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Data-driven discovery of a novel sepsis pre-shock state predicts impending septic shock in the ICU.

ABSTRACT: Septic shock is a life-threatening condition in which timely treatment substantially reduces mortality. Reliable identification of patients with sepsis who are at elevated risk of developing septic shock therefore has the potential to save lives by opening an early window of intervention. We hypothesize the existence of a novel clinical state of sepsis referred to as the "pre-shock" state, and that patients with sepsis who enter this state are highly likely to develop septic shock at some future time. We apply three different machine learning techniques to the electronic health record data of 15,930 patients in the MIMIC-III database to test this hypothesis. This novel paradigm yields improved performance in identifying patients with sepsis who will progress to septic shock, as defined by Sepsis- 3 criteria, with the best method achieving a 0.93 area under the receiver operating curve, 88% sensitivity, 84% specificity, and median early warning time of 7?hours. Additionally, we introduce the notion of patient-specific positive predictive value, assigning confidence to individual predictions, and achieving values as high as 91%. This study demonstrates that early prediction of impending septic shock, and thus early intervention, is possible many hours in advance.

SUBMITTER: Liu R

PROVIDER: S-EPMC6467982 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Data-driven discovery of a novel sepsis pre-shock state predicts impending septic shock in the ICU.

Liu Ran R Greenstein Joseph L JL Granite Stephen J SJ Fackler James C JC Bembea Melania M MM Sarma Sridevi V SV Winslow Raimond L RL

Scientific reports 20190416 1

Septic shock is a life-threatening condition in which timely treatment substantially reduces mortality. Reliable identification of patients with sepsis who are at elevated risk of developing septic shock therefore has the potential to save lives by opening an early window of intervention. We hypothesize the existence of a novel clinical state of sepsis referred to as the "pre-shock" state, and that patients with sepsis who enter this state are highly likely to develop septic shock at some future ...[more]

PMID: 30992534

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Project description:ObjectivesSepsis and septic shock are leading causes of in-hospital mortality. Timely treatment is crucial in improving patient outcome, yet treatment delays remain common. Early prediction of those patients with sepsis who will progress to its most severe form, septic shock, can increase the actionable window for interventions. We aim to extend a time-evolving risk score, previously developed in adult patients, to predict pediatric sepsis patients who are likely to develop septic shock before its onset, and to determine whether or not these risk scores stratify into groups with distinct temporal evolution once this prediction is made.DesignRetrospective cohort study.SettingAcademic medical center from July 1, 2016, to December 11, 2020.PatientsSix-thousand one-hundred sixty-one patients under 18 admitted to the Johns Hopkins Hospital PICU.InterventionsNone.Measurements and main resultsWe trained risk models to predict impending transition into septic shock and compute time-evolving risk scores representative of a patient's probability of developing septic shock. We obtain early prediction performance of 0.90 area under the receiver operating curve, 43% overall positive predictive value, patient-specific positive predictive value as high as 62%, and an 8.9-hour median early warning time using Sepsis-3 labels based on age-adjusted Sequential Organ Failure Assessment score. Using spectral clustering, we stratified pediatric sepsis patients into two clusters differing in septic shock prevalence, mortality, and proportion of patients adequately fluid resuscitated.ConclusionsWe demonstrate the applicability of our methodology for early prediction and stratification for risk of septic shock in pediatric sepsis patients. Through analyses of risk score evolution over time, we corroborate our past finding of an abrupt transition preceding onset of septic shock in children and are able to stratify pediatric sepsis patients using their risk score trajectories into low and high-risk categories.

