Sepsis 2019 – New Trends and Their Implications for Multiple Trauma PatientsArticle in several languages: English | deutsch
09 September 2019 (online)
In spring 2016, an updated sepsis definition (Sepsis-3) introduced a new explanation for the clinical picture of sepsis. Until then, sepsis had been understood as a “systemic inflammatory response syndrome (SIRS)” resulting from infection. An improved understanding of the molecular mechanisms and broad epidemiological studies of the clinical appearance shifted the focus from the inflammatory response to the multicausal tissue damage resulting in organ dysfunction. This paradigm shift highlights organ failure as a result of a dysregulated response of an organism to infection. Central to the new definition is the understanding that sepsis patients form a heterogeneous group and that the clinical picture requires alternative explanation patterns: e.g. sepsis is insufficiently explained by an overwhelming inflammatory response, it also comprises “immune paralysis” as another important pattern. Furthermore, severity of sepsis reflects the capacity of an organism to adapt and to mitigate the tissue damage through metabolic changes and repair mechanisms. Consistent with the paradigm of the new sepsis definition, adaptation in the presence of infections is crucial for the organism. Seriously injured or multiple trauma patients represent a patient group at particular risk, as sepsis often complicates the courses of these patients due to nosocomial infections. Along with comorbidities, past infections and age, leakage of skin and intestinal barriers as well as impaired defence and repair mechanism predispose trauma patients for a septic course. New pathophysiological insights suggest that the control of extracellular haem is of paramount significance. Haemolysis, transfusion and the consecutive expression of haem binding (such as haemopexin) or haem catabolic pathways (such as haem oxygenase) impair the ability of an organism to adapt, correlate with the prognosis and/or are strongly influenced by the surgical treatment concepts. Established treatment concepts of early causal and supportive therapy (damage control, antibiotic and fluid therapy) contribute to the reduction of mortality, depending on stringent implementation as part of Standard Operating Procedures (SOPs) and quality management. The paradigm shift in sepsis research offers an improved understanding of the underlying pathogenic factors within complex and heterogeneous patient groups, such as nosocomial sepsis following trauma. These novel approaches will allow developing new treatment strategies potentially contributing to a significant reduction in morbidity and mortality of trauma patients.
1) According to the new paradigm, the ability to adapt to the pathogenic load associated with trauma and infection is crucial for an organism.
2) Seriously injured or multiple trauma patients are predisposed for septic courses due to impaired adaptation mechanisms.
3) Established treatment concepts of early causal and supportive therapy (damage control, antibiotic treatment, restrictive transfusion, and volume resuscitation) reduce mortality, in particular as part of SOPs and quality management strategies.
4) Newly emerging treatment concepts that focus on the control of extracellular haem are promising, but require more evidence for translation into clinical practice.
- 1 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-810 doi:10.1001/jama.2016.0287
- 2 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: 762-774 doi:10.1001/jama.2016.0288
- 3 Soares MP, Gozzelino R, Weis S. Tissue damage control in disease tolerance. Trends Immunol 2014; 35: 483-494 doi:10.1016/j.it.2014.08.001
- 4 Ranzani OT, Prina E, Menendez R. et al. New sepsis definition (Sepsis-3) and community-acquired pneumonia mortality. A validation and clinical decision-making study. Am J Respir Crit Care Med 2017; 196: 1287-1297 doi:10.1164/rccm.201611-2262OC
- 5 Churpek MM, Snyder A, Han X. et al. Quick Sepsis-related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med 2017; 195: 906-911 doi:10.1164/rccm.201604-0854OC
- 6 Kolditz M, Scherag A, Rohde G. et al. Comparison of the qSOFA and CRB-65 for risk prediction in patients with community-acquired pneumonia. Intensive Care Med 2016; 42: 2108-2110 doi:10.1007/s00134-016-4517-y
- 7 Schottmüller H. Wesen und Behandlung der Sepsis. Verh Dtsch Ges Inn Med 1914; 31: 257-261
- 8 Payen D, Mateo J, Cavaillon JM. et al. Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial. Crit Care Med 2009; 37: 803-810 doi:10.1097/CCM.0b013e3181962316
- 9 Bauer M, Marzi I, Ziegenfuss T. et al. Prophylactic hemofiltration in severely traumatized patients: effects on post-traumatic organ dysfunction syndrome. Intensive Care Med 2001; 27: 376-383
- 10 Bone RC. The sepsis syndrome. Definition and general approach to management. Clin Chest Med 1996; 17: 175-181
- 11 Bone RC, Balk RA, Cerra FB. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644-1655
- 12 Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992; 101: 1481-1483
