A roadmap for developing an emergency department based critical care consultation service: Building the early intervention team (EIT).

Emergency Department (ED) crowding and boarding impact safe and effective health care delivery. ED clinicians must balance caring for new arrivals who require stabilization and resuscitation as well as those who need longitudinal care and re-evaluation. These challenges are magnified in the setting of critically ill patients boarding for the intensive care unit. Boarding is a complex issue that has multiple solutions based on resources at individual institutions. Several different models have been described for delivery of critical care in the ED. Here, we describe the development of an ED based critical care consultation service, the early intervention team, at an urban academic ED.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.

OBJECTIVES: Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test. DESIGN: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results. SETTING: Four U.S. emergency departments. PATIENTS: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis. INTERVENTIONS: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes. MEASUREMENTS AND MAIN RESULTS: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance. CONCLUSIONS: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.

Performance of PCR/Electrospray Ionization-Mass Spectrometry on Whole Blood for Detection of Bloodstream Microorganisms in Patients with Suspected Sepsis.

Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the United States (n = 13) and Europe (n = 3). First, on testing of 2,754 contrived whole blood samples, with or without spiked microorganisms, PCR/ESI-MS produced 99.1% true-positive and 97.2% true-negative results. Second, among 1,460 patients with suspected sepsis (sepsis-2 definition), BC and PCR/ESI-MS on whole blood were positive in 14.6% and 25.6% of cases, respectively, with the following result combinations: BC positive and PCR/ESI-MS negative, 4.3%; BC positive and PCR/ESI-MS positive, 10.3%; BC negative and PCR/ESI-MS positive, 15.3%; and BC negative and PCR/ESI-MS negative, 70.1%. Compared with BC, PCR/ESI-MS showed the following sensitivities (coagulase-negative staphylococci not included): Gram-positive bacteria, 58%; Gram-negative bacteria, 78%; and Candida species, 83%. The specificities were >94% for all individual species. Patients who had received prior antimicrobial medications (n = 603) had significantly higher PCR/ESI-MS positivity rates than patients without prior antimicrobial treatment-31% versus 22% (P < 0.0001)-with pronounced differences for Gram-negative bacteria and Candida species. In conclusion, PCR/ESI-MS showed excellent performance on contrived samples. On clinical samples, it showed high specificities, moderately high sensitivities for Gram-negative bacteria and Candida species, and elevated positivity rates during antimicrobial treatment. These promising results encourage further development of molecular diagnostics to be used with whole blood for detection of bloodstream microorganisms in sepsis.

F-Actin is associated with a worsening qSOFA score and intensive care unit admission in emergency department patients at risk for sepsis.

Objective: We previously demonstrated that plasma levels of F-actin and Thymosin Beta 4 differs among patients with septic shock, non-infectious systemic inflammatory syndrome and healthy controls and may serve as biomarkers for the diagnosis of sepsis. The current study aims to determine if these proteins are associated with or predictive of illness severity in patients at risk for sepsis in the Emergency Department (ED).Methods: Prospective, biomarker study enrolling patients (>18 years) who met the Shock Precautions on Triage Sepsis rule placing them at-risk for sepsis.Results: In this study of 203 ED patients, F-actin plasma levels had a linear trend of increase when the quick Sequential Organ Failure Assessment (qSOFA) score increased. F-actin was also increased in patients who were admitted to the Intensive Care Unit (ICU) from the ED, and in those with positive urine cultures. Thymosin Beta 4 was not associated with or predictive of any significant outcome measures.Conclusion: Increased levels of plasma F-actin measured in the ED were associated with incremental illness severity as measured by the qSOFA score and need for ICU admission. F-actin may have utility in risk stratification of undifferentiated patients in the ED presenting with signs and symptoms of sepsis.

Change in Lactate Levels After Hemodialysis in Patients With End-Stage Renal Disease.

