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Endothelial Damage During Septic Shock

2017; Elsevier BV; Volume: 152; Issue: 1 Linguagem: Inglês

10.1016/j.chest.2017.02.016

1931-3543

Elliott D. Crouser, Michael A. Matthay,

Respiratory Support and Mechanisms

FOR RELATED ARTICLE SEE PAGE 22A comprehensive understanding of sepsis-induced organ failure is lacking, which explains in part why therapeutic options for this condition are limited primarily to supportive care with antibiotics, fluid resuscitation, vasopressors, mechanical ventilation, and dialysis when organ dysfunction is severe.1Gotts J.E. Matthay M.A. Sepsis: pathophysiology and clinical management.BMJ. 2016; 353: i1585Crossref PubMed Scopus (505) Google Scholar There is strong clinical evidence supporting an important mechanistic role for endothelial damage and related organ dysfunction. For instance, impaired vascular endothelial barrier function is sufficient to initiate acute lung injury (noncardiogenic pulmonary edema) and the associated respiratory failure due to ventilation-perfusion mismatching and reduced lung compliance.2Matthay M.A. Zimmerman G.A. Esmon C. et al.Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute Working Group.Am J Respir Crit Care Med. 2003; 167: 1027-1035Crossref PubMed Scopus (467) Google Scholar Altered microvascular tone contributes to distributive shock (increased intravascular capacitance), manifesting as systemic hypotension and regional blood flow dysregulation. These mechanisms promote inadequate delivery of the substrates needed for high-energy phosphate production, resulting in energy failure and loss of cell function, particularly in highly metabolic tissues such as the brain, liver, kidneys, and heart. Furthermore, ischemic damage consequent to microvascular injury can promote further microvascular injury, leading to a cycle of injury and progressive organ failures.3Sawant D.A. Tharakan B. Hunter F.A. Childs E.W. Glycogen synthase kinase 3 inhibitor protects against microvascular hyperpermeability following hemorrhagic shock.J Trauma Acute Care Surg. 2015; 79: 609-616Crossref PubMed Scopus (4) Google Scholar A workshop on "Blood Systems Response to Sepsis" organized by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute in June 2010 concluded that "the endothelium…is vital to maintaining the function of all major organs" and encouraged research that would advance the understanding of endothelial injury in the setting of sepsis.4National Heart, Lung, and Blood Institute. Sepsis meeting: summary of discussion. https://www.nhlbi.nih.gov/research/reports/2010-bsrts. Accessed February 21, 2017.Google Scholar FOR RELATED ARTICLE SEE PAGE 22 Current recommendations by the Surviving Sepsis Campaign, referred to as Early Goal-Directed Therapy (EGDT), are designed to interrupt the cycle of vital organ injury during the early phases of sepsis by optimizing blood flow to vital organs. Core components of the EGDT protocol include early recognition of sepsis, and the rapid identification of signs of tissue hypoperfusion (shock), such as low mean arterial pressure (< 65 mm Hg) and elevated blood lactate levels. In response to the detection of tissue hypoperfusion, EGDT dictates that six measures be taken to rapidly expand intravascular volumes through the administration of isotonic IV fluids or blood products, and if this fails, with vasopressor agents, to achieve hemodynamic optimization, as reflected by central venous pressures of 8 to 12 mm Hg, mean arterial pressure > 65 mm Hg, and normalization of blood lactate levels. EGDT for sepsis is labor intensive (eg, 6-h duration) and carries some risk relating to the need for a central venous catheter for central venous pressure monitoring, and in some cases the administration of blood products, and for this reason the Protocol-Based Care for Early Septic Shock (ProCESS) study was conducted to determine whether EGDT provided by a dedicated team of experts confers a survival benefit compared with standard therapy. ProCESS recruited 1,341 subjects presenting with septic shock from 31 EDs with 60-day in-hospital mortality as the primary clinical end point. The results conclusively showed no survival benefit of EGDT; however, given that several mechanisms may contribute to mortality during septic shock, questions remained regarding the possible benefits of EGDT in terms of other potential benefits, including the development of acute organ damage, as reflected by microvascular injury. In the current issue of CHEST, Hou et al5Hou P.C. Filbin M.R. Wang H. et al.ProCESS Investigators. Endothelial permeability and hemostasis in septic shock: results from the ProCESS trial.Chest. 