- 13 Bellani G, Laffey JG, Pham T. et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315: 788-800 doi:10.1001/jama.2016.0291
- 14 Kaukonen KM, Bailey M, Bellomo R. Systemic Inflammatory Response Syndrome Criteria for Severe Sepsis. N Engl J Med 2015; 373: 881 doi:10.1056/NEJMc1506819
- 15 Singer M. Critical illness and flat batteries. Crit Care 2017; 21: 309 doi:10.1186/s13054-017-1913-9
- 16 Singer M, De Santis V, Vitale D. et al. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 2004; 364: 545-548 doi:10.1016/S0140-6736(04)16815-3
- 17 Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 2012; 335: 936-941
- 18 Bauer M, Weis S, Netea MG. et al. Remembering pathogen dose: long-term adaptation in innate immunity. Trends Immunol 2018; 39: 438-445 doi:10.1016/j.it.2018.04.001
- 19 Bauer M, Giamarellos-Bourboulis EJ, Kortgen A. et al. A transcriptomic biomarker to quantify systemic inflammation in sepsis – a prospective multicenter phase ii diagnostic study. EBioMedicine 2016; 6: 114-125 doi:10.1016/j.ebiom.2016.03.006
- 20 Bauer M, Coldewey SM, Leitner M. et al. Deterioration of organ function as a hallmark in sepsis: the cellular perspective. Front Immunol 2018; 9: 1460 doi:10.3389/fimmu.2018.01460
- 21 Cockrell C, An G. Sepsis reconsidered: identifying novel metrics for behavioral landscape characterization with a high-performance computing implementation of an agent-based model. J Theor Biol 2017; 430: 157-168 doi:10.1016/j.jtbi.2017.07.016
- 22 Ciriello V, Gudipati S, Stavrou PZ. et al. Biomarkers predicting sepsis in polytrauma patients: current evidence. Injury 2013; 44: 1680-1692 doi:10.1016/j.injury.2013.09.024
- 23 Zhang Q, Raoof M, Chen Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104-107 doi:10.1038/nature08780
- 24 Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol 2018; 19: 327-341 doi:10.1038/s41590-018-0064-8
- 25 Larsen R, Gozzelino R, Jeney V. et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2010; 2: 51ra71 doi:10.1126/scitranslmed.3001118
- 26 Sponholz C, Huse K, Kramer M. et al. Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis. Shock 2012; 38: 459-465 doi:10.1097/SHK.0b013e31826ae951
- 27 Weis S, Carlos AR, Moita MR. et al. Metabolic Adaptation Establishes Disease Tolerance to Sepsis. Cell 2017; 169: 1263-1275.e14 doi:10.1016/j.cell.2017.05.031
- 28 Larsen R, Gouveia Z, Soares MP. et al. Heme cytotoxicity and the pathogenesis of immune-mediated inflammatory diseases. Front Pharmacol 2012; 3: 77 doi:10.3389/fphar.2012.00077
- 29 Schleser FS, Raphael A, Galler K. et al. Labile heme impairs hepatic microcirculation and promotes hepatic injury. Sci Rep [Under review].
- 30 Rittirsch D, Schoenborn V, Lindig S. et al. An integrated clinico-transcriptomic approach identifies a central role of the heme degradation pathway for septic complications after trauma. Ann Surg 2016; 264: 1125-1134 doi:10.1097/SLA.0000000000001553
- 31 Gozzelino R, Jeney V, Soares MP. Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol 2010; 50: 323-354 doi:10.1146/annurev.pharmtox.010909.105600
- 32 Camus SM, Gausseres B, Bonnin P. et al. Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease. Blood 2012; 120: 5050-5058 doi:10.1182/blood-2012-02-413138
- 33 Donadee C, Raat NJ, Kanias T. et al. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 2011; 124: 465-476 doi:10.1161/CIRCULATIONAHA.110.008698
- 34 Schaer DJ, Buehler PW, Alayash AI. et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013; 121: 1276-1284 doi:10.1182/blood-2012-11-451229
- 35 Rittirsch D, Schoenborn V, Lindig S. et al. Improvement of prognostic performance in severely injured patients by integrated clinico-transcriptomics: a translational approach. Crit Care 2015; 19: 414 doi:10.1186/s13054-015-1127-y
- 36 Wafaisade A, Lefering R, Bouillon B. et al. Epidemiology and risk factors of sepsis after multiple trauma: an analysis of 29,829 patients from the Trauma Registry of the German Society for Trauma Surgery. Crit Care Med 2011; 39: 621-628 doi:10.1097/CCM.0b013e318206d3df
- 37 Perel P, Clayton T, Altman DG. et al. Red blood cell transfusion and mortality in trauma patients: risk-stratified analysis of an observational study. PLoS Med 2014; 11: e1001664 doi:10.1371/journal.pmed.1001664
- 38 Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006; 34: 943-949 doi:10.1097/01.ccm.0000206112.32673.d4
- 39 Borgert M, Binnekade J, Paulus F. et al. Implementation of a transfusion bundle reduces inappropriate red blood cell transfusions in intensive care – a before and after study. Transfus Med 2016; 26: 432-439 doi:10.1111/tme.12364
- 40 Pavenski K, Stanworth S, Fung M. et al. Quality of evidence-based guidelines for transfusion of red blood cells and plasma: a systematic review. Transfus Med Rev 2018; DOI: 10.1016/j.tmrv.2018.05.004.
- 41 Laffey JG, Bellani G, Pham T. et al. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med 2016; 42: 1865-1876 doi:10.1007/s00134-016-4571-5
- 42 Cohen J, Vincent JL, Adhikari NK. et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015; 15: 581-614 doi:10.1016/S1473-3099(15)70112-X