STUDY OBJECTIVE: Patients with end-stage renal disease commonly visit the emergency department (ED). The purpose of this investigation is to examine the prevalence of baseline abnormal lactate levels and to evaluate the effects of hemodialysis on serum lactate levels. METHODS: This was a prospective observational cohort study performed at an outpatient dialysis facility at an urban tertiary care hospital. The study consisted of 226 patients with end-stage renal disease who were receiving long-term hemodialysis and were enrolled during a 2-day period at the beginning of December 2015. Blood drawn for lactate levels was immediately analyzed before and after hemodialysis sessions. All patients completed their hemodialysis sessions. RESULTS: The prevalence of an abnormal lactate level (greater than 1.8 mmol/L) before hemodialysis was 17.7% (n=40). Overall, lactate levels decreased by 27% (SD 35%) after hemodialysis, with a decrease of 37% (SD 31%) for subgroups with a lactate level of 1.9 to 2.4 mmol/L, and 62% (SD 14%) with a lactate of 2.5 to 3.9 mmol/L. CONCLUSION: The data presented help providers understand the prevalence of abnormal lactate values in an outpatient end-stage renal disease population. After hemodialysis, lactate levels decreased significantly. This information may help medical providers interpret lactate values when patients with end-stage renal disease present to the ED.

Nonlinear Imputation of PaO2/FIO2 From SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study.

OBJECTIVES: In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is accurate, but this has not been established prospectively among mechanically ventilated ICU patients. The objective was to validate the superiority of nonlinear imputation of PaO2/FIO2 among mechanically ventilated patients and understand what factors influence the accuracy of imputation. DESIGN: Simultaneous SpO2, oximeter characteristics, receipt of vasopressors, and skin pigmentation were recorded at the time of a clinical arterial blood gas. Acute respiratory distress syndrome criteria were recorded. For each imputation method, we calculated both imputation error and the area under the curve for patients meeting criteria for acute respiratory distress syndrome (PaO2/FIO2 ≤ 300) and moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150). SETTING: Nine hospitals within the Prevention and Early Treatment of Acute Lung Injury network. PATIENTS: We prospectively enrolled 703 mechanically ventilated patients admitted to the emergency departments or ICUs of participating study hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied 1,034 arterial blood gases from 703 patients; 650 arterial blood gases were associated with SpO2 less than or equal to 96%. Nonlinear imputation had consistently lower error than other techniques. Among all patients, nonlinear had a lower error (p < 0.001) and higher (p < 0.001) area under the curve (0.87; 95% CI, 0.85-0.90) for PaO2/FIO2 less than or equal to 300 than linear/log-linear (0.80; 95% CI, 0.76-0.83) imputation. All imputation methods better identified moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 150); nonlinear imputation remained superior (p < 0.001). For PaO2/FIO2 less than or equal to 150, the sensitivity and specificity for nonlinear imputation were 0.87 (95% CI, 0.83-0.90) and 0.91 (95% CI, 0.88-0.93), respectively. Skin pigmentation and receipt of vasopressors were not associated with imputation accuracy. CONCLUSIONS: In mechanically ventilated patients, nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 seems accurate, especially for moderate-severe hypoxemia. Linear and log-linear imputations cannot be recommended.

Protocolized care for early shock resuscitation.

PURPOSE OF REVIEW: Protocolized care for early shock resuscitation (PCESR) has been intensely examined over the last decade. The purpose is to review the pathophysiologic basis, historical origin, clinical applications, components and outcome implications of PCESR. RECENT FINDINGS: PCESR is a multifaceted systems-based approach that includes early detection of high-risk patients and interventions to rapidly reverse hemodynamic perturbations that result in global or regional tissue hypoxia. It has been applied to perioperative surgery, trauma, cardiology (heart failure and acute myocardial infarction), pulmonary embolus, cardiac arrest, undifferentiated shock, postoperative cardiac surgery and pediatric septic shock. When this approach is used for adult septic shock, in particular, it is associated with a mortality reduction from 46.5 to less than 30% over the last 2 decades. Challenges to these findings are seen when repeated trials contain enrollment, diagnostic and therapeutic methodological differences. SUMMARY: PCESR is more than a hemodynamic optimization procedure. It also provides an educational framework for the less experienced and objective recognition of clinical improvement or deterioration. It further minimizes practices' variation and provides objective measures that can be audited, evaluated and amendable to continuous quality improvement. As a result, morbidity and mortality are improved.

