,p=0.83

28-day in-hospital mortality

Χ =9.4,p=0.31

Mechanical ventilation

Χ =11.4,p=0.20

Bundle Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

2

Antibiotic and Fluids Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

60-day in-hospital mortality

Χ =11.6,p=0.20

28-day in-hospital mortality

Χ =7.4,p=0.49

Mechanical ventilation

Χ =18.1,p=0.02

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Secondary Outcomes

Antibiotic and Fluids Compliance Lactate ≥4.0mmol/L Compliance*Lactate Interaction

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Models were adjusted for the following variables: age, whether sepsis was identified in the emergency department, pre-existing heart failure, preexisting renal failure, active malignancy, whether there was a positive chest radiographic finding at the time of initial sepsis episode, acutely altered mental status, hypoxia, acute kidney injury, and coagulopathy. Hosmer-Lemeshow tests assessed goodness-of-fit, where the null hypothesis that the model fit the data was accepted for p>0.05.

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The interaction coefficient is the ratio of the odds ratio for a variable at one value of a second variable over the odds ratio for the first variable at the alternate value of the second variable. A significant, positive number in this table therefore indicates that the odds ratio for bundle compliance increases from the reference value of lactate (2.2-3.9) to a larger number for the alternate value of lactate (≥4.0), i.e., a less pronounced association.

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ACCEPTED MANUSCRIPT Table 4 – Final Logistic Model for Predictors of 60-Day In-Hospital Mortality 95% Confidence-Interval 1.51 2.63 0.42 0.90 1.10 3.31 1.17 1.37 2.63 4.76 0.82 1.58 0.86 1.78 1.04 3.12 1.40 2.29 1.04 1.86 1.06 1.98 1.41 2.62 1.58 2.90

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Odds Ratio 1.99 0.62 1.91 1.27 3.57 1.14 1.23 1.80 1.79 1.39 1.45 1.93 2.14

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Hosmer and Lemeshow test for goodness-of-fit: Χ =5.3, p=0.73.

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Variable Lactate > 3.9 mmol/L Full 3-Hour Bundle Compliance Bundle Compliance x Lactate Interaction Age Initial Sepsis Episode Not in the ED Congestive Heart Failure Chronic Renal Failure Active Malignancy Positive Chest Radiography Acutely Altered Mental Status Hypoxia* Acute Kidney Injury† Coagulopathy‡

p value < 0.001 0.013 0.022 < 0.001 < 0.001 0.44 0.26 0.035 < 0.001 0.025 0.020 < 0.001 < 0.001

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Age was a continuous variable with a base unit equal to 10 years. All other variables were treated as binary variables with the negative state set as the referent. There were 424 events occurring in the sample. * Hypoxia defined as PaO2 /FiO2 < 300 or an increased O2 requirement to maintain SaO2 >90%. † Acute Kidney Injury defined as creatinine >2.0 or 50% increase from a known baseline 3 ‡ Coagulopathy defined as platelet count < 150,000 cells/µm or an international normalized ratio > 1.5 or a partial thromboplastin time > 60 seconds

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Table 4b – Final Sensitivity Model for Predictors of 60-Day In-Hospital Mortality Variable Lactate > 3.9 mmol/L Compliance with Antibiotic and Fluids Bundle Elements Antibiotic and Fluids Compliance x Lactate Interaction Age Initial Sepsis Episode Not in the ED Congestive Heart Failure Chronic Renal Failure Active Malignancy Positive Chest Radiography Acutely Altered Mental Status Hypoxia* Acute Kidney Injury† Coagulopathy‡

Odds Ratio 1.72 0.70 2.02 1.27 3.70 1.76 1.16 1.24 1.83 1.40 1.47 1.90 2.14

95% Confidence-Interval 1.25 2.37 0.51 0.96 1.24 3.28 1.17 1.38 2.70 5.00 1.37 2.26 0.83 1.60 0.86 1.79 1.06 3.16 1.05 1.88 1.07 2.01 1.40 2.59 1.58 2.90

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p value 0.001 0.029 0.004 < 0.001 < 0.001 < 0.001 0.39 0.25 0.030 0.022 0.016 < 0.001 < 0.001

Hosmer and Lemeshow test for goodness-of-fit: Χ =11.6, p=0.20. Age was a continuous variable with a base unit equal to 10 years. All other variables were treated as binary variables with the negative state set as the referent. There were 424 events occurring in the sample. * Hypoxia defined as PaO2 /FiO2 < 300 or an increased O2 requirement to maintain SaO2 >90%. † Acute Kidney Injury defined as creatinine >2.0 or 50% increase from a known baseline 3 ‡ Coagulopathy defined as platelet count < 150,000 cells/µm or an international normalized ratio > 1.5 or a partial thromboplastin time > 60 seconds

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