Project description:BackgroundAlthough sepsis accounts for 1 in 5 deaths globally, few molecular therapies exist for this condition. The development of effective biomarkers and treatments for sepsis requires a more complete understanding of host responses and pathogenic mechanisms at early stages of disease to minimize host-driven pathology.MethodsAn alternative to the current symptom-based approach used to diagnose sepsis is a precise assessment of blood proteomic changes during the onset and progression of Salmonella Typhimurium (ST) murine sepsis.FindingsA distinct pattern of coagulation factor protein abundance was identified in the pre-septic state- prior to overt disease symptoms or bacteremia- that was predictive of the dysregulation of fibrinolytic and anti-coagulant activities and resultant consumptive coagulopathy during ST murine sepsis. Moreover, the changes in protein abundance observed generally have the same directionality (increased or decreased abundance) reported for human sepsis. Significant overlap of ST coagulopathic activities was observed in Gram-negative Escherichia coli- but not in Gram-positive staphylococcal or pneumococcal murine sepsis models. Treatment with matrix metalloprotease inhibitors prevented aberrant inflammatory and coagulopathic activities post-ST infection and increased survival. Antibiotic treatment regimens initiated after specific changes arise in the plasma proteome post-ST infection were predictive of an increase in disease relapse and death after cessation of antibiotic treatment.InterpretationAltered blood proteomics provides a platform to develop rapid and easy-to-perform tests to predict sepsis for early intervention via biomarker incorporation into existing blood tests prompted by patient presentation with general malaise, and to stratify Gram-negative and Gram-positive infections for appropriate treatment. Antibiotics are less effective in microbial clearance when initiated after the onset of altered blood proteomics as evidenced by increased disease relapse and death after termination of antibiotic therapy. Treatment failure is potentially due to altered bacterial / host-responses and associated increased host-driven pathology, providing insight into why delays in antibiotic administration in human sepsis are associated with increased risk for death. Delayed treatment may thus require prolonged therapy for microbial clearance despite the prevailing notion of antibiotic de-escalation and shortened courses of antibiotics to improve drug stewardship.FundingNational Institutes of Health, U.S. Army.

Project description:ObjectiveTo identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.DesignA consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.MethodsEach committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science.ResultsThe Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?ConclusionsWhile the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

Project description:BackgroundWe hypothesized that the cardiovascular responses to Surviving Sepsis Guidelines (SSG)-defined resuscitation are predictable based on the cardiovascular state.MethodsFifty-five septic patients treated by SSG were studied before and after volume expansion (VE), and if needed norepinephrine (NE) and dobutamine. We measured mean arterial pressure (MAP), cardiac index (CI), and right atrial pressure (Pra) and calculated pulse pressure and stroke volume variation (PPV and SVV), dynamic arterial elastance (Eadyn), arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees), Ees/Ea (VAC), LV ejection efficiency (LVeff), mean systemic pressure analogue (Pmsa), venous return pressure gradient (Pvr), and cardiac performance (Eh), using standard formulae.ResultsAll patients were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beat min-1), with increased lactate levels (lactate = 5.0 ± 4.2 mmol L-1) with a worsened VAC. CI was variable but > 2 L min-1 M-2 in 74%. Twenty-eight-day mortality was 48% and associated with admission lactate, blood urea nitrogen (BUN), and creatinine levels but not cardiovascular state. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Fluid administration improved Pra, Pmsa, and Pvr in all patients, whereas both HR and Ea decreased after VE, thus normalizing VAC. CI increases were proportional to baseline PPV and SVV. CI increases proportionally decreased PPV and SVV. VE increased MAP > 65 mmHg in 35/55 patients. MAP responders had higher PPV, SVV, and Eadyn than non-responders. NE was given to 20/55 patients in septic shock, but increased MAP > 65 mmHg in only 12. NE increased Ea, Eadyn, Pra, Pmsa, and VAC while decreasing HR, PPV, SVV, and LVeff. MAP responders had higher pre-NE Ees and lower VAC. Dobutamine was given to 6/8 patients who remained hypotensive following NE. It increased Ees, MAP, CI, and LVeff, while decreasing HR, Pra, and VAC. At all times and all steps of the protocol, CI changes were proportional to Pvr changes independent of treatment.ConclusionsThe cardiovascular response to SSG-based resuscitation is highly heterogeneous but predictable from pre-treatment measures of cardiovascular state.

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Data-driven discovery of a novel sepsis pre-shock state predicts impending septic shock in the ICU.

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Data-driven discovery of a novel sepsis pre-shock state predicts impending septic shock in the ICU.

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