Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

Cover Page

Cite item

Abstract

Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a nonhomogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the proinflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology.

About the authors

E. Yu. Gusev

Institute of Immunology and Physiology of the Ural Branch of RAS

Email: gusev36@mail.ru

PhD, MD (Medicine), Professor, Head of the Laboratory of Inflammation Immunology

Yekaterinburg 

Russian Federation

N. V. Zotova

Institute of Immunology and Physiology of the Ural Branch of RAS; Ural Federal University named after the first President of Russia B.N. Yeltsin

Author for correspondence.
Email: zotovanat@mail.ru
ORCID iD: 0000-0001-9788-1243

Natalia V. Zotova,  PhD (Biology), Senior Researcher, Laboratory of Inflammation Immunology; Associate Professor, Department of Medical Biochemistry and Biophysics

620049, Yekaterinburg, Pervomayskaya str., 106

Phone: +7 (343) 374-00-70 

Russian Federation

V. A. Chereshnev

Institute of Immunology and Physiology of the Ural Branch of RAS

Email: mchereshneva@mail.ru

RAS Full Member, PhD, MD (Medicine), Professor, Research Supervisor

Yekaterinburg 

Russian Federation

References

  1. Гусев Е.Ю., Журавлева Ю.А., Зотова Н.В. Взаимосвязь эволюции иммунитета и воспаления у позвоночных // Успехи современной биологии. 2019. Т. 139, № 1. С. 59–74. [Gusev E.Yu., Zhuravleva Yu.A., Zotova N.V. Correlation of immunity evolution and inflammation in vertebrates. Uspekhi sovremennoi biologii = Biology Bulletin Reviews, 2019, vol. 139, no. 1, pp. 59–74. (In Russ.)] doi: 10.1134/S0042132419010058
  2. Гусев Е.Ю., Зотова Н.В., Журавлева Ю.А., Черешнев В.А. Физиологическая и патогенетическая роль рецепторовмусорщиков у человека // Медицинская иммунология. 2020. Т. 22, № 1. С. 7–48. [Gusev E.Y., Zotova N.V., Zhuravleva Y.A., Chereshnev V.A. Physiological and pathogenic role of scavenger receptors in humans. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, vol. 22, no. 1, pp. 7–48. (In Russ.)] doi: 10.15789/1563-0625-PAP-1893
  3. Гусев Е.Ю., Черешнев В.А. Системное воспаление: теоретические и методологические подходы к описанию модели общепатологического процесса. Часть. 1. Общая характеристика процесса // Патологическая физиология и экспериментальная терапия. 2012. Т. 56, № 4. С. 3–14. [Gusev E.Yu., Chereshnev V.A. Systemic inflammation: theoretical and methodological approaches to description of general pathological process model. Part I. General characteristics of the process. Patologicheskaya fiziologiya i eksperimental’naya terapiya = Pathological Physiology and Experimental Therapy, 2012, vol. 56, no. 4, pp. 3–14. (In Russ.)]
  4. Гусев Е.Ю., Юрченко Л.Н., Черешнев В.А., Зотова Н.В., Журавлева Ю.А., Зубова Т.Э., Руднов В.А., Кузьмин В.В., Макарова Н.П., Лейдерман И.Н., Левит Д.А., Суханов В.А., Сипачев А.С., Бражников А.Ю., Решетникова С.Ю., Засорин А.А., Дрозд А.В. Варианты развития острого системного воспаления // Цитокины и воспаление. 2008. Т. 7, № 2. С. 9–17. [Gusev E.Yu., Yurchenko L.N., Chereshnev V.A., Zotova N.V., Zhuravleva J.A., Zubova Т.E., Rudnov V.A., Kuzmin V.V., Makarova N.P., Leiderman E.N., Levit D.A., Sukhanov V.A., Sipachev A.S., Bragnikov A.Y., Reshetnikova S.Y., Zasorin A.A., Drozd A.V. The variants of acute systemic inflammation evolution. Tsitokiny i vospalenie = Cytokines and Inflammation, 2008, vol. 7, no. 2, pp. 9–17. (In Russ.)]
