Abstract
Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Knowledge of the pathophysiology of organ failure in sepsis is crucial for optimizing the management and treatment of patients and for the development of potential new therapies. In clinical practice, six major organ systems — the cardiovascular (including the microcirculation), respiratory, renal, neurological, haematological and hepatic systems — can be assessed and monitored, whereas others, such as the gut, are less accessible. Over the past 2 decades, considerable amounts of new data have helped improve our understanding of sepsis pathophysiology, including the regulation of inflammatory pathways and the role played by immune suppression during sepsis. The effects of impaired cellular function, including mitochondrial dysfunction and altered cell death mechanisms, on the development of organ dysfunction are also being unravelled. Insights have been gained into interactions between key organs (such as the kidneys and the gut) and organ–organ crosstalk during sepsis. The important role of the microcirculation in sepsis is increasingly apparent, and new techniques have been developed that make it possible to visualize the microcirculation at the bedside, although these techniques are only research tools at present.
Key points
-
Organ dysfunction is an integral part of sepsis, and the presence of unexplained organ dysfunction in a patient who is acutely ill should raise suspicion of the possible presence of sepsis and encourage an appropriate diagnostic examination.
-
The pathophysiology of organ dysfunction in sepsis is similar for all organs and involves complex haemodynamic and cellular mechanisms.
-
The first goal in the prevention of organ dysfunction in sepsis is to restore and maintain adequate oxygen delivery to cells.
-
Single-organ dysfunction in sepsis is rare, and several organs are usually affected; mortality in patients with sepsis correlates with the number of organs that are affected.
-
Most organ dysfunction in sepsis is reversible.
-
Current treatment for sepsis aims to limit the development of organ dysfunction by providing rapid control of infection, haemodynamic stabilization and organ support when possible to ensure recovery of organ function.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).
Vincent, J. L. et al. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir. Med. 2, 380–386 (2014).
SepNet Critical Care Trials Group. Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study. Intensive Care Med. 42, 1980–1989 (2016).
Iwashyna, T. J., Ely, E. W., Smith, D. M. & Langa, K. M. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304, 1787–1794 (2010).
van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 17, 407–420 (2017).
De Backer, D., Orbegozo, C. D., Donadello, K. & Vincent, J. L. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence 5, 73–79 (2014).
Gomez, H., Kellum, J. A. & Ronco, C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat. Rev. Nephrol. 13, 143–151 (2017).
Delano, M. J. & Ward, P. A. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J. Clin. Invest. 126, 23–31 (2016).
Haak, B. W. & Wiersinga, W. J. The role of the gut microbiota in sepsis. Lancet Gastroenterol. Hepatol. 2, 135–143 (2017).
Ranieri, V. M. et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 307, 2526–2533 (2012).
Vincent, J. L. et al. Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34, 344–353 (2006).
Sakr, Y. et al. Patterns and early evolution of organ failure in the intensive care unit and their relation to outcome. Crit. Care 16, R222 (2012).
Vincent, J. L. et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 22, 707–710 (1996).
Aakre, C. A., Kitson, J. E., Li, M. & Herasevich, V. Iterative user interface design for automated Sequential Organ Failure Assessment score calculator in sepsis detection. JMIR Hum. Factors 4, e14 (2017).
Antonucci, E. et al. Myocardial depression in sepsis: from pathogenesis to clinical manifestations and treatment. J. Crit. Care 29, 500–511 (2014).
Honore, P. M. et al. Prevention and treatment of sepsis-induced acute kidney injury: an update. Ann. Intensive Care 5, 51 (2015).
Linder, A. et al. Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill. Am. J. Respir. Crit. Care Med. 189, 1075–1081 (2014).
McCullough, P. A. et al. Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib. Nephrol. 182, 13–29 (2013).
Hosokawa, K. et al. Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review. Crit. Care 18, 674 (2014).
Gofton, T. E. & Young, G. B. Sepsis-associated encephalopathy. Nat. Rev. Neurol. 8, 557–566 (2012).
Simmons, J. & Pittet, J. F. The coagulopathy of acute sepsis. Curr. Opin. Anaesthesiol. 28, 227–236 (2015).
Levi, M. & van der Poll, T. Coagulation and sepsis. Thromb. Res. 149, 38–44 (2017).
Yan, J., Li, S. & Li, S. The role of the liver in sepsis. Int. Rev. Immunol. 33, 498–510 (2014).
Hotchkiss, R. S. et al. Sepsis and septic shock. Nat. Rev. Dis. Primers. 2, 16045 (2016).
Beutler, B. & Rietschel, E. T. Innate immune sensing and its roots: the story of endotoxin. Nat. Rev. Immunol. 3, 169–176 (2003).
Hu, H. & Sun, S. C. Ubiquitin signaling in immune responses. Cell Res. 26, 457–483 (2016).
Ajibade, A. A., Wang, H. Y. & Wang, R. F. Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307–316 (2013).
Lawrence, T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb. Perspect. Biol. 1, a001651 (2009).
Liu, S. F. & Malik, A. B. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L622–L645 (2006).
Timmermans, K., Kox, M., Scheffer, G. J. & Pickkers, P. Danger in the intensive care unit: DAMPS in critically ill patients. Shock 45, 108–116 (2016).
Yang, H., Wang, H., Chavan, S. S. & Andersson, U. High mobility group box protein 1 (HMGB1): The prototypical endogenous danger molecule. Mol. Med. 21 (Suppl. 1), S6–S12 (2015).
Ma, K. C., Schenck, E. J., Pabon, M. A. & Choi, A. M. K. The role of danger signals in the pathogenesis and perpetuation of critical illness. Am. J. Respir. Crit. Care Med. 197, 300–309 (2017).
Liaudet, L., Rosenblatt-Velin, N. & Pacher, P. Role of peroxynitrite in the cardiovascular dysfunction of septic shock. Curr. Vasc. Pharmacol. 11, 196–207 (2013).
Arulkumaran, N. et al. Mitochondrial function in sepsis. Shock 45, 271–281 (2016).
Souza, A. C., Yuen, P. S. & Star, R. A. Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. Kidney Int. 87, 1100–1108 (2015).
Kaplan, M. J. & Radic, M. Neutrophil extracellular traps: double-edged swords of innate immunity. J. Immunol. 189, 2689–2695 (2012).
Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011).
Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).
Wang, D. W., Yin, Y. M. & Yao, Y. M. Vagal modulation of the inflammatory response in sepsis. Int. Rev. Immunol. 35, 415–433 (2016).
Kox, M. & Pickkers, P. Modulation of the innate immune response through the vagus nerve. Nephron 131, 79–84 (2015).
Kanashiro, A. et al. Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis. Pharmacol. Res. 117, 1–8 (2017).
Song, X. M. et al. The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats. Shock 30, 468–472 (2008).
Vincent, J. L. & De Backer, D. Circulatory shock. N. Engl. J. Med. 369, 1726–1734 (2013).
Levy, B. et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 36, 2019–2029 (2010).
De Backer, D. et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit. Care Med. 41, 791–799 (2013).
Post, E. H., Kellum, J. A., Bellomo, R. & Vincent, J. L. Renal perfusion in sepsis: from macro- to microcirculation. Kidney Int. 91, 45–60 (2017).
De Backer, D. et al. How to evaluate the microcirculation: report of a round table conference. Crit. Care 11, R101 (2007).
Ince, C. et al. Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine. Intensive Care Med. 44, 281–299 (2018).
Kopterides, P. et al. Microdialysis-assessed interstitium alterations during sepsis: relationship to stage, infection, and pathogen. Intensive Care Med. 37, 1756–1764 (2011).
Galley, H. F. & Webster, N. R. Physiology of the endothelium. Br. J. Anaesth. 93, 105–113 (2004).
Opal, S. M. & van der Poll, T. Endothelial barrier dysfunction in septic shock. J. Intern. Med. 277, 277–293 (2015).
Tressel, S. L. et al. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol. Med. 3, 370–384 (2011).
Chelazzi, C., Villa, G., Mancinelli, P., De Gaudio, A. R. & Adembri, C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit. Care 19, 26 (2015).
Prowle, J. R., Kirwan, C. J. & Bellomo, R. Fluid management for the prevention and attenuation of acute kidney injury. Nat. Rev. Nephrol. 10, 37–47 (2014).
Legrand, M. et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit. Care 17, R278 (2013).
Acheampong, A. & Vincent, J. L. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit. Care 19, 251 (2015).
Brotfain, E. et al. Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after ICU discharge. Am. J. Emerg. Med. 34, 2122–2126 (2016).
Sakr, Y. et al. Higher fluid balance increases the risk of death from sepsis: Results from a large international audit. Crit. Care Med. 45, 386–394 (2017).
Wiedemann, H. P. et al. Comparison of two fluid-management strategies in acute lung injury. N. Engl. J. Med. 354, 2564–2575 (2006).
Mikkelsen, M. E. et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am. J. Respir. Crit. Care Med. 185, 1307–1315 (2012).
Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death. Differ. 19, 107–120 (2012).
Pinheiro da Silva, F. & Nizet, V. Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection. Apoptosis 14, 509–521 (2009).
Aziz, M., Jacob, A. & Wang, P. Revisiting caspases in sepsis. Cell Death. Dis. 5, e1526 (2014).
Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).
Girardot, T., Rimmele, T., Venet, F. & Monneret, G. Apoptosis-induced lymphopenia in sepsis and other severe injuries. Apoptosis 22, 295–305 (2017).
Taneja, R. et al. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit. Care Med. 32, 1460–1469 (2004).
Murphy, M. P. & Caraher, E. Mcl-1 is vital for neutrophil survival. Immunol. Res. 62, 225–233 (2015).
Suzuki, T. et al. Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells. Am. J. Respir. Cell. Mol. Biol. 33, 231–247 (2005).
Kobayashi, S. D., Malachowa, N. & DeLeo, F. R. Influence of microbes on neutrophil life and death. Front. Cell. Infect. Microbiol. 7, 159 (2017).
Storek, K. M. & Monack, D. M. Bacterial recognition pathways that lead to inflammasome activation. Immunol. Rev. 265, 112–129 (2015).
Bierschenk, D., Boucher, D. & Schroder, K. Salmonella-induced inflammasome activation in humans. Mol. Immunol. 86, 38–43 (2017).
Gunst, J. et al. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit. Care Med. 41, 182–194 (2013).
Thiessen, S. E. et al. The role of autophagy in critical illness-induced liver damage. Sci. Rep. 7, 14150 (2017).
Singer, M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5, 66–72 (2014).
Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49–63 (2014).
Mannam, P. et al. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L604–L619 (2014).
Carre, J. E. et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am. J. Respir. Crit. Care Med. 182, 745–751 (2010).
Carrico, C. J., Meakins, J. L., Marshall, J. C., Fry, D. & Maier, R. V. Multiple-organ-failure syndrome. Arch. Surg. 121, 196–208 (1986).
Klingensmith, N. J. & Coopersmith, C. M. The gut as the motor of multiple organ dysfunction in critical illness. Crit. Care Clin. 32, 203–212 (2016).
Mittal, R. & Coopersmith, C. M. Redefining the gut as the motor of critical illness. Trends Mol. Med. 20, 214–223 (2014).
Schirmer, M. et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167, 1125–1136 (2016).
Schuijt, T. J. et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 65, 575–583 (2016).
Dickson, R. P. The microbiome and critical illness. Lancet Respir. Med. 4, 59–72 (2016).
Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).
Piton, G. & Capellier, G. Biomarkers of gut barrier failure in the ICU. Curr. Opin. Crit. Care 22, 152–160 (2016).
Machado, M. C., Barbeiro, H. V., Pinheiro da, S. F. & de Souza, H. P. Circulating fatty acid binding protein as a marker of intestinal failure in septic patients. Crit. Care 16, 455 (2012).
Piton, G., Manzon, C., Cypriani, B., Carbonnel, F. & Capellier, G. Acute intestinal failure in critically ill patients: is plasma citrulline the right marker? Intensive Care Med. 37, 911–917 (2011).
Piton, G. et al. Enterocyte damage in critically ill patients is associated with shock condition and 28-day mortality. Crit. Care Med. 41, 2169–2176 (2013).
Piton, G. et al. Catecholamine use is associated with enterocyte damage in critically ill patients. Shock 43, 437–442 (2015).
Altmann, C. et al. Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 302, F421–F432 (2012).
Klein, C. L. et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int. 74, 901–909 (2008).
Ahuja, N. et al. Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice. Am. J. Physiol. Renal Physiol. 303, F864–F872 (2012).
Hoke, T. S. et al. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J. Am. Soc. Nephrol. 18, 155–164 (2007).
Park, S. W. et al. Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab. Invest. 91, 63–84 (2011).
Liu, M. et al. Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370 (2008).
Siew, E. D. et al. Acute kidney injury as a risk factor for delirium and coma during critical illness. Am. J. Respir. Crit. Care Med. 195, 1597–1607 (2017).
Selimoglu, E. Aminoglycoside-induced ototoxicity. Curr. Pharm. Des. 13, 119–126 (2007).
Matzke, G. R. et al. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 80, 1122–1137 (2011).
Seyler, L. et al. Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit. Care 15, R137 (2011).
Ronco, C. et al. Renal replacement therapy in acute kidney injury: controversy and consensus. Crit. Care 19, 146 (2015).
Hites, M., Dell’Anna, A. M., Scolletta, S. & Taccone, F. S. The challenges of multiple organ dysfunction syndrome and extra-corporeal circuits for drug delivery in critically ill patients. Adv. Drug Deliv. Rev. 77, 12–21 (2014).
Husain-Syed, F., Slutsky, A. S. & Ronco, C. Lung-kidney cross-talk in the critically ill patient. Am. J. Respir. Crit. Care Med. 194, 402–414 (2016).
van den Akker, J. P., Egal, M. & Groeneveld, A. B. Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis. Crit. Care 17, R98 (2013).
Bouferrache, K. & Vieillard-Baron, A. Acute respiratory distress syndrome, mechanical ventilation, and right ventricular function. Curr. Opin. Crit. Care 17, 30–35 (2011).
Rogers, W. K. & Garcia, L. Intraabdominal hypertension, abdominal compartment syndrome, and the open abdomen. Chest 153, 238–250 (2017).
Tam, V. C. Lipidomic profiling of bioactive lipids by mass spectrometry during microbial infections. Semin. Immunol. 25, 240–248 (2013).
Dalli, J. et al. Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes. Crit. Care Med. 45, 58–68 (2017).
Gunst, J. Recovery from critical illness-induced organ failure: the role of autophagy. Crit. Care 21, 209 (2017).
Pierrakos, C. & Vincent, J. L. Sepsis biomarkers: a review. Crit. Care 14, R15 (2010).
Karlsson, S. et al. Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study. Crit. Care 14, R205 (2010).
Lobo, S. M. et al. C-Reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 123, 2043–2049 (2003).
Wang, X. et al. Neutrophil CD64 expression as a diagnostic marker for sepsis in adult patients: a meta-analysis. Crit. Care 19, 245 (2015).
Zhang, X., Liu, D., Liu, Y. N., Wang, R. & Xie, L. X. The accuracy of presepsin (sCD14-ST) for the diagnosis of sepsis in adults: a meta-analysis. Crit. Care 19, 323 (2015).
Su, L., Liu, D., Chai, W., Liu, D. & Long, Y. Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis. BMJ Open. 6, e010314 (2016).
Rhodes, A. et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit. Care Med. 45, 486–552 (2017).
Vincent, J. L. & Weil, M. H. Fluid challenge revisited. Crit. Care Med. 34, 1333–1337 (2006).
Nadeau-Fredette, A. C. & Bouchard, J. Fluid management and use of diuretics in acute kidney injury. Adv. Chron. Kidney Dis. 20, 45–55 (2013).
Rosenberger, C. et al. Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. Kidney Int. 67, 531–542 (2005).
Kidney Disease Outcomes Quality Initiative. KDIGO clinical practice guidelines for acute kidney injury. Kidney Int. Suppl. 2, 1–138 (2012).
Balakumar, V. et al. Both positive and negative fluid balance may be associated with reduced long-term survival in the critically ill. Crit. Care Med. 45, e749–e757 (2017).
Khanna, A. et al. Angiotensin II for the treatment of vasodilatory shock. N. Engl. J. Med. 377, 419–430 (2017).
Bellomo, R., Chapman, M., Finfer, S., Hickling, K. & Myburgh, J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356, 2139–2143 (2000).
Gillies, M. A., Kakar, V., Parker, R. J., Honore, P. M. & Ostermann, M. Fenoldopam to prevent acute kidney injury after major surgery-a systematic review and meta-analysis. Crit. Care 19, 449 (2015).
Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014).
Hotchkiss, R. S., Monneret, G. & Payen, D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect. Dis. 13, 260–268 (2013).
Leentjens, J., Kox, M., van der Hoeven, J. G., Netea, M. G. & Pickkers, P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am. J. Respir. Crit. Care Med. 187, 1287–1293 (2013).
Rimmele, T. et al. Immune cell phenotype and function in sepsis. Shock 45, 282–291 (2016).
Tang, B. M., Huang, S. J. & McLean, A. S. Genome-wide transcription profiling of human sepsis: a systematic review. Crit. Care 14, R237 (2010).
Cavaillon, J. M., Eisen, D. & Annane, D. Is boosting the immune system in sepsis appropriate? Crit. Care 18, 216 (2014).
Vincent, J. L. & Grimaldi, D. Novel Interventions — what’s new and the future. Crit. Care Clin. 34, 161–173 (2018).
van Vught, L. A. et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA 315, 1469–1479 (2016).
Wong, H. R. et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am. J. Respir. Crit. Care Med. 191, 309–315 (2015).
Davenport, E. E. et al. Genomic landscape of the individual host response and outcomes in severe sepsis. Lancet Respir. Med. 4, 259–271 (2016).
Maslove, D. M. & Marshall, J. C. Diagnostic utility of different blood components in gene expression analysis of sepsis. Shock 45, 292–298 (2016).
Peters, E. et al. Study protocol for a multicentre randomised controlled trial: Safety, Tolerability, efficacy and quality of life Of a human recombinant alkaline Phosphatase in patients with sepsis-associated Acute Kidney Injury (STOP-AKI). BMJ Open 6, e012371 (2016).
Sharfuddin, A. A. et al. Soluble thrombomodulin protects ischemic kidneys. J. Am. Soc. Nephrol. 20, 524–534 (2009).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01598831 (2018).
Khowailed, A., Younan, S. M., Ashour, H., Kamel, A. E. & Sharawy, N. Effects of ghrelin on sepsis-induced acute kidney injury: one step forward. Clin. Exp. Nephrol. 19, 419–426 (2015).
Kiss, J. et al. IFN-beta protects from vascular leakage via up-regulation of CD73. Eur. J. Immunol. 37, 3334–3338 (2007).
Bellingan, G. et al. Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial. Trials 18, 536 (2017).
Vincent, J. L. et al. Perioperative cardiovascular monitoring of high-risk patients: a consensus of 12. Crit. Care 19, 224 (2015).
Author information
Authors and Affiliations
Contributions
Both authors contributed to researching data for the article and writing, reviewing and editing the article before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Apoptosis
-
A discrete form of genetically programmed cell death that results in the efficient, non-inflammatory removal of redundant, senescent, transformed or infected cells. The basic mechanisms of apoptosis are highly conserved, and, in mammalian cells, two principal pathways of apoptosis (extrinsic and intrinsic) have been described.
- NETosis
-
A specific cell death modality of granulocyte cells (for example, neutrophils) related to the extracellular release of neutrophil extracellular traps (NETs), which are microbicidal structures comprising nuclear chromatin, histones and granular antimicrobial proteins. NETosis shares characteristics with autophagy and regulated necrosis.
- Pyroptosis
-
A term that was initially introduced to describe an atypical cell death modality of macrophages infected with Salmonella enterica subsp. enterica serovar Typhimurium. However, further studies showed that this process is not macrophage-specific and might be triggered by numerous other bacterial or non-bacterial stimuli. Early induction of caspase 1 is a biochemical hallmark of pyroptosis.
- Hypovolaemia
-
An abnormally low volume of blood plasma.
- Hypervolaemia
-
An abnormally high volume of blood plasma.
- Autophagy
-
A process whereby organelles and portions of the cytoplasm are sequestered in vesicles (termed autophagosomes) that are delivered to lysosomes for degradation.
- Necrosis
-
A type of premature cell death that lacks the features of apoptosis and autophagy. Although necrosis is usually considered to be uncontrolled and accidental, it may also occur in a regulated manner (regulated necrosis) and includes distinct subtypes (for example, necroptosis).
- Gut microbiome
-
The human gut microbiome refers to the genomic elements of the >1,000 different species of microorganisms that are present in the digestive tract.
- Gastric tonometry
-
A technique enabling measurement of the partial pressure of carbon dioxide inside the stomach (using a saline-filled balloon) to assess and monitor splanchnic (gut) mucosal perfusion.
Rights and permissions
About this article
Cite this article
Lelubre, C., Vincent, JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol 14, 417–427 (2018). https://doi.org/10.1038/s41581-018-0005-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41581-018-0005-7
This article is cited by
-
Role of ATF3 triggering M2 macrophage polarization to protect against the inflammatory injury of sepsis through ILF3/NEAT1 axis
Molecular Medicine (2024)
-
Peritoneal sepsis caused by Escherichia coli triggers brainstem inflammation and alters the function of sympatho-respiratory control circuits
Journal of Neuroinflammation (2024)
-
The value of five scoring systems in predicting the prognosis of patients with sepsis-associated acute respiratory failure
Scientific Reports (2024)
-
A pairwise cytokine code explains the organism-wide response to sepsis
Nature Immunology (2024)
-
The gasdermin family: emerging therapeutic targets in diseases
Signal Transduction and Targeted Therapy (2024)