Mechanisms and treatment of organ failure in sepsis

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.

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Fig. 1: The major organ systems that are clinically monitored in patients with sepsis.
Fig. 2: Pathophysiology of acute kidney injury in patients with sepsis.
Fig. 3: Microvascular and cellular alterations in sepsis.
Fig. 4: Complications associated with hypovolaemia and hypervolaemia in sepsis.
Fig. 5: Interplay between the gut and other organs in sepsis.

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Both authors contributed to researching data for the article and writing, reviewing and editing the article before submission.

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Correspondence to Jean-Louis Vincent.

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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.

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Lelubre, C., Vincent, J. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol 14, 417–427 (2018). https://doi.org/10.1038/s41581-018-0005-7

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