  5. Сепсис: классификация, клинико-диагностическая концепция и лечение / Под ред. Б.Р. Гельфанда. 4-е изд., доп. и перераб. Москва: ООО «Медицинское информационное агентство», 2017. 408 с. [Sepsis: classification, clinical diagnostic concept, and treatment / Ed. by B.R. Gelfand. 4th ed., revised. Moscow: LLC “Medical information agency”, 2017. 408 p. (In Russ.)]
  6. Черешнев В.А., Гусев Е.Ю., Зотова Н.В. Фундаментально-прикладные аспекты системного воспаления с позиции теории физиологических и типовых патологических процессов // Российский физиологический журнал им. И.М. Сеченова. 2010. T. 96, № 7. С. 696–707. [Chereshnev V.A., Gusev E.Yu., Zotova N.V. Fundamental applied aspects of systemic inflammation in terms of physiologic and typical pathological process. Rossiyskiy fiziologicheskiy zhurnal imeni I.M. Sechenova = Russian Journal of Physiology, 2010, vol. 96, no. 7, pp. 696–707. (In Russ.)]
  7. Alcock J. The emperor has no clothes? searching for dysregulation in sepsis. J. Clin. Med., 2018, vol. 7, no. 9: E247. doi: 10.3390/jcm7090247
  8. Bezemer R., Bartels S.A., Bakker J., Ince C. Clinical review: clinical imaging of the sublingual microcirculation in the critically ill – where do we stand? Critical Care, 2012, vol. 16: 224. doi: 10.1186/cc11236
  9. Bone R.C., Balk R.A., Cerra F.B., Dellinger R.P., Fein A.M., Knaus W.A., Schein R.M., Sibbald W.J. 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, vol. 101, no. 6, pp. 1644–1655. doi: 10.1378/chest.101.6.1644
  10. Carneiro A.H., Póvoa P., Gomes J.A. Dear Sepsis-3, we are sorry to say that we don’t like you. Rev. Bras. Ter. Intensiva, 2017, vol. 29, no. 1, pp. 4–8. doi: 10.5935/0103-507X.20170002
  11. Cecconi M., Evans L., Levy M., Rhodes A. Sepsis and septic shock. Lancet, 2018, vol. 392, no. 10141, pp. 75–87. doi: 10.1016/S0140-6736(18)30696-2
  12. Christaki E., Giamarellos-Bourboulis E.J. The complex pathogenesis of bacteremia: from antimicrobial clearance mechanisms to the genetic background of the host. Virulence, 2014, vol. 5, no. 1, pp. 57–65. doi: 10.4161/viru.26514
  13. Churpek M.M., Snyder A., Han X., Sokol S., Pettit N., Howell M.D., Edelson D.P. 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, vol. 195, no. 7, pp. 906–911. doi: 10.1164/rccm.201604-0854OC
  14. Cortés-Puch I., Hartog C.S. Opening the debate on the new sepsis definition change is not necessarily progress: revision of the sepsis definition should be based on new scientific insights. Am. J. Respir. Crit. Care Med., 2016, vol. 194, no. 1, pp. 16–18. doi: 10.1164/rccm.201604-0734ED
  15. Deppermann C., Kubes P. Platelets and infection. Semin. Immunol., 2016, vol. 28, no. 6, pp. 536–545. doi: 10.1016/j.smim.2016.10.005
  16. Fischetti V.A. Surface proteins on Gram-positive bacteria. Microbiol. Spectr., 2019, vol. 7, no. 4: 10. doi: 10.1128/microbiolspec. GPP3-0012-2018
  17. Gaudette S., Hughes D., Boller M. The endothelial glycocalyx: structure and function in health and critical illness. J. Vet. Emerg. Crit. Care (San Antonio), 2020, vol. 30, no. 2, pp. 117–134.
  18. Godinjak A., Iglica A., Rama A., Tančica I., Jusufović S., Ajanović A., Kukuljac A. Predictive value of SAPS II and APACHE II scoring systems for patient outcome in a medical intensive care unit. Acta Med. Acad., 2016, vol. 45, no. 2, pp. 97–103. doi: 10.5644/ama2006-124.165
  19. Gusev E.Y., Zotova N.V. Cellular stress and general pathological processes. Curr. Pharm. Des., 2019, vol. 25, no. 3, pp. 251–297. doi: 10.2174/1381612825666190319114641
  20. Henning D.J., Puskarich M.A., Self W.H., Howell M.D., Donnino M.W., Yealy D.M., Jones A.E., Shapiro N.I. An emergency department validation of the SEP-3 sepsis and septic shock definitions and comparison with 1992 Consensus definitions. Ann. Emerg. Med., 2017, vol. 70, no. 4, pp. 544–552.e5. doi: 10.1016/j.annemergmed.2017.01.008
  21. Hernández G., Kattan E., Ospina-Tascón G., Bakker J., Castro R. Capillary refill time status could identify different clinical phenotypes among septic shock patients fulfilling Sepsis-3 criteria: a post hoc analysis of ANDROMEDA-SHOCK trial. Intensive Care Med., 2020, vol. 46, no. 4, pp. 816–818. doi: 10.1007/s00134-020-05960-4
  22. Horak J., Martinkova V., Radej J., Matejovič M. Back to basics: recognition of sepsis with new definition. J. Clin. Med., 2019, vol. 8, no. 1: 1838. doi: 10.3390/jcm8111838
  23. Hurley J.C., Nowak P., Öhrmalm L., Gogos C., Armaganidis A., Giamarellos-Bourboulis E.J. Endotoxemia as a diagnostic tool for patients with suspected bacteremia caused by Gram-negative organisms: a meta-analysis of 4 decades of studies. J. Clin. Microbiol., 2015, vol. 53, no. 4, pp. 1183–1191. doi: 10.1128/JCM.03531-14
  24. Jacobs L., Wong H.R. Emerging infection and sepsis biomarkers: will they change current therapies? Expert Rev. Anti-Infect. Ther., 2016, vol. 14, no. 10, pp. 929–941. doi: 10.1080/14787210.2016.1222272
  25. Kawasaki T. Update on pediatric sepsis: a review. J. Intensive Care, 2017, vol. 5: 47. doi: 10.1186/s40560-017-0240-1
  26. Langley R.J., Wong H.R. Early diagnosis of sepsis: is an integrated omics approach the way forward? Mol. Diagn. Ther., 2017, vol. 21, no. 5, pp. 525–537. doi: 10.1007/s40291-017-0282-z
  27. Levy M.M., Fink M.P., Marshall J.C., Abraham E., Angus D., Cook D., Cohen J., Opal S.M., Vincent J.L., Ramsay G. International sepsis definitions conference 2001 SCCM/ESICM/ACCP/ATS/SIS. Intensive Care Med., 2003, vol. 29, no. 4, pp. 530–538. doi: 10.1097/01.CCM.0000050454.01978.3B
  28. Lin G.L., McGinley J.P., Drysdale S.B., Pollard A.J. Epidemiology and immune pathogenesis of viral sepsis. Front. Immunol., 2018, vol. 9: 2147. doi: 10.3389/fimmu.2018.02147
  29. Macdonald S.P.J., Kinnear F.B., Arendts G., Ho K.M., Fatovich D.M. Near-infrared spectroscopy to predict organ failure and outcome in sepsis: the assessing risk in sepsis using a tissue oxygen saturation (ARISTOS) study. Eur. J. Emerg. Med., 2019, vol. 26, no. 3, pp. 174–179. doi: 10.1097/MEJ.0000000000000535
  30. Maharaj B., Coovadia Y., Vayej A.C. An investigation of the frequency of bacteraemia following dental extraction, tooth brushing and chewing. Cardiovasc. J. Afr., 2012, vol. 23, no. 6, pp. 340–344. doi: 10.5830/CVJA-2012-016
  31. Marik P.E., Taeb A.M. SIRS, qSOFA and new sepsis definition. J. Thorac. Dis., 2017, vol. 9, no. 4, pp. 943–945. doi: 10.21037/jtd.2017.03.125
  32. Marschall J., Agniel D., Fraser V.J., Doherty J., Warren D.K. Gram-negative bacteraemia in non-ICU patients: factors associated with inadequate antibiotic therapy and impact on outcomes. J. Antimicrob. Chemother., 2008, vol. 61, no. 6, pp. 1376–1383. doi: 10.1093/jac/dkn104
  33. Marshall J.C., Vincent J.-L., Fink M.P., Cook D.J., Rubenfeld G., Foster D., Fisher C.J.Jr., Faist E., Reinhart K. Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25–26, 2000. Crit. Care Med., 2003, vol. 31, no. 5, pp. 1560–1567. doi: 10.1097/01.CCM.0000065186.67848.3A
  34. Mat-Nor M.B., Md Ralib A., Abdulah N.Z., Pickering J.W. The diagnostic ability of procalcitonin and interleukin-6 to differentiate infectious from noninfectious systemic inflammatory response syndrome and to predict mortality. J. Crit Care, 2016, vol. 33, pp. 245–251. doi: 10.1016/j.jcrc.2016.01.002
  35. McGovern M., Giannoni E., Kuester H., Turner M.A., van den Hoogen A., Bliss J.M., Koenig J.M., Keij F.M., Mazela J., Finnegan R., Degtyareva M., Simons S.H.P., de Boode W.P., Strunk T., Reiss I.K.M., Wynn J.L., Molloy E.J. Challenges in developing a consensus definition of neonatal sepsis. Pediatr. Res., 2020, vol. 88, pp. 14–26. doi: 10.1038/s41390-020-0785-x
  36. McLymont N., Glover G.W. Scoring systems for the characterization of sepsis and associated outcomes. Ann. Transl. Med., 2016, vol. 4, no. 24: 527. doi: 10.21037/atm.2016.12.53
  37. Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet, 2020, vol. 395, no. 10229, pp. 1033–1034. doi: 10.1016/S0140-6736(20)30628-0
  38. Minasyan H. Sepsis and septic shock: pathogenesis and treatment perspectives. J. Crit. Care, 2017, vol. 40, pp. 229–242. doi: 10.1016/j.jcrc.2017.04.015
  39. Mtaweh H., Trakas E.V., Su E., Carcillo J.A., Aneja R.K. Advances in monitoring and management of shock. Pediatr. Clin. North. Am., 2013, vol. 60, no. 3, pp. 641–654. doi: 10.1016/j.pcl.2013.02.013
  40. Niebauer J., Volk H.D., Kemp M., Dominguez M., Schumann R.R., Rauchhaus M., Poole-Wilson P.A., Coats A.J., Anker S.D. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet, 1999, vol. 353, no. 9167, pp. 1838– 1842. doi: 10.1016/S0140-6736(98)09286-1
  41. Opal S.M. Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr. Crit. Care Med., 2005, vol. 6, no. 3, pp. 55–60. doi: 10.1097/01.PCC.0000161580.79526.4C
  42. Pierrakos C., Vincent J.-L. Sepsis biomarkers: a review. Crit. Care, 2010, vol. 14, no. 1: R15. doi: 10.1186/cc8872
  43. Pietzner M., Kaul A., Henning A.K., Kastenmüller G., Artati A., Lerch M.M., Adamski J., Nauck M., Friedrich N. Comprehensive metabolic profiling of chronic low-grade inflammation among generally healthy individuals. BMC Med., 2017, vol. 15, no. 1: 210. doi: 10.1186/s12916-017-0974-6
  44. Radeva M.Y., Waschke J. Mind the gap: mechanisms regulating the endothelial barrier. Acta Physiol. (Oxf.), 2018, vol. 222, no. 1. doi: 10.1111/apha.12860
  45. Raeven P., Zipperle J., Drechsler S. Extracellular vesicles as markers and mediators in sepsis. Theranostics, 2018, vol. 8, no. 12, pp. 3348–3365. doi: 10.7150/thno.23453
  46. Rodríguez-Baño J., López-Prieto M.D., Portillo M.M., Retamar P., Natera C., Nuño E., Herrero M., del Arco A., Muñoz A., Téllez F., Torres-Tortosa M., Martín-Aspas A., Arroyo A., Ruiz A., Moya R., Corzo J.E., León L., Pérez-López J.A., SAEI/ SAMPAC Bacteraemia group. Epidemiology and clinical features of community-acquired, healthcare-associated and nosocomial bloodstream infections in tertiary-care and community hospitals. Clin. Microbiol. Infect., 2010, vol. 16, no. 9, pp. 1408–1413. doi: 10.1111/j.1469-0691.2009.03089.x
  47. Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., Bellomo R., Bernard G.R., Chiche J.D., Coopersmith C.M., Hotchkiss R.S., Levy M.M., Marshall J.C., Martin G.S., Opal S.M., Rubenfeld G.D., van der Poll T., Vincent J.L., Angus D.C. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016, vol. 315, no. 8, pp. 801–810. doi: 10.1001/jama.2016.0287
  48. Spahn D.R., Bouillon B., Cerny V., Duranteau J., Filipescu D., Hunt B.J., Komadina R., Maegele M., Nardi G., Riddez L., Samama C.M., Vincent J.L., Rossaint R. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit. Care, 2019, vol. 23, no. 1: 98. doi: 10.1186/s13054-019-2347-3
  49. Standl T., Annecke T., Cascorbi I., Heller A.R., Sabashnikov A., Teske W. The nomenclature, definition and distinction of types of shock. Dtsch Arztebl. Int., 2018, vol. 115, no. 45, pp. 757–768. doi: 10.3238/arztebl.2018.0757
  50. Su M., West C.A., Young A.J., He C., Konerding M.A., Mentzer S.J. Dynamic deformation of migratory efferent lymph-derived cells “trapped” in the inflammatory microcirculation. J. Cell Physiol., 2003, vol. 194, no. 1, pp. 54–62. doi: 10.1002/jcp.10190
  51. Suffredini A.F., Munford R.S. Novel therapies for septic shock over the past 4 decades. JAMA, 2011, vol. 306, no. 2, pp. 194–199. doi: 10.1001/jama.2011.909
  52. Tao X., Wang H., Min C., Yu T., Luo Y., Li J., Hu Y., Yan Q., Liu W.E., Zou M. A retrospective study on Escherichia coli bacteremia in immunocompromised patients: microbiological features, clinical characteristics, and risk factors for shock and death. J. Clin. Lab. Anal., 2020, vol. 34, no. 8: e23319. doi: 10.1002/jcla.23319
  53. Tomás I., Alvarez M., Limeres J., Potel C., Medina J., Diz P. Prevalence, duration and aetiology of bacteraemia following dental extractions. Oral Dis., 2007, vol. 13, no. 1, pp. 56–62. doi: 10.1111/j.1601-0825.2006.01247.x
  54. Vincent J.L. Dear SIRS, I’m sorry to say that I don’t like you... Crit. Care Med., 1997, vol. 25, no. 2, pp. 372–374. doi: 10.1097/00003246-199702000-00029
  55. Wittekind C., Gradistanac T. Post-mortem examination as a quality improvement instrument. Dtsch Arztebl. Int., 2018, vol. 115, no. 39, pp. 653–658. doi: 10.3238/arztebl.2018.0653
  56. Wu F., Peng Z., Park P.W., Kozar R.A. Loss of syndecan-1 abrogates the pulmonary protective phenotype induced by plasma after hemorrhagic shock. Shock, 2017, vol. 48, no. 3, pp. 340–345. doi: 10.1097/SHK.0000000000000832
  57. Yang N., Shi X.L., Zhang B.L., Rong J., Zhang T.N., Xu W., Liu C.F. The trend of β3-adrenergic receptor in the development of septic myocardial depression: a lipopolysaccharide-induced rat septic shock model. Cardiology, 2018, vol. 139, no. 4, pp. 234– 244. doi: 10.1159/000487126
  58. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., Xiang J., Wang Y., Song B., Gu X., Guan L., Wei Y., Li H., Wu X., Xu J., Tu S., Zhang Y., Chen H., Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020, vol. 395, no. 10229, pp. 1054–1062. doi: 10.1016/S0140-6736(20)30566-3
  59. Zotova N.V., Chereshnev V.A., Gusev E.Yu. Systemic Inflammation: methodological approaches to identification of the common pathological process. PLoS One, 2016, vol. 11, no. 5: e0155138. doi: 10.1371/journal.pone.0155138
  60. Zotova N.V., Zhuravleva Y.V., Zubova T.E., Gusev E.Yu. Integral estimation of systemic inflammatory response under sepsis. Gen. Physiol. Biophys., 2020, vol. 39, no. 1, pp. 13–26. doi: 10.4149/gpb_2019043

Supplementary files

There are no supplementary files to display.


Copyright (c) 2021 Gusev E.Y., Zotova N.V., Chereshnev V.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies