Pathophysiology of sepsis

INTRODUCTION — The normal host response to infection is a complex process that localizes and controls bacterial invasion, while initiating the repair of injured tissue. It involves the activation of circulating and fixed phagocytic cells, as well as the generation of proinflammatory and anti-inflammatory mediators. Sepsis results when the response to infection becomes generalized and involves normal tissues remote from the site of injury or infection.

The pathophysiology of sepsis and mechanisms of multiple organ system dysfunction are reviewed here. The definition and management of sepsis are discussed separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Evaluation and management of suspected sepsis and septic shock in adults".)

NORMAL RESPONSE TO INFECTION — The host response to an infection is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components. This may occur by several pathways:

●Causative pathogen replicates and releases microbial components such as endotoxins, exotoxins, and DNA that are designated pathogen-associated molecular patterns (PAMPs). Pattern recognition receptors (PRRs) on the surface of host immune cells may recognize and bind to microbial PAMPs [1]. PRRs include several families, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and intracellular DNA-sensing molecules. Examples include the peptidoglycan of gram-positive bacteria binding to TLR-2 on host immune cells, as well as the lipopolysaccharide of gram-negative bacteria binding to TLR-4 and/or lipopolysaccharide-binding protein (CD14 complex) on host immune cells. PAMPs may be sensed by non-PRRs, which include receptors for advanced glycation end products (RAGE), triggering receptors expressed on myeloid cells (TREM), and G-protein-coupled receptors (GPCRs).

●PRRs can also recognize endogenous danger signals, so-called alarmins or danger-associated molecular patterns (DAMPs) that are released during the inflammatory insult. DAMPs are nuclear, cytoplasmic, or mitochondria structures acquiring new functions when released in the extracellular environment. Examples of DAMPs include high mobility group box-1 protein HMGB1, S100 proteins, heat shock proteins, and mitochondrial DNA and metabolic molecules such as ATP [2].

●The triggering receptor expressed on myeloid cell (TREM-1) and the myeloid DAP12-associating lectin (MDL-1) receptors on host immune cells may recognize and bind to microbial components [3].

In addition, other cell structures may be released during infection that may influence host response.

●Microparticles from circulating and vascular cells also participate in the deleterious effects of sepsis-induced intravascular inflammation [4].

●Neutrophils are phagocytic cells defending against pathogens. Mechanisms of defense include engulfing and destroying the offending microorganism, secretion of antimicrobial peptides, and the release of neutrophil extracellular traps (NETs). During NET processing, neutrophils decondense their nuclear chromatin and DNA into the cytoplasm that are mixed with granule-derived antimicrobial peptides. NETs are extruded into the extracellular space to aid in pathogen clearance but may also promote inflammation and tissue damage in sepsis. Studies suggest a crucial role of NETs in the pathogenesis of disseminated intravascular coagulation and intravascular thrombosis [5].

The binding of immune cell surface receptors to microbial components has multiple effects:

●The engagement of TLRs elicits a signaling cascade via the activation of cytosolic nuclear factor-kb (NF-kb). Activated NF-kb moves from the cytoplasm to the nucleus, binds to transcription sites, and induces activation of a large set of genes involved in the host inflammatory response, such as proinflammatory cytokines (tumor necrosis factor alpha [TNFa], interleukin-1 [IL-1]), chemokines (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]), and nitric oxide.

●Polymorphonuclear leukocytes (PMNs) become activated and express adhesion molecules that cause their aggregation and margination to the vascular endothelium. This is facilitated by the endothelium expressing adherence molecules to attract leukocytes. The PMNs then go through a series of steps (rolling, adhesion, diapedesis, and chemotaxis) to migrate to the site of injury [6]. The release of mediators by PMNs at the site of infection is responsible for the cardinal signs of local inflammation: warmth and erythema due to local vasodilation and hyperemia, and protein-rich edema due to increased microvascular permeability.

This process is highly regulated by a mixture of proinflammatory and anti-inflammatory mediators secreted by macrophages, which have been triggered and activated by the invasion of tissue by bacteria [7-9]:

●Proinflammatory mediators – Important proinflammatory cytokines include TNFa and interleukin-1 (IL-1), which share a remarkable array of biological effects (table 1). The release of TNFa is self-sustaining (ie, autocrine secretion), while non-TNF cytokines and mediators (eg, IL-1, IL-2, IL-6, IL-8, IL-10, platelet activating factor, interferon, and eicosanoids) increase the levels of other mediators (ie, paracrine secretion). The proinflammatory milieu leads to the recruitment of more PMNs and macrophages.

●Anti-inflammatory mediators – Cytokines that inhibit the production of TNFa and IL-1 are considered anti-inflammatory cytokines. Such anti-inflammatory mediators suppress the immune system by inhibiting cytokine production by mononuclear cells and monocyte-dependent T helper cells. However, their effects may not be universally anti-inflammatory. As examples, IL-10 and IL-6 both enhance B cell function (proliferation, immunoglobulin secretion) and encourage the development of cytotoxic T cells [10].

The balance of proinflammatory and anti-inflammatory mediators regulates the inflammatory processes, including adherence, chemotaxis, phagocytosis of invading bacteria, bacterial killing, and phagocytosis of debris from injured tissue. If the mediators balance each other and the initial infectious insult is overcome, homeostasis will be restored [11]. The end result will be tissue repair and healing.

TRANSITION TO SEPSIS — Sepsis occurs when the release of proinflammatory mediators in response to an infection exceeds the boundaries of the local environment, leading to a more generalized response (figure 1). When a similar process occurs in response to a noninfectious condition (eg, pancreatitis, trauma), the process is referred to as systemic inflammatory response syndrome (SIRS). The focus of our review is on sepsis, but much of our discussion is applicable to SIRS. Definitions of sepsis are discussed separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

Sepsis can be conceptualized as malignant intravascular inflammation [12].

●Malignant because it is uncontrolled, unregulated, and self-sustaining

●Intravascular because the blood spreads mediators that are usually confined to cell-to-cell interactions within the interstitial space

●Inflammatory because all characteristics of the septic response are exaggerations of the normal inflammatory response

It is uncertain why immune responses that usually remain localized sometimes spread beyond the local environment causing sepsis. The cause is likely multifactorial and may include the direct effects of the invading microorganisms or their toxic products, release of large quantities of proinflammatory mediators, and complement activation. In addition, some individuals may be genetically susceptible to developing sepsis.

Effects of microorganisms — Bacterial cell wall components (endotoxin, peptidoglycan, muramyl dipeptide, and lipoteichoic acid) and bacterial products (staphylococcal enterotoxin B, toxic shock syndrome toxin-1, Pseudomonas exotoxin A, and M protein of hemolytic group A streptococci) may contribute to the progression of a local infection to sepsis [13]. This is supported by the following observations regarding endotoxin, a lipopolysaccharide found in the cell wall of gram negative bacteria:

●Endotoxin is detectable in the blood of septic patients.

●Elevated plasma levels of endotoxin are associated with shock and multiple organ dysfunction (table 2).

●Endotoxin reproduces many of the features of sepsis when it is infused into humans, including activation of the complement, coagulation, and fibrinolytic systems [14,15]. These effects may lead to microvascular thrombosis and the production of vasoactive products, such as bradykinin.

Excess proinflammatory mediators — Large quantities of proinflammatory cytokines released in patients with sepsis may spill into the bloodstream, contributing to the progression of a local infection to sepsis. These include tumor necrosis factor alpha (TNFa) and interleukin-1 (IL-1), whose plasma levels peak early and eventually decrease to undetectable levels. Both cytokines can cause fever, hypotension, leukocytosis, induction of other proinflammatory cytokines, and the simultaneous activation of coagulation and fibrinolysis (table 1). The evidence indicating that TNFa has an important role in sepsis is particularly strong. It includes the following: circulating levels of TNFa are higher in septic patients than non-septic patients with shock [16], infusion of TNFa produces symptoms similar to those observed in septic shock [17], and anti-TNFa antibodies protect animals from lethal challenge with endotoxin [18]. The high levels of TNFa in sepsis are due in part to the binding of endotoxin to lipopolysaccharide (LPS)-binding protein and its subsequent transfer to CD14 on macrophages, which stimulates TNFa release [19].

Complement activation — The complement system is a protein cascade that helps clear pathogens from an organism [20,21]. It is described in detail separately (see "Complement pathways"). There is evidence that activation of the complement system plays an important role in sepsis; most notably, inhibition of the complement cascade decreases inflammation and improves mortality in animal models:

●In a rodent model of sepsis, a complement fragment 5a receptor (C5aR) antagonist decreased mortality, inflammation, and vascular permeability [22,23]. In contrast, increased production of complement fragment 5a (C5a) and increased expression of C5aR enhanced neutrophil trafficking [24,25].

●In several animal models of sepsis (lipopolysaccharide injection in mice and rats, Escherichia coli infusion in dogs and baboons, and cecal ligation and puncture in mice), a complement fragment 1 (C1) inhibitor decreased mortality, inflammation, and vascular permeability [26-30].

Genetic susceptibility — The single nucleotide polymorphism (SNP) is the most common form of genetic variation. SNPs are stable substitutions of a single base that have a frequency of more than one percent in at least one population and are strewn throughout the genome, including promoters and intergenic regions. At most, only 2 to 3 percent alter the function or expression of a gene. The total number of common SNPs in the human genome is estimated to be more than 10 million. SNPs are used as genetic markers.

Various SNPs are associated with increased susceptibility to infection and poor outcomes. They include SNPs of genes that encode cytokines (eg, TNF, lymphotoxin-alpha, IL-10, IL-18, IL-1 receptor antagonist, IL-6, and interferon gamma), cell surface receptors (eg, CD14, MD2, toll-like receptors 2 and 4, and Fc-gamma receptors II and III), lipopolysaccharide ligands (lipopolysaccharide binding protein, bactericidal permeability increasing protein), mannose-binding lectin, heat shock protein 70, angiotensin I-converting enzyme, plasminogen activator inhibitor, and caspase-12 [31].

SYSTEMIC EFFECTS OF SEPSIS — Widespread cellular injury may occur when the immune response becomes generalized; cellular injury is the precursor to organ dysfunction. The precise mechanism of cellular injury is not understood, but its occurrence is indisputable as autopsy studies have shown widespread endothelial and parenchymal cell injury. Mechanisms proposed to explain the cellular injury include: tissue ischemia (insufficient oxygen relative to oxygen need), cytopathic injury (direct cell injury by proinflammatory mediators and/or other products of inflammation), and an altered rate of apoptosis (programmed cell death).

Tissue ischemia — Significant derangement in metabolic autoregulation, the process that matches oxygen availability to changing tissue oxygen needs, is typical of sepsis.

In addition, microcirculatory and endothelial lesions frequently develop during sepsis. These lesions reduce the cross-sectional area available for tissue oxygen exchange, disrupting tissue oxygenation and causing tissue ischemia and cellular injury:

●Microcirculatory lesions – The microcirculatory lesions may be the result of imbalances in the coagulation and fibrinolytic systems, both of which are activated during sepsis.

●Endothelial lesions – The endothelial lesions may be a consequence of interactions between endothelial cells and activated polymorphonuclear leukocytes (PMNs). The increase in receptor-mediated neutrophil-endothelial cell adherence induces the secretion of reactive oxygen species, lytic enzymes, and vasoactive substances (nitric oxide, endothelin, platelet-derived growth factor, and platelet activating factor) into the extracellular milieu, which may injure the endothelial cells. Lipopolysaccharide (LPS) may also induce cytoskeleton disruption and microvascular endothelial barrier integrity, in part, through nitric oxide synthase (NOS), Ras homolog gene family member A (RhoA), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation [32].

Another factor contributing to tissue ischemia in sepsis is that erythrocytes lose their normal ability to deform within the systemic microcirculation [33-35]. Rigid erythrocytes have difficulty navigating the microcirculation during sepsis, causing excessive heterogeneity in the microcirculatory blood flow and depressed tissue oxygen flux.

Cytopathic injury — Proinflammatory mediators and/or other products of inflammation may cause sepsis-induced mitochondrial dysfunction (eg, impaired mitochondrial electron transport) via a variety of mechanisms, including direct inhibition of respiratory enzyme complexes, oxidative stress damage, and mitochondrial DNA breakdown [36]. Such mitochondrial injury leads to cytotoxicity. There are several lines of evidence that support this belief:

●Cell culture experiments have shown that endotoxin, tumor necrosis factor alpha (TNFa), and nitric oxide cause destruction and/or dysfunction of inner membrane and matrix mitochondrial proteins, followed by degeneration of the mitochondrial ultrastructure. These changes are followed by measurable changes in other cellular organelles by several hours [37]. The end result is functional impairment of mitochondrial electron transport, disordered energy metabolism, and cytotoxicity.

●Studies using various animal models have found normal or supranormal oxygen tension in organs during sepsis, suggesting impaired oxygen utilization at the mitochondrial level. As examples, a study in resuscitated endotoxemic pigs found a supranormal ileomucosal oxygen tension [38], while a study in endotoxemic rats found an elevated oxygen tension in the bladder epithelium [39].

The clinical relevance of mitochondrial dysfunction in septic shock was suggested by a study of 28 critically ill septic patients who underwent skeletal muscle biopsy within 24 hours of admission to the intensive care unit (ICU) [40]. Skeletal muscle adenosine triphosphate (ATP) concentrations, a marker of mitochondrial oxidative phosphorylation, were significantly lower in the 12 patients who died of sepsis than in 16 survivors. In addition, there was an association between nitric oxide overproduction, antioxidant depletion, and severity of clinical outcome. Thus, cell injury and death in sepsis may be explained by cytopathic (or histotoxic) anoxia, which is an inability to utilize oxygen even when present.

Mitochondria can be repaired or regenerated by a process called biogenesis. Mitochondrial biogenesis may prove to be an important therapeutic target, potentially accelerating organ dysfunction and recovery from sepsis [41].

Cell death pathways — Various cell death pathways can be activated during sepsis, including necrosis, apoptosis, necroptosis, pyroptosis, and autophagy-induced cell death. Many of these cell death pathways are altered during sepsis, either as a direct result of the pathophysiology of sepsis and associated inflammation or via direct interaction with pathogens.

Apoptosis — Apoptosis (also called programmed cell death) describes a set of regulated physiologic and morphologic cellular changes leading to cell death. This is the principal mechanism by which senescent or dysfunctional cells are normally eliminated and the dominant process by which inflammation is terminated once an infection has subsided.

During sepsis, proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, thereby prolonging or augmenting the inflammatory response and contributing to the development of multiple organ failure. Sepsis also induces extensive lymphocyte and dendritic cell apoptosis, which alters the immune response efficacy and results in decreased clearance of invading microorganisms. Apoptosis of lymphocytes has been observed at autopsies in both animal and human sepsis. The extent of lymphocyte apoptosis correlates with the severity of the septic syndrome and the level of immunosuppression. Apoptosis has been also observed in parenchymal cells, endothelial, and epithelial cells. Several animal experiments show that inhibiting apoptosis protects against organ dysfunction and lethality [42,43].

Pyroptosis — Pattern recognition receptors (PRRs) can assemble into molecular complexes termed inflammasomes. Inflammasomes are macromolecular protein complexes that finely regulate the activation of caspase-1 and the production and secretion of proinflammatory cytokines such as interleukin (IL)-1beta and IL-18. Activation of NOD-like receptor protein (NLRP) 3 can trigger highly inflammatory programmed cell death by caspase mediated rapid rupture of the plasma membrane, termed pyroptosis. Some studies have highlighted the important role of the NLRP3 inflammasome in sepsis [44].

Autophagy — Autophagy refers to the natural process by which a cytoplasmic substance or pathogen is engulfed by the autophagosome, which is then fused with a lysosome to be degraded. Autophagy is a critical defense mechanism used by the host to resist external pathogens and “alarmin” signals. Autophagy plays a critical role in the induction and regulation of natural immune-cell inflammatory response. In sepsis, induction of autophagy can protect the host against organ failure via preventing apoptotic cell death of immune cells, maintaining the homeostatic cytokine balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. On the other hand, a decrease in autophagy during sepsis aggravates the tissue and organ injury [45].

Mitochondrial dysfunction in sepsis-induced multiple organ failure — In patients dying from sepsis, light and electron microscopy as well as immunohistochemical staining for markers of cellular injury and stress, revealed that cell death was rare in sepsis-induced cardiac and renal dysfunction. Moreover, the degree of cell injury or death did not account for severity of sepsis-induced organ dysfunction [46]. The presence of subtle mitochondrial morphological changes could indicate that mitochondrial energetic crisis may be involved in organ dysfunction, in the absence of cell death. During sepsis, many mitochondrial functions are altered, including metabolic substrate utilization and mitochondrial OXPHOS machinery perturbations, increased ROS production, altered mitochondrial biogenesis and dynamics, as well as reduced autophagy of damaged mitochondria [47].

Immunosuppression — Clinical observations and animal studies suggest that the excess inflammation of sepsis may be followed by immunosuppression [48-50]. Among the evidence supporting this hypothesis, an observational study removed the spleens and lungs from 40 patients who died with active severe sepsis and then compared them with the spleens from 29 control patients and the lungs from 30 control patients [51]. The median duration of sepsis was four days. The secretion of proinflammatory cytokines (ie, tumor necrosis factor, interferon gamma, interleukin-6, and interleukin-10) from the splenocytes of patients with severe sepsis was generally less than 10 percent that of controls, following stimulation with either anti-CD3/anti-CD28 or lipopolysaccharide. Moreover, the cells from the lungs and spleens of patients with severe sepsis exhibited increased expression of inhibitory receptors and ligands, as well as expansion of suppressor cell populations, compared with cells from control patients. The inability to secrete proinflammatory cytokines combined with enhanced expression of inhibitory receptors and ligands suggests clinically relevant immunosuppression.

Activation of coagulation system and vascular endothelium — Sepsis is associated with disseminated intravascular coagulation (DIC) and endothelial cell activation, which play a critical role in the development of organ dysfunction.

DIC may be defined as an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from sepsis. Typically, sepsis-associated DIC is characterized as the systemic activation of the coagulation with suppressed fibrinolysis in combination with systemic inflammation leading to organ dysfunction [52].

Along with proinflammatory stimulation elicited by sepsis, endothelial cells lose their anticoagulant function, while the expression of thrombomodulin on the cell surface is decreased and expression of tissue factor is increased. Endothelial dysfunction induced by sepsis includes glycocalyx shedding that results in increased leucocyte adhesion to endothelial cells, thereby exacerbating tissue damage and the coagulation cascade. In addition, adherent monocytes and leukocytic microparticles (neutrophil extracellular traps [NETs]) contribute to the coagulation cascade activation. Overall, the endothelium contributes significantly to the aggravation of inflammation through the release of proinflammatory substances, recruitment of inflammatory cells, procoagulant activity, and hyperpermeability.

In sepsis, platelets are implicated in sepsis-induced coagulation dysfunction through the release of proinflammatory mediators, such as platelet activating factor, and increasing fibrin formation via the expression of procoagulant molecules, including P-selectin. Mechanisms leading to persistent thrombocytopenia in sepsis are not fully understood. Growing evidence suggests that thrombocytopenia may be attributed to reduced platelet production, enhanced turnover, or spontaneous aggregation of platelets and enhanced platelet consumption through the formation of microthrombi.

The release of NETs is further linked to the aggravation of DIC in sepsis. Persistence of NETs in sepsis is attributed to changes in plasma DNase 1 activity. DNA is a negatively charged surface for the autocatalytic activation of factor XII and the intrinsic pathway of coagulation, leading to increased thrombin generation and microthrombosis. Histones released with DNA are potent platelet activators, causing degranulation and release of polyphosphate, activating the contact pathway of coagulation [53].

ORGAN-SPECIFIC EFFECTS OF SEPSIS — The cellular injury described above, accompanied by the release of proinflammatory and anti-inflammatory mediators, often progresses to organ dysfunction. No organ system is protected from the consequences of sepsis; those listed included in this section are the organ systems that are most often involved. Multiple organ dysfunction is common.

Circulation — Hypotension due to diffuse vasodilation is the most severe expression of circulatory dysfunction in sepsis. It is probably an unintended consequence of the release of vasoactive mediators, whose purpose is to improve metabolic autoregulation (the process that matches oxygen availability to changing tissue oxygen needs) by inducing appropriate vasodilation. Mediators include the vasodilators prostacyclin and nitric oxide (NO), which are produced by endothelial cells.

NO is believed to play a central role in the vasodilation accompanying septic shock, since NO synthase can be induced by incubating vascular endothelium and smooth muscle with endotoxin [54,55]. When NO reaches the systemic circulation, it depresses metabolic autoregulation at all of the central, regional, and microregional levels of the circulation. In addition, NO may trigger an injury in the central nervous system that is localized to areas that regulate autonomic control [56].

Another factor that may contribute to the persistence of vasodilation during sepsis is impaired compensatory secretion of antidiuretic hormone (vasopressin). This hypothesis is supported by a study that found that plasma vasopressin levels were lower in patients with septic shock than in patients with cardiogenic shock (3.1 versus 22.7 pg/mL), even though the groups had similar systemic blood pressures [57]. It is also supported by numerous small studies that demonstrated that vasopressin improves hemodynamics and allows other pressors to be withdrawn [58-61]. (See "Use of vasopressors and inotropes", section on 'Vasopressin and analogs'.)

Vasodilation is not the only cause of hypotension during sepsis. Hypotension may also be due to redistribution of intravascular fluid. This is a consequence of both increased endothelial permeability and reduced arterial vascular tone leading to increased capillary pressure.

In addition to these diffuse effects of sepsis on the circulation, there are also localized effects:

●In the central circulation (ie, heart and large vessels), decreased systolic and diastolic ventricular performance due to the release of myocardial depressant substances is an early manifestation of sepsis [62,63]. Despite this, ventricular function may still be able to use the Frank Starling mechanism to increase cardiac output, which is necessary to maintain the blood pressure in the presence of systemic vasodilation. Patients with preexisting cardiac disease (eg, older adult patients) are often unable to increase their cardiac output appropriately.

●In the regional circulation (ie, small vessels leading to and within the organs), vascular hyporesponsiveness (ie, inability to appropriately vasoconstrict) leads to an inability to appropriately distribute systemic blood flow among organ systems. As an example, sepsis interferes with the redistribution of blood flow from the splanchnic organs to the core organs (heart and brain) when oxygen delivery is depressed [64].

●The microcirculation (ie, capillaries) may be the most important target in sepsis. Sepsis is associated with a decrease in the number of functional capillaries, which causes an inability to extract oxygen maximally (algorithm 1) [65,66]. Techniques including reflectance spectrophotometry and orthogonal polarization spectral imaging have allowed in vivo visualization of the sublingual and gastric microvasculature [67,68]. Compared to normal controls or critically ill patients without sepsis, patients with severe sepsis have decreased capillary density [68]. This may be due to extrinsic compression of the capillaries by tissue edema, endothelial swelling, and/or plugging of the capillary lumen by leukocytes or red blood cells (which lose their normal deformability properties in sepsis).

●At the level of the endothelium, sepsis induces phenotypic changes to endothelial cells. This occurs through direct and indirect interactions between the endothelial cells and components of the bacterial wall. These phenotypic changes may cause endothelial dysfunction, which is associated with coagulation abnormalities, reduced leukocytes, decreased red blood cell deformability, upregulation of adhesion molecules, adherence of platelets and leukocytes, and degradation of the glycocalyx structure [69]. Diffuse endothelial activation leads to widespread tissue edema, which is rich in protein.

Lung — Endothelial injury in the pulmonary vasculature during sepsis disturbs capillary blood flow and enhances microvascular permeability, resulting in interstitial and alveolar pulmonary edema [70,71]. Neutrophil entrapment within the lung's microcirculation initiates and/or amplifies the injury in the alveolocapillary membrane. The result is pulmonary edema, which creates ventilation-perfusion mismatch and leads to hypoxemia. Such lung injury is prominent during sepsis, likely reflecting the lung's large microvascular surface area. Acute respiratory distress syndrome is a manifestation of these effects. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults".)

Gastrointestinal tract — The circulatory abnormalities typical of sepsis may depress the gut's normal barrier function, allowing translocation of bacteria and endotoxin into the systemic circulation (possibly via lymphatics, rather than the portal vein) and extending the septic response [70-73]. This is supported by animal models of sepsis, as well as a prospective cohort study that found that increased intestinal permeability (determined from the urinary excretion of orally administered lactulose and mannose) was predictive of the development of multiple organ dysfunction syndrome [74].

Increasing evidence suggests that the intestinal microbiome has a critical role in mediating the pathology associated with sepsis. Importantly, changes in the composition and diversity of the intestinal microbiome have been shown to negatively affect morbidity and mortality in patients with sepsis [75].

Liver — The reticuloendothelial system of the liver normally acts as the first line of defense in clearing bacteria and bacteria-derived products that have entered the portal system from the gut. Liver dysfunction can prevent the elimination of enteric-derived endotoxin and bacteria-derived products, which precludes the appropriate local cytokine response and permits direct spillover of these potentially injurious products into the systemic circulation [70,71].

Kidney — Sepsis is often accompanied by acute renal failure. The mechanisms by which sepsis and endotoxemia lead to acute renal failure are incompletely understood. Acute tubular necrosis due to hypoperfusion and/or hypoxemia is one mechanism [70,71]. However, systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, tumor necrosis factor [TNF]), and activation of neutrophils by endotoxin and FMLP (a three amino acid [fMet-Leu-Phe] chemotactic peptide in bacterial cell walls) may also contribute to renal injury. (See "Pathogenesis and etiology of ischemic acute tubular necrosis".)

Growing evidence suggest that septic acute renal failure is only in part sustained by renal hypoperfusion [46,76-78]. It has been shown that sepsis is associated with normal or even elevated renal blood flow, which is associated with redistribution of blood flow from cortical to medullary region. These macrovascular changes are associated with microcirculatory dysfunction, inflammatory response induced by pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) and bio-energetic adaptation response including tubular cell cycle arrest machinery. Hence, the mechanism of kidney injury during sepsis may be viewed as a bio-energetics adaptation of tubular epithelial cells induced by deregulated inflammation in response to peritubular microvascular dysfunction.

The role of renal replacement therapy (RRT) in septic patients has been evaluated both for renal support and immunomodulation [79-82]. Retrospective clinical studies have suggested that early initiation of RRT and use of continuous methods are associated with a better hemodynamic tolerance and outcome [83]. Timing and dose of RRT are ongoing sources of debate, yet available randomized clinical trials fails to demonstrate any beneficial impact [84,85].

Of note, likelihood of death is increased in patients with sepsis who develop renal failure. It is not well understood why this occurs. One factor may be the release of proinflammatory mediators as a result of leukocyte-dialysis membrane interactions when hemodialysis is necessary. Use of biocompatible membranes can prevent these interactions and may improve survival and the recovery of renal function [86]. However, these findings have not been universal or consistent [87,88]. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)", section on 'Infection risk'.)

Nervous system — Central nervous system (CNS) complications occur frequently in septic patients, often before the failure of other organs. The most common CNS complications are an altered sensorium (encephalopathy). The pathogenesis of the encephalopathy is poorly defined. A high incidence of brain microabscesses was noted in one study, but the significance of hematogenous infection as the principal mechanism remains uncertain because of the heterogeneity of the observed pathology.

CNS dysfunction has been attributed to changes in metabolism and alterations in cell signaling due to inflammatory mediators. Dysfunction of the blood brain barrier probably contributes, allowing increased leukocyte infiltration, exposure to toxic mediators, and active transport of cytokines across the barrier [89]. Mitochondrial dysfunction and microvascular failure both precede functional CNS changes, as measured through somatosensory evoked potentials [90].

In addition to these neurological consequences of sepsis, there is growing recognition that the parasympathetic nervous system may be a mediator of systemic inflammation during sepsis. This is supported by numerous observations in various animal models. Afferent vagus nerve stimulation during sepsis increases the secretion of corticotropin-releasing hormone (CRH), ACTH, and cortisol; the last effect can be suppressed by subdiaphragmatic vagotomy [91,92]. Parasympathetic tone affects thermoregulation, as experimental vagotomy attenuates the hyperthermic response to IL-1 [92,93]. Efferent parasympathetic activity, mediated by acetylcholine, has an anti-inflammatory effect on the cytokine profile, with decreased in vitro expression of the proinflammatory cytokines TNF, interleukin (IL)-1, IL-6 and IL-18 [94]. And, external vagal stimulation prevents the onset of shock following vagotomy [94], while an acetylcholine receptor agonist diminishes the pathologic response to sepsis [95].

Delayed neurological consequences of sepsis, such as peripheral neuropathy, are discussed separately. (See "Neuromuscular weakness related to critical illness".)

SUMMARY

●Normal response to infection – Typically, a bacterial pathogen enters a sterile site in which resident cells can detect the invader and initiate the host response. The host response is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components. Binding immune cell surface receptors to microbial components initiates a series of steps that result in the phagocytosis of invading bacteria, bacterial killing, and phagocytosis of debris from injured tissue. (See 'Normal response to infection' above.)

These processes are associated with the production and release of a range of proinflammatory cytokines by macrophages, leading to the recruitment of additional inflammatory cells, such as leukocytes. This response is highly regulated by a mixture of proinflammatory and anti-inflammatory mediators.

When a limited number of bacteria invade, the local host responses are generally sufficient to clear the pathogens. The end result is normally tissue repair and healing.

●Transition to sepsis – Sepsis occurs when the release of proinflammatory mediators in response to an infection exceeds the boundaries of the local environment, leading to a more generalized response. It is uncertain why immune responses that usually remain localized sometimes spread beyond the local environment causing sepsis. (See 'Transition to sepsis' above.)

The cause is likely multifactorial and may include the direct effects of invading microorganisms or their toxic products, release of large quantities of proinflammatory mediators, and complement activation. (See 'Excess proinflammatory mediators' above and 'Complement activation' above.)

In this context, an anti-inflammatory response may reduce the toxic effects of the excessive inflammatory response but may also compromise effective host protection from the infection.

Some individuals may be genetically susceptible to developing sepsis. (See 'Genetic susceptibility' above.)

●Systemic effects of sepsis – Despite a clear understanding of the inflammatory and coagulation mechanisms triggered during the early stage of severe sepsis, not much is known about the cellular aspects underlying the mechanisms that ultimately lead to organ dysfunction and death. (See 'Systemic effects of sepsis' above.)

Cellular injury is the precursor to organ dysfunction. Widespread cellular injury may occur when the immune response spreads beyond the site of infection causing sepsis. The precise mechanism of cellular injury is not understood, but proposed mechanisms include tissue ischemia (insufficient oxygen relative to oxygen need), cytopathic injury (direct cell injury by proinflammatory mediators and/or other products of inflammation), and an altered rate of apoptosis (programmed cell death). (See 'Tissue ischemia' above and 'Cytopathic injury' above and 'Apoptosis' above.)

The mechanism of organ failure in sepsis may relate to decreased oxygen utilization associated with mitochondrial dysfunction rather than or in addition to poor oxygen delivery to tissues.

●Organ dysfunction – The cellular injury, accompanied by the release of proinflammatory and anti-inflammatory mediators, often progresses to organ dysfunction. No organ system is protected from the consequences of sepsis. Those that are most commonly involved include the circulation, lung, gastrointestinal tract, kidney, and nervous system. (See 'Organ-specific effects of sepsis' above.)