Plasma levels of F-actin and F:G-actin ratio as potential new biomarkers in patients with septic shock.

OBJECTIVE: To compare plasma levels of F-actin, G-actin and thymosin beta 4 (TB4) in humans with septic shock, noninfectious systemic inflammatory response syndrome (SIRS) and healthy controls. RESULTS: F-actin was significantly elevated in septic shock as compared with noninfectious SIRS and healthy controls. G-actin levels were greatest in the noninfectious SIRS group but significantly elevated in septic shock as compared with healthy controls. TB4 was not detectable in the septic shock or noninfectious SIRS group above the assay's lowest detection range (78 ng/ml). CONCLUSIONS: F-actin is significantly elevated in patients with septic shock as compared with noninfectious SIRS. F-actin and the F:G-actin ratio are potential biomarkers for the diagnosis of septic shock.

Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.

Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.

Relationship between Central and Peripheral Venous Oxygen Saturation and Lactate Levels: A Prospective Study.

BACKGROUND: Optimization of tissue oxygen delivery to meet consumption demands is important in the resuscitation of critically ill patients. Central venous oxygen saturation (ScvO2) and lactate levels are often used to guide resuscitation; however, invasive monitoring is required for the former. Clinicians searching for less invasive alternatives may consider using peripheral venous oxygen saturation (SpvO2) and lactate levels as a substitute. OBJECTIVES: To determine the relationship between SpvO2 and ScvO2 and peripheral and central lactate levels. METHODS: All patients with a central venous catheter in an academic emergency department and intensive care unit were eligible for the study. Blood was obtained simultaneously from a central and peripheral vein and measured for oxygen saturation and lactate levels. Results were analyzed using intraclass correlation coefficient (ICC), Bland-Altman plots, and receiver operating characteristic curves. RESULTS: Seventy-nine paired blood samples were analyzed. SpvO2 and ScvO2 have moderate agreement: ICC = 0.53 (95% confidence interval [CI] 0.35-0.67). A Bland-Altman plot revealed substantial bias (-4.47; limits of agreement -38.6, 29.6). SpvO2 ≥ 85% was 90% specific for ScvO2 ≥ 70%, and SpvO2 of ≤ 55% had a 94% sensitivity for ScvO2 < 70%. Central and peripheral venous lactate levels showed almost perfect agreement: ICC = 0.92 (95% CI 0.87-0.95), bias of 0.46 (limits of agreement -1.78-2.70). CONCLUSION: SpvO2 and ScvO2 have moderate agreement. There was excellent agreement between peripheral and central lactate levels, making them interchangeable. The clinical implications of these substitutions in real-time patient management require further study.

Renal systems biology of patients with systemic inflammatory response syndrome.

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.

Oxygen extraction and perfusion markers in severe sepsis and septic shock: diagnostic, therapeutic and outcome implications.

PURPOSE OF REVIEW: The purpose of this study is to review the recent literature examining the clinical utility of markers of systemic oxygen extraction and perfusion in the diagnosis, treatment and prognosis of severe sepsis and septic shock. RECENT FINDINGS: When sepsis is accompanied by conditions in which systemic oxygen delivery does not meet tissue oxygen demands, tissue hypoperfusion begins. Tissue hypoperfusion leads to oxygen debt, cellular injury, organ dysfunction and death. Tissue hypoperfusion can be characterized using markers of tissue perfusion (central venous oxygen saturation and lactate), which reflect the interaction between systemic oxygen delivery and demands. For the last two decades, studies and quality initiatives incorporating the early detection and interruption of tissue hypoperfusion have been shown to improve mortality and altered sepsis care. Three recent trials, while confirming an all-time improvement in sepsis mortality, challenged the concept that rapid normalization of markers of perfusion confers outcome benefit. By defining and comparing haemodynamic phenotypes using markers of tissue perfusion, we may better understand which patients are more likely to benefit from early goal-directed haemodynamic optimization. SUMMARY: The phenotypic haemodynamic characterization of patients using perfusion markers has diagnostic, therapeutic and outcome implications in severe sepsis and septic shock. However, irrespective of haemodynamic phenotype, the outcome reflects the quality of care provided at the point of presentation. Utilizing these principles may allow more objective interpretation of resuscitation trials and translate these findings into current practice.

Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.

RATIONALE: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. OBJECTIVES: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. METHODS: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. MEASUREMENTS AND MAIN RESULTS: The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). CONCLUSIONS: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

A phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of talactoferrin in patients with severe sepsis.

OBJECTIVES: Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial. SETTING: Adult ICUs and emergency departments in the United States. PATIENTS: One hundred ninety-four adults within 24 hrs of the onset of severe sepsis. INTERVENTIONS: Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU. MEASUREMENTS AND MAIN RESULTS: Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo. CONCLUSIONS: Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

The GENESIS project (GENeralized Early Sepsis Intervention Strategies): a multicenter quality improvement collaborative.

BACKGROUND: Improved outcomes for severe sepsis and septic shock have been consistently observed with implementation of early best practice intervention strategies or the 6-hour resuscitation bundle (RB) in single-center studies. This multicenter study examines the in-hospital mortality effect of GENeralized Early Sepsis Intervention Strategies (GENESIS) when utilized in community and tertiary care settings. METHODS: This study was comprised of 2 strategies to assess treatment. The first was a prospective before-and-after observational comparison of historical controls to patients receiving the RB after implementation of GENESIS in 4 community and 4 tertiary hospitals. The second was a concurrent examination comparing patients not achieving all components of the RB to those achieving all components of the RB in 1 community and 2 tertiary care hospitals after implementation of GENESIS. These 4 subgroups merged to comprise a control (historical controls treated before GENESIS and RB not achieved after GENESIS) group and treatment (patients treated after GENESIS and RB achieved after GENESIS) group for comparison. RESULTS: The control group comprised 1554 patients not receiving the RB (952 before GENESIS and 602 RB not achieved after GENESIS). The treatment group comprised 4801 patients receiving the RB (4109 after GENESIS and 692 RB achieved after GENESIS). Patients receiving the RB (treatment group) experienced an in-hospital mortality reduction of 14% (42.8%-28.8%, P < .001) and a 5.1 day decrease in hospital length of stay (20.7 vs 15.6, P < .001) compared to those not receiving the RB (control group). Similar mortality reductions were seen in the before-and-after (43% vs 29%, P < .001) or concurrent RB not achieved versus achieved (42.5% vs 27.2%, P < .001) subgroup comparisons. CONCLUSIONS: Patients with severe sepsis and septic shock receiving the RB in community and tertiary hospitals experience similar and significant reductions in mortality and hospital length of stay. These findings remained consistent when examined in both before-and-after and concurrent analyses. Early sepsis intervention strategies are associated with 1 life being saved for every 7 treated.

CLINICAL, MOLECULAR, AND EXOSOMAL MECHANISMS OF CARDIAC AND BRAIN DYSFUNCTION IN SEPSIS.

ABSTRACT: Sepsis is a complex disease resulting from a dysregulated inflammatory response to an infection. Initiation of sepsis occurs from a localized infection that disseminates to the bloodstream placing all organ systems at risk. Septic shock is classically observed to manifest itself as systemic hypotension with hyporesponsiveness to vasopressor agents. Myocardial dysfunction occurs resulting in an inability to perfuse major organ systems throughout the body. Most importantly, the brain is hypoperfused creating an ischemic and inflammatory state resulting in the clinical observation of acute mental status changes and cognitive dysfunction commonly known as sepsis-associated encephalopathy. This short review describes the inflammatory molecular mechanisms of myocardial dysfunction, discusses the evidence of the dual roles of the microglia resulting in blood-brain barrier disruption, and suggests that septic-derived exosomes, endosome-derived lipid bilayer spheroids released from living cells, influence cardiac and neurological cellular function.