2017; 152: 22-31Google Scholar carried out a post-hoc analysis of the ProCESS data to determine whether EGDT, compared with current standards of care (protocolized or nonprotocolized), provided benefits reflected by the release into the plasma of biomarkers of acute endothelial damage. A secondary study aim was to determine whether biomarkers of endothelial injury also would predict mortality. The measured biomarkers reflect endothelial cell injury and activation (vascular endothelial growth factor [VEGF], soluble Fms-like tyrosine kinase [sFLT-1], angiopoietin-2 [Ang-2]) and hemostasis (von Willebrand factor [VWF], thrombomodulin [TM], tissue-type plasminogen activator [t-PA]). Despite good adherence to the protocol (88% in the EGDT group; 95% in the standard-therapy group), there was no effect of the resuscitation strategies on the levels of any of the measured biomarkers. And importantly, regardless of the mode of resuscitation, there was a strong correlation between baseline endothelial markers and mortality rate, especially elevated sFLT-1, the performance of which was comparable to lactate and Sequential Organ Failure Assessment (SOFA) score.5Hou P.C. Filbin M.R. Wang H. et al.ProCESS Investigators. Endothelial permeability and hemostasis in septic shock: results from the ProCESS trial.Chest. 2017; 152: 22-31Google Scholar There are at least two interpretations to the results of this well-done study: (1) resuscitation strategies, while different, were equally effective in terms of achieving hemodynamic goals; and (2) early and effective resuscitation had no impact on the levels of endothelial injury or coagulation profile over the first 24 h in septic shock. Regarding the relative efficacies of the three resuscitation strategies for the treatment of septic shock in the ProCESS trial, the resuscitation strategy had no effect on the duration of cardiovascular support,6Yealy D.M. Kellum J.A. Huang D.T. et al.ProCESS InvestigatorsA randomized trial of protocol-based care for early septic shock.N Engl J Med. 2014; 370: 809-817Crossref PubMed Scopus (295) Google Scholar although there was a lack of information to assess how rapidly hemodynamic goals were achieved with each resuscitation strategy. In terms of septic shock, the timing of resuscitation relative to the duration of sepsis may be important. By the time infection progresses to severe sepsis or septic shock, it may be too late in some patients to reduce acute endothelial damage, organ failure, or, in some cases, death. Endothelial cell damage (detachment from basement membrane, loss of tight junctions, cell death), once initiated, may progress despite interventions that are otherwise beneficial when administered earlier in the course of severe infections. The biomarkers of endothelial damage evaluated in this study have distinct mechanistic implications as reflected by the levels of circulating endothelial cells (CECs; reflected by VWF) or circulating putative endothelial progenitor cells (CPEPCs; VGEF is a marker), reflecting endothelial damage and repair, respectively.7Thomson A. Garbuzova-Davis S. Vascular endothelial cells as biomarkers of microvascular endothelium damage and repair in cardiovascular and neurodegenerative diseases.J Cardiovasc Disord. 2016; 3: 1026Google Scholar The timing of the release of each cell type may reflect the stage of endothelial damage. Moreover, if EGDT were beneficial in septic shock, it may be best reflected by signs of earlier or more active endothelial recovery (increasing VGEF levels) and more rapid resolution of endothelial damage (declining VWF levels) following EGDT initiation. This study monitored biomarker levels over the first 24 h of hospital admission from the ED, during which VWF levels remained elevated and VEGF levels were declining, suggesting ongoing acute damage and no evidence of recovery. Considering that the endothelium is relatively resistant to ischemic damage,8Singhal A.K. Symons J.D. Boudina S. Jaishy B. Shiu Y.T. Role of endothelial cells in myocardial ischemia-reperfusion injury.Vasc Dis Prev. 2010; 7: 1-14Crossref PubMed Google Scholar alternative mechanisms of endothelial damage may prevail during septic shock. Direct damage to endothelium may occur during activation of pattern-recognizing receptors by various bacterial components to promote neutrophil adherence via expression of endothelial binding proteins (eg, intercellular adhesion molecule [ICAM]9Salvador B. Arranz A. Francisco S. et al.Modulation of endothelial function by Toll like receptors.Pharmacol Res. 2016; 108: 46-56Crossref PubMed Scopus (54) Google Scholar). Damaged endothelium, in turn, promotes coagulation pathway activation, leading to microthrombosis, consumptive coagulopathy, and activation of inflammatory pathways (eg, via tissue factor).10Keller T.T. Mairuhu A.T. de Kruif M.D. et al.Infections and endothelial cells.Cardiovasc Res. 2003; 60: 40-48Crossref PubMed Scopus (95) Google Scholar It seems that endothelial damage progressing through these pathways is unlikely to be attenuated by interventions, such as EGDT, aimed simply to achieve hemodynamic stability. More fundamental therapies that can reverse endothelial injury may be needed. It is also possible that restoration of macroscopic blood flow, such as is achieved by EGDT, fails to address some of the critical mechanisms of organ damage. In this context, endothelial damage during septic shock may serve as a surrogate for severe cytopathic changes in several organs. Despite the presence of widespread vascular damage and associated microvascular dysfunction, it appears that oxygen delivery to the tissues may not be the rate-limiting step for the production of high-energy phosphates in various tissues during established sepsis.11Brealey D. Singer M. Tissue oxygenation in sepsis.Sepsis. 1999; 2: 291-302Crossref Scopus (3) Google Scholar Instead, a large body of evidence indicates that sepsis is associated with altered use of oxygen at the subcellular level within various tissues. Many acute forms of cell stress, including sepsis, starvation, and hypoxia, promote a transition away from aerobic (oxygen-dependent) metabolism to anaerobic (glycolysis, ketolysis) metabolism.11Brealey D. Singer M. Tissue oxygenation in sepsis.Sepsis. 1999; 2: 291-302Crossref Scopus (3) Google Scholar, 12Whelen S.P. Carchman E.H. Kautza B. et al.Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile.J Surg Res. 2014; 186: 297-303Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 13Exline M.C. Crouser E.D. Mitochondrial mechanisms of sepsis-induced organ failure.Front Biosci. 2008; 13: 5030-5041PubMed Google Scholar, 14Altman B.J. Rathmell J.C. Metabolic stress in autophagy and cell death pathways.Cold Spring Harb Perspect Biol. 2012; 4: a008763Crossref Scopus (138) Google Scholar, 15Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10144) Google Scholar Under these circumstances the cells adopt a catabolic state wherein ATP formation is devoted to cell repair (eg, DNA repair, protein replacement) and proliferation, during which normal cell functions are suppressed.13Exline M.C. Crouser E.D. Mitochondrial mechanisms of sepsis-induced organ failure.Front Biosci. 2008; 13: 5030-5041PubMed Google Scholar, 14Altman B.J. Rathmell J.C. Metabolic stress in autophagy and cell death pathways.Cold Spring Harb Perspect Biol. 2012; 4: a008763Crossref Scopus (138) Google Scholar, 15Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10144) Google Scholar This metabolic transition could contribute to impaired function of highly metabolic tissues, such as the brain, heart, liver, and kidneys, and would not respond to measures, such as EGDT, that are designed to increase tissue oxygen delivery. Are there other biomarkers that may provide pathogenic and prognostic information in septic shock? A recent publication reported studies from this ProCESS trial in which plasma markers of inflammation (IL-8, IL-6, tumor necrosis factor-α), coagulation (D-dimers, thrombin-anti-thrombin complexes), oxidative stress (urine isoprostane), and tissue hypoxia (lactate) were also measured at baseline and later time points. Higher baseline levels of these biomarkers predicted higher mortality, but as in this study of endothelial and hemostatic markers, there was no effect of the treatment strategies on the biomarker levels at 24 or 72 h.16Kellum J.A. Pike F. Yealy D.M. et al.Protocol-Based Care for Early Septic Shock (ProCESS) Investigators. Relationship between alternative resuscitation strategies, host response and injury biomarkers, and outcome in septic shock: analysis of the Protocol-Based Care for Early Septic Shock study.Crit Care Med. 2017; 45: 438-445Crossref PubMed Scopus (36) Google Scholar Given the strong association between endothelial injury markers in this study5Hou P.C. Filbin M.R. Wang H. et al.ProCESS Investigators. Endothelial permeability and hemostasis in septic shock: results from the ProCESS trial.Chest. 2017; 152: 22-31Google Scholar and inflammatory and coagulation markers in the companion study16Kellum J.A. Pike F. Yealy D.M. et al.Protocol-Based Care for Early Septic Shock (ProCESS) Investigators. Relationship between alternative resuscitation strategies, host response and injury biomarkers, and outcome in septic shock: analysis of the Protocol-Based Care for Early Septic Shock study.Crit Care Med. 2017; 45: 438-445Crossref PubMed Scopus (36) Google Scholar for predicting higher mortality in septic shock, further studies are needed to understand the basic mechanisms of organ failure in patients with sepsis. We know that inhibition of single cytokines was not effective in reducing sepsis mortality,1Gotts J.E. Matthay M.A. Sepsis: pathophysiology and clinical management.BMJ. 2016; 353: i1585Crossref PubMed Scopus (505) Google Scholar but it is possible that combination therapies that inhibit more than one of these pathways of injury might be effective in reducing organ failure and mortality. For example, interest in cell-based therapy for sepsis has been stimulated in part because there are multiple pathways of potential benefit with cell-based therapy,17Matthay M.A. Pati S. Lee J.W. Concise review: mesenchymal stem (stromal) cells: biology and preclinical evidence for therapeutic potential for organ dysfunction following trauma or sepsis.Stem Cells. 2017; 35: 316-324Crossref PubMed Scopus (110) Google Scholar similar to the advantages of combination chemotherapy for some neoplastic diseases. Also, in order to reduce the heterogeneity of patients with sepsis in clinical trials, a predictive enrichment strategy could be used to select patients with point-of-care measurements of key markers of inflammation and endothelial injury along with clinical indices to target therapies to a more homogeneous group of patients that might be more likely to respond.18Prescott H.C. Calfee C.S. Thompson B.T. Angus D.C. Liu V.X. Towards smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design.Am J Respir Crit Care Med. 2016; 194: 147-155Crossref PubMed Scopus (195) Google Scholar Endothelial Permeability and Hemostasis in Septic Shock: Results From the ProCESS TrialCHESTVol. 152Issue 1PreviewWe studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality. Full